Pocket Radiation Oncology

Pocket
RADIATION
ONCOLOGY
The MD Anderson Cancer Center
Handbook of Radiation Oncology
Edited by
C T , MD
A F , MD, PhD
Advisors
S H , MD
P D , MD, MPH
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Library of Congress Cataloging-in-Publication Data

Names: Tang, Chad, editor. | Farooqi, Ahsan, editor. | University of Texas M.D.
Anderson Cancer Center, sponsoring body.
Title: Pocket radiation oncology : the MD Anderson Cancer Center handbook
of radiation oncology / [edited by] Chad Tang, Ahsan Farooqi.
Other titles: MD Anderson Cancer Center handbook of radiation oncology |
Pocket notebook.
Description: Philadelphia : Wolters Kluwer, 2019. | Series: Pocket notebook
series | Includes index.
Identifiers: LCCN 2019005774 | ISBN 9781496398574 (loose-leaf)
Subjects: | MESH: Neoplasms—radiotherapy | Handbook
Classification: LCC RC270.3.T65 | NLM QZ 39 | DDC 616.99/407572—dc23
LC record available at https://lccn.loc.gov/2019005774
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DEDICATION
We dedicate this book in memory of Dr. James D. Cox, MD, who
dedicated much of his life to MDACC, RTOG, ABR, and the Red
Journal. He was and will always be a lifelong mentor to all past,
current, and future trainees in radiation oncology.
CONTRIBUTORS
Mitchell S. Anscher, MD
Professor and Genitourinary Section Chief
Department of Radiation Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
Alexander Augustyn, MD, PhD

Resident Physician
Houston, Texas
Zeina Ayoub, MD
Clinical Instructor
American University of Beirut Cancer Center
Beirut, Lebanon
Alexander F. Bagley, MD, PhD

Resident Physician
Houston, Texas
Houda Bahig, MD
Staff Radiation Oncologist
Centre hospitalier de l’Université de Montréal
Montréal, Quebec, Canada
Peter Balter, PhD

Professor, Department of Radiation Physics
Division of Radiation Oncology
Houston, Texas
Vincent Bernard, PhD

Postdoctoral Fellow
Translational Molecular Pathology
Houston, Texas
Michael Bernstein, MD
Assistant Attending
Memorial Sloan Kettering Cancer Center
New York City, New York
Andrew J. Bishop, MD
Assistant Professor
Houston, Texas
Eric D. Brooks, MD, MHS

Resident Physician
Houston, Texas
Samantha M. Buszek, MD
Resident Physician
Houston, Texas
Joe Y. Chang, MD, PhD, FASTRO
Professor
Houston, Texas
Bhavana S. Vangara Chapman, MD

Resident Physician
Houston, Texas
Seungtaek Choi, MD
Associate Professor
Houston, Texas
Kaitlin Christopherson, MD
Resident Physician
Houston, Texas
Caroline Chung, MD, MSc

Associate Professor
Houston, Texas
Lauren Elizabeth Colbert, MD, MSCR

Resident Physician
Houston, Texas
Bouthaina Dabaja, MD
Professor and Lymphoma Section Chief
University of Texas MD Anderson cancer center
Houston, Texas
Prajnan Das, MD, MPH

Professor and GI Section Chief
Deputy Department Chair for Education
Residency and Fellowship Program Director
Houston, Texas
Brian J. Deegan, MD, PhD

Radiation Oncologist
Cancer Specialists of North Florida
Jacksonville, Florida
Patricia J. Eifel, MD
Professor
Houston, Texas
Adnan Elhammali, MD, PhD

Resident Physician
Houston, Texas
Penny Fang, MD, MBA
Resident Physician
Houston, Texas
Ahsan Farooqi, MD, PhD

Resident PhysicianDepartment of Radiation Oncology
Houston, Texas
Steven J. Frank, MD
Professor and Deputy Division Head
Houston, Texas
Clifton David Fuller, MD, PhD

Associate Professor
Houston, Texas
Adam Seth Garden, MD

Professor
Houston, Texas
Amol Jitendra Ghia, MD

Associate Professor
Houston, Texas
Daniel Gomez, MD
Associate Professor and Thoracic Section Chief
Houston, Texas
Stephen Grant, MD
Resident Physician
Houston, Texas
Aaron Joseph Grossberg, MD, PhD

Assistant Professor
Department of Radiation Medicine
Cancer Early Detection Advanced Research Center
Brenden-Colson Center for Pancreatic Care
Oregon Health and Science University
Portland, Oregon
David Grosshans, MD, PhD

Associate Professor
Houston, Texas
B. Ashleigh Guadagnolo, MD, MPH

Professor and Sarcoma Section Chief
Houston, TX
Jillian Gunther, MD, PhD

Assistant Professor
Houston, Texas
Stephen Hahn, MD
Professor
Chief Medical Executive
Houston, Texas
Jennifer C. Ho, MD
Resident Physician
Houston, Texas
Karen Elizabeth Hoffman, MD, MPH

Associate Professor
Houston, Texas
Emma B. Holliday, MD
Assistant Professor
Houston, Texas
Anuja Jhingran, MD
Professor
Houston, Texas
Ann H. Klopp, MD
Associate Professor and Gynecology Section Chief
Houston, Texas
Albert C. Koong, MD, PhD

Professor and Chair
Houston, Texas
Rachit Kumar, MD
Adjunct Assistant Professor
Banner MD Anderson Cancer Center
Gilbert, Arizona
Jing Li, MD, PhD

Associate Professor and CNS/Pediatric Section co-Chief
Houston, Texas
Anna Likhacheva, MD, MPH

Gilbert, Arizona
Lilie L. Lin, MD
Associate Professor
Houston, Texas
Jennifer Logan, MD
Resident Physician
Houston, Texas
Ethan Bernard Ludmir, MD

Resident Physician
Houston, Texas
Geoffrey V. Martin, MD
Resident Physician
Houston, Texas
Mary Frances McAleer, MD, PhD

Associate Professor
Houston, Texas
Shane Mesko, MD, MBA

Resident Physician
Houston, Texas
Sarah Milgrom, MD
Assistant Professor
University of Colorado
Denver Colorado
Bruce Minsky, MD
Professor and Frank T. McGraw Memorial Chair
Houston, Texas
Shalini Moningi, MD
Resident Physician
Houston, Texas
Amy C. Moreno, MD
Resident Physician
Houston, Texas
Quynh-Nhu Nguyen, MD
Associate Professor
Houston, Texas
Hubert Young Pan, MD

Resident Physician
Houston, Texas
Dario Pasalic, MD
Resident Physician
Houston, Texas
Arnold C. Paulino, MD
Professor and CNS/Pediatric Section co-Chief
Houston, Texas
Curtis A. Pettaway, MD
Professor
Department of Urology
Houston, Texas
Jack Phan, MD, PhD

Associate Professor
Houston, Texas
Chelsea C. Pinnix, MD, PhD

Associate Professor
Houston, Texas
Courtney Pollard III, MD, PhD
Resident Physician
Houston, Texas
Jay Paul Reddy, MD, PhD

Assistant Professor
Houston, Texas
Mohammed Salehpour, PhD

Professor and Director of Education
Department of Radiation Physics
Houston, Texas
Tommy Sheu, MD, MPH

Resident Physician
Houston, Texas
Shervin ‘Sean’ Shirvani, MD, MPH

Gilbert, Arizona
Lisa Singer, MD, PhD

Instructor
Dana-Farber Cancer Institute and Brigham and Women’s Hospital
Boston, Massachusetts
Shane R. Stecklein, MD, PhD

Resident Physician
Houston, Texas
Erik P. Sulman, MD, PhD

Professor and Vice-Chair of Research
Co-Director, Brain Tumor Center
Laura and Isaac Perlmutter Cancer Center
New York City, New York
Chad Tang, MD
Assistant Professor
Houston, Texas
Cullen Taniguchi, MD, PhD

Assistant Professor
Houston, Texas
Nikhil G. Thaker, MD
Radiation Oncologist
Arizona Oncology/The US Oncology Network
Tucson, Arizona
Jeena Varghese, MD
Assistant Professor
Department of Endocrine Neoplasia and Hormonal Disorders
Houston, Texas
Gary Walker, MD, MPH

Staff Physician
Gilbert, Arizona
Christopher Wilke, MD, PhD

Assistant Professor
University of Minnesota
Minneapolis, Minnesota
Wendy Woodward, MD, PhD

Associate Professor and Breast Section Chief
Houston, Texas
Debra Nana Yeboa, MD

Assistant Professor
Houston, Texas
FOREWORD
In the fast-paced world we live in today, it can be challenging to find
time to keep abreast of the current standards of care and the
constantly evolving technologic and practical innovations. National
guidelines are often too vague when it comes to how we deliver
radiation therapy for specific disease sites, and textbooks are either
too broad or too lengthy for practitioners to interpret key concepts
necessary to deliver care. While we recognize that there are other
pocket books available, we have intentionally narrowed our focus
and scope of this pocket handbook to include the best practices that
we have determined are necessary to deliver safe, multidisciplinary
evidence-based care to our patients. This was accomplished through
capturing years of experience and expertise of senior radiation
oncologists at MD Anderson, many of which created the cutting edge
technologies discussed in this handbook. The MD Anderson
residents and fellows both past and current played a major part in
the creation of this pocket handbook and reviewed each of the
chapters.
The goal of this pocket handbook is to provide a snapshot in a
user-friendly presentation that can be used to guide the active
management and review of specific cases. While we acknowledge
that it is not a comprehensive resource, the handbook provides the
basic fundamentals that can guide the practitioner with the
necessary tools and information to dig deeper into specific cases.
In this handbook, we have covered all of the major stages of
commonly treated diseases and included treatment techniques for
both common and rare malignancies. Unlike most pocket references,
we have a section that is dedicated to treatment planning and dose
constraints. This section also includes specific figures which are
helpful in determining how blocks should be drawn and which areas
should be avoided during radiation therapy. We also provide insight
into emerging technologies and identify clinical pearls related to
these technologies as well as areas of concern that could lead to
catastrophic complications.
Recognizing the limited time that physicians and trainees have,
we included only those specific references that drive the current
clinical standards. We hope that this handbook will serve as a
valuable resource for you and your peers as we endeavor to provide
appropriate, safe, and quality care to our patients.
A C. K , MD, PhD
Professor and Department Chair, Radiation Oncology
J M. H , MD
Professor and Division Head, Radiation Oncology
PREFACE
We are delighted to introduce the first edition of Pocket Radiation
Oncology: The MD Anderson Cancer Center Handbook of Radiation
Oncology. While there are many excellent textbooks on radiation
oncology, in an era of constantly evolving evidence and rapidly
changing technology, there appears to be great need for an easily
accessible handbook with clinically relevant and evidence-based
information, presented in a concise and easily accessible format. We
feel that this handbook will appeal to the learning styles of today’s
generation of adult learners.
We are grateful to all the contributors at the University of Texas
MD Anderson Cancer Center who made Pocket Radiation Oncology
possible. All chapters were created by current or past members of
the MD Anderson Cancer Center, Department of Radiation
Oncology. The chapters were created by resident and attending
pairs, and all chapters were reviewed by a senior attending who
specialized in that disease site. We are also grateful to the past and
present faculty at the University of Texas MD Anderson Cancer
Center, whose clinical experience and knowledge is reflected in this
handbook.
S H P D ,A
CONTENTS
Contributors
Foreword
Preface
RADIATION ONCOLOGY PRINCIPLES

Section Editors: Aaron Joseph Grossberg, Albert C. Koong
Radiation Biology
Radiation Physics
Imaging and Radiology
Chemotherapy and Immunotherapy
Clinical Statistics
SPECIAL RADIATION TECHNIQUES

Section Editors: Penny Fang, Jennifer C. Ho, Steven J. Frank
Brachytherapy
Proton Therapy
Oligometastatic Disease
Stereotactic Body Radiation Therapy
Stereotactic CNS Radiosurgery
CENTRAL NERVOUS SYSTEM

Section Editors: Hubert Young Pan, Erik P. Sulman
Low-Grade Gliomas
High-Grade Gliomas
Meningioma
Benign CNS
Pituitary Adenoma and Craniopharyngioma
PEDIATRICS
Section Editors: Ethan Bernard Ludmir, Arnold C. Paulino
Medulloblastoma
Ependymoma
Intracranial Germ Cell Tumor
Wilms Tumor
Neuroblastoma
Ewing Sarcoma
Rhabdomyosarcoma
Osteosarcoma/Retinoblastoma/Brainstem Glioma
Late Effects
HEAD & NECK

Section Editors: Brian J. Deegan, Courtney Pollard III, Adam Seth
Garden
Oral Cavity
Oropharynx
Sinonasal and Nasopharynx
Larynx and Hypopharynx
Salivary Gland Neoplasms
Thyroid Cancer
Unknown Head and Neck Primary
THORACIC
Section Editors: Eric D. Brooks, Daniel Gomez
Early-Stage NSCLC
Stage III NSCLC
Small Cell Lung Cancer
Thymoma and Thymic Carcinoma
Mesothelioma
Esophageal Cancer
GASTROINTESTINAL
Section Editors: Lauren Elizabeth Colbert, Prajnan Das
Colorectal Cancer
Anal Cancer
Pancreatic Cancer
Gastric Cancer
Hepatobiliary Cancer
BREAST
Section Editors: Jennifer Logan, Amy C. Moreno, Wendy Woodward
General Breast Cancer
Ductal Carcinoma In Situ (DCIS)
Early-Stage Breast Cancer (ESBC)
Locally Advanced Breast Cancer (LABC)
Inflammatory/Recurrent Breast Cancer
GENITOURINARY
Section Editors: Geoffrey V. Martin, Shalini Moningi, Mitchell S.
Anscher
Prostate Cancer (Definitive)
Prostate Cancer (Adjuvant/Salvage)
Bladder Cancer
Testicular Cancer
Penile Cancer
GYNECOLOGIC
Section Editors: Shane R. Stecklein, Ann H. Klopp
Cervical Cancer
Endometrial Cancer
Vaginal Cancer
Vulvar Cancer
Ovarian Cancer
SKIN/SARCOMA
Section Editors: Kaitlin Christopherson, B. Ashleigh Guadagnolo
Soft Tissue Sarcoma
Melanoma
Non-melanoma Skin Cancer
Merkel Cell Carcinoma
LYMPHOMA
Section Editors: Tommy Sheu, Bouthaina Dabaja
Hodgkin Lymphoma
Diffuse Large B-Cell Lymphoma
Miscellaneous Hematologic Malignancies
RADIATION EMERGENCIES, BENIGN DISEASE, AND

PALLIATION
Section Editors: Adnan Elhammali, Amol Jitendra Ghia
Brain Metastases
Spine Metastases
Non-spine Bone Metastases
Radiation Emergencies
Benign Disease: Non-neural
Clinical Setup
Abbreviations
Index
RADIATION BIOLOGY
AARON JOSEPH GROSSBERG • AHSAN FAROOQI •
CULLEN TANIGUCHI
4R R
Repair
Lethal and sublethal damage repair increases cell survival after
fractionated radiation
Reoxygenation
Hypoxic cells are radioresistant; hypoxic fraction ↑ with
treatment.
Redistribution
Lethality increases as cells redistribute to more radiosensitive
stages of cell cycle .
Repopulation
Repopulation increases cell survival over long treatment time ;
accelerated in some cancers.
M S P
Oncogene: Normal function is to positively regulate cellular
growth, that is RAS, MYC, ABL, ERBB2.
Tumor suppressor gene: Normal function is to negatively
regulate cellular growth, that is TP53, RB, VHL, PTEN.
Cellular signaling pathways
EGFR-MAPK: Pro-survival pathway involving the EGFR
family of tyrosine kinases
EGFR (ErbB-1): Targeting by cetuximab
HER2/neu (ErbB-2): Targeted by trastuzumab
Her3 and Her4: Not as commonly mutated in cancer
Ras: G protein bound to cellular membrane that transmits
signals from activated tyrosine kinases
K-RAS: Mutated in colon and lung cancer
N-RAS: Mutated in neuroblastoma
H-RAS: Bladder cancer
VEGFR: Leads to angiogenesis, also involves tyrosine kinase
pathways. Targeted by bevacizumab
PI3K-Akt-mTOR pathway: PI3K is a membrane-bound protein
that is negatively regulated by PTEN, and whose downstream
targets include Akt and mTOR, which activate cellular survival,
proliferation, and angiogenesis. Targeted by rapamycin,
temsirolimus, and everolimus (immune-suppressive drugs), which
can also inhibit various cancers that activate this pathway (ie,
renal cell carcinoma)
BCR-ABL: Tyrosine kinase pathway activated in chronic
myelogenous leukemia (via classic 9:22 translocation) that is
targeted by imatinib
ALK: Tyrosine kinase that is pro-survival and found mutated in
NSCLC and hereditary neuroblastoma. Targeted by ALK inhibitor
crizotinib
T ,T C
Due to the end-replication problem, a cell loses between 50 and
200 bp per cell division.
Telomeres are repetitive elements consisting of the (TTAGGG)n
repeats found at the ends of our chromosomes that serve as a
buffer to our coding DNA.
After ~40-50 population doublings, most cell lines in culture reach
critically short telomere lengths, which triggers
senescence/apoptosis (Hayflick limit).
Cancer cells counteract telomere shortening by activating
telomere maintenance mechanisms.
Telomerase: Activated in ~85% of all cancers. Increased
telomerase activity has been associated with mutations in
the TERT promoter gene (which encodes the catalytic
component of telomerase) seen in tumors of neural or
mesenchymal origin (Killela PNAS 2013).
Alternative lengthening of telomeres: Activated in 10%-15%
of cancers. Poorly understood mechanism but thought to
utilize homologous recombination machinery to maintain
telomere length
DNA D R
DNA damage: Defined as any covalent modifications of the
nucleotide backbone (exception being cytosine methylation)
Occurs at a high frequency from both endogenous and
exogenous sources
Approximately 1 Gy of ionizing radiation leads to ~40 double-
strand breaks (DSBs), >1000 base damages, and ~1000 single-
strand breaks (SSBs)
DNA repair pathways
Base excision repair (APE1, PCNA, FEN1, XRCC1):
Functions to repair base damage utilizing DNA glycosylase
and endonucleases
Nucleotide excision repair: Can be initiated by either the
global genomic pathway (ERCC1, XPF, XPG) or transcription
coupled (stalled RNA polymerase complexes). Defects in
this pathway lead to hereditary xeroderma pigmentosum.
Mismatch repair: MLH1 MSH2, MSH4, MSH6. Functions to
excise the incorrect nucleotide and replace with the correct
one. Mutations in genes involved in this pathway lead to
microsatellite instability (MSI) and hereditary nonpolyposis
colorectal cancer (HNPCC).
Nonhomologous end joining (NHEJ): Immediate response of
a cell to correct a DNA double-strand break. Compared to
homologous recombination, this process is rapid but is more
prone to errors. First there is end recognition by binding of
Ku proteins → recruitment of DNA-dependent protein
kinases (DNA-PKcs) → end-processing, bridging, and
ligation. Typically active in the G1 phase of the cell cycle,
where there is no sister chromatid
Homologous recombination: High-fidelity mechanism
compared to NHEJ for repair of DNA DSBs. Requires
sequence homology to rejoin the broken DNA ends; hence
this repair process is active in the S and G2 phases of the
cell cycle. Following ATM-mediated DNA DSB recognition,
the Mre11/Rad50/NBS1 complex is recruited for 3′ end
resection. RAD51/RAD52 then mediate strand invasion of
the homologous strand on the sister chromatid in conjunction
with BRCA1 and BRCA2 proteins. Inactivation of HRR genes
greatly increase radiosensitivity in in vitro models.
M C D
DNA is the target of radiation-induced cell lethality.
Apoptosis: Programmed cell death mechanism that is common in
embryonic development. Primary mode of cell death in
hemopoietic and lymphoid cells following radiation. Importantly,
this is a p53-mediated cellular death pathway (which is mutated
in numerous cancers). BCL-2 counteracts the initiation of
apoptosis. Can be initiated by the extrinsic pathway (via FAS-L
and TRAILR) or intrinsic pathway (as a result of DNA damage,
hypoxia, and metabolic stress). Both pathways lead to activation
of caspases that disrupt mitochondrial outer membrane
permeabilization leading to cytochrome c release and
subsequent chromatin condensation → DNA fragmentation →
cell death.
Mitotic catastrophe: Results from aberrated mitosis due to
radiation-induced lethal DNA DSBs. Primary mode of death
following radiation in nonhematopoietic cells. Many tumors have
deficient p53 and abrogated cell-cycle checkpoints that allow
cells to progress into G2/M despite sustaining DNA DSBs as a
result of radiation. The three major lethal chromosomal
aberrations induced from radiation are formation of dicentric
chromosomes, rings, and anaphase bridges.
Radiation-induced senescence: Has been reported in in vitro
models following extensive stress due to DNA damage induced
from radiation. Classically, senescence (or permanent cellular
arrest) occurs as a result of telomere shortening due to aging.
However, DNA damage that results from low doses of radiation
can induce accelerated senescence due to a persistently up-
regulated DNA damage response proteins. There is some clinical
evidence of radiation-induced senescence in slow growing
tumors following radiation (ie, prostate cancer).
A E T B
I
LD 50
3.25-4 Gy (without treatment)
~7 Gy (with antibiotics, supportive care)
~10 Gy (with BMT)
No survivors >10 Gy exposure
Prodromal syndrome
<50% lethal dose: Easy fatigability, anorexia, vomiting
Supralethal dose: Fever, hypotension, immediate diarrhea
REAC/TS triage based on vomiting onset time
Vomit <4 hours → immediate hospital evaluation (median
dose 3.6 Gy)
Vomit >4 hours → delayed (1-3 days) hospital evaluation
(median dose 0.9 Gy)
Hematopoietic syndrome
Dose: 2.5-5 Gy
Time: Death within 4-8 weeks
Symptoms: (1) Prodromal syndrome; (2) latent period; (3) ~3
weeks → chills, fatigue, petechial hemorrhages, loss of hair,
infections (usually anemia not seen)
GI syndrome
Dose: 5-12 Gy
Time: Death in 9-10 days, due to loss of intestinal lining
Symptoms: (1) Prodromal syndrome; (2) prolonged diarrhea
(indicates dose >10 Gy)
Cerebrovascular syndrome
Dose: >100 Gy
Time: Death in hours, due to capillary leakage in brain
Symptoms: (1) Nausea/vomiting in minutes; (2)
disorientation, loss of coordination of muscular movement,
respiratory distress, diarrhea, convulsive seizures, coma
Treatment
<2 Gy: No treatment
2-5 Gy: Expectant management (eg, antibiotics,
transfusions)
5-7 Gy: Prophylactic antibiotics, transfusions
8-10 Gy: Bone marrow transplant
>10 Gy: GI death; supportive care
Colony-stimulating factors given for >2-3 Gy within 24-72
hours
N T T
Early effects <60 days; rapid cell turnover, due to acute cell
killing; repaired within 2 months
High α/β; less sensitive to fraction size; toxicity based on
total Gy and Gy/week
Prolonging radiation allows for repopulation (↓ acute effects)
Latency period = lifespan of functional cell
Late effects >60 days; tissues without rapid turnover; never
completely repaired
Low α/β; more sensitive to fraction size; toxicity based on
total Gy and Gy/fx
Fractionation decreases late effects, but not over a clinically
relevant time.
Serial organ: Loss of function in one part causes whole organ
dysfunction (CNS; GI tract).
No threshold volume; probability of damage proportional to
volume irradiated
Risk dominated by D max
Parallel organ: Loss of function in one part only impacts that part
(kidney; lung; liver).
Threshold volume effect
Risk dominated by average dose or volume receiving
threshold dose
Skin tolerance: ~60 Gy (depending on volume irradiated and
fractionation)
Acute effects occur in epidermis: Erythema (rapid);
desquamation (~14 days); epilation (~2-3 weeks, takes ~3
months to regrow)
Late effects occur in dermis: Telangiectasias and fibrosis
O E
Most potent modifying factor of cell kill by ionizing radiation
Must be present within microseconds of IR
“Oxygen fixation”: Formation of peroxyl radical
permanently changes DNA structure.
Hydroxyl radical (·OH) most important radical for indirect
damage to DNA
Oxygen enhancement ratio

OER range 2.5-3.0 (typically 2.8)
Requires very little O2 (3 mm Hg or ~0.5% O2)
Higher LET reduces OER.
Optimal LET: 100 keV/μM (width of double helix)
Tumor hypoxia
Hypoxic cells thought to be “treatment resistant”
Diffusional capacity of O2 ~180 μM from capillary
Typical hypoxic fraction ~10%-15% with standard
fractionation
Hypoxic fraction ↑ as tumor size ↑
Hypoxic fraction ↑ as dose/fx ↑
Therapeutic approaches to hypoxia
Raising tumor oxygenation: 100% O2, hyperbaric, carbogen,
transfusion, nicotinamide
Hypoxic cell sensitization
Nimorazole was tested as a hypoxic radiosensitizer in
supraglottic laryngeal and pharyngeal cancer by the Danish
HNC. It was found to improve LRC (49% vs 33%) and DSS
(52% vs 41%) w/ minor side effects (Overgaard et al.
Radiother Oncol 1998)
Hypoxic cell cytotoxins: Mitomycin C, doxorubicin,
metronidazole, tirapazamine (no clear hypoxia-modulating
clinical benefit shown)
R
Goal: Enhance therapeutic ratio
Reoxygenation: Vasoconstriction or free radical scavenging

Sulfhydryl compounds (amifostine), SOD, DMSO, CO,
NaCN, epinephrine
Repair: H donation to facilitate repair
Sulfhydryl compounds (amifostine), glutathione, cysteine
Reassortment: Induce senescence via p53; cell-cycle arrest
Repopulation: Enhance stem cell growth
For example R-spondin for intestinal stem cells
Amifostine is the only FDA-approved radioprotector
Administer 30 minutes prior to RT; reduces mucositis and

xerostomia (head and neck ca); pneumonitis and esophagitis
(lung ca)
More effective if given in morning
Selective for normal tissue because
Requires alk phos to activate (low in tumor tissue)
Hypovascularity and hypoxia of tumor limits amifostine
penetration
Acidic environment of tumor prevents activation
Side effects: Nausea and hypotension (~60% of pts; BP reverts
w/in 15 minutes)
C H E
Effective dose-Sievert (Sv) weighted for both radiation type and
volume of tissue irradiated
Effective dose (Sv) = dose (Gy) ◦ WF ◦ fraction of tissue irradiated
Photon/e− WF = 1; proton WF = 2; neutron WF up to 20; heavy

ion WF = 20
Can be calculated per tissue or per whole body
Average annual human exposure to ionizing radiation
World: 3 mSv/y
USA: 6 mSv/y
Deterministic: Effect occurs after exceeding threshold dose and

severity correlates with dose.
For example skin erythema, epilation, sterility, cataracts,
lethality, fetal abnormality
Stochastic: Effect occurs randomly with probability proportional
to dose (no safe threshold).
For example secondary malignancies and heritable effects
Data from the National Council on Radiation Protection and
Measurements (NCRP). Report No. 93, Ionizing Radiation
Exposure of the Population of the United States, 1987.
Radiation carcinogenesis
Solid tumors
Within radiation field receiving >50 cGy
latency ≥5 years
Usually different tumor type than original
Leukemia
latency ≥5 years
bone marrow >50 cGy
non-CLL
Cancer induction: Carcinogen dominant
↑ incidence of uncommon cancers assoc. w/ ↑ carcinogen
exposure
Exposure stigmata (long-standing changes in affected
tissues)
Radium-bone, aniline dye-bladder, uranium-lung,
chimney sweep-scrotal, ALL
Cancer enhancement: Predominant mechanism—carcinogen
participant
↑ incidence of common cancers assoc. w/ ↓ carcinogen
exposure
Normal-appearing affected tissue
Thyroid (well-diff), breast, skin (SCC/BCC ≫ sarcoma),
ovary, lung, colon
RT for Hodgkin’s ↑ breast ca risk (RR = 3.2 at 4 Gy; RR
= 8 at 40 Gy)
RT for prostate ↑ secondary ca (rectal, bladder,
sarcoma) RR = 1.34 at 10 years
Risk estimate for malignancy

10%/Sv for entire population and high dose (>0.2 Gy) or dose
rate (>0.1 Gy/h)
8%/Sv for working population and high dose or dose rate
5%/Sv for entire population and low dose or dose rate
4%/Sv for working population and low dose or dose rate
Hereditary effects: Radiation effects that can be transferred from

parent to progeny
Radiation-caused changes in the genetic material of sex cells

(germ-line mutations)
Radiation does not produce new, unique mutations but increases
the incidence of the same mutations that occur spontaneously.
Doubling dose (increase spontaneous mutation rate two-fold) = 1
Gy
Fertility effects
Male: >0.15 Gy causes temporary infertility.

3.5-6 Gy causes permanent sterility.
10-week delay for onset of infertility after exposure
can take up to 6 months for fertility to return
Female: 2.6-6 Gy causes permanent infertility
sensitivity ↑ with age
ICRP risk estimate for hereditary effects (calculated using gonad

dose)
0.41%-0.64%/Sv/child of an irradiated individual
Total population 0.2%/Sv/individual; working population
0.1%/Sv/individual
Not more than 1%-6% of spontaneous mutations ascribed to
background radiation
Individual dose limits
General public: 5 mSv total body, 15 mSv lens, 50 mSv other

single organ
Continuous exposure: 1 mSv total body
Radiation worker: 50 mSv total body, 150 mSv lens, 500 mSv
other single organ
Monthly limit of declared pregnant woman is 0.5 mSv/mo
Area dose limits
Uncontrolled area: ≤0.02 mSv/h and ≤0.1 mSv/wk

Controlled area: ≤1 mSv/wk
E E F
Sensitive period: 10 days to 26 weeks of gestation
Preimplantation (0-9 days)
Very low dose (0.05-0.15 Gy) leads to prenatal death; all or
nothing effect
Organogenesis (10 days to 6 weeks)
Structural malformation and IUGR most common; growth
restriction resolves over time
Threshold dose >0.2 Gy
Fetal stage (>6 weeks)
LD50 approaches that of adults (~3.5 Gy)
Permanent growth disturbances without malformation
Dose
Microcephaly >10-19 cGy
Cognitive decline as low as 10 cGy; <5 cGy probably
acceptable risk
Discussion of birth defects and possible actions at doses
>0.1 cGy
Therapeutic abortion considered above 10 cGy to embryo
during 10 days to 26 weeks
Max permissible dose to fetus is 5 mSv (0.5 rem); 0.5
mSv/mo (0.05 rem)
Teratogenesis
Exposure of 1 cGy ↑ relative risk of cancer by 40%
Absolute excess risk is ~6%/Gy.
E D
n = no. of fractions
d = dose/fraction
L E T
A /B R
RADIATION PHYSICS
AARON JOSEPH GROSSBERG • MOHAMMED
SALEHPOUR
P D
Hand calcs (make sure to include appropriate corrections for
extended SSD/SAD)
SAD
Dose to a different depth (SAD)
SSD
Mayneord F factor (at distance d)
Dose to a different depth (SSD)
OF = output factor calibrated at SCD

SCD = source to calibration distance
• Typically SCD = 100 cm for SAD and 100 cm + d max for SSD
SPD = source to point distance
S c = collimator scatter factor
S p = phantom scatter factor
TMR = tissue maximum ratio
PDD = percent depth dose = dose at depth/d max
• if SSD ≠ 100, then: PDD new = Mayneord F factor × PDD (SSD =
100)
Equivalent square:
a 1 cm lung ~ 0.3 cm tissue

E D
Factors that affect PDD
↑ energy → ↑ PDD
↑ field size → ↑ PDD
↑ SSD → ↑ PDD
↑ depth → ↓ PDD
Factors that affect skin dose
↑ energy → ↓ skin dose

↑ field size → ↑ skin dose
↑ SSD → ↓ skin dose
↑obliquity → ↑ skin dose
beam spoiler → ↑ skin dose
bolus → ↑ skin dose
underwedging → ↑ skin dose
Hand Calculations
OF = output factor (typically 1 MU = 1 cGy for 10 × 10 applicator at d
max, 100 cm SSD)
AF = applicator factor
Electron shielding: Lead block thickness to attenuate 95% (mm)

Lead: t Pb(mm) = (0.5 × e− energy(MeV)) + 1
Cerrobend: t Cerr(mm) = t Pb(mm) × 1.2
T T
Matched photon/electron
High electron isodose lines pull in

Low electron isodose lines bow out
Hotspot always on photon side
Cold triangle on e− side
Wedges
Wedge pair
Wedge angle (WA): Angle between wedged isodose line and a
straight line at 10 cm depth
Hinge angle (HA): Angle between central axes of incident beams
WA = 90 -HA / 2
Craniospinal irradiation
B
1 Becquerel (Bq) = 1 disintegration/second
1 curie (Ci) = 3.7 × 1010 Bq
Source strength = air kerma rate at distance of 1 m. 1 U = 1
μGy/h/m2
Hand calcs
S k: Air kerma rate

Λ: Lambda (dose rate) constant. Converts kerma in air to dose in
water
G(r, Θ): Geometry Factor. Inverse square equation
Point source, G(r) = 1/r 2
Line source, G(r, Θ) = (Θ2 − Θ1)/Ly
If r ≫ source length, G(r, Θ) ≈ 1/r 2
F(r, Θ): Anisotropy factor
At perpendicular angles (Θ = π/2), F(r, Θ) = 1
Value changes as you move off axis
g(r): Radial dose function
High-energy γ sources (192Ir), scatter ≈ attenuation (r < 5 cm)
g(r) ≈ 1
Low-energy sources (125I), attenuation ≫ scatter
g(r) ≪ 1
Brachytherapy loading
Uniform loading: More dose at center

Peripheral loading: Uniform dose achieved by increasing source
strength at ends
Brachytherapy systems
Fletcher-Suit: Intracavitary tandem and ovoids; classically

prescribed to point A
Patterson-Parker: Interstitial crossed needles, peripheral loaded
for uniform dose
Quimby: Interstitial crossed needles, uniform loading, hot in
center
Paris: Interstitial parallel needles, hot in center
Modified peripheral loading: Prostate interstitial implants
C R
D S
ICRU 50
GTV: gross tumor volume—visually, palpably or radiographically

apparent disease
CTV: clinical target volume—GTV + volume suspected to harbor
microscopic disease
PTV: planning target volume—CTV + margin for setup error and
target motion
TV: treated volume—volume receiving prescribed dose
IV: irradiated volume—volume receiving dose appropriate for
normal tissue toxicity
Dose reported to ICRU reference point (PTV within 95%-107%
of Rx dose)
Relevant and representative of PTV dose
Easy to unambiguously define
Located where dose can be accurately calculated
Away from penumbra/steep dose gradients
ICRU 62
IM: internal margin—physiologic variation in shape and position

ITV: internal target volume—GTV + IM
SM: setup margin—uncertainty in dose calc, machine alignment,
and pt setup
PRV: planning risk volume—organs at risk (OARs) + IM and SM
CI: conformity index = TV/PTV
ICRU reference point not valid for IMRT
Report DVHs for target volumes and OARs instead
S
Half-value layer: HVL = ln 2/μ; Tenth-value layer: TVL = HVL × 3.3
μ = linear attenuation coefficient; dependent on material, energy, field
size, and depth
Attenuation: , where n is number of HVLs
Primary barrier:
Secondary barrier:
P = permissible dose-equivalent:
Controlled area: 0.1 cGy/wk
Uncontrolled area: 0.01 cGy/wk (infrequent exposure)
W = workload (# patients/wk × dose/pt = cGy/wk)
U = use factor (floor = 1, ceiling = ¼–½, walls = ¼, secondary barrier
= 1)
T = occupancy factor (fraction of working day occupied; work
areas/office/nurse station = 1, corridors/restrooms = ¼, waiting
rooms/stairways/elevators = 1/16–1/8
d = distance (m)
B = transmission factor (HVLs or TVLs)
Neutron shielding : Wax, concrete, or borated polyethylene
B R P
Radioactive decay
α-decay: Releases a helium nucleus. Very heavy nuclei (Z > 52),

monoenergetic, 2-8 MeV
β-decay: Releases either b− (negatron) or b+ (positron). No

change in A. Polyenergetic, energy shared between β and
neutrino/antineutrino. Typical energy is 1/3 of maximum.
Gamma emission: Photon emitted by excited nucleus, typically

after α- or β-decay
Electron capture: Proton-rich nuclei; converts P→N and releases
gamma ray/internal conversion electrons and characteristic x-
rays or Auger e−
Photon interactions
Rayleigh scatter: Dominant <10 keV. Probability (P) ∝ Z. Photon

“bounces off” e−. No dose contribution
Photoelectric effect: Dominant at 10-26 keV. P ∝ Z 3/E 3. Photon
ejects e− and characteristic x-ray/Auger e−. Responsible for
high-contrast imaging
Compton scatter: Dominant at 26 keV to 24 MeV. Photon hits e−
and sends it at angle ≤90 degrees. P ∝ electron density (Z-
independent). Underlies radiotherapy dose delivery. Poor for
imaging
Pair production: Dominant at >10 MeV. P ∝ Z 2 and dramatically
increases with E. Photon splits energy of 1.02 MeV into electron
and positron, which then release two additional photons (0.511
MeV each) via annihilation reaction. Adds scatter and widens
margin around target
Energy to produce an ion pair in gas: 33.97 eV

Bremsstrahlung: Inelastic interaction between e− and nucleus
releases photon. Produces x-rays in x-ray tubes and linacs.
IMAGING AND RADIOLOGY
AARON JOSEPH GROSSBERG • CLIFTON DAVID FULLER
I R B
kVp: Peak x-ray energy (kV). Photons generated will have a range of
energies with E max = kVp.
mAs: E-current (milliamps) × time (seconds)
Quantity of x-rays produced in an exposure ∝ mAs × kV 2
X-ray exposure that passes through patient to film ∝ mAs × kV 4
Exposure of film/detector is very dependent on kV
Adapted from Dixon RL, Whitlow CT. In: Chen MYM, Pope TL, Ott DJ, eds.
Basic Radiology . 2nd ed., 2011.
X-R R
Production of two-dimensional images using (15-
150 kV) low-energy x-rays
Use: Plain films (CXR, AXR, axial skeleton, extremities, etc.),
mammography, kV IGRT
Physical interaction: Photoelectric (dominant) and Compton.
Because interaction (P) ∝ atomic number (Z)3/photon energy (E)3,
interactions are more likely with higher Z material (bone, metal) and
lower kVp x-ray.
X-ray generation: Bremsstrahlung (energy-dependent) and

characteristic (anode material-dependent)
X-ray tube:
↑ kV: ↓ contrast, ↓ pt exposure (dose), ↓ exposure time (lower

likelihood of interaction)
↑ mAs: ↓ exposure time
↑ size of focal spot (anode): ↑ penumbra, ↓ sharpness
Noise: Randomness of interactions within tissue. Compton
interactions cause scatter electrons and increasing noise (energy
independent in diagnostic range).
Mammography: To resolve glandular tissue or microcalcifications
from fat, very low energy photons are needed. This is typically
resolved by using an anode made from molybdenum (17.5 and 19.5
keV) or rhodium (20.2 and 22.7 keV), which emit characteristic x-rays
of lower energy than tungsten (60-70 keV). Beryllium replaces glass
as window of x-ray tube as it is lower Z and less attenuating.
C T
Computer-processed combinations of multiple x-ray measures taken
circumferentially around the patient to produce cross-sectional images
(tomography). Because attenuation is closely related to tissue density
and the probability of a Compton interaction is proportional to tissue
density, CT number is used to calculate RT dose deposition.
Contrast: Dependent on differential attenuation, which reflects
physical density. CT uses higher kVp and filtration (beam hardness),
so interactions are mostly Compton scattering.
Hounsfield units (HU): Linear CT contrast scale that normalizes

the original linear attenuation coefficient measurement to the
radio densities of water and air.
Window (width) = range of HU to be displayed

Level = midpoint of the window
Image noise
Noise (graininess) is due to low number of x-rays contributing to each
detector measurement.
↑ mAs → ↑ number of x-rays → ↓ noise; can be impacted by

changing mA or scan time(s)
↑ slice thickness → ↑ number of x-rays → ↓ noise but
decreased spatial resolution
↑ kVp → ↑ number of x-rays → ↓ noise but decreased contrast
(slightly)
↑ patient thickness → ↓ number of x-rays → ↑ noise
Artifact: Any structure seen on an image that is not representative of

actual anatomy
Shading artifact: Lower than expected HU in regions

downstream from high-density material—most commonly due to
beam hardening that exceeds correction
Ring artifact: Arise from errors, imbalances, or calibration drifts
in part of the detector array. Errors are back projected along ray
path to that detector, creating a ring.
Streak artifact: Causes include bad detector measurement,
motion, metal, insufficient x-ray intensity, partial volume effects,
and tube arcing or system misalignment.
Additional limitations include bore size and field of view (FOV).

Patient must be able to fit within the bore. FOV is always smaller than
bore size. Contact with the CT bore or FOV limit, can cause
incomplete scanning and artifact that impact dose deposition
calculations.
Special CT protocols
Head and neck: Thin-slice (<3 mm) IV contrast-enhanced with single
phase collected ~70 seconds after contrast injection +/− upper and
lower angles (in which case ½ the contrast is used for the angle
scans)
Pancreatic (3-phase): Thin-slice (<3 mm) multidetector CT with
triple-phase IV contrast and low-density/water oral contrast. Arterial
phase (<30 seconds) shows arterial anatomy/involvement;
parenchymal phase (45-50 seconds) shows parenchymal masses as
hypointense lesions (PDAC) vs isodense (neuroendocrine); portal
venous phase (75 seconds)—delineates venous structures and liver
metastases.
Liver (3 phase): Includes late arterial phase (20-35 seconds after
contrast administration), portal venous phase (60-90 seconds), and
delayed phase (>3 minutes). Hypervascular tumors identified during
arterial phase, hypovascular tumors during portal venous phase,
washout evaluated during delayed phase
4DCT: Continuous CT scan collected during breathing cycle. Tumor
and normal tissue can be identified throughout breathing cycle, and
the degree of movement can be represented on their simulation
planning scan. Requires some level of respiratory management to
ensure even, full breathing cycle during scan. The pitch of the scan is
adjusted per the patient’s respiratory rate.
M R I
Measures magnetic resonance: Frequency of energy released by
protons as they “relax” from an energy pulse in a different direction
from bore of the magnet (B0). The local environment of each proton
after excitation influences its return to alignment with B0, yielding
contrast. By changing the magnetic sequences and measured
parameters, one can image different tissue characteristics.
T1: (spin-lattice relaxation) Time taken for spinning protons to realign
with B0 after 90 degrees pulse. “Longitudinal relaxation time.”
Dependent upon energy exchange with surrounding material
Fat is bright; fluid (CSF) is dark.

White matter is lighter than gray matter.
Gadolinium increases brightness of blood/fluid by improving
energy exchange (T1 + C = T1 with contrast).
T2: The component of T2* (transverse relaxation time) that is due to

proton-proton interactions and thus tissue dependent. “Spin-spin
relaxation”
Fat is intermediate-bright, fluid (CSF) is bright.

White matter is darker than gray matter.
Gadolinium shortens T2 relaxation time → hypointense signal of
blood/fluid.
Special MRI sequences
STIR: Short T1 inversion recovery. Used for fat suppression in
T2-weighted images. Lower signal, poorer signal-to-noise,
therefore often run at poorer spatial resolution to compensate
FLAIR: Fluid-attenuation inversion recovery. Usually used in T2-
weighted brain images to suppress CSF signal and improve
sensitivity to pathology.
Fat is dark; fluid (CSF) is dark.
White matter is darker than gray matter.
Diffusion-weighted imaging: detects random movements of
water protons by adding sequential diffusion gradients in
opposing directions to T2-weighted sequences. Diffusion
weighting depends on:
1. Gradient amplitude
2. Gradient pulse application time
3. Interval between gradients
Apparent diffusion coefficient (ADC): Calculated by comparing
multiple diffusion-weighted scans with different b-values (a
measure of the strength and duration of applied gradients). Areas
of low diffusion lose the least signal on high b-value images
(small ADC). Areas of fast diffusion appear bright (lose more
signal on high b-value images).
P E T
Allows imaging of biological uptake of radiolabeled tracer that
emits positrons. Positron annihilation results in pairs of 511 keV
photons at 180 degrees, which are detected by coincidence detection
allowing for back calculation of location in 2D space in each slice.
Coincidence detection: Photons released by positron

annihilation detected at same time by detectors at 180 degrees
from each other. Detection within 6-12 ns considered “in
coincidence.” Majority (~99%) of photons are thus excluded from
results.
↑ accumulated tracer → ↑ signal
18 FDG-PET images glucose uptake (nonmetabolized glucose
analog builds up in metabolically active cells). Most common use for
PET imaging
SUV: Standardized uptake value. FDG uptake in a

region/tumor/tissue normalized to the injected radiotracer and
patient’s weight
SUV more accurate if normalized to patient’s lean body
mass or body surface area, but this is not standard practice
Normal tissues: SUV 0.5-2.5, tumor—SUV > 2.5 (usually)
Patient preparation
NPO 4-6 hours: FDG-PET to enhance FDG uptake by tumors. No
caffeine/alcohol either. Blood glucose at time of injection <150
mg/dL
No strenuous activity prior to imaging
Typical dose of FDG 10 mCi. Imaging initiated 60 minutes after
tracer injection
Position: For HN, arms down; if below neck, arms above the
head (decrease beam hardening during CT). Patient must be
comfortable enough to lie for 45 minutes and instructed not to
move.
PET can be done in treatment position (with immobilization)
for better treatment planning image fusion. This is
particularly important for INRT in lymphoma management.
Duration: PET scanning typically takes 30-45 minutes.
Other PET tracers
Na 18 F: Images blastic and lytic bone lesions (alternative to
traditional 99mTc bone scan)
11 C acetate PET: Ketone body uptake. Related to enhanced lipid
synthesis in prostate cancer tumor cells. Not cancer specific—

also accumulates in BPH. 71% accuracy ( Jambor J Nucl Med
2010)
11 C or 18 F choline PET: Choline is used in cell membrane
synthesis, which is increased in cancer cells. Highly sensitive for

lymph node involvement or metastasis. High levels of uptake in
liver, spleen, kidneys, pancreas, and salivary glands.
Inflammation can confound interpretation of increased uptake.
18 F fluciclovine (Axumin) PET: Analogue of -leucine. Uptake
increased in prostate cancer. No physiologic accumulation in

urinary tract or brain allowing for sensitive detection of localized
and metastatic disease. Used for metastatic or recurrent disease,
proven by rising PSA
11 C metomidate: 11β-hydroxlase inhibitor, key enzyme in
biosynthesis of cortisol and aldosterone. Used for detection of

adrenocortical tumors
O N M I
Bone scan: 99mTc with methylene diphosphonate (MDP). MDP
adsorbs to bone hydroxyapatite, which is present at sites of bone
growth/increased turnover. Patient is typically injected with 740
MBq of tracer and scanned with a gamma camera (planar
images).
Myocardial perfusion: 99mTc tracers include teboroxime and
sestamibi. Evaluates areas of infarction, ischemia, or reduced
blood flow
Renal scan: aka renogram or MAG3 scan. May use 99mTc-
conjugated mercaptoacetyltriglycine (MAG3) or
diethylenetriaminepentaacetate (DTPA) injected intravenously.
Progress through renal system tracked with gamma camera.
Measures effective renal plasma flow. 40%-50% of MAG3 (20%
of DTPA) is removed by the proximal tubules during each pass.
V/Q scan: Evaluates circulation of air and blood within patients’
lungs. Used for pre-op/pre-RT estimate of lung function pts with
lung ca. or mesothelioma. For the ventilation scan, aerosolized
radionuclides are inhaled by the patient through nonrebreathing
mask. Perfusion scan is 99mTc microaggregated albumin.
MIBG: Metaiodobenzylguanidine labeled with 123I or 131I.
Localized to adrenergic tissue and can be used to identify
pheochromocytomas and neuroblastomas. Use of 131I allows for
treatment as well as imaging. Must undertake thyroid precautions
by pretreating with potassium iodide
Sentinel node identification: Injection of 99mTc-labelled sulfur
colloid or albumin colloid injected 2-24 hours prior to operation.
Preoperative lymphoscintigram is obtained to map axillary
drainage patter from tumor. Intraoperatively, a gamma counter is
used to find the area of highest radioactivity.
123 I iodine scan: Supplied as Na131I and administered orally vs
IV Iodine is taken up by the thyroid and images obtained by

gamma camera.
131 I iodine scan: Like 123I, it is taken up by the thyroid. 90% of
decay is by β-decay, allowing for short-range therapeutic effects,
with the remaining 10% via gamma decay, allowing for detection
using gamma camera. Dose ranges from 2220 to 7400 MBq.
Patients cannot be discharged until activity falls below 1100 MBq.
Patients advised to collect urine, wear clothes and socks, and to
regularly clean toilets, sinks, etc. Patients who undergo treatment
may trigger airport radiation detectors up to 95 days after tx.
I -G R T (IGRT)
Goal of IGRT is to minimize geometric uncertainty during treatment.
Sources of geometric uncertainties
Intrafraction
Seconds: Cardiac cycle, breathing
Minutes: Patient movement, setup variation
Interfraction
Hours: Patient movement, setup variation
Days to months: Anatomic changes, tumor response, normal
tissue response
Corrections
Remember that you are moving the patient, not the imager. Often
corrections involve moving patient in opposite direction to apparent
misalignment.
Isocenter too superior (target too inferior on daily imaging): Move

patient in
Isocenter too inferior (target too superior on daily imaging): Move
patient out
Isocenter too far on patient’s left (target too far on patient’s right
on daily imaging): Move patient left
Isocenter too far on patient’s right (target too far on patient’s left
on daily imaging): Move patient right
IGRT approaches
Surface markers: Use surface anatomy to infer internal
anatomy. Usually in conjunction with immobilization devices.
Establish position of multiple surface markers at simulation and in
treatment room (relative to isocenter or ODI). Not a good
approach for mobile internal targets
Stereotaxy: 3D localization of structures using mechanical frame
and precise coordinate system. Allows for reduction in PTV. Most
commonly used for intracranial targets (1-2 mm PTV). Concepts
have been adapted using 4DCT simulation and full-body
immobilization to apply stereotaxy to extracranial sites, including
lung cancer (~5 mm PTV).
MV electronic portal imaging devices (EPIDs): Creating of
radiographic images using RT x-ray beam. Advantage is that
imaging represents actual treatment field. Disadvantage is that
MV imaging exhibits negligible photoelectric effect, limiting
contrast to detect only bony anatomy. Very difficult to align to soft
tissue
Single exposure: Only images treatment field
Double exposure: Treatment field and open field both imaged
for better anatomy
Localization film: A few cGy for imaging verification of setup
Verification film: Full fraction (~2 Gy) of exposure
kV imaging: Most new teletherapy machines have built in x-ray
tube and EPID orthogonal to treatment ray. Advantage is that it
offers increased contrast compared to MV. Also frequently
incorporate fluoroscopy for real-time monitoring. Due to
increased contrast detection due to greater influence of
photoelectric effect, can also be used to localize implanted
radiopaque markers. Excellent translational (x-, y-, and z-axis)
resolution. Disadvantage is that images are not collected from
treatment beam, so there is an opportunity for misalignment
between kV imager and treatment beam. Insensitive to rotational
error. Other vendors, including ExacTrac, offer floor-to-ceiling
noncoplanar imaging that can be compared to on-board imaging
in real time to detect intra- or interfraction motion.
Ultrasound: Allows for soft tissue imaging with the transducer
calibrated and coregistered with the isocenter, both in the CT
scanner and in treatment rooms. Most commonly transabdominal
ultrasound used for prostate cancer treatment setup. Bladder
ultrasounds can also be used to assess bladder fullness during
treatment for pelvic malignancies (uterus, prostate, cervix, and
bladder cancers). Advantages are that it is relatively inexpensive
and shows soft tissue contrast for targets that do not reliably align
to bone. Disadvantages are that it requires technical skill,
pressure may displace target or OARs, and that it cannot image
through bone or air cavities.
Cone beam CT (CBCT): Allows for volumetric imaging on
conventional linac using onboard orthogonal x-ray tube and
detector. CT reconstructions are acquired in the treatment
position just prior to treatment. Images may be acquired in whole-
fan or half-fan mode. FOV can approach 50 cm in the transverse
plane ×25 cm in the craniocaudal plane, but may not include full
thickness of patient. Total dose delivered is usually <3 cGy.
Advantages include the ability to align soft tissue with good
contrast in the treatment position, can see inter- and
intrafractional changes in tumor and patient anatomy, and six-
directional image verification. Disadvantages include limited FOV,
which may not show patient to surface; slow image acquisition,
making it susceptible to motion artifact and difficult to use with
respiratory gating; and relatively high radiation dose delivered.
CT on rails: Conventional CT scanner located in treatment room
moves over patient and treatment table “on rails” to acquire
images. Typically treatment table is rotated 180 degrees from
treatment position for scanning. Treatment table is made of
special low-attenuation material. Advantages include faster CT
imaging, allowing for verification of intrafractional immobilization
(eg, breath hold). Disadvantages include the need for extra
equipment, relative scarcity of CT on rail-enabled treatment
vaults, and requirement to rotate table out of treatment position
for verification scans, introducing potential new source of error.
Tomotherapy imaging: Tomotherapy devices include MV CT
image system that uses a fan beam and helical acquisition.
Images are acquired using a 3.5-MV x-rays with suppressed
photon output. Typically imaging administers dose of 0.5-3 cGy.
Advantages include images collected in treatment position and
MV imaging not susceptible to artifact. Disadvantages include low
contrast in MV images.
Electromagnetic 4-D tracking: Electromagnetic transponders
implanted in the target tissue for improving both intrafraction
motion of the tissue and interfraction setup error. Includes
beacons, electromagnetic console, receiver array, and three
ceiling-mounted infrared optical cameras. Currently in use for
prostate radiotherapy (Calypso). Less than 2 mm accuracy
Optical (surface) imaging: Optical, often infrared camera
system tracks patient surface during actual treatment. Used to
monitor intrafraction motion. Current systems include AlignRT
and C-Rad Sentinel. Advantages include speed, ability to monitor
respiratory motion, and absence of ionizing radiation.
Disadvantages include inability to use for tumors that poorly
correlate to patient surface.
Magnetic resonance imaging: Uses hybrid MRI/radiation units
to provide continuous real time assessment of internal soft tissue
anatomy and motion. Advantages include excellent soft tissue
contrast, no ionizing radiation exposure, and excellent resolution.
Disadvantages include inability to use for patients with metal
implants or pacemakers and susceptibility to motion artifact.
Incorporating IGRT into margination: ICRU 50 & 62 define
target (PTV) and avoidance (PRV) volumes to account for setup
and organ positional uncertainty. IGRT can be used to minimize
magnitude of both random and systematic error, allowing reduced
PTV margin.
Random error, σ: Fluctuations in patient position due to
unknown and unpredictable factors (eg, changes in organ
positions, bladder filling, minor fluctuations in immobilization
devices). Execution Errors. Equal in all directions
Root mean square of SDs of measured fluctuations from all
patients = σ
Systematic error, Σ: Error in patient setup due to incorrect
positioning information (eg, inaccurate isocenter determination,
laser positioning, or setup documentation). Preparation Errors.
Typically in a specific direction
SD of means per patient of observed fluctuations = Σ
Require 3-4x more margin than random errors
Can be minimized using multimodality imaging, clear
delineation protocols, and electronic portal imaging with
decision rules
Margin recipes
CTV Margin = 2. 5 ¥ Σ + 0. 7 ¥ σ (van Herk et al. IJROBP 2000)
* Minimum dose to CTV is 95% for 90% of patients.OAR Margin
= 1. 3 ¥ Σ + 0. 5 ¥ σ (McKenzie et al. Radiother Oncol 2002)
*DVH of PRV will not underrepresent high dose to OAR for 90%
of patients.
CHEMOTHERAPY AND IMMUNOTHERAPY
AARON JOSEPH GROSSBERG • CHAD TANG
C C
Chemotherapy delivered concurrently with radiotherapy to
increase efficacy
Preclinical synergy with XRT: Gemcitabine, cisplatin, bleomycin,
5-FU, MMC, bevacizumab, cetuximab, PARP inhibitors,
doxorubicin, dactinomycin, dacarbazine
Associated with increased and earlier toxicity
Rule of thumb: OAR dose constraints often reduced by ~10%
C A T
Underline = dose limiting toxicity
Alkylating Agents: Add alkyl group to 7-N guanine → DNA cross-link
and strand breaks. Inhibit DNA repair and/or synthesis.
Cisplatin (Platinol) (20-100 mg/m2 d1-5 q3-4wk; 40 mg/m2 qwk—
CCRT): N/V, nephrotox, ototox (irreversible), neuropathy
(reversible), ↓PLT, anemia, taste changes
Carboplatin (Paraplatin) (AUC 3-7.5 q3-4wk; AUC2 qwk—CCRT):
Myelosuppression (nadir 3-4 weeks), N/V, nephrotox, ototox,
neuropathy, ↑LFTs
Oxaliplatin (Eloxatin) (85-140 mg/m2 q2-3wk): Neurotox,
neuropathy, fever, ↑LFTs, nephrotox
Bendamustine (Treanda, Bendeka) (70-120 mg/m2 ×2d q3-5wk):
Myelosuppression (nadir 3 weeks), N/V, fever, edema, rash,
diarrhea
Cyclophosphamide (Cytoxan) (1-5 mg/kg/d po or 250-1800
mg/m2 q3-4wk): Myelosuppression (recovery 1 week),
hemorrhagic cystitis, nephrotox, N/V, cardiotox, infertility, alopecia
Chlorambucil (Leukeran) (0.1-0.2 mg/kg/d): Myelosuppression
(nadir 3 weeks), hepatotox, rash, CNS tox, 2° malignancy
Melphalan (Alkeran) (2-10 mg/d PO): Myelosuppression (nadir 4
weeks), mucositis, diarrhea, pulm fibrosis, 2° malignancy
Ifosfamide (Ifex) (1200-3000 mg/m2/d ×3-5d q2-3wk):
Myelosuppression (nadir 1-2 weeks), hemorrhagic cystitis,
nephrotox, reversible neurotox N/V, alopecia
Mechlorethamine (Mustargen, Valchlor) (0.1-0.4 mg/kg/d):
Myelosuppression, N/V, alopecia, mucositis, infertility, CNS tox
Carmustine (BCNU, Gliadel) (150-200 mg/m2 q6-8wk):
Myelosuppression (nadir 4 weeks), N/V, hepatotox, hypotension,
pulm fibrosis
Lomustine (CCNU, Gleostine) (100-130 mg/m2 q6wk):
Myelosuppression (nadir 4 weeks), N/V, hepatotox, nephrotox,
pulm fibrosis **Crosses BBB
Busulfan (Busulfex, Myleran) (1.8 mg/m2/d): Myelosuppression,
N/V, diarrhea, anorexia, mucositis, infertility
Dacarbazine (375 mg/m2 d1 and 15 q4wk): N/V,
myelosuppression, flulike symptoms, inj site pain
Temozolomide (Temodar) (100-200 mg/m2 d1-5 q4wk; 75
mg/m2/d—CCRT): Myelosuppression (nadir 3 weeks), N/V, HA,
fatigue, constipation, edema
Antimetabolites: Replace building blocks in DNA synthesis. Groups
include nucleotide analogues (5-FU, -MP, Ara-C, fludarabine), folate
antagonists (MTX, pemetrexed), ribonucleotide reductase inhibition
(hydroxyurea)
5-FU (Adrucil) ([IVP] 325-425 mg/m2 × 5d q4wk or [CI] 750-1000
mg/m2 × 5d q4wk): Diarrhea, mucositis, N/V, marrow
suppression, alopecia, nail changes, hand-foot
6-MP (Purinethol) (1.5-2.5 mg/m2/d): Myelosuppression, jaundice,
N/V, diarrhea, infxn
Capecitabine (Xeloda) (1000-1250 mg/m2 bid ×2 wk q3wk; 825-
1000 mg/m2 BID-CCRT): diarrhea, hand-foot, mucositis,
neurotox, coronary vasospasm, XRT recall
Cytarabine (Ara-C) ([CI] 100-200 mg/m2/d ×5-7d; high dose: 1500-
3000 mg/m2/d ×3d): Myelosuppression (nadir 7-9 days/15-24
days), N/V, diarrhea, neurotox, ↑LFTs **Crosses BBB
Fludarabine (20-30 mg/m2/d ×3-5d q4wk): Myelosuppression
(nadir 10-14 days, recovery 5-7 weeks), fever, infxn, weakness,
cough, anorexia
Gemcitabine (Gemzar) (1000 mg/m2 qwk or 800-1250 mg/m2 d1,
8 q3wk): Myelosuppression, edema, flulike symptoms, fever,
fatigue, N/V pneumonitis, ↑LFTs
Hydroxyurea (Droxia, Hydrea) (20-30 mg/kg/d):
Myelosuppression (2-5 days), GI ulcer, rash, squamous cell ca.,
XRT recall
Methotrexate (MTX, Trexall) (range from 30-40 mg/m2/wk to 100-
12 000 mg/m2 × 1): Myelosuppression, mucositis, N/V, neurotox,
nephrotox, ↑LFTs
Pemetrexed (Alimta) (500 mg/m2 q3wk): Myelosuppression,
mucositis, hand-foot, anorexia, fatigue, ↑LFTs
Plant alkaloids: Inhibit enzymes used in DNA replication, mitosis, or
cell division. Includes antimicrotubular agents (docetaxel, paclitaxel,
vincristine, vinblastine, vinorelbine) and topoisomerase inhibitors
(irinotecan, etoposide, topotecan)
Docetaxel (Taxotere) (60-100 mg/m2 q3wk): Myelosuppression (7
days), neuropathy, edema, alopecia, nail changes, N/V, XRT
recall
Paclitaxel (Taxol) (60-250 mg/m2 q1-3wk; 50 mg/m2 qwk—CCRT):
Myelosuppression (11 days), alopecia, neuropathy, arthralgias,
N/V, diarrhea
Nab-paclitaxel (Abraxane): Myelosuppression, alopecia, ECG
changes, neuropathy, arthralgias, N/V, weakness, fatigue
Vincristine (Oncovin) (0.5-1.5 mg/m2 qwk; 1.5 mg/m2 qwk—
CCRT): Neuropathy, alopecia, constipation, N/V, weight loss
**Crosses BBB
Vinblastine (Velban) (3.7-6 mg/m2 qwk): Myelosuppression (~1
week), constipation, HTN, alopecia, bone pain, N/V
Vinorelbine (Navelbine) (25-30 mg/m2 qwk): Myelosuppression
(~1 week), N/V, alopecia, diarrhea, neuropathy
Etoposide (Toposar) (50-120 mg/m2 ×3d q3-4wk):
Myelosuppression (1-2 weeks), menopause, infertility, N/V,
hypotension, rash, ↑LFTs, XRT recall
Irinotecan (Camptosar) (240-350 mg/m2 q3wk): Diarrhea, abdmnl
cramping, myelosupp, N/V, alopecia, wt. loss, weakness
Topotecan (Hycamtin) (1.5 mg/m2 ×5d q3wk): Myelosuppression
(1-2 weeks), N/V, alopecia, diarrhea, fever, rash, weakness
Antibiotics: Streptomyces antibiotics that interfere with cell cycle or
DNA replication. Anthracyclines (-rubicin) and actinomycins inhibit
topoisomerase II by intercalation. Bleomycin and mitomycin generate
free radicals causing DNA breaks. Commonly cause radiation recall.
Actinomycin D (Cosmegen) (400-600 μg/m2/d ×5d):
Myelosuppression (nadir 14-21 days), alopecia, N/V, fatigue,
mucositis, hepatotox, diarrhea, infertility, XRT recall
Daunorubicin (Cerubidine) (30-60 mg/m2/d ×3d):
Myelosuppression (nadir 10-14 days), alopecia, dark urine, N/V,
mucositis, pain, cardiotox. Max lifetime cumulative dose = 550
mg/m 2
Doxorubicin (Adriamycin) (20 mg/m2 qwk or 40-60 mg/m2 q3wk):
Myelosuppression (nadir 10-14 days), cardiotox, N/V, mucositis
XRT recall, 2ndary leukemia, tumor lysis. Max lifetime cumulative
dose = 500 mg/m 2 , less if >65, mediastinal XRT, heart disease
or cyclophosphamide
Epirubicin (Ellence) (100-120 mg/m2/d q3-4wk, 50 mg/m2 q3wk):
Myelosuppression (nadir 10-14 days), alopecia, hot sweats, N/V,
diarrhea, cardiotox. Max lifetime cumulative dose = 1000 mg/m 2
Bleomycin (Blenoxane) (5-15 units/m2/wk ×3wk): Pulmonary
tox/pneumonitis, skin rxn, mucositis, hypotension,
hypersensitivity rxn, XRT recall
Mitomycin-C (Mutamycin) (10-15 mg/m2 q6-8wk or 20-40 mg qwk
or 10-15 mg/m2 q4wk-CCRT): Myelosuppression (nadir 4-6
weeks), mucositis, rash, interstitial pneumonitis, HUS
T T
Adapted from: Abramson, 2017 Overview of Targeted Therapies for Cancer.

C N S
A
H T
Androgen
Enzalutamide (Xtandi) Androgen receptor signaling inhibitor
Indications: Metastatic castrate-resistant prostate cancer
(mCRPC)
Dose: 160 mg po daily
Side effects: Edema, fatigue, HA, hot flashes, diarrhea, arthralgia,
gynecomastia
Bicalutamide (Casodex) Nonsteroidal androgen receptor antagonist
Indications: Intermediate- to high-risk prostate cancer
Dose: 50 mg po daily × ≥14d w/ LHRH analogue or 150 mg daily
(monotherapy)
Side Effects: Edema, constipation, hot flashes, diarrhea, bone
pain, gynecomastia
Flutamide (Eulexin) Nonsteroidal androgen receptor antagonist
Indications: Intermediate- to high-risk prostate cancer; PCOS,
congenital adrenal hyperplasia
Dose: 250 mg po tid
Side Effects: Hepatotoxicity (black box warning), hot flashes, bone
pain, gynecomastia, N/V, diarrhea
Nilutamide (Nilandron, Anandron) Nonsteroidal androgen receptor
antagonist
Indications: Intermediate- to high-risk prostate cancer;
transgender hormone therapy
Dose: 300 mg PO daily ×30 d, then 150 mg po daily
Side Effects: Interstitial pneumonitis (black box warning), HA, hot
flashes, insomnia, gynecomastia, impotence, breast tenderness,
hepatitis
Apalutamide (Erleada) Nonsteroidal androgen receptor antagonist
Indications: Metastatic prostate cancer
Dose: 240 mg PO daily
Side Effects: Fatigue, nausea, vomiting, rash, bone fractures,
seizures
Abiraterone (Zytiga) decreases production of androgen precursors
by inhibiting CYP17A1
Indications: Used in combination with prednisone (5 mg daily) in
mCRPC
Side Effects: Edema, HTN, hypokalemia, fatigue, ↑glucose, ↑TG,
↑LFTs, joint swelling, hot flashes, cough insomnia, UTI, diarrhea
Estrogen
Anastrozole (Arimidex) aromatase inhibitor; blocks conversion of
androgens to estrogens in extragonadal tissues
Indications: Hormone receptor–positive breast cancer in
postmenopausal women; breast cancer prophylaxis
Dose: 1 mg po daily
Side Effects: Decreased bone mineral density, flushing, HTN,
fatigue, HA, hot flashes, mood disturbance, arthralgia, ↑CV risk,
↑cholesterol
Letrozole (Femara) aromatase inhibitor
postmenopausal women
Dose: 2.5 mg po daily
Side Effects: Decreased bone mineral density, flushing,
weakness, edema, fatigue, HA, hot flashes, mood disturbance,
arthralgia, ↑cholesterol
Exemestane (Aromasin) aromatase inhibitor
Side Effects: HTN, fatigue, insomnia, HA, decreased bone mineral
density, flushing, hot flashes, diaphoresis, mood disturbance,
arthralgia
Fulvestrant (Faslodex) selective estrogen receptor degrader
(SERD): Binds to ER and causes degradation
Side Effects: Hot flashes, ↑LFTs, joint disorders, bone pain fatigue,
HA, nausea, pharyngitis
Tamoxifen (Nolvadex, Tamifen, Genox) selective estrogen receptor
modulator (SERM): Competitive inhibitor of ER
premenopausal women
Side Effects: ↑uterine cancer, ↑VTE risk, flushing, hot flashes,
nausea, wt loss, vaginal discharge, weakness arthralgia, amenorrhea
Raloxifene (Evista, Optruma) SERM: Competitive inhibitor of ER
Indications: Breast cancer prophylaxis
Dose: 60 mg po daily × 5y
Side Effects: ↑VTE risk, ↑CVA risk, edema, hot flashes, arthralgia,
leg cramps
Gonadotropin-releasing hormone (GnRH)
Goserelin (Zoladex) GnRH agonist: Chronic activation leads to
↓LH/FSH and ↓steroidogenesis
Indications: Prostate cancer, breast cancer
Dose: 3.6 mg SC q4wk or 10.8 mg q12wk
Side Effects: Edema, fatigue, HA, hot flashes, mood disturbance,
acne, ↓bone mineral density, ↓libido, vaginal dryness, ↑glucose
Leuprolide (Lupron) GnRH agonist
Indications: Prostate cancer, breast cancer
Dose: 7.5 mg q4wk/22.5 mg q12wk/30 mg q16wk/45 mg q24wk
Side Effects: Edema, fatigue, HA, hot flashes, mood disturbance,
↓bone mineral density, ↓libido, vaginal dryness, ↑glucose
Degarelix (Firmagon) GnRH antagonist
Indications: Prostate cancer; especially h/o CV disease
Dose: 240 mg loading dose SC × 1; then 80 mg SC q4wk
Side Effects: Hot flashes, ↑LFTs, wt gain, arthralgia
B - A
Bisphosphonates inhibit bone resorption by osteoclasts
Drugs: Alendronate (Fosamax), etidronate (Didronel),
ibandronate (Boniva), risedronate (Actonel), pamidronate
(Aredia), zoledronate (Zometa)
Indications: Reduce risk of fracture and bone pain in metastatic
solid tumors or multiple myeloma. May reduce mortality in MM,
breast, prostate ca
Side Effects: Osteonecrosis of the jaw, GI irritation, esophageal
erosion, muscle pain, ↓Ca
Denosumab RANKL inhibitor; inhibits osteoclasts
Drugs: Xgeva, Prolia
Indications: Prevention of bone loss and skeletal events in solid
tumors
Dose: Xgeva—120 mg SC q4wk (prevention of skeletal events);
Prolia—60 mg SC q6mo (bone loss)
Side Effects: Osteonecrosis of the jaw, rash, fatigue, peripheral
edema, GI irritation, ↓Ca
I
Basic immunology
Innate immunity: Immunogenic pattern recognition by
macrophages, dendritic cells, and NK cells. Respond to
pathogen-associated molecular patterns and damage-associated
molecular patterns. Activation leads to cytokine production,
recruitment of other immune cells, and phagocytosis. Antigen-
presenting cells then present antigens, leading to activation of
adaptive immune system
Adaptive immunity: Lymphocyte-mediated (B and T cells)
immune “memory” via activation of B-cell receptors and T-cell
receptors. B-cell activation leads to humoral immunity (mediated
by antibody production) in response to a Th2 response; T cells
mediate cellular immunity in response to Th1 response (thought
to be more important for cancer surveillance).
Cell types
Macrophages (MΦ): Monocyte derived. Function as
antigen-presenting cells (APCs), phagocytes (in response to
Fc, complement, or mannose), and innate immune
surveillance/activation (activated by PAMPs, DAMPs). Often
resident in tumor tissue (TAMs), where they can promote
invasion and metastasis. Two subtypes with prognostic
implications in cancer:
M1:“Antitumor”; produce tumoricidal TNF and NO;
improved prognosis
M2: “Pro-tumor”; produce IL-10, arginase, TGF-β;
prevent Th1 response
Dendritic cells: APCs that respond to PAMPs, cytokines.
Play role in activating tumor-specific cytotoxic T cells.
B Cells: Lymphocytes that produce antibodies in response
to B-cell receptor activation via Th2 response to antigens.
Found in circulation, lymph nodes, spleen, MALT lymphoma
T Cells: Thymus-conditioned lymphocytes that recognize
antigen-MHC complex. Mediate cellular immunity
CD4: Helper T cells; activate immune depending on
cytokine and antigen context. Required for activation of
cytotoxic responses that underlie cancer immune
surveillance. HIV immunosuppression via CD4 depletion
→ increased cancer incidence
CD8: Cytotoxic T cell; activated by MHC class I;
produce IFNγ, IL-2. Can directly kill infected/tumor cells
via Th1 cytokine response to tumor-expressed MHC
class I. Tumor down-regulation of MHC-I is a common
means of immune evasion. Activation requires
coincident TCR-MHC and CD-28/B7 signals. Immune
checkpoint receptors can inhibit or stimulate CD-8
activation. Immunotherapeutics target checkpoint
ligands/receptors.
Th17: Produce IL-17 in response to IL-1, IL-6, and TGF-
β. Regulate mucosal immunity and modulate
inflammation. Pro- and antitumor effects
Treg: Maintain self-tolerance by inhibiting anti-self
lymphocyte expansion. May play a role in suppressing
antitumor immunity. Activated by IL-10 and TGF-β
MDSCs: Myeloid-derived suppressor cells.
Immunosuppressive myeloid cells that can be found in
tumor microenvironment and are associated with poor
prognosis and outcome
NK Cells: Cytotoxic innate immune lymphocytes activated
by MΦ cytokines. Important for containing viral infections
during adaptive immune activation. Key role in preventing
relapse after BMT
C I A
I R
Several trials evaluated safety and effectiveness of radiation with
immunotherapy.
XRT → ipilumumab: Improved OS (not SS) in metastatic CRPC

phase 3 trial (Kwon Lancet Oncol 2014)
Concurrent chemoRT → durvalumab: Increased PFS and OS
in stage III NSCLC in phase 3 PACIFIC trial (Antonia NEJM 2017
and Antonia NEJM 2018)
Concurrent WBRT or SRS + ipilumumab: Phase I safe for
melanoma patients with brain mets (Williams IJROBP 2017)
SBRT and ipilumumab: Concurrent or sequential
XRT/ipilumumab safe in metastatic solid cancers in phase I (Tang
Clin Cancer Res 2017)
Several ongoing studies are evaluating possible synergy

between radiation and immunotherapy in localized and
metastatic solid cancer.
Radiation may act as “tumor vaccine,” exposing neoantigens

after radiation-induced immunogenic cell death
Thought to be most effective in the context of hypofractionated or
stereotactic XRT
I C I –
A A E
Side effects much different from cytotoxic therapy. Due to stimulation
of autoimmunity.
General management principles:
Grade 1: Local/symptomatic treatment (topical steroids,

antidiarrheal)
Grade 2: Rule out infection/disease progression; oral steroids
(eg, dexamethasone 4 mg every 6 hours). Treat symptoms.
Grade 3-4: Hold or discontinue Rx; IV steroids +/− additional
immunosuppressants (eg, infliximab 5 mg/kg single dose)
Hypophysitis: Clinical hypopituitarism and radiographic pituitary

enlargement. Symptoms—Headache, fatigue/weakness. Decreased
thyroid, adrenal, gonadal hormones. DI and vision Δ rare. Rule out
brain mets with MRI; full endocrine workup. Can resume
immunotherapy with hormone replacement.
Pneumonitis: Rule out infection and hold treatment with G1. G2
—add steroids; G3-4—d/c Rx; hospitalize with high-dose IV steroids
Diarrhea/Colitis: Diarrhea and radiographic changes such as
diffuse bowel thickening or colitis. First rule out Clostridium difficile or
other infection. In severe instances colonoscopy may help to
diagnose. Treat diarrhea with antidiarrheal agents (eg, loperamide
and atropine) and anti-immune medications (eg, steroids and
infliximab).
Rash: Most common adverse event, occurring with 40%-50% of
Pd-1 and CTLA-4 inhibitors. G1-2—supportive treatment with cold
compresses, topical corticosteroids, and hydroxyzine, G3—hold
treatment until return to G1. If G4 consider infliximab, mycophenolate
mofetil, or cyclophosphamide. Rarely Stevens-Johnson
syndrome/toxic epidermal necrolysis has been reported.
A T- T
Transplantation of more effective antitumor T cells to induce direct
tumor killing
Chimeric antigen receptor (CAR-T cells) autologous or

allogeneic T cells genetically engineered to express a chimeric T-
cell receptor that includes tumor antigen–specific monoclonal Ab
variable regions fused with the TCR and a costimulatory receptor
(CD28). Activation is MHC independent, and response to antigen
is supraphysiologic.
Indications (FDA approved): Pediatric ALL; refractory large
B-cell lymphoma
Adverse effects: Cytokine release syndrome, off target
effects (B-cell aplasia), cerebral edema, neurotoxicity; GVHD
(if allogeneic T cells are used)
Engineered TCR T cells are isolated from blood or tumor tissue
and tumor antigen–responsive T cells are selected TCR from
these cells are cloned and autologous lymphocytes are
engineered to express selected tumor-specific TCR and infused
into patient. Activation is MHC dependent.
Tumor-infiltrating lymphocytes (TIL) lymphocytes are isolated
from tumors, expanded in vitro in the presence of IL-2, and
infused back into the patient after lymphodepletion with TBI or
chemotherapy.
Donor lymphocyte infusion Adoptive transfer of lymphocytes
from a donor to a patient who has already received an HLA-
matched transplant from the same donor. The goal is to augment
antitumor immune response or ensure durable engraftment. Used
to treat relapse after allogeneic SCT for CML, AML, and ALL
Adverse effects: Acute and chronic GVHD; bone marrow
aplasia, immunosuppression
O V
Modified viruses that replicate preferentially in cancer cells. Many
designed to stimulate immune system and induce antitumor immunity.
Primary mechanism of action is virus replication in tumor cells causing
oncolysis.
T-Vec (Imlygic) modified HSV-1 expressing GM-CSF. Approved

for inoperable melanoma. Delivered by intratumoral injection
Reolysin unmodified human reovirus systemically administered
oncolytic virus. Replicates in cells with activated Ras. Currently in
phase III for HNSCC and CRC
JX-594 (Pexa-Vec) attenuated vaccinia virus that expresses GM-
CSF. Selectively replicates in cells with high levels of thymidine
kinase (eg, p53 or Ras mutation). Currently in phase I-III clinical
trials
DNX-2401 (Delta-24-RGD) replication-competent adenovirus that
selectively replicates in tumor cells with nonfunctional Rb
pathway. Expresses RGD that enables uptake in tumor cells
expressing integrins αvβ3 or αvβ5. Currently in phase I/II.
PVSRIPO: Polio-rhinovirus chimera that recognizes the poliovirus
receptor CD155, which is widely expressed in neoplastic cells of
solid tumors. Recent phase I/II trial highlighted its use in recurrent
glioblastoma, as it improved survival to 24-36 months, which is
improved relative to historical controls (Desjardins et al. NEJM
2018).
C
GM-CSF (sargramostim)
Indications: Chemo-induced neutropenia; myeloid
reconstitution for HSCT
Mechanism: Stimulate expansion of myeloid cells (PMNs,
DCs, MΦ)
Side Effects: Bone pain, myalgias, arthralgias, injection site
rxn
G-CSF (filgrastim)
Indications: Chemo-induced neutropenia; myeloid
reconstitution for HSCT
Mechanism: Stimulate expansion of myeloid cells (PMNs)
Side Effects: Bone pain, myalgias, arthralgias, injection site
rxn
IL-2 (aldesleukin)
Indications: RCC, melanoma, adjuvant for autologous BMT
Mechanism: Expansion of lymphocytes (↑CD4, CD8, Treg, B
cells, NK cells)
Side Effects: Capillary leak, shock, flulike symptoms
V
Induce immune response to shared or unique tumor antigens
Preventive vaccines: Vaccinate against cancer-causing viruses
HPV vaccines: Inoculation of viruslike particles assembled from

recombinant HPV coat proteins. Elicit virus-neutralizing antibody
responses. 100% protection vs cervical CIN (Harper Lancet
2006)
Gardasil and Cervarix HPV types 6, 11, 16, and 18
Gardasil-9 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
HBV vaccines: Contain HBsAg, produced by yeast cells. Three
vaccinations ~85%-90% protection
Engerix-B and Recombivax HB: HBV infection only (all
ages)
Twinrix HAV and HBV (18 and older)
Pediarix infants whose mothers are negative for HBsAg (as
early as 6 weeks old)
Therapeutic vaccines: Vaccinate against tumor-specific antigens to

induce a T-cell response.
Can be made from whole cells, modified whole cells (eg, express
immunostimulatory molecules), peptides (HLA-restricted), DNA,
DC conditioning, or Ag presentation in vectors (eg, virus)
containing immunostimulatory molecules
Sipuleucel-T (Provenge): Dendritic cell vaccine FDA approved
for metastatic prostate cancer. Stimulate immune response to
prostatic acid phosphatase. Patient’s DCs collected and cultured
with PAP-GM-CSF, then reinfused. ↑OS in mCRPC by 4 months
(Kantoff NEJM 2010)
Prostvac-VF: Recombinant vaccinia virus encoding PSA and
costimulatory molecule. ↑OS in mCRPC by 4 months in phase II
(Kantoff JCO 2010)
CLINICAL STATISTICS
LAUREN ELIZABETH COLBERT • CLIFTON DAVID FULLER
• BRUCE MINSKY
B B
Statistical testing requires defining a study hypothesis and thus
a null hypothesis (H o) to be tested. Applying the appropriate
statistical test to this null hypothesis results in a P-value (α) →
the probability of a result equal to or beyond that observed
assuming H o is true.
The test, H o, and thus the α can all be either one sided (only
tests data on one side of the H o) or two sided (tests data on
both sides of the H o).
Type I (or α) error occurs when we conclude there is a difference
when none exists; Type II error (or β) occurs when we conclude
there is no difference when one exists; Power (1-β) is the
probability of correctly rejecting H o.
Sensitivity and specificity are used to evaluate diagnostic tests.
Sensitivity is ratio of True Positives/Actual Positives. Actual
Positives includes True Positives + False Negatives. Sensitivity
is the ratio of True Negatives/Actual Negatives. Actual Negatives
includes True Negatives + False Positives.
Positive predictive value (PPV) and negative predictive value

(NPV) predict the likelihood of accuracy of a given test result.
They both depend on the frequency of the disease in the
underlying population. PPV = True Positives / (True Positives +
False Positives); NPV = True Negatives / (True Negatives +
False Negatives).
Figure 5.1 2 × 2 contingency table showing expected test and
condition results and their combinations.
C S T
Univariate analyses (one independent variable)
Multivariate analyses (two or more independent
variables)
Note: A Cox multivariate analysis requires 10 events per

variable analyzed. For example, if there are 100 local failures,
then a total of 10 variables can be analyzed.
C T D
I C —C S
Phase I study designs
Traditional rule-based designs (Classical 3 + 3,
pharmacologically guided, accelerated titration)
3 + 3 Design: Based on traditional Fibonacci sequence.
Cohorts of 3 patients are treated at a time and followed until
specified time period before escalating. Once there is one
patient with grade 3+ toxicity, a total of 6 are entered at that
dose level. If a total of 2 or 3 of the 6 have grade 3+ toxicity,
then that dose level is the maximal tolerated dose (MTD).
The recommended dose level (RDL) for the phase II is one
dose level below the MTD. Advantages: Simple and easy to
follow/implement. Disadvantages: can be very slow and can
treat unnecessary patients at below the MTD
Accelerated titration (AT): Allows escalating to next dose
levels within cohort due to <3 patient cohorts (1 or 2). Only
requires 3 patient cohort if a prespecified toxicity occurs.
Advantages: Can increase pace of accrual and escalation.
Disadvantages: Excessive/unsafe dose escalation may
occur before toxicity is realized. May expose too many
patients to toxic dose, particularly with radiation toxicities that
may occur later
Model-based designs (continual reassessment method [CRM,
TITE-CRM], EffTox, Time to event, TriCR)
Continual reassessment model (CRM): Bayesian-based
adaptive modeling accounts for known prior probabilities of
toxicity including previously available data and previously
accrued patients; adjusts dose as prior probabilities change.
Advantages: May be more likely to treat patients at
appropriate dose levels, does not throw out known data, may
escalate more quickly. Disadvantages: Requires intensive
statistical support and appropriate/trustworthy prior data.
TITE-CRM is a variety of CRM that incorporates time-to-
event rather than only dichotomous toxicity data.
EffTox is a variety of CRM that incorporates both efficacy
and toxicity into decision-making for dose assignment.
Investigators set “rules” for requirements for efficacy and
toxicity in order to escalate/de-escalate dose. Advantages:
More efficient in diseases where some toxicity trade-off may
be acceptable for increased efficacy (ie, pancreatic cancer,
glioblastoma, diffuse intrinsic pontine glioma, etc.) or for
extremely low toxicity studies (some RT studies). The Late
Onset EffTox model (LOET) can be effective in radiation
studies, where onset of toxicity may be later than in drug
studies, for example.
Phase I/II trials are designed to initiate a phase II trial at a
prespecified criterion. Often the MTD identified in the phase I
component of the trial is utilized in the phase II component.
Phase II study designs
Single-arm designs generally compare only to known historical
outcomes, with no built-in comparison arm. Outcomes may be
response/no response, recurrence-free survival, or overall
survival. Advantages: These require small sample size and
allow for choice of comparison arm. Disadvantages: Historical
comparisons are limited; comparisons may be biased.
Randomized phase II: Two-arm studies that may be either
comparative, with the intent to choose a winner for a phase III
trial, or noncomparative. Advantages: Avoids limitations of
historical comparison. Disadvantages: Require a much larger
sample size. Allowed type I and type II error rates may be
clinically futile given limitations in sample size.
Randomized phase II/III study designs
Patients are entered on the phase II portion and if an interim analysis
meets a prespecified criterion (eg, does not show a difference
between treatment arms), the trial continues as a phase III. The
patients entered on the phase II become part of the phase III.
Advantages: More efficient since there is only one trial.
Disadvantage: The primary endpoint of the phase II must be different
than the phase III. For example, the primary endpoint of the phase II
could be local control whereas the primary endpoint of the phase III
would be survival.
Phase III study designs
Randomized controlled trial (RCT) represents “gold standard”
of clinical testing. A double-blinded trial involves both the
investigators and patients being blinded to treatment arm.
Randomization can occur in many methods but involves
randomly assigning patients to treatment arms. Advantages:
Chance is only source of potential imbalance (eliminates
selection and time biases), and randomization lends validity to
statistical testing. Disadvantages: May require very large patient
sample; not acceptable to some patients; administratively and
financially complex. Placebo controls can be used for the control
arm; this is difficult in radiation trials.
Superiority trials are intended to show efficacy of a test
treatment to be superior to that of a control (generally standard of
care).
Noninferiority trial is considered positive if efficacy is similar to
a known effective treatment, and involves a one-sided statistical
test (ie, an experimental arm is not worse by an allowable
amount determined by investigators). Equivalence trials are
similar, but require two-sided statistical tests. In general, an
equivalence (and most noninferiority) trial requires about twice as
many patients as a superiority trial.
Crossover design trials allow patients to “cross over” from
assigned arm to other arm. Advantages: Each patient can be
his/her own control; more palatable to patients. Disadvantages:
Difficult to interpret statistically; disease must be stable over time;
one arm must not affect the other arm. Lastly, a crossover trial
cannot use overall survival as the primary endpoint.
Two-by-two or “Factorial” design involves more than one
randomization or treatment arm assignment. Advantages:
Allows testing of more potential treatments within one trial.
Disadvantages: Difficult to analyze statistically; interactions
between randomization factors may complicate interpretation;
requires large patient sample sizes for reliability
I C
Odds ratio (OR) represents the ratio of odds of an event (#
currently with event/# currently without event) for the “exposed”
cases divided by the “non-exposed” cases; often used in a case-
control study.
Risk ratio or relative risk (RR) is a measure of incidence (over
time) and is expressed as ratio of cases who have or will develop
an event in “exposed” group vs those in the “nonexposed” group.
Absolute risk reduction (ARR) is the absolute difference
between the RR in the experimental arm and the baseline RR of
an event.
Number needed to treat (NNT) is calculated as 1/Absolute risk
reduction and represents the number of patients that would need
to be treated to avoid one event.
Hazard ratio (HR) is an Odds Ratio that compares risk over time
instead of at a static time. It can be interpreted as the ratio of
hazard of time in the “experimental” arm vs “baseline” arm.
Median overall survival (OS) is calculated using actuarial
methods and represents the time at which <50% of patients
remain alive. It accounts for “time contributed” of patients lost to
follow up.
Recurrence/relapse-free survival (RFS) is calculated based on
patients who survive without either recurring or dying.
Selection bias occurs when the studied population does not
represent the population of interest. Classification bias occurs
when the variables are not clearly measured (have subjectivity)
and misclassification affects outcome. Confounding bias occurs
when the factor and outcome are erroneously linked, when they
may be a confounding factor.
Randomization attempts to eliminate selection bias by randomly
assigning patients to groups. Clearly defining outcomes and
variables up front can help eliminate classification bias. Some
trials from the NSABP as well as the German Rectal Cancer Trial
used “prerandomization.” This approach increased enrollment;
however, due to ethical concerns, it is no longer allowed.
Inclusion and exclusion criteria are used to determine
eligibility. Patients must meet all inclusion criteria and not meet
exclusion criteria to be eligible.
An Institutional Review Board (IRB) is generally institution
specific and is responsible for ensuring that trials are safely and
ethically conducted.
Intention-to-treat analysis indicates that results were evaluated
based on treatment arms originally assigned, even if patients
change arms or do not complete therapy. An intention-to-treat
analysis should be used whenever possible in a superiority study.
Per protocol analysis analyzes only patients who were treated
according to intended protocol arm (and completed therapy).
CONSORT guidelines were designed to simplify and
standardize reporting of parallel group controlled trials.
L E ( USPSTF)
L E ( NCCN)
BRACHYTHERAPY
ANNA LIKHACHEVA • CHAD TANG
B
Definition: Brachytherapy is a type of radiotherapy in which
radioactive sources are placed inside or near target tissues.
Rationale: Brachytherapy is arguably the most conformal form of
radiotherapy. It can deliver ablative doses to the target while
sparing adjacent uninvolved tissues.
Critical considerations: Correct source placement is of outmost
importance in brachytherapy. As opposed to EBRT where dose
distribution is relatively homogenous, brachytherapy dose
distribution is heterogenous with maximum doses inside the
target being orders of magnitude higher than the prescription. 3D
treatment planning is imperative.
D D R
LDR: 0.4-2 Gy/h
MDR: 2-12 Gy/h
HDR: >12 Gy/h
PDR (pulsed dose rate): HDR delivered in small fractions over a
period of time typical for LDR implants. It is thought to mimic
radiobiological quality of LDR, while providing the radiation safety of a
remote afterloader and the 3D planning benefit of a stepping source.
Generally requires inpatient admission
HDR BED calculation (Nag and Gupta IJROBP 2000):
LDR BED calculation (Stock et al. IJROBP 2006):
R (initial dose rate) = D90 × λ

λ (radioactive decay constant) = 0.693/t 1/2
N = number of fractions, d = dose per fraction, and t 1/2 = half-life
μ = sublethal damage repair constant (typical values: prostate cancer
= 0.693 h−1, cervix cancer = 0.55 h−1)
α/β = characteristic parameter of the cell survival curve from the linear
quadratic model (typical values: normal tissues = 2-4 Gy, tumors = 2-
10 Gy)
C I
P
Screening colonoscopy within the last 3 years prior to prostate
brachytherapy procedures
Labs <7 days prior to procedure or after last cycle of chemo: Hct
> 25, Plt > 50k for intracavitary and >100k for interstitial and for
epidural/spinal anesthesia; coag panel
NPO after midnight for conscious/deep sedation
1× antibiotic at procedure (eg, Ancef) with gram-negative
coverage if preexisting orthopedic hardware (eg, gentamicin).
Discharge 1-2 weeks of oral antibiotics (eg, fluoroquinolone).
Stop Lovenox/heparin 12-24 hours prior,
Xarelto/Eliquis/Fragmin/Arixtra 24-48 hours prior, Pradaxa 3-5
days prior, and 325 mg aspirin/Coumadin/Plavix/Effient/Pletal 5-7
days prior. If on Coumadin, bridge with heparin and hold heparin
24 hours prior. If ≤6 months from cardiac stent, discuss with
cardiologist prior to stopping anticoagulation. Ok to continue 81
mg baby aspirin during procedure. Resume coagulation earliest
next day and when signs of bleeding have ceased.
Bowel prep for gyn and prostate: Clear liquid diet in the prior
to procedure, two tabs of bisacodyl at 2 , bisacodyl
suppository at night, saline Fleet Enema in
C B I
P T A
Contraindications: IPSS > 15-20 and postvoid residual >100 cc,

large median lobe, gross ECE, seminal vesicle involvement,
large-volume TURP, prostate volume >60 cc, IBD, or unable to
undergo anesthesia
LDR P P M
Normal tissue constraints: U150 = 0 cc and U125% < 1 cc.

Rectal V100 < 1 cc
D0 evaluation metrics: Consider the location of disease
identified on pretreatment biopsy and MRI. Otherwise, D90 >
90% prescription dose and V100 > 90%. Immediate postimplant
CT and/or MRI to evaluate dose distribution and confirm high-
quality implant. Post-op day 30 evaluation if there is concern
following day 0 dosimetry. Consider additional seed placement if
inadequate coverage.
SIM: 2-4 weeks prior to implant with MRI or endorectal US: (1)
Identify the base and apex; (2) Obtain length; and (3) Evaluate
pubic arch interference. If PAI, consider cytoreduction with 3
months Casodex + Lupron; make sure to obtain LFTs prior to
initiation of Casodex
Target: PTV depends on risk of ECE and imaging uncertainties.
General expansion from CTV: 2-5 mm in all directions except 0-2
mm posterior (Fig. 6.1)
Side effects and management:
Infection: IV cefazolin and discharge home with PO
ciprofloxacinUrinary (dysuria, hematuria, polyuria): Prophylactic
use of alpha-blockers, discharge home with a Medrol Dosepak. If
continued dysfunction, consider 2-week trial of ibuprofen 400 mg
bid, increase alpha-blocker dose, or another Medrol Dosepak.
Urinary retention: If unable to urinate, acutely prompt placement
of a Foley catheter is imperative. Consider other causes
specifically postanesthesia (opioid-induced) retention.
Erectile dysfunction: Consider daily Cialis prior to and after
treatment.
Proctitis and bleeding—steroid suppository → steroid enema →
referral to gastroenterology → Argon plasma coagulation
Follow-up: 1-month symptom phone call (and reevaluation if D0
implant concerns) → 6-month follow-up → regular intervals in the
first 5 years with PSA and EPIC QOL. PSA bounce can happen
12-30 months after implant.
Figure 6.1 Example MRI LDR preplan (A) and D0 (B) plan for
144 Gy I-125 brachytherapy monotherapy implant to treat
intermediate-risk prostate cancer. Showing the 100%, 150%,
and 200% isodose lines. See color insert.
High-dose rate
Common indications: Same as low dose rate
Contraindications: IPSS > 20; prostate volume >60 cc can be
overcome with a freehand technique. Proximal seminal vesicles
can be implanted if involved. HDR is an option for patients with
prior TURP if done >6 months prior and TURP defect can be well
visualized. IBD is a relative contraindication. Colonoscopy within
<3 years prior (Hsu et al. Practical Radiation Oncology 2014)
SIM: Typically, no preplan is required. CT-based or US-based
planning used. MR-based planning is under investigation.
Target: Same as LDR, except can include ECE and proximal SV
disease. No expansion from CTV to PTV if using real-time US
planning (Fig. 6.2)
Evaluation metrics: V100 > 97%, 105% < D90 < 115%; V150 <
35%; urethra V125% = 0; rectum V75% < 1 cc
Dose:
Boost: 15 Gy/1 fx or 19 Gy/2 fx.
Monotherapy: 42 Gy/6 fx (two implants, 1 week apart), 38 Gy/4 fx
(two implants, 1 week apart), 12-13.5 Gy/2 fx (one implant). All
bid treatments should be delivered >6 hours apart.
Loading technique: Start on a midgland slice. Peripheral
catheter placement techniques (~2/3 peripheral, 1/3 central)
Side effects and management: Same as LDR
Follow-up: Regular intervals in the first 5 years with PSA and
EPIC QOL. PSA bounce can happen 12-30 months after implant.
G
Endometrial (see Endometrial chapter)
Indications: Early-stage high-intermediate risk cancer. Start 4-12
weeks post-op for brachy alone, within 2 weeks after EBRT.
Examine the patient prior to placement to ensure adequate
healing of vaginal cuff. Inoperable early-stage endometrial cancer
Technique: Vaginal cuff dome HDR (Fig. 6.3)
SIM: Place fiducial seed at vaginal cuff; size dome for largest
diameter cylinder that patient can tolerate.
Target: Top 2-3 cm of upper vagina
Dose: 6 Gy × 5 fx (prescribed to mucosal surface) treated qod.
for brachy alone; 5 Gy × 2 fx if post-EBRT
Dose constraints: None
Follow-up: q3mo for 2 years; q6mo until 5 years, then annually.
Ca-125 if initially elevated
Cervical (see Cervix chapter)
Indications: Definitive treatment combined with EBRT and
concurrent chemotherapy (total package time <8 weeks).
Adjuvant/salvage
Technique: Types of implants: intracavitary, interstitial, or hybrid.
Ovoids/ring flush with cervix, tandem bisects ovoids, tandem 1/3 of
the distance between the sacrum and pubic symphysis
SIM: X-ray film immediately after device placement. CT simulation
after device placement. MRI for at least first implant
Target: (GEC-ESTRO definition)
GTV = T2 lesion on MRI
HR-CTV = GTV + cervix + any extension beyond cervix
Dose:
EQD2 dose to HR-CTV D90 = 80-90 Gy
PDR: 40-45 Gy/0.5 Gy/h in two implants of 44-48 hours each
HDR: 5.5-6 Gy × 5 fx; 7 Gy × 4 fx (in resource constrained
environment)
Dose constraints: ABS provides online Excel form for calculating
combined EQD2 at
https://www.americanbrachytherapy.org/guidelines/LQ_spreadsheet.xl
s
Rectum, sigmoid, small bowel D2cc < 70 Gy
Bladder D2cc < 80-90 Gy
Follow-up: 1 month after treatment; q3mo for 2 years; q6mo until 5
years, then annually. PET/CT at 3 months; cervical cytology annually
B
Indications: see ESBC chapter.
Target/technique:
Multicatheter interstitial brachytherapy: PTV_EVAL =
(surgical cavity + 15 mm), limited by 5 mm from skin surface
and posterior breast tissue (excludes CW + pectoralis)
MammoSite brachytherapy: PTV_EVAL = (balloon + 10 mm)
− balloon volume, limited 5 mm from skin surface and limited
by posterior breast tissue
Conformal external beam APBI: PTV_EVAL = (surgical
cavity + 25 mm), limited 5 mm from skin surface and limited
by posterior breast tissue (see ESBC chapter)
Contura MLB: PTV_EVAL = (balloon + 10 mm) − balloon
volume, limited 5 mm from skin surface and limited by
posterior breast tissue
SAVI: PTV_EVAL = (SAVI device + 10 mm) − lumpectomy
cavity volume, limited 2 mm from skin surface (or periphery
of SAVI device if closer than 2 mm from skin surface) and
limited by posterior breast tissue
SIM: Thin-slice CT scan <3 days prior to first fraction
Dose:
HDR primary treatment: 34 Gy in 10 fractions; boost is 10 Gy in 2
fractions.
LDR primary treatment: 45-50 Gy/0.5 Gy/h; boost is 15-20 Gy/0.5
Gy/h.
Evaluation metrics/dose constraints:
S
Indications: Early-stage nonmelanoma skin cancer (BCC and SCC).
Contraindications, PNI (>0.1 mm), depth >3-4 mm, young age (<50),
genetic disorders predisposing to skin cancer, previous RT or burn at
treatment site
Technique: Variable, including Ir-192 interstitial brachytherapy and
superficial kV contact radiation.
SIM: Clinical setup for fixed geometry applicators; thin-slice CT SIM
for custom applicators
Target: CTV = GTV + 4-10 mm (depending on size and histology)
Dose:
LDR: 60-70 Gy over 5 days
HDR: 40 Gy (5 Gy/fx); 44Gy (4.4 Gy/fx) delivered twice or thrice per
week, at least 48 hours apart (Fig. 6.4)
Dose constraints: D min > 95% and D max < 135%
Follow-up: H&P q3-12mo for 2 years, then q6-12; clinical photograph
of treatment site at every visit
N P
Prostate brachytherapy boost improves outcomes for high-risk
prostate cancer
ASCENDE-RT (Morris et al. IJROBP 2017). Prospective

randomized trial. 398 men with mostly high-risk disease
randomized to 78 Gy in 39 fractions or 46 Gy in 23 fractions
followed by LDR boost. Both arms received 12 months of ADT
and pelvic radiation. The 5-, 7-, and 9-year b-PFS was 89%,
86%, and 83%, respectively, for the LDR-PB boost vs 84%, 75%,
and 62% for the DE-EBRT boost (P < .001). No overall survival
benefit
Kishan et al. JAMA 2018. Retrospective multi-institution cohort
study comparing RP, EBRT with ADT, EBRT + BT with ADT. 1809
patients with GS 9-10 treated in 12 tertiary centers between 2000
and 2013. 5-Year CSS better for EBRT + BT (97%) vs RP (88%)
vs EBRT (87%). 5-Year DM rates were lower for EBRT + BT (8%)
vs RP (24%) vs EBRT (24%). Adjusted 7.5-year all-cause
mortality rates were lower for EBRT + BT (10%) vs RP (17%) vs
EBRT (18%).
Brachytherapy for cervical cancer
RetroEMBRACE (Sturdaza et al. Radiother Oncol 2016).

Retrospective cohort study investigating 731 patients from 12
tertiary cancer centers treated with EBRT ± concurrent
chemotherapy followed by IGBT followed by image-guided
brachytherapy (IGBT) for locally advanced cervical cancer.
Results demonstrated excellent LC (91%), PC (87%), OS (74%),
CSS (79%) with limited morbidity. The 3/5-year actuarial LC, PC,
CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%,
respectively. Actuarial LC at 3/5 years for IB, IIB, IIIB was
98%/98%, 93%/91%, 79%/75%, respectively. Actuarial PC at 3/5
years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%,
respectively. Actuarial 5-year G3-G5 morbidity was 5%, 7%, and
5% for the bladder, gastrointestinal tract, and vagina,
respectively.
Breast brachytherapy
Strnad et al. Lancet 2016. Randomized, noninferiority trial. 1184

patients with low-risk invasive and ductal carcinoma in situ
treated with breast-conserving surgery randomized to either
whole-breast irradiation (50-50.4 Gy in 25-28 fractions) or APBI
using multicatheter brachytherapy (32 Gy/8 fx or 30.3 Gy/7 fx
treated bid). At 5 years, local recurrence rates were similar
between APBI (1.4%) and whole-breast radiation (0.9%). No
difference in 5-year late skin toxicity, fibrosis, DFS, or OS
Figure 6.2 Example ultrasound HDR brachytherapy 15-Gy

boost plan in a patient with high-risk prostate cancer after
receiving 46 Gy/23 fx pelvic radiation.
Figure 6.3 X-ray image of dome inserted in the vaginal cuff of
an endometrial cancer patient ~6 weeks postoperatively. Note
how the dome is up against the fiducial seed confirming
adequate placement prior to HDR treatment.
Figure 6.4 Example HDR brachytherapy monotherapy plan
utilizing a “Freiburg Flap” (A) to treat superficial cutaneous
squamous cell carcinoma involving the nose and bilateral ala.
Patient was treated to 40 Gy (B) in 8 fractions given twice a
week.
PROTON THERAPY
ALEXANDER F. BAGLEY • DAVID GROSSHANS
B
Brief history:
1946: First description of therapeutic protons
1954: First patient treated with proton therapy at UC
Berkeley synchrocyclotron
1990: First hospital proton facility at Loma Linda University
Medical Center, CA
2006: MD Anderson Proton Therapy first to offer scanning
beam capability
2014: 15 active proton therapy facilities in the United States,
15 under construction, >110 000 patients treated with proton
therapy with improved patient selection and advances in
physics (Mohan and Grosshans Adv Drug Deliv Rev 2017)
Principles of proton therapy:
Interactions with matter:
Three mechanisms: (1) Coulombic force with atomic
electrons; (2) Coulombic force with atomic nuclei; (3)
nuclear interactions (rare)
Linear energy transfer (LET): Stopping power or
average rate of energy loss of particle per unit path
length (−dE/dx); inversely proportional to square of
particle velocity
Bragg peak: Protons lose energy at increasing rate as
particle slows, with peak in dose deposition known as
the Bragg peak just prior to stopping. Singular peak is
referred to as “monoenergetic” or “pristine” Bragg peak
(Fig. 7.1, below).
Spread-out Bragg peak (SOBP): Superposition of
monoenergetic proton beams with differing intensities to
sufficiently cover target volume (Fig. 7.2, next page)
Biological effectiveness:
Protons and photons assumed to be biologically similar
Relative biological effectiveness (RBE) proportional to
linear energy transfer (LET). LET (and therefore RBE)
continuously increases with depth.
Protons with estimated 10% higher average biological
effectiveness relative to protons (RBE = 1.1)
Clinical approximation: Proton dose (Gy [RBE]) = 1.1 ×
photon dose (Gy)
Limitations of using fixed RBE 1.1:
Underestimates complexity of proton-tissue
interactions
Based on limited in vitro and in vivo experiments
under varied conditions in cell lines and tissues
For passively scattered beam, LET and RBE at end
of range (distal portion of beam) may be higher than
clinical approximation. This uncertainty necessitates
consideration of proton beams direction so that
Bragg peak ends proximal to critical structures.
For scanning beam, distal edge of beam does not
conform to distal edge of target. RBE may differ
significantly compared to passively scattered beam
covering similar volume.
Variable RBE models in development; estimates
range from <1.0 to >1.7.
Proton accelerators:
Cyclotron:
Produces continuous stream of fixed-energy
protons
More compact, higher beam intensity
Maximum energy 250 MeV; range ~38 cm in water
Uses energy degraders of varying widths in beam
path to create lower energy beams for SOBP
Synchrotron:
Produces batches of protons at variable energies
Better energy flexibility and lower power
consumption
Produces SOBP at any depth without energy
degraders
Figure 7.1 Summation of pristine Bragg peaks to generate a
spread-out Bragg peak for proton therapy.
Figure 7.2 Comparative plan showing intensity-modulated

proton therapy (left) vs a VMAT/IMRT plan (middle). Excess
radiation dose (right) is calculated by subtracting the proton
therapy plan from the VMAT/IMRT plan. See color insert.
P T T
Passive scattering proton therapy (PSPT):
More mature technology with greater clinical data available
Beam is spread laterally and longitudinally in the treatment
head (nozzle).
Longitudinal: Using range modulators (ie, rotating
modulator wheel) to create SOBP over the PTV; range
compensator (eg, Lucite) to conform dose to distal edge
of target
Lateral: Using dual scattering foils of high-Z materials;
brass apertures to laterally conform dose to target
Limitation: SOBP is constant across field → no control of
dose distribution proximal to target (Mohan and Grosshans
Adv Drug Deliv Rev 2017)
Intensity-modulated proton therapy (IMPT):
Increasing use of spot scanning or “pencil beam” scanning
due to increased dose uniformity with preserved treatment
range
Two categories of IMPT:
Single-field optimization (SFO)
Individual beams optimized by inverse planning to
conform dose to target volume
Each field optimized separately to deliver uniform
dose to target
Less sensitive to uncertainties
Integrated boost possible
Multifield optimization (MFO)
All beams simultaneously optimized to deliver
homogeneous target dose
Multiple fields required to cover target
More sensitive to uncertainties
QA more demanding
Potential to place higher LET/RBE regions of proton
beam within tumor volume for dose escalation with
improved normal tissue sparing
Proton treatment planning and treatment
Protons more sensitive to anatomy and beam direction due
to (1) scattering properties; (2) sharp distal dose falloff; (3)
range uncertainty
Simulation:
Position must be reproducible and provide adequate
patient comfort.
Use proton-compatible immobilization devices.
Special considerations for high-Z materials. Generally,
try to avoid placing these materials in the beam’s path.
Use dual-energy CT for more accurate electron density
mapping of tissues.
Target delineation: Use beam directions with short path to
distal edge of target, minimal transit through heterogeneous
tissue intensities, and avoidance of distal edge close to
critical normal structures (increased RBE at end of proton
beam).
Conventional “PTV” definitions for photons do not
directly translate to protons due to range uncertainty
(related to target depth and beam direction). Therefore,
use of these terms in proton therapy literature should be
interpreted with this understanding. At MDACC the STV
(“scanning target volume”) and ETV (“evaluation target
volume”) are analogous to the PTV for scanning beam
and passive scatter, respectively.
Beam-specific PTV with different lateral margins and in
each beam direction. See below for PTV margins in
representative disease.
Beam selection: Use energy absorber (attached to the
nozzle of the aperture) if target depth <3 cm, and avoid
high–Hounsfield Unit materials.
Dose and fractionation: Use RBE adjustment as described
above; RBE may vary from <1.0 to >1.7, but variable RBE
models are not currently part of clinical treatment planning.
Image guidance: Use daily kV imaging or volumetric imaging
during treatment to minimize setup variation, similar to
conventional photon-based treatment.
Prompt gamma imaging (PGI): Formation of gamma-
emitting nuclear isotopes after proton therapy used to
approximate dose deposition; using “Compton cameras”
or single gamma ray detectors
Adaptive planning: Consider verification simulation during 1st
and 4th week of therapy and/or if any drastic changes in
patient volume is noted during treatment.
Deformable registration with planning CT
Monitor weight loss and other anatomical changes that
can alter dose distribution and DVH data.
C I
Standard indications (selected):
Craniopharyngioma (Bishop et al. IJROBP 2014; Boehling et
al. IJROBP 2012)
Target: GTV, operative cavity and residual disease; CTV,
2-5 mm customized margin; PTV, 3-mm uniform margin
Intent: Postoperative, definitive, salvage
Adverse effects: Endocrinopathy (hypopituitarism)
Considerations: PTV margin for lateral border especially
close to optic apparatus and brainstem and CTV for
proximal/distal borders
Rhabdomyosarcoma (Ladra et al. JCO 2014)
Intent: Postoperative
Adverse effects: Radiation dermatitis, mucositis
Considerations: Dose dependent on extent of residual
tumor and primary site of disease (COG protocols)
Atypical teratoid/rhabdoid tumor (McGovern et al. IJROBP
2014)
Target: GTV, operative cavity and residual disease; CTV,
anatomically constrained 1-cm margin; PTV,
distal/proximal 3-mm margin
Adverse effects: Erythema, alopecia, cytopenia (with
concurrent chemotherapy)
Craniospinal (Brown et al. IJROBP 2013; Barney et al. Neuro
Oncol 2014)
Target: CTV, entire CSF (brain; upper, middle, and lower
spine); PTV, posterior spine 7 mm (decreased 1-2 mm in
c-spine)
Adverse effects: Myelosuppression, nausea, vomiting,
dermatitis
Considerations: Junctions shifted 1 cm every 5 fractions;
block anterior orbit, posterior neck, trachea, oral cavity
Prostate (Pugh et al. IJROBP 2013; Zhu et al. Radiat Oncol
2014)
Target: CTV, prostate +/− seminal vesicles; ETV, uniform
radial 6 mm margin except 5 mm posteriorly, 9-12 mm
proximal/distally; STV, 12 mm lateral, 5 mm posterior, 6
mm all others to CTV
Intent: Definitive
Adverse effects: Bowel and urinary function, sexual
function
Considerations: Use opposed R/L lateral beams.
Skull base—Chordoma/Chondrosarcoma (Grosshans et al.
IJROBP 2014)
Target: GTV, gross residual disease; CTV, 5-8 mm
margin (to include areas of gross disease before
resection) (CTV1—higher risk, CTV2—lower
risk/surgical path); PTV, 2-3 mm
Intent: Postoperative, progression, recurrence
Adverse effects: Fatigue, nausea
Considerations: Use multiple CTVs: CTV1 = GTV + 5-8
mm margin (higher risk, higher dose), CTV2 = additional
expansion to cover lower risk and surgical pathway;
PTV with small margin to avoid optic chiasm, brainstem,
temporal lobes
Seminoma (Haque et al. PRO 2015)
Target: CTV (para-aortic and ipsilateral iliac vessels + 7
mm); GTV (involved LN + 10 mm); STV, uniform 5-mm
margin for both CTV and GTV
Intent: Definitive
Adverse effects: Nausea
Considerations: Consider extended SSD technique and
gantry rotation.
Sites under study (selected):
Nasopharynx, oropharynx, larynx (Frank et al. IJROBP 2014;
Holliday et al. IJROBP 2014)
Target: CTV1, gross disease; CTV2, high-risk nodal
volume; CTV3, subclinical disease; PTV, 3-5 mm margin
outside of critical structures
Intent: Definitive
Adverse effects: Xerostomia, mucositis
Considerations: Use three fields from three beam
directions to treat bilateral neck (LAO and RAO with
distal Bragg peaks lateral to spinal cord and single
posterior beam with distal Bragg peak posterior to
parotid).
Esophageal (Lin et al. IJROBP 2012)
Target: GTV, all disease present on PET and EGD; CTV,
areas of potential spread; PTV, 1-1.5 cm margin
Intent: Preoperative, definitive
Adverse effects: Esophagitis, nausea, anorexia,
radiation dermatitis
Considerations: AP/PA, PA/LLO, or 3-beam (RPO or PA,
LL with LPO tilt, and LPO); brass blocks/Plexiglas
compensators to deliver SOBP to encompass treatment
volume
Lung (Chang et al. Cancer 2011; Koay et al. IJROBP 2012;
Liao et al. JCO 2017)
Target: iGTV, envelope of motion of GTV on MIP image;
iCTV, 8 mm isotropic margin
Intent: Definitive (with chemotherapy)
Adverse effects: Dermatitis, esophagitis, pneumonitis
Considerations: Use 4DCT for simulation/planning.
Breast (Strom et al. IJROBP 2014; Strom et al. Pract Radiat
Oncol 2015)
Target: CTV, 15 mm expansion of tumor bed (including
clips/seroma) with 5 mm contraction from skin and
edited to exclude chest wall/muscle; PTV, radial 5 mm
Intent: APBI postoperative (see ESBC chapter)
Adverse effects: Radiation dermatitis
Considerations: Proximal/distal beam margins 3.5% of
range + 1 mm from CTV
Liver—unresectable hepatocellular carcinoma and
intrahepatic cholangiocarcinoma (Hong et al. JCO 2016)
Target: CTV, 10 mm expansion on GTV (depending on
proximity of normal tissues), PTV 5-10 mm expansion
Intent: Definitive
Adverse effects: Thrombocytopenia, transaminitis, and
liver failure
Considerations: Use 4DCT for simulation/planning.
Postop prostate
Target: CTV, prostate, and seminal vesicle fossa; ETV,
uniform radial 7 mm margin except 5 mm posteriorly, 9-
12 mm proximal/distally; STV, 12 mm lateral, 5 mm
posterior, 6 mm all others to CTV
Intent: Postoperative/salvage
Adverse effects: Bowel and urinary function, sexual
function
Considerations: Use opposed R/L lateral beams.
OLIGOMETASTATIC DISEASE
MICHAEL BERNSTEIN • DANIEL GOMEZ
B
Definition: First coined by Hellman and Weichselbaum
representing a state of intermediate prognosis between localized
disease and metastatic disease (Hellman et al. J Clin Oncol
1995). Number of metastases accepted as “oligo” are ≤5 in no
more than 3 different organs.
Classification (Ricardi et al. J Radiat Res 2016):
Oligometastatic (synchronous): ≤5 metastatic lesions in ≤3
organ systems at diagnosis
Oligoprogressive: Disease progression in ≤5 metastatic
lesions in ≤3 organ systems
Oligorecurrent (metachronous): Disease recurrence with ≤5
metastatic lesions in ≤3 organ systems after definitive
therapy for initially nonmetastatic disease
Biologic basis for oligometastatic disease (Reyes et al.
Oncotarget 2015):
Intermediate metastatic state, which manifests with limited
sites of widespread metastatic disease. Numerous plausible
rationales:
Environmental conditions in primary tumor forestalling
clonal pressure
Sloughed-off cancer cells lacking properties (or genomic
alterations) to survive circulation and invade target
organ sites
Cancer cells landing in inhospitable target organs
Common oligometastatic subtypes: Non–small cell lung
cancer (NSCLC), breast, prostate, colorectal (CRC), and kidney
Common sites of treatment: Brain, spine, lung, liver, lymph
node, and bone
L T O
S
Rationale: If primary site is controlled, or resected, and
metastatic sites are ablated, prolonged disease-free interval, or
cure, can be achieved (Reyes et al. Oncotarget 2015). Patients
may never progress to widespread metastases.
Surgery (metastasectomy)
Historically centered on hepatic resection in patients with
primary CRC
5-Year survival 53% after hepatic resection despite
progression on chemotherapy (Uppal et al. Eur J Surg Oncol
2014)
Cryoablation
10% recurrence rate after treatment in largest series (Littrup
et al. J Vasc Interv Radiol 2013). Sites included
retroperitoneal, bone, head, and neck with average tumor
size 3.4 cm.
Radiation therapy: Stereotactic radiosurgery (SRS), stereotactic
ablative body radiotherapy (SBRT)
S R
(SRS)/S A B
R (SBRT)
Utilization of multiple beams originating from many
directions/angles to converge on target
Completed in 1-5 sessions, exceeding 5 Gy/fx with high level of
conformity and sharp dose falloff
Optimal regimen yet to be defined; however, general consensus
that BED > 100 Gy is sufficient
Local control rates between 70% and 90% for spinal
(Bhattacharya et al. J Clin Oncol 2015), lung (Huang et al. Radiat
Oncol 2014), and liver (Aitken et al. J Clin Oncol 2015)
metastases have been achieved.
P S
Favorable prognostic factors include the following:
Metachronous metastases (vs synchronous ones)

Breast cancer histology may have significantly improved survival
than nonbreast primaries (Milano et al. Int J Radiat Oncol Phys
2012).
Time to recurrence >12 months
Limited number of involved sites (1-3) (Salama et al. Cancer
2011)
Higher performance status
T S T
Optimal therapy not known and likely variable with histology, but
MDACC protocols generally prefer the following: neoadjuvant
systemic therapy × 3-6 months > definitive local treatment >
observation or maintenance systemic therapy.
Consider continuing systemic therapy during definitive local
therapy if low chance of interaction. Otherwise, for newer
systemic therapy or proven increased risk of toxicity, hold
systemic therapy during local therapy.
C MDA D /F
S O
Brain (stereotactic radiosurgery; all in 1 fraction, see SRS
chapter): <2 cm, 20-24 Gy; 2-3 cm, 18 Gy; 3-4 cm, 15 Gy
Spine (stereotactic spine radiosurgery; all in 1 fraction, see SSRS
chapter): 24 Gy in 1 fraction (radioresistant), or 18 Gy in 1
fraction (radiosensitive)
Lung: 50 Gy in 4 fractions (peripheral) or 70 Gy in 10 fractions
(central)
Liver: 50 Gy in 4 fractions
Adrenal gland: 70 Gy in 10 fractions
Lymph node: Varies by location; consider treating 46 Gy/23 fx or
50.4 Gy/28 fx to elective lymph node chain. Boost gross LNs to
>55 Gy with conventional fractionation, variable fractionation for
SBRT.
Bone: Varies by location; consider 24 Gy in 1 fraction.
N T
Non–small cell lung cancer
De Ruysscher et al. J Thoracic Oncol 2012: Single-arm

prospective phase II trial examining radical treatment (surgery or
radiation therapy) of 40 stage IV patients with <5 synchronous
metastatic lesions. 95% had chemotherapy as part of primary
therapy. Median overall survival (OS) was 13.5 months. Only two
patients (5%) had local recurrence.
Gomez et al. Lancet Oncol 2016: Multicenter randomized phase
II study assessing role of aggressive local consolidative therapy
(radiation or resection of all lesions) vs observation or
maintenance therapy in patients with stage IV NSCLC with stable
or responding disease involving ≤3 sites after neoadjuvant first
line systemic therapy. 74 patients enrolled, and 49 patients were
randomized. Median progression-free survival (PFS) in local
consolidative group was significantly higher than that of
observation arm (11.9 months vs 3.9 months, P = .005). Similar
toxicity rates between arms
Iyengar et al. JAMA Oncol 2017: Single-institution phase II
randomized study investigating role of SBRT plus maintenance
therapy vs maintenance chemotherapy alone in 29 patients with
oligometastatic NSCLC (primary plus ≤5 metastatic sites) who
exhibited stable or responding disease to prior first line systemic
therapy. Significant improvement in PFS in SBRT-plus-
maintenance chemotherapy arm compared to maintenance-alone
arm (9.7 months vs 3.5 months, P = .01). No in-field failures and
no difference in toxicities between arms
Colon cancer
Bae et al. J Surg Oncol 2012: Retrospective analysis

investigating efficacy of SBRT in 41 oligometastatic CRC patients
with 1-4 metastatic lesions confined to 1 organ. Doses between
45 and 60 Gy in 3 fractions utilized to treat metastatic sites
including lymph node, lung, and liver. 3-Year LC and OS were
64% and 60%, respectively.
Comito et al. BMC Cancer 2014: Observational study examining
safety and efficacy of SBRT in 82 patients with oligometastatic
disease. 1-3 inoperable metastases confined to one organ (liver
or lung) treated with doses ranging from 48 to 75 Gy in 3 or 4
consecutive fractions. 3-Year LC rates were 70% for lung and
85% for liver metastases, respectively. Median OS was 32
months. Difference in LC rates was significantly lower with doses
<60 Gy vs >60 Gy.
EORTC 40004 (Ruers et al. JNCI 2017): Randomized multi-
institution phase II trial randomizing 119 oligometastatic CRC
patients with liver-only metastatic disease with up to 10
metastatic lesions randomized to radiofrequency ablation +/−
surgical resection followed by systemic therapy or systemic
therapy alone. After a median follow-up of 9.7 years, median OS
was significantly longer with upfront local therapy and systemic
therapy vs systemic therapy alone (45.6 months vs 40.5 months,
P = .01).
Other sites
Milano et al. Breast Cancer Res Treat 2009: Prospective pilot

study examining efficacy of SBRT in 40 patients with metastatic
breast cancer with ≤5 metastatic foci treated with curative intent.
4-Year OS was 59%, LC 89%.
STOMP (Ost J Clin Oncol 2017): Multicenter randomized phase II
study assessing aggressive local therapy (radiation or resection
of all lesions) vs surveillance in 62 prostate cancer patients with
biochemical recurrence and ≤3 extracranial metastases.
Aggressive local therapy associated with trend in ADT-free
survival (median 13 months vs 21 months, P = .11). QOL of life
was similar between groups. No grade 2-5 toxicities were
observed.
Wong et al. Cancer 2016: Prospective dose-escalation trial for 61
patients with solid tumors with ≤5 metastatic foci who received
SBRT to all sites of disease. Median survival was 2.4 years.
Longer time from initial cancer diagnosis to metastasis, longer
time from diagnosis of metastasis to SBRT, and breast cancer
histology were associated with improved overall survival.
STEREOTACTIC BODY RADIATION
THERAPY
SAMANTHA M. BUSZEK • PENNY FANG • STEVEN J.
FRANK
B
Definition: Stereotactic body radiation therapy (SBRT), also
known as stereotactic ablative radiotherapy (SABR), refers to
treatment of extracranial sites using >6 Gy/fx given over ≤5
fractions (ACR and ASTRO).
Unique radiobiological characteristics cause dramatic tumor
response (“ablative” RT).
Critical considerations: High-resolution imaging, reproducible
immobilization (acceptable daily error setup margin is <2 mm),
breathing management, conformal radiation delivery techniques
L C
Indication: Stage I or II NSCLC—peripheral tumor (50 Gy/4 fx,
plan for 60 Gy hot spot within GTV) or central tumor (70 Gy/10 fx,
plan for 80 Gy hot spot within GTV)
BED ≥ 100 Gy: Better local control and survival (Onishi et al.
Cancer 2004)
SIM: 4DCT. If tumor moves ≤1 cm, use free breathing—contour
on MIP; otherwise, consider breathing management such as
breath hold to reduce tumor motion if patient is able to hold
breath.
Treatment setup: Daily CBCT, daily MV, IMRT, or VMAT
Target: iGTV: Gross tumor taking into account motion; no CTV;
PTV = GTV + 0.5 cm
Dose constraints (for 50 Gy in 4 fractions):
Chest wall: V30 < 30 cc
Spinal cord: D max < 25 Gy, V20 < 1 cm3
Heart: D max < 45 Gy
Skin: V30 < 50 cc
Major hilar or other great vessels: D max < 49 Gy (NCCN)
Brachial plexus: V30 < 0.2 cc, D max 35 Gy
Esophagus: V30 < 1 cm3, D max 35 Gy
Spinal cord: V20 < 1 cm3, D max 25 Gy
Total lungs: Mean < 6 Gy, V20 < 12%
Ipsilateral lung: Mean < 10 Gy, V30 < 15%
Follow-up: 1 month after treatment; q3mo for 2 years; q6mo until
5 years. CT of the chest for surveillance
P C MDACC P
Indication: Low- and intermediate-risk prostate cancer (T1-T2b),
pretreatment PSA < 10, Gleason score sum ≤ 7
SIM: 3-4 gold fiducials placed in prostate via TRUS; noncon CT,
supine, Alpha Cradle
Treatment setup: Daily kV imaging with alignment on fiducials
Target: GTV, prostate; no CTV; PTV = GTV + 3-4 mm posteriorly
and GTV + 5-6 mm elsewhere
Dose: 40 Gy/5 fx (qod); 95% of PTV getting 95%-110% of the
prescription dose
Dose constraints:
Rectum: V20 ≤ 50%, V32 ≤ 20%, V36 ≤ 14%, V40 ≤ 5%
(consider rectal spacing, eg, SpaceOAR, if constraints cannot be
met)
Bladder: V20 ≤ 40%, V32 ≤ 20%, V36 ≤ 15%, V40 ≤ 10%
Femoral head: V16 ≤ 10%
Small bowel: V20 ≤ 1%
Follow-up: PSA q3mo for 2 years, PSA q6mo after 2 years
H C
C
Indication: Definitive treatment or bridge to liver transplant. If
unable to meet dose constraints, consider hypofractionated
regime (67.5 Gy/15 fx).
SIM: Stereotactic cradle, MedTec Immobilizer, T-bar, 4DCT with
breath hold, consider fiducial marker placement prior to SIM if
difficult to visualize, IV contrast with delayed arterial phase
Treatment setup: Daily CT-on-rails with alignment to fiducials if
placed, daily MV port
Target: GTV, hypodensity on CT; CTV = GTV + 0.5 cm; PTV =
CTV + 0.5 cm
Dose: 50 Gy/4 fx
Dose constraints:
Esophagus, large bowel: D max 32 Gy
Stomach, duodenum, small bowel: D max 28 Gy
Large bowel: D max 30 Gy
Spinal cord: D max 18 Gy
Kidney: Combined mean < 10 Gy
Chest wall: V30 < 30 cc
Gallbladder: D max < 55 Gy
Spleen: Mean < 6 Gy
Common bile duct: D max < 55 Gy
Liver GTV: 700 cc spared < 15 Gy, Mean < 16 Gy
Follow-up: Imaging and AFP q3-6mo for 2 years and then q6-
12mo
P C ALLIANCE
A021501
Indication: Locally advanced pancreatic cancer (T1-4N0-1 or
NxM0); adenocarcinoma of the pancreatic head or uncinated
process
SIM: Fiducial markers in or within 1 cm of tumor placed prior to
SIM; supine, arms above head; Alpha Cradle and wingboard;
NPO 3 hours prior to CT SIM; IV and oral contrast highly
recommended; 4DCT scan; expiratory phase gating (move OARs
away)
Treatment setup: Daily CBCT along with kV alignment to gold
fiducials (placed by GI endoscopist within the target)
Target: GTV = gross tumor on FB scan; iGTV = GTV; TVI =
tumor vessel interface for each vessel, separately, at the level of
the tumor; iTVI = TVI; PRV = planning risk volume = (duodenum
+ small bowel + stomach) + 3 mm
Dose: 6.6-8 Gy × 5 fractions; PTV1 D min > 22.5 Gy, PTV2 D min
> 29.7 Gy, PTV3 D min > 32.4 Gy with max of 40 Gy within the
GTV
PTV1 = (iGTV + iTVI) + 3 mm = 25 Gy/5 fx
PTV2 = PTV1 − PRV = 33 Gy/5 fx
PTV3 = (iTVI + 3 mm) − PRV = 36 Gy/5 fx
Dose constraints:
Stomach, duodenum, bowel: V20 < 20 cc; V35 < 1 cc, D max < 40
Gy
Liver: V12 < 50%
Combined kidneys: V12 < 25%
Spinal cord: V20 < 1 cc
Spleen: No constraint
Follow-up: CA-19-9 and abdominal CT scans q16wk for 2 years
O NRG-LU002
Indication: Stage IV NSCLC s/p 4 cycles of first-line systemic
therapy with no evidence of progression and ≤3 discrete sites of
extracranial metastatic disease (met locations—lung-peripheral,
lung-central [GTV within 2 cm of proximal bronchial tree],
mediastinal/cervical LN, liver [includes rib mets adjacent to liver],
spinal/paraspinal [GTV arises within the vertebral bodies
expanded by 1 cm], osseous, abdominal-pelvic)
Treatment setup: Depending on organ targeted
SIM: Proper immobilization; motion assessment (eg, fluoroscopy,
4DCT, beacon tracking, etc.), and motion control—strongly
encouraged when GTV excursion is >1 cm in any direction. CT
slice thickness ≤2 mm. IV contrast recommended. Ideally all mets
will be treated in one treatment position.
Target:
Lung-central, lung-peripheral, liver, abdominal-pelvic, and
mediastinal/cervical LN: CTV = iGTV; PTV axial = CTV + 0.5 cm;
PTV craniocaudal = CTV + 0.7 cm
Osseous: CTV = GTV; PTV = CTV + 0.3-0.5 cm
Spinal: CTV = iGTV; PTV = CTV + 0.3-0.5 cm
Dose: Depending on site. 1 or 3 fractions completed within 2
weeks of first SBRT dose; 5 or 15 fractions completed within 3
weeks of first SBRT dose
Dose constraints: OAR should be contoured in their entirety if a
portion of that organ is located within 10 cm of the metastasis.
Follow-up: CT q3mo for 2 years, then q6mo for 3 years, and
then annually
H N MDACC P
(SOAR-HN—NCT03164460)
Indication: Recurrent H&N cancer s/p RT or second 1° H&N
cancer within previous RT field
SIM: CT sim, supine, customized neck cushion, thermoplastic
head, neck, and shoulder mask indexed to neck cushion, and
customized bite block. Volumetric MRI, dual-energy CT with
contrast, and PET/CT all in treatment position
Target: GTV = tumor from all fused images (MRI, CT, PET); CTV
= GTV + 0.8 mm; PTV = CTV + 0.2 cm for skull base or CTV +
0.3 cm if below C1
Treatment setup: ExacTrac with daily bony alignment (verified
and corrected in 6 degrees of freedom) and daily CBCT for
treatment. ExacTrac before each arc
Dose: 45 Gy to PTV in 5 fractions qod
Dose constraints:
Cochlea, optic nerve(s), temporal lobe: Max < 20 Gy
Optic chiasm: Max < 18 Gy
Brainstem: Max < 15 Gy
Spinal cord: Max < 15 Gy
Brachial plexus: Max < 25 Gy
Parotid(s), carotid(s), and lingual artery: As low as possible. Goal
is to maintain total max dose to <100 Gy.
Follow-up: CT of the head and neck with contrast at 2 months
and then q3mo
N T O P
Lung cancer
Pooled analysis of STARS (MDACC) and ROSEL (Dutch) trial

(Chang et al. Lancet Oncol 2015): 48 pts, T1-T2aN0M0 NSCLC,
<4 cm diameter, randomized to SBRT vs surgery. STARS: SBRT
54/3 Gy peripheral, 50/4 Gy central over 5 days. ROSEL: SBRT
54/3 Gy peripheral (5-8 days), 60/5 Gy central lesions (10-14
days). Median follow-up 3.4 years. Outcomes: 3-year OS 95%
(SBRT) vs 79% (surgery) P = .04. Toxicity: SBRT, grade 3 in
10%, no grade 4-5; surgery, grade 3-4 in 44%; 1 pt with grade 5.
Conclusion: SBRT is better tolerated than surgery; SBRT might
lead to better OS; SBRT could be an option for operable stage I
NSCLC.
Prostate cancer
UCLA/Stanford Phase II (King et al. IJROBP 2012): 67 low-risk

prostate cancer patients treated with 36.25 Gy in 5 fractions;
median follow-up 2.7 years. 4-Year relapse-free survival 94%.
Toxicity: late GU grade 3 toxicity 3.5%, no grade 4 toxicity. No
late GI grade 3 toxicity. Reduced grade 1-2 rectal (5% vs 44%, P
= .001) and grade 1-2 urinary (17% vs 56%, P = .007) toxicities
with qod vs daily treatments. Conclusion: Early and late toxicity
and PSA response highly encouraging
Hepatocellular carcinoma and cholangiocarcinoma
Princess Margaret Phase I (Tse et al. J Clin Oncol 2008): 41 pts,

unresectable HCC (n = 31) or IHC (n = 10) with Child-Pugh A
liver function and ≥800-cc uninvolved liver. SBRT with 6 fractions;
dose dependent on NTCP calculations and was escalated
throughout the trial. Median dose 36 Gy (24-54 Gy). 3-Month
toxicity: no dose-limiting toxicity or RILD; 24% grade 3 liver
enzymes, no grade 4/5; 23% progression to Child-Pugh B liver
function. Late toxicity 6%. Outcome: median OS for HCC 11.7
months, intrahepatic cholangiocarcinoma 15 months. Conclusion:
Individualized 6-fraction SBRT is safe.
Pancreatic cancer
Stanford Retrospective (Chang et al. Cancer 2009). 77 pts with

unresectable pancreatic cancer (58% locally advanced, 14%
medically inoperable, 19% metastatic, 8% locally recurrent), ≤7.5
cm diameter. SBRT 25 Gy/1 fx. Prior EBRT 45-54 Gy in 21%.
Median F/U 6 months. Outcome: 12-month LC 84%. 12-month
PFS 9%. 12-month OS 21%. Grade ≥3 toxicities in 9% of patients
ALLIANCE A021501 Trial “Preoperative extended chemotherapy
vs chemotherapy + hypofractionated RT for borderline resectable
adenocarcinoma of the head of the pancreas” (Katz et al. 2017,
Ongoing). Inclusion: borderline resectable adenocarcinoma of the
pancreatic head. T1-4N0-1 or NxM0. Exclusion: prior chemo.
Randomized to 8 cycles of systemic FOLFIRINOX vs 7 cycles of
systemic FOLFIRINOX followed by short-course hypofractionated
RT. RT with 6.6 Gy × 5 fractions. AIM: 18-month OS and R0
resection rate.
Head and neck cancer
French Phase II (Lartigau Radiother Oncol 2013). 60 pts with

inoperable recurrent or new primary head and neck tumor in
previously irradiated area. SBRT with 36 Gy in 6 fractions to the
85% isodose line with concomitant cetuximab. Median follow-up
11.4 months. 3-month response rate of 58.4% and disease
control rate 91.7%. 1-Year OS 47.5%. Grade 3 toxicities
observed in 32% of patients and 1 grade 5 toxicity. Conclusion:
Short SBRT with cetuximab is an effective salvage treatment with
good response rate.
Stereotactic CNS Radiosurgery
PENNY FANG • JING LI
B
Stereotactic radiosurgery (SRS) utilizes multiple beams to
administer high doses to tumor while sparing normal brain tissue
and can be given using Gamma Knife (192 individual Cobalt-60
sources) or through modern linear accelerators.
Indications: Brain metastases, meningioma, pituitary
macroadenoma, acoustic neuroma, trigeminal neuralgia
For clinical considerations including patient selection for SRS vs
other treatment modalities such as surgical resection, whole brain
radiotherapy, and systemic therapies, consider multidisciplinary
consultation and evaluation.
Local control rates: 1-year local control 96.3% for lesions <2 cm
and 87.3% for lesions ≥2 cm and <4 cm in diameter (Likhacheva
et al. IJROBP 2013)
W
Imaging: High-resolution, thin slice MRI imaging
SRS D - -P (G K )
Application of a Leksell invasive stereotactic headframe for rigid head
fixation prior to simulation MRI (Fig. 10.1):
Figure 10.1 Representative axial, sagittal, and coronal
images of a Gamma Knife plan to treat an intact brain
metastasis.
Simulation MRI: Axial postcontrast 3D fast spoiled gradient echo

images (1 mm slice thickness). Steps are as follows:
1. Contrast administration: Intravenous MultiHance

(gadobenate dimeglumine) injection at 0.1 mmol/kg (0.2
mL/kg)
2. On import, check image quality.
3. Discussion with neuroradiologist to identify all lesions
4. Contour all lesions: Performed collaboratively by a radiation
oncologist and neurosurgeon
5. Place shots (see plan evaluation)
6. Physics QA: On image import, check for fiducial definition
errors, typically within 0.4 mm (mean) and 0.8 mm (max).
Large deviations indicate stereotactic frame was incorrectly
placed.
7. Perform plan review including patient information, target
coverage, prescription dose, collision checks, etc. For most
cases, the minimum collision value should be >4 mm.
Troubleshooting collision issues: Change angle, removal of a
post from the stereotactic frame, and replacement of the
stereotactic frame
8. Consider giving a short course of dexamethasone to patients
on treatment day who have large lesions and/or significant
edema seen on MRI T2/flair sequence.
SRS D S
MDACC approach to brain mets is adapted from RTOG 90-05 dose
selection guidelines (Shaw et al. IJROBP 2000). All treatments are
given with a single fraction.
Prescription isodose contour: 50% isodose line

Brain metastases (and postoperative cavity) SRS doses
guidelines:
Lesion diameter ≤2 cm: 20-24Lesion diameter 2-3 cm: 18
GyLesion diameter 3-4 cm: 15 Gy
Meningioma: 12-16 Gy
Pituitary adenoma: 22-24 Gy for secreting, ~15 Gy for
nonsecreting
Acoustic neuroma: 12-13 Gy
Trigeminal neuralgia: See Benign Disease chapter.
P E
Conformality index = prescription isodose volume/target volume
(1 is perfect; ~1.2 is good)
Gradient index = volume of 50% prescription isodose/volume of
entire treatment isodose (~sharpness of dose fall off: want <3).
Can turn on 25% isodose line when placing shots
Heterogeneity index = maximum dose/prescription dose (~hot
spots)
Dose constraints:
Brainstem: V12 Gy < 1 ccOptic apparatus: Max 8 GyBrain: V12
Gy < 5-10 cc. For several lesions in proximity, minimize normal
brain volume covered by 12-Gy isodose line.Cochlea: Max 4.2
Gy
F -
4-Week follow-up post-SRS and then every 3 months with
contrast-enhanced MRI at each visit
N T
Radiosurgery efficacy and toxicity
RTOG 90-05 (Shaw et al. IJROBP 2000): 156 pts with solitary
nonbrainstem tumors ≤40 mm max diameter previously treated
with partial or whole brain fractionated RT. Dose prescribed to the
50%-90% isodose line. Doses escalated as long as RTOG grade
≥3 CNS toxicity <20% within 3 months of SRS. Identified MTD to
be 24 Gy for tumors ≤20 mm, 18 Gy for tumors 21-30 mm, and
15 Gy for tumors 31-40 mm
Alliance N0574 (Brown et al. JAMA 2016): 213 pts with 1-3 brain
mets randomized to SRS +/− WBRT 30 Gy/25 fx. Primary
endpoint cognitive decline >1 standard deviation from baseline
on at least 1 cognitive test at 3 months. Identified less cognitive
decline at 3 months after SRS alone (63.5% vs 91.7%, P < .001).
Time to intracranial failure at 3 months worse with SRS (75% vs
94%, P < .001). No significant difference in OS
Chang et al. Lancet Oncol 2009: Single-institution trial
randomizing 58 pts with 1-3 brain mets to SRS +/− WBRT.
Primary endpoint neurocognitive function as measured by
deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R)
total recall at 4 months. SRS + WBRT significantly more likely
(mean posterior probability of decline 52%) to be associated with
a decline in learning and memory at 4 months vs SRS alone
(mean posterior probability of decline 24%). At SRS + WBRT
associated with improved 1-year intracranial control (27% vs
73%, P < .001).
JLGK0901 (Yamamoto et al. Lancet Oncol 2014): Multi-
institutional prospective observation study enrolling 1194 patients
with 1-10 new brain mets. Tumors <4 mL were treated with 22 Gy
and 4-10 mL treated with 20 Gy. Overall survival was longer in
patients with 1 brain met (median 13.9 months) compared with 2-
4 and 5-10 (both median 10.8 months). New intracranial lesion
recurrence was lower in patients with 1 brain met (23.9% at 6
months) compared with 2-4 (40% at 6 months) at 5-10 (46% at 6
months). Neurologic death, deterioration of neurologic function,
was not different with respect to lesion number.
Benefit of postoperative SRS
Mahajan et al. Lancet Oncol 2017: Single-institution phase III

study randomizing 132 patients with completely resected 1-3
brain metastases to observation vs SRS demonstrated increased
12-month freedom from local recurrence (43% vs 72%, P = .015).
No difference in OS
NCCTG N107C/CEC·3 (Brown et al. Lancet Oncol 2017):
Multicenter phase III trial that randomized 194 patients with one
resection cavity <5 cm to SRS vs WBRT 30 Gy/10 fx or 37.5
Gy/15 fx. Improved cognitive deterioration–free survival with SRS
(median 3 months vs 3.7 months, P < .001). SRS associated with
shorter time to intracranial tumor progression (median 6.4 months
vs 27.5 months, P < .001) and lower frequency of 6-month
surgical bed disease control (80.4% vs 87.1%, P < .001). No
difference in OS
LOW-GRADE GLIOMAS
AHSAN FAROOQI • DEBRA NANA YEBOA • ERIK P. SULMAN
B
Incidence/prevalence: Estimated to be 2000 cases diagnosed per
year. Low-grade gliomas are defined as WHO grade I and II gliomas
(grade 3 and 4 are considered high grade).
Outcomes: Median survival for low-grade IDH wild-type astrocytomas
estimated at ~5 years. Median survival for low-grade
oligodendrogliomas (1p19q codel) and IDH mutant astrocytomas is
estimated at >10 years.
Demographics: The median age of low-grade gliomas is estimated to
be between 35 and 40 years. Males > Females
Risk factors: Gliomas are largely sporadic without any clear risk
factors aside from exposure to ionizing radiation.
T
Genetics: Increased risk of developing low-grade astrocytomas in
patients with NF1 and NF2. Tuberous sclerosis is associated with
increased risk of developing subependymal giant cell astrocytomas.
Increased risk also seen in Li-Fraumeni syndrome patients.
Pathology: Historically, gliomas were classified based upon the
histopathologic grade, although the diagnosis now includes molecular
stratification (WHO 2016 update; David et al. Acta Neuropathol 2016).
Grade I gliomas have low proliferation potential. Grade II gliomas are
infiltrative, often recur, and have the potential to dedifferentiate into a
higher grade (possibly by acquiring additional mutations). TP53
mutations commonly seen in astrocytomas and 1p/19q codeletions
seen in tumors with oligodendroglial histology. Recently, IDH
mutations have been found in up to 80% of all low-grade gliomas and
are associated with improved outcomes, independent of grade
(Ichimura et al. Neurooncology 2009; Olar et al. Acta Neuropathol
2015).
Imaging: Low-grade gliomas are typically lobar in location (most
commonly in frontal or temporal lobes) and are contrast
nonenhancing compared to high-grade gliomas. Because of the
infiltrative nature of low-grade gliomas, they are associated with a
hyperintense signal on T2 sequences, best seen on the T2/FLAIR
sequence (Fig. 11.1).
Figure 11.1 T1+contrast MRI image (left) shows an ill-defined
non–contrast-enhancing hypointense lesion in the left frontal lobe
without any necrotic features. The lesion is associated with a
significant edematous component seen on T2-FLAIR sequence
(right), indicating associated edema and infiltrative pattern of
spread.
A
LGGs typically arise from supratentorial cortex.
Frontal lobe: Functions in regulating personality, behavior, emotions,

and decision-making. Precentral gyrus (motor strip) lies anterior to
central sulcus. Speech (Broca’s)
Parietal lobe: Interprets language, words, and sensory information
Postcentral gyrus (sensory cortex) lies posterior to central sulcus.
Occipital lobe: Vision

Temporal lobe: Language comprehension (Wernicke’s), memory,
hearing, sequencing
Cerebellum: Balance, movement, and spatial positioning
W
History and physical: Including presenting symptoms, history of
seizures (most common presenting symptom), and family history.
Assessment of neurologic deficits and performance status important.
Establish preoperative neurocognitive evaluation if applicable.
Labs: CBC, CMP
Procedures/biopsy: Neurosurgery evaluation for maximal safe
resection or biopsy
Imaging: MRI of the brain with and without contrast is the gold
standard (Fig. 11.1) to evaluate location, grade, and extent of disease.
Obtain postoperative MRI within 3 days of surgery to determine extent
of resection and whether there is any residual disease. After 3 days,
blood products make MRI interpretation difficult.
S /G
Grade I glioma: Subependymal giant cell astrocytoma and pilocytic
astrocytoma
Grade II glioma: Pilomyxoid astrocytoma, diffuse astrocytoma,
oligodendroglioma, and oligoastrocytoma. The 2016 WHO
classification system (WHO 2016 update; David et al. Acta
Neuropathol 2016) includes not just histopathologic grade but also
molecular features. Specifically, mixed oligoastrocytomas are
classified as either diffuse astrocytoma (1p19q noncodel) or
oligodendroglioma (1p19q codel) to guide treatment decisions.
T A
a Low-grade gliomas have multiple options and are managed with

institutional variation. Important considerations for early radiation therapy
may include large size (>5 cm), tumor crossing midline, astrocytic
histology, neurologic symptoms/seizures (Pignatti criteria), or IDH wild-
type molecular features in astrocytic histology.
R T T
SIM: Supine, holding A-bar, aquaplast mask with isocenter placed at
midbrain. MRI fusions—T1 + C sequence and T2 FLAIR sequences.
Dose: 50.4-54 Gy in 28-30 fractions at 1.8 Gy/fx (can consider 2
Gy/fx)
Target:
GTV—surgical cavity
CTV—GTV + 1 cm (+hyperintense signal on FLAIR sequence)
PTV—CTV + 0.3 cm (daily kV) or 0.5 cm (weekly kV)
Considerations: Limit CTV expansions to anatomic boundaries of

disease spread (eg, bones, falx, brainstem, and ventricles).
Technique: IMRT/VMAT. Consider use of protons on trial depending

on anatomy and age.
IGRT: Daily kV imaging
Planning directive:
Brainstem: V30Gy < 33%. Max < 54 Gy. If necessary may allow point
max <60 Gy.
Brain: V30Gy < 50%
Optic chiasm: Max ≤ 54 Gy
Cochlea: Max < 54 Gy. Mean < 30 Gy
Lens: Max < 5 Gy
Optic nerves: Max ≤ 54 Gy
Pituitary: Mean < 36 Gy
Eyes: Max < 40 Gy. Mean < 30 Gy
Hippocampus (young patients, if concern): D100% < 9 Gy, Max ≤ 16
Gy
Spinal cord: Max ≤ 45 Gy
C
Adjuvant:
Procarbazine, lomustine, vincristine (PCV) regimen (as per RTOG
9802)—procarbazine 60 mg/m2 on days 8-21, lomustine 110 mg/m2
on day 1, and vincristine 1.4 mg/m2 on days 8 and 29. Cycle length is
8 weeks.
Temozolomide (TMZ)—150-200 mg/m2 daily for 5 days, every 28
days for 6 cycles.
S E M
Nausea: First-line Zofran (4 mg q8h prn)
Headaches/worsening neuro deficits: Likely due to increased edema.
Consider treatment with dexamethasone at low dose (2 mg bid) with
taper following resolution of symptoms.
Scalp irritation/dryness: Aquaphor (OTC).
Thrombocytopenia/lymphopenia/neutropenia: Likely due to PCV or
TMZ. Refer to oncologist.
F -
Every 2-3 months with MRI of the brain w/ and w/o contrast for the
first year following treatment, q4mo during years 2-4, and q6mo
thereafter. Patients with age >40 years, large size (>5 cm), incomplete
resection, astrocytic histology, and high proliferative index (MIB >
1%-3%) at high risk for recurrence (Pignatti et al. JCO 2002).
Consider reirradiation on protocol or enrollment in investigational
clinical trials at progression.
N T
Lack of improved efficacy with increasing RT doses
EORTC 22844 (“Believer’s Trial” Karim et al. IJROBP 1996)—Phase

III randomized two-arm controlled trial. 379 patients underwent
randomization following surgical resection to RT with either 45 Gy/25
fx or 59.4 Gy/33 fx. 5-year OS 58% for low-dose arm and 59% for
high-dose arm (nonsignificant). 5-year PFS (47% vs 50%) also not
significantly different between the two arms
RT timing
EORTC 22845 (“Non-believer’s Trial” Van den Bent et al. Lancet

2005). Phase III randomized two-arm controlled trial. 311 patients
underwent biopsy, bulk, or GTR and were randomized to RT (54
Gy/30 fx) or observation (RT given when there is recurrence, ~65% of
patients on this arm). RT arm had improved PFS vs observation arm
(5.3 vs 3.4 years, P < .0001), but OS not significantly different.
Importantly, early RT improved seizure control at 1 year (41% vs
25%).
Improvement in outcomes with chemotherapy
RTOG 9802 (Shaw et al. JCO 2012; Buckner et al. NEJM 2016).
Phase III randomized two-arm controlled trial. 251 patients aged >40
years or <40 with subtotal resection randomized to RT alone (54
Gy/30 fx) vs RT followed by adjuvant PCV (6 total cycles). Median OS
13.3 years in RT + PCV arm vs 7.8 years in RT alone (HR for death
0.59, P = .003). Median PFS was 10.4 years in RT + PCV arm vs 4.0
years in RT alone (HR for progression or death 0.50, P < .001).
Histologic finding of oligodendroglioma favorable prognostic variable
for both PFS and OS
RTOG 0424 (Fisher et al. IJROBP 2015). Phase II trial of 129 high-
risk (as defined by ≥3 high-risk factors) LGG treated with RT (54
Gy/30 fx) with concurrent and adjuvant TMZ. 3 year OS rate was
73.1% (95% CI 65.3%-80.8%), which was significantly improved
compared to historical control of 54% (P < .001). 3 year PFS was
59.2%. Suggests adjuvant TMZ may offer similar OS and PFS benefit
as PCV but randomized control trial between the two pending
(CODEL trial)
HIGH-GRADE GLIOMAS
AHSAN FAROOQI • DEBRA NANA YEBOA • ERIK P. SULMAN
B
Incidence/prevalence: There are ~20 000 new high-grade glioma
(HGG) cases per year diagnosed in the United States. Of all
malignant brain tumors, glioblastomas constitute ~60%.
Outcomes: 5-Year OS rates for glioblastoma estimated between 5%
and 10%. 5-Year OS rates for grade III gliomas estimated at 25%
Demographics: The mean age at diagnosis of high-grade gliomas is
65 years. Males > females
Risk factors: Gliomas are largely sporadic without any clear risk
factors aside from prior exposure to ionizing radiation and genetic
syndromes as noted below. There is no evidence that cell phone use
leads to increased risk of developing gliomas.
T B C
Genetics: Associated with various familial genetic syndromes
including Li-Fraumeni (germ-line mutations in TP53),
neurofibromatosis type 1, and Turcot syndrome. Glioblastoma was the
first cancer type to be systematically studied via The Cancer Genome
Atlas (TCGA). P53, RB, and receptor tyrosine kinase (RAS) signaling
pathways were found to be abrogated across nearly all glioblastomas
(Cancer Genome Atlas Network Nature 2008). TERT promoter
mutations, leading to increased expression and activity of telomerase,
are also found in ~80% of glioblastoma (Killela et al. Proc Natl Acad
Sci 2013). IDH and ATRX mutations are common among
astrocytomas and are mutually exclusive with TERT promoter
mutations. TCGA has now established four subtypes of glioblastoma:
classical (EGFR mutated without TP53 mutations), proneural
(associated with TP53 and IDH1 mutations), mesenchymal
(associated with NF1 mutations), and neural (resembling normal brain
tissue) (Verhaak et al. Cancer Cell 2010). Methylation of the MGMT
promoter leads to improved response to concurrent chemoradiation
with temozolomide (Monika et al. NEJM 2005).
Pathology: Historically, gliomas were all classified based upon the
histopathologic grade, although the diagnosis now includes molecular
data (WHO 2016 update; David et al. Acta Neuropathol 2016). Grade
III astrocytomas and grade IV GBMs are highly cellular and infiltrative.
Classically, glioblastomas are characterized by foci of microvascular
proliferation and pseudopalisading necrosis. Consideration that IDH
wt status may trump pathology when determining GBM diagnosis in
the future
Imaging: High-grade gliomas are contrast-enhancing on T1 scans
with an associated edematous component best seen on T2-FLAIR
sequences (Fig. 12.1). Additionally, glioblastomas commonly show a
centrally necrotic pattern on imaging and can routinely cross midline
(“butterfly” pattern).
Figure 12.1 T1+contrast MRI image (left) shows large contrast-
enhancing lesion in the right frontoparietal lobe with necrotic
features consistent with glioblastoma. The lesion is associated
with a significant edematous component seen on T2-FLAIR
sequence (right).
A
Commonly present in the frontal lobe compared to parietal/temporal
and occipital lobes. Infratentorial tumors are uncommon. See LGG
chapter for review of neuroanatomy.
W
History and physical: Including presenting symptoms, history of
seizures, and family history. Assessment of neurologic deficits and
performance status important. Important to ask about whether they
are on steroids and whether their symptoms have improved
Labs: CBC, CMP
Procedures/biopsy: Neurosurgery evaluation for biopsy and/or
resection
Imaging: MRI of the brain with and without contrast is the gold
standard (Fig. 12.1) to evaluate location, grade, and extent of
disease.
S /G
Grade III gliomas: Anaplastic astrocytoma, anaplastic oligodendroglioma,
anaplastic oligoastrocytoma, and anaplastic ependymoma. 1p19q
codeletion commonly associated with oligodendroglioma histologic
subtype. IDH and ATRX mutations associated with anaplastic astrocytoma
or mixed histologies. Cases with mutant IDH and/or 1p19q codeletion
associated with improved prognosis compared to IDH wild-type tumors
Grade IV glioblastoma: Important to assess IDH mutational status (if
mutated, likely to be secondary as opposed to de novo). IDH mutant cases
are associated with improved survival although inevitably these recur as
well.
T A
a Elderlypatients with glioblastoma have a multitude of options and can be

treated with any of the above options. Important considerations include life
expectancy, PS, methylation, and comorbidities.
R T T
midbrain. MRI fusions (unless obtaining MRI SIM)—T1 + C sequence
and T2/FLAIR sequences.
Dose and target:
High-Grade Glioma
MDACC approach: Simultaneous integrated boost (SIB) to

CTV1 within CTV2.
CTV1: GTV (cavity + residual contrast enhancement)—57 Gy in
30 fractions at 1.9 Gy/fx
CTV2: GTV + 1.5 cm (+uncovered hyperintense signal on FLAIR
sequence)—50 Gy in 30 fractions at 1.66 Gy/fx
Alternative RTOG approach, sequential radiation:
CTV1: GTV (cavity + residual contrast enhancement) + 1 cm—
59.4 Gy in 33 fractions at 1.8 Gy/fx
50.4 Gy in 30 fractions at 1.8 Gy/fx
Alternative EORTC approach
PTV1: GTV (cavity + residual contrast enhancement) + T2/FLAIR
+ 1.5 cm—45 Gy in 30 fractions at 1.8 Gy/fx
PTV2: GTV + 1.5 cm—additional 14.4 Gy in 8 fractions of 1.8 Gy
for a total of 59.4 Gy
Glioblastoma
MDACC approach: SIB to CTV1 within CTV2 (Fig. 12.2).
CTV1: GTV (cavity + residual contrast enhancement)—60 Gy in
30 fractions at 2 Gy/fx
CTV2: GTV + 2 cm (+uncovered hyperintense signal on FLAIR
sequence)—50 Gy in 30 fractions at 1.66 Gy/fx
Alternative RTOG approach, sequential radiation:
CTV1: GTV (cavity + residual contrast enhancement) + edema
on T2/FLAIR + 2 cm—46 Gy in 23 fractions at 2.0 Gy/fx
additional 14 Gy in 7 fractions at 2.0 Gy/fx for a total of 60 Gy
in 30 fractions
Alternative EORTC approach
CTV: GTV (surgical cavity + residual enhancing tumor) + 2 cm—
60 Gy in 30 fractions at 2.0 Gy/fx
Alternative hypofractionated regimes:
50 Gy/20 fx, 40 Gy/15 fx, 34 Gy/10 fx, or 25 Gy/5 fx if poor PS or
elderly.
Figure 12.2 Representative plan for a patient with a grade IV
glioblastoma. The 60-Gy isodose line (white) can be seen
surrounding the red GTV/resection cavity (red color wash). The
50-Gy isodose line (blue) covers GTV + 2 cm (tan color wash),
which is expanded to include hyperintense signal on T2-FLAIR
sequence. See color insert.
Considerations: Limit CTV expansions to anatomic boundaries of
disease spread (bones, falx, brainstem), unless T2 hyperintense
signal spreads beyond these barrier areas indicating probable
disease.
For all high-grade gliomas, PTV expansions on CTV1 and CTV2
are generally 0.3 cm (daily kV) or 0.5 cm (weekly kV), at our
institution.
Technique: IMRT/VMAT. Consider use of protons on trial depending

on anatomy and age.
IGRT: Daily kV imaging.
Planning directive:
max <60 Gy.
Brain: V30Gy < 50%
Lens: Max < 5 Gy
Gy
C
Concurrent: Temozolomide (TMZ) 75 mg/m2 daily during RT, 7 days
a week.
Adjuvant: TMZ 150-200 mg/m2 daily for 5 days, every 28 days for 6
cycles (or indefinitely). Procarbazine, lomustine, vincristine (PCV)
regimen historically used in an adjuvant setting for grade III gliomas
although most oncologists are now giving TMZ due to decreased
toxicities and retrospective studies suggest equivalent efficacy.
S E M
See LGG chapter.
F -
Every 2-3 months with MRI of the brain w/ and w/o contrast for the first
year following treatment, q4mo during years 2-4 and q6mo thereafter.
Offer NovoTTF to patients after they have completed RT if they are willing.
Many patients will recur in the first year following treatment. Consider
reirradiation on protocol or enrollment in investigational clinical trials.
N T
Glioblastomas
EORTC 26981/22981-NCIC (Stupp et al. NEJM 2005; Stupp et al.

Lancet Oncol 2009): Two-arm prospective randomized phase III trial.
573 patients underwent surgical resection (40% GTR) and then
randomized to RT alone vs RT with concurrent TMZ, both followed by
6 cycles of adjuvant TMZ. Radiation dose was 60 Gy/30 fx. Median
OS RT alone 12.1 months vs RT + TMZ 14.6 months, 2-year OS 10%
RT alone vs 26% RT + TMZ (HR 0.63; P < .001). Grade 3 or 4
hematologic toxicity with TMZ 7%. MGMT methylation status greatest
predictor for outcome and benefit from TMZ chemotherapy (Stupp et
al. Lancet Oncol 2009)
EF-14 NovoTTF (Stupp et al. JAMA 2015): Two-arm prospective
randomized phase III trial. Glioblastoma patients randomized
following completion of chemoradiation (2:1) to receive maintenance
treatment with TTFields plus temozolomide vs temozolomide alone.
TTFields treatment was delivered continuously (>18 h/d) via four
transducer arrays placed on a shaved scalp. Interim analysis at
median f/u of 38 months. Median OS in TTF + TMZ arm 20.5 vs 15.6
months (HR 0.64, P = .004).
Grade III gliomas
EORTC 26951 (Van den Bent et al. JCO 2006, 2013). Two-arm
prospective randomized phase III trial. 368 anaplastic astrocytoma
and oligodendroglioma patients underwent surgical resection followed
by RT (59.4 Gy/33 fx) and randomized to observation vs 6 cycles of
PCV. 82% of patients in the observation arm received chemotherapy
at progression. 38% of patients in RT→ PCV arm had discontinuation
of chemotherapy due to toxicity. RT→ PCV arm had improved OS
(42.3 vs 30.6 months, HR 0.75) and PFS.
CATNON (Van den Bent et al. Lancet 2017). 2 × 2 factorial phase III
randomized trial. 1p19q noncodeleted anaplastic glioma patients
randomized to RT (59.4 in 33 fractions) alone, RT + adj TMZ,
chemoRT, or chemoRT + adj TMZ. Interim analysis shows OS at 5
years improved with adj TMZ (55.9% vs 44.1%, P = .0014).
MENINGIOMA
HUBERT YOUNG PAN • DEBRA NANA YEBOA • ERIK P.
SULMAN
B
Incidence/prevalence: Meningioma is the most common benign
brain tumor (1/3 of primary intracranial neoplasms), ~25-30 000 cases
per year in the United States.
Outcomes: Typically long natural history. Recurrence rate is strongly
correlated with WHO grade (~10% for G1, 40% for G2, 70% for G3).
Demographics: Female > male (2:1), incidence peaks in sixth to
seventh decades
Risk factors: Prior radiation at long interval (~20 years) from even
low dose (1-2 Gy), NF2, MEN1, and long-term hormonal replacement
usage are all identifiable risk factors.
T B C
Genetics: Loss of chromosome 22 is the most common alteration,
associated with NF2 mutation (50%). Less common alterations
include AKT1 (~10%), SMO, TRAF7 (~25%), and PI3KA.
Pathology: WHO grading based on mitotic activity—Grade I
(85%-90% of cases, benign histology), grade II (5%-10%, atypical,
clear cell, choroid), and grade III (<5%, anaplastic, papillary,
rhabdoid). Characteristically, psammoma bodies and calcifications are
seen in grade I meningioma. Grade II is defined by ≥4 mitoses/10
HPF. And grade III is defined as ≥20 mitoses/10 HPF or the presence
of carcinomatous, sarcomatous, and melanomatous features and/or
with brain invasion. Subset expresses hormone receptors
(progesterone and/or estrogen).
Imaging: MRI is preferred as dural tail can be seen on 2/3 of cases
(Fig. 13.1), typically T1 isointense, T2 hyperintense, and strongly
enhancing. CT shows extra-axial mass displacing normal brain,
isodense, with ~25% having calcification.
Figure 13.1 T1+C MRI sequence showing enhancing lesion with
dural origin, consistent with meningioma. Note enhancing dural
tail seen in ~2/3 of cases.
A
Meningiomas have dural origin, most commonly within the skull (90%)
at sites of dural reflection (falx cerebri, tentorium cerebelli, venous
sinuses) but can also present in the optic nerve sheath and choroid
plexus. Common sites of presentation include cerebral convexity and
parafalcine/parasagittal regions.
W
History and physical: History with careful attention to neurologic
deficits and exam
Labs: CBC, CMP
Procedures/biopsy: Neurosurgery evaluation for maximal safe
resection and/or biopsy
Imaging: Head CT and MRI of the brain to evaluate extent of
disease. Evaluate for perilesional edema and/or bony invasion.
S G ( T 13.1)
Table 13.1 Simpson Grading System for Meningioma

T A
R T T
SIM: Supine, thermoplastic mask, scan vertex to shoulders. Isocenter
placed at midbrain. MRI fusions (unless obtaining MRI SIM)—T1+C
sequence and T2-FLAIR sequences.
Dose and target:
Technique: IMRT/VMAT. PTV 3 mm if daily kV, 5 mm if weekly kV.

Consider SRS if G1, <3-4 cm size, with sufficient distance from critical
structures, that is, optic apparatus (>2 mm). For SRS, prescribe 14-16
Gy to 50% isodose line, to be as conformal as possible.
IGRT: Daily kV
Planning directive:
Fractionated EBRT
max <60 Gy.
Brain: V30Gy < 50%
Lens: Max < 5 Gy
Gy
For single-fraction SRS, limit dose to optic apparatus to 8 Gy (can push up
to 10-Gy point dose). Can consider dose escalation to 16 Gy in single
fraction if higher grade. We typically do not recommend SRS for grade 3
tumors.
C
Experience with systemic therapy is limited to observational studies in the
recurrent setting with limited efficacy. Studied options include Sutent,
hydroxyurea, somatostatin analogs (octreotide), and various inhibitors
(progesterone, estrogen, PDGF, EGFR, VEGF).
F -
Grade 1: MRI at 6 months and then annually
Grade 2: MRI q3-6mo × 1 year and then annually
Grade 3: MRI q3-6mo × 5 years and then q6-12mo
Depending on location of RT, important to assess for potential hormonal
deficiencies (ie, pituitary hormones).
N S
RTOG 0539 (Rogers et al. J Neurosurg 2018; ASTRO abstract
IJROBP 2016): Phase II trial of risk-stratified postoperative
management of meningioma. Only prospective trial for RT in
meningioma that we have data for currently. Low risk (newly
diagnosed G1) observed with 3-year PFS 92%, but 40% 5-year crude
LF if STR (abstract). Intermediate risk (recurrent G1 or new G2 s/p
GTR) received 54 Gy in 30 fractions with 3-year PFS 93.8% (P =
.0003 when compared to 3-year PFS in historical control). High risk
(any G3, recurrent G2, or new G2 s/p STR) received 60 Gy in 30
fractions with 3-year PFS 59% (abstract).
BENIGN CNS
CHRISTOPHER WILKE • CAROLINE CHUNG
V S
Background
Incidence/prevalence: Vestibular schwannoma (acoustic neuroma)

accounts for 8% of adult intracranial tumors and 85% of
cerebellopontine angle tumors. Incidence is ~1 per 100 000 person-
years although true rate may be higher based upon incidental findings
on autopsy and MRI studies. Almost always presents with unilateral
involvement except for patients with NF2
Outcomes: Typically slow-growing with long natural history. 40% will
show no growth.
Demographics: Median age of diagnosis 50 years. 1:2 M/F ratio
Risk factors: NF1 and NF2 (bilateral lesions), acoustic trauma (loud
noise), childhood exposure to low-dose radiation
Tumor biology and characteristics
Genetics: Inactivation of NF2 gene (produces tumor suppressor

schwannomin) is found in most sporadic schwannomas.
Pathology: Benign (WHO Grade I) tumor arises from perineural
elements of Schwann cell of the 8th CN with S-100+ on IHC.
Malignant transformation is rare.
Imaging: MRI with contrast is the gold standard and preferred,
including mm sections through internal auditory canal (IAC), seen as
well-circumscribed, heterogeneously T2 hyperintense, contrast-
enhancing lesions (Fig. 14.1).
Figure 14.1 T1 + C MRI sequencing showing a 1.3 × 1.0 cm
schwannoma on the left intracanalicular space. The tumor
extends slightly into the left cerebellopontine angle.
Anatomy
Schwannomas are the most common peripheral nerve sheath tumor

and can involve other extracranial or intracranial (trigeminal, facial,
jugular foramen) nerves. The internal acoustic canal is a short
segment (~1 cm) in the temporal bone that contains CN VII and VIII;
vestibular schwannomas typically affect the intracanalicular segment
of the vestibular portion of CN VIII.
Workup
History and physical: History with careful attention to neurologic

deficits and exam (Weber and Rinne tests). If facial/trigeminal
involvement, patients may present with altered taste and paresis
Procedures/biopsy: Audiometry should be done to establish
baseline. Neurosurgical evaluation for resection/biopsy
Imaging: MRI of the brain w/ contrast. High-resolution CT if MRI not
available
Koos grading scale for vestibular schwannoma

Treatment algorithm
Radiation treatment technique
SIM: Supine, thermoplastic mask. MRI fusions (unless obtaining MRI

sim)—T1 + C sequence.
Dose, target, technique, IGRT:
Figure 14.2 Axial and coronal sections demonstrating treatment
of an acoustic neuroma with Gamma Knife SRS. A dose of 12.5
Gy was prescribed with 50% isodose.
Planning directive:
SRS
Brainstem: 0.01 cc ≤ 12 Gy
Optic nerves and chiasm: Max < 8 Gy
Cochlea: Limit central cochlear dose to <4.2 Gy (Kano et al.
Neurosurgery 2009).
Fractionated radiotherapy (1.8 Gy/fx):

Optic nerves and chiasm: Max < 54 Gy
Cochlea: Max < 35 Gy
Pituitary: Max < 40 Gy
Follow-up
First follow-up at 3-6 months and then annual MRI is typically

recommended for 10 years with less frequent studies if no evidence of
tumor progression
All patients should undergo baseline audiology evaluation prior to
treatment and regularly with follow-up posttreatment.
Surgery
Technique:
Middle cranial fossa approach: Best suited for small tumors with
focus on hearing preservation
Translabyrinthine approach: Usually reserved for larger tumors in
patients who have already lost functional hearing, as this
approach sacrifices hearing in the operated ear
Retrosigmoid (keyhole) approach: Most often used for moderate
or large tumors in patients with functional hearing with the goal of
hearing preservation
Outcomes: Excellent if GTR, but about 15% LR if STR.
Notable studies
German retrospective (Combs et al. Int J Radiat Oncol Biol Phys

2010): Prospective cohort study of 200 pts treated to median dose of
57.6 Gy at 1.8 Gy/fx or Linac-based SRS. No difference in 10-year LC
of 96%. Hearing preservation of 78% at 5 years for standard
fractionation and patients with SRS < 13 Gy
Japan retrospective (Hasegawa et al. Int J Radiat Oncol Bio Phys
2013): Single-institution review of 440 pts using Gamma Knife SRS
with median marginal dose of 12.8 Gy showed 10-year PFS of 92%
and <5% rate of CN palsy.
P (J )
Background
Incidence/prevalence: Rare, typically benign, neuroendocrine tumor,

which most commonly presents during the fifth to sixth decade of life
Clinical presentation: Less than 5% of all paragangliomas present in
the head and neck. Most symptoms result from mass effect of the
tumor and may include pulsatile tinnitus, hearing loss, and cranial
nerve palsies. Paragangliomas of the head and neck are more often
non–catecholamine secreting compared with other organ sites.
Pathology: Mutations in the succinate dehydrogenase enzyme
complex have been shown to predispose to the development of head
and neck paragangliomas (Neumann et al. Cancer Res 2009).
Imaging: Reliably imaged with both CT and MR angiography. CT is
beneficial for visualizing destruction of the temporal bone. Octreotide
imaging has demonstrated a sensitivity of 94% in patients with head
and neck paragangliomas (Telischi et al. Otolaryngol Head Neck Surg
2000).
Treatment
Observation
Initial observation and close follow-up may be considered for small

asymptomatic tumors.
Median growth rate for head and neck paragangliomas is ~1 mm/y (
Jansen et al. Cancer 2000).
Surgery
Typically preferred for small tumors in which there is felt to be a low

risk of serious complications or functional deficits
Resection is also preferred for immediate relief of symptomatic tumors
or catecholamine-secreting tumors.
Local control rates with surgery alone exceed 80%-90% following
gross total resection.
Radiotherapy
Stereotactic radiosurgery:
Provides excellent local control (>95% at 3 years; Guss et al.
IJROBP 2011) and is a good option for smaller tumors that are at
high risk of potential surgical complications
Typically prescribed as 16 Gy to the 50%-80% isodose
Fractionated radiotherapy:
Useful for larger tumors, which cannot be safely treated with SRS
due to tumor volume and/or potential dose to critical structures
Doses of 45-50.4 Gy in 1.8 Gy/fx are associated with local control
similar to surgical series.
Dose constraints
See dose constraints for vestibular schwannomas.
Follow-up
Imaging every 6-12 months for 3 years and then annually for 10 years
Serum markers should be tested in secretory tumors.
T N
Background
Incidence/prevalence: Annual incidence is ~5 per 100 000 person-

years. Approximately 50% more prevalent among females vs males.
Most commonly seen in patients aged 50 years and older.
Clinical presentation: Brief, recurrent episodes of severe unilateral
shooting/stabbing pain localized to one or more divisions of the
trigeminal nerve in the absence of other neurologic deficits
Pathology: Majority of cases are thought to be caused by
compression of the trigeminal nerve root, which leads to
demyelination and disrupted neuronal signaling.
Imaging: Volumetric acquisitions with thin slice MRI/MRA are useful
in the detection of neurovascular compression.
Treatment
Medical management
Preferred as upfront treatment prior to consideration of surgery or

radiotherapy
Carbamazepine is the most commonly used agent for front-line
therapy. Others shown to be efficacious include oxcarbazepine,
baclofen, and lamotrigine.
Surgery
Usually reserved for patients with medically intractable symptoms.

Very effective for initial pain relief although efficacy tends to fall over
time
Surgical options include
Microvascular decompression to relieve the pressure of vascular
structures off the trigeminal nerve
Rhizotomy with destruction of the gasserian ganglion by RF
ablation, mechanical compression, or chemical lysis
Radiosurgery
Mechanism of pain relief remains poorly understood although animal
models have demonstrated axonal degradation, fragmentation, and
edema following ablative SRS doses to the trigeminal nerve root
(Kondziolka et al. Neurosurgery 2000).
When performed using Gamma Knife SRS, a maximum point dose of
70-90 Gy is delivered using a single 4-mm isocenter targeting the
proximal ipsilateral trigeminal nerve (Fig. 14.3). Several institutional
series have also demonstrated efficacy of CyberKnife/Linac
modalities with acceptable rates of toxicity.
Prospective data demonstrate pain relief in a proportion of patients
with low rates of toxicity (Regis et al. J Neurosurg 2006). However,
the efficacy over time also declines similar to reported surgical series.
Figure 14.3 Axial and sagittal sections demonstrating treatment of

a right-sided trigeminal neuralgia using Gamma Knife SRS. A
maximum point dose of 80 Gy was delivered using a single shot
with a 4-mm collimator.
A M
Background
Incidence/prevalence: Annual incidence of ~1 per 100 000 person-

years. Median age at diagnosis of 30.
Clinical presentation: Wide range of initial presentation from
detection as an incidental finding to intracranial hemorrhage, seizures,
headaches, and focal neurologic deficits. Most are supratentorial
(90%) and present with a single lesion (90%). The presence of
multiple AVMs is strongly associated with Osler-Weber-Rendu
syndrome (hereditary hemorrhagic telangiectasia).
Pathology: Abnormal communication between arteries and veins
without usual intervening capillary network. The high flow rates can
create vessel enlargement and both arterial and venous aneurysms.
Imaging: Cerebral angiography is the gold standard for evaluating the
location of feeding vessels and drainage patterns. Contrast-enhanced
CT and MR angiography can also be useful for initial diagnosis.
Treatment
Medical therapy
Historically, interventional therapy for AVMs has been favored due to

the 2% annual rate of hemorrhage in patients with untreated lesions.
The role of routine interventional therapy in asymptomatic patients
has come into question with the results of the ARUBA trial
demonstrating a significantly elevated risk of stroke and death
following intervention as compared with those receiving medical
management alone (Mohr et al. Lancet 2014).
Microsurgery
Treatment of choice for patients felt to be at high risk of hemorrhage,

as it provides immediate treatment of symptomatic AVMs and
immediately reduces risk of hemorrhage postprocedure.
The Spetzler-Martin grading system is used to assess the risk of
postoperative neurologic complications and aids in treatment modality
decision-making (Spetzler and Martin J Neurosurg 1986).
Embolization
Endovascular embolization is commonly used to reduce the size of

large AVMs prior to treatment with radiotherapy or surgery, but it can
result in complete obliteration of the nidus in some instances.
Radiosurgery
Usually reserved for lesions that are inaccessible or felt to be at very

high risk with surgical intervention due to operative complications or
medical comorbidities.
Mechanism of action is thought to be induction of progressive
thrombosis and fibrosis.
Approximately 80%-90% of patients will have eventual obliteration of
the nidus although the mean time to obliteration following SRS is ~2-3
years. The elevated risk of hemorrhage is not eliminated until
complete obliteration of the AVM.
A prescription dose of 20 Gy covering the nidus is associated with in-
field obliteration rates in excess of 90% (Flickinger et al. IJROBP
1996).
MRI/MRA can be used for posttreatment surveillance with cerebral
angiography used to confirm resolution.
PITUITARY ADENOMA AND
CRANIOPHARYNGIOMA
HUBERT YOUNG PAN • DEBRA NANA YEBOA • ERIK P.
SULMAN
B
Incidence/prevalence: The most common sellar mass is pituitary
adenoma (90%-95%), which accounts for 10% of intracranial tumors.
12 000 cases per year in the United States (Ostrom et al. Neuro
Oncol 2017). Female > males
Outcomes: Long natural history as incidental imaging finding,
endocrine abnormality, or local compressive symptoms; RT provides
90+% LC
Demographics: Pituitary adenoma presents 30-50 years,
craniopharyngioma bimodal (1/3 at 0-14 years, 2/3 at 45-60 years)
Risk factors: MEN-1 (parathyroid, pancreas, pituitary), history of
colorectal cancer
T B C
Pituitary adenoma: Classified by size (<1 cm microadenoma vs >1
cm macroadenoma, >4 cm giant adenoma), functional vs
nonfunctional, and cell origin. 75% of pituitary adenomas are
secretory (50% PRL, 25% GH, 20% ACTH, <1% TSH).
Craniopharyngioma: Epithelial tumor derived from Rathke pouch,
the embryonic precursor to anterior pituitary; adamantinomatous (Wnt
activation) vs papillary (BRAF mutation)
Pathology: Mallory trichrome staining helps differentiate functional vs
nonfunctional adenomas.
Imaging: Craniopharyngioma often presents with calcification
(60%-80%) and mixed solid-cystic (75%) components. Adenomas
appear hypointense in the early phase of dynamic contrast-enhanced
MRI (due to poor vasculature relative to normal tissue).
A
Pituitary fossa: Located within the sphenoid bone, bounded by
hypothalamus and optic chiasm (superior), sphenoid sinus (inferior),
and cavernous sinus (lateral)
Pituitary gland: Divided into anterior (GH, PRL, TSH, ACTH, FSH,
LH) and posterior (oxytocin, ADH)
W
History and physical: History with careful attention to potential
endocrinopathies
Procedures/biopsy: Neurosurgical evaluation for resection/biopsy.
Endocrine evaluation if medical management desirable
Labs: CBC, CMP, endocrine function tests (TSH, ACTH, cortisol,
prolactin, IGF-1)
Imaging: MRI of the brain w/ contrast
T A
Pituitary adenoma:
First line: Medical management if functional (see Medical
management section)
Second line: Surgical resection for all other functional and
nonfunctional
adenomas to relieve compression
Third line: Consideration for RT (if inoperable, persistent post-op
hormone elevation, macroadenoma with STR, recurrent disease)
Craniopharyngioma:
Maximal safe resection (shunt if hydrocephalus) → consideration
for RT (if STR)
Consider observation for asymptomatic pituitary adenomas without lab

abnormalities.
R T T
SIM: Supine, thermoplastic mask, bite block, scan vertex to shoulders
Dose, target, and technique:
IGRT: Daily kV, weekly-biweekly reimaging for craniopharyngioma to

monitor changes in cyst shape/size, which may necessitate
replanning
Considerations: We favor fractioned EBRT for larger (>3 cm) tumors
or for tumors close (<2 mm) to critical structures (ie, optic chiasm).
Repeat imaging during treatment of craniopharyngioma to assess cyst
volume changes. See LGG chapter for normal tissue constraints.
S
Transsphenoidal resection: Endoscope inserted through one nostril
and opening made in the nasal septum and sphenoid sinus to access
the sella. Fat graft placed in resection bed and cartilage craft to seal
sella hole. Complications include diabetes insipidus, CSF leaks, and
hemorrhage.
Pterional craniotomy: Temporal craniotomy may be required to
access extrasellar disease, particularly for craniopharyngioma.
M M
F -
Endocrine evaluation and MRI q6mo, normalization of hormones can
take years.
N S
Pituitary adenoma UVA retrospective (Sheehan et al. J Neurosurg
2011). Review of 418 patients treated with Gamma Knife. LC 90%,
median time to endocrine remission 48 minutes, new pituitary
hormone deficiency in 24% of patients. Smaller adenoma volume
correlated with improved endocrine remission rates
Craniopharyngioma UCSF retrospective (Shoenfeld et al. J
Neurooncol 2012). Review of 122 pts showed no difference in PFS (P
= .54) and OS (P = .74) when treated with GTR vs STR + XRT but
significantly shorter PFS if STR alone (P < .001). Additionally, GTR
was associated with greater risk of DI (56% vs 13%, P < .001) and
panhypopituitarism (55% vs 27%, P = .01) vs STR + XRT.
Craniopharyngioma (Bishop et al. Int J Radiat Oncol 2014).
Retrospective study of 52 children treated with protons (21) or IMRT
(31) at two institutions. Of 24 pts with imaging during RT, 10 (42%)
had cyst growth and 5 (21%) required change in treatment plan.
Outcomes similar with IMRT and protons
MEDULLOBLASTOMA
SHANE R. STECKLEIN • ARNOLD C. PAULINO
B
Incidence/prevalence: Second most common pediatric brain tumor.
Most common malignant tumor in the posterior fossa. There are ~500
cases per year in the United States.
Outcomes: 5-Year survival 80%-85% for average-risk disease and
60%-65% for high-risk disease.
Demographics: Bimodal age distribution; peak incidence 6 years in
children and 25 years in adults.
Risk factors: Gorlin syndrome (nevoid basal cell carcinoma
syndrome, due to mutations in PTCH, which regulates Sonic
Hedgehog [SHH] signaling), Turcot syndrome (familial adenomatous
polyposis [FAP] with brain tumors, due to mutations in APC, which
regulates Wnt signaling)
T B C
Pathology: Small, round, blue cell tumor. Primitive neuroectodermal
tumor (PNET) of the superior medullary velum (germinal matrix) of the
cerebellum or cerebellar vermis. Classic histologic finding is the
Homer-Wright pseudorosette (tumor cells concentrically arranged
around a lumen containing neuropil).
Imaging: Typically hypointense to isointense on T1-weighted images
and generally shows avid enhancement on postcontrast sequences
A
Tumors most commonly arise from the cerebellar vermis and often
protrude into the 4th ventricle and may grow through the lateral foramina
of Luschka and the posteromedial foramen of Magendie into the
subarachnoid space. Midline tumors are most commonly associated with
Wnt subtype, extensive anterior growth (including into the brainstem) is
seen in Group 3/4 tumors, and lateral tumors are most likely to be SHH.
Obstruction of the cerebral aqueduct can cause obstructive
hydrocephalus.
S M (T
.A N 2012)
aI, infants; C, children; A, adults.

W
History and physical: Patients should have baseline evaluations by
endocrinology, ophthalmology, audiology, and neuropsychology.
Neurologic examination may reveal cerebellum deficits including gait
or truncal ataxia, cranial nerve deficits, or signs of increased
intracranial pressure including papilledema and loss of vision.
Postoperatively surgical resection associated with posterior fossa
syndrome, which appears 1-2 days after surgery and includes mutism
and emotional lability.
Labs: General labs and CSF evaluation 10-14 days after surgery
Procedures/biopsy: Lumbar puncture often contraindicated prior to
surgery secondary to risk of herniation. Perform lumbar puncture 10-
14 days after surgery.
Imaging: Contrast MRI is the preferred examination. Preoperative
and postoperative (within 48 hours of surgery) contrast-enhanced
brain MRI. Spine MRI (if not done preoperatively) 10-14 days after
surgery.
S R S
T A
All patients should be considered for a clinical trial.

R T T
SIM: Supine on foam board, thermoplastic mask. Anesthesia often
required for young children.
Dose:
Average risk: CSI to 23.4 Gy in 17 fractions (1.8 Gy/fx),
sequential boost to tumor bed plus margin to 54.0 Gy
High risk: CSI to 36.0 Gy in 20 fractions (1.8 Gy/fx), sequential
boost to tumor bed plus margin to 54.0 Gy
Target:
CSI:
Entire craniospinal axis
Ensure coverage of cribriform plate and thecal sac
Tumor bed boost:
Collapsed tumor bed and gross residual disease if present
1.0-1.5 cm anatomically constrained expansion for CTV
Technique: Passive scatter proton radiotherapy to spare anterior
structures. RAO and LAO cranial fields (10-15 degrees from
horizontal plane to reduce dose to contralateral lens; do not
compromise cribriform plate coverage to spare lenses) and posterior
spinal fields. Multiple ways to handle junctions, including junction
shifts every 4-5 fractions to feather overlap at brain-spine and spine-
spine junctions. For growing children, ensure coverage of entire
vertebral body to prevent asymmetric growth and reduce risk of
lordosis.
IGRT: Daily kV.
Dose constraints:
C
Standard adjuvant regimens include cisplatin, vincristine, and
lomustine (CCNU) or cyclophosphamide.
Use of targeted agents (eg, vismodegib [Erivedge] for SHH
medulloblastoma) emerging
Some protocols (COG) include weekly vincristine given during
radiotherapy.
T M
C <3 Y A
Goal is to delay radiotherapy as long as possible to mitigate long-term
toxicity.
Standard approach is maximal safe resection followed by intensive
chemotherapy (high-dose methotrexate followed by carboplatin,
thiotepa, and etoposide) with autologous stem cell rescue.
Focal radiotherapy to tumor bed may be considered in select cases,
but patients are at significantly higher risk for failure at non–tumor
bed-irradiated sites.
F -
MRI of the brain and spine 4-6 weeks after radiotherapy, then every 3
months for the 1st year, every 4 months for the 2nd year, every 6
months until year 5, and then annually thereafter
Patients should have periodic evaluations by endocrinology,
ophthalmology, audiology, nd neuropsychology to detect and manage
long-term sequelae of treatment.
N T /P
Radiation dose and field in medulloblastoma
CCG 9892 (Packer JCO 1999). Pilot study evaluating low-dose CSI
(23.4 Gy) followed by posterior fossa boost to 55.8 Gy with concurrent
vincristine and then adjuvant lomustine/vincristine/cisplatin in
average-risk patients. PFS at 3 years was 86% and at 5 years was
79%, as good as historical controls with CSI to 35 Gy.
COG ACNS0331 (Michalski IJROBP 2016 [abstract form only]).
Average-risk patients age 3-7 randomized to low-dose CSI (18.0 Gy
with posterior fossa boost to 23.4 Gy) vs standard-dose CSI (23.4
Gy). Second randomization for boost to posterior fossa vs tumor bed
with margin to 54.0 Gy. Average-risk patients age 8-22 all received
standard-dose CSI but underwent posterior fossa vs tumor bed with
margin boost to 54.0 Gy. Preliminary data show that reducing the
boost volume to the tumor bed with margin is acceptable, but there is
increased risk of recurrence with reduced dose (18.0 Gy) CSI, and
this is therefore not recommended.
Proton therapy for CSI (Howell Radiat Oncol 2012). Evaluation of
passive scatter proton vs photon radiotherapy for CSI at MDACC.
Proton CSI reduced dose to the esophagus, heart, liver, thyroid,
kidneys, and lungs.
Deferment of radiation for infants <3 years old
Baby POG I (Duffner NEJM 1993; Duffner Neuro-oncology 1999).
Postoperative chemotherapy and delayed radiation in children <3
years of age with malignant brain tumors. 198 patients with biopsy-
proven malignant brain tumor (medulloblastoma, ependymoma,
PNET, brainstem glioma, malignant glioma, choroid plexus carcinoma,
other gliomas) received two 28-day cycles of cyclophosphamide plus
vincristine followed by one 28-day cycle of cisplatin plus etoposide;
repeated until disease progression or for 2 years in patients <24
months at age of diagnosis or for 1 year in patients ≥24-36 months of
age at diagnosis. High response rate in patients with
medulloblastoma, malignant gliomas, and ependymomas. Minimal
response in brainstem glioma and PNET. Update for medulloblastoma
showed 5-year PFS 32% and OS 40% with no difference if RT
delayed by 1 or 2 years.
EPENDYMOMA
COURTNEY POLLARD III • ARNOLD C. PAULINO
B
Incidence/prevalence: The third most common childhood brain
tumor. Bimodal distribution with peaks at 4 and 35 years old.
Approximately 200 cases per year in the United States
Outcomes: Degree of resection most important predictor of
outcomes. 5-Year overall survival ~75% with gross total resection
(GTR) and ~35% with subtotal resection (STR)
Demographics: Infratentorial lesions occur more commonly in
younger children. Supratentorial lesions are more common in
adolescents and adults. In children, 90% of tumors are intracranial.
Risk factors: Spinal cord ependymomas are associated with
neurofibromatosis type 2.
T B C
Genetics: Greater than 2/3 of supratentorial ependymomas have
oncogenic fusions between RELA (which drives NF-κB) and
C11orf95, leading to uncontrolled activation of NF-κB signaling
pathway and driving tumorigenesis (Parker et al. Nature 2014).
Among posterior fossa tumors, a poor prognostic subgroup is one
which exhibits a CpG island methylator phenotype, which silences
genes that prevent neuronal differentiation. This is prognostic of PFS
and OS (Mack et al. Nature 2014).
Pathology: Origin is the ependymal cells lining the ventricular system
and spinal canal. Classic features are ependymal and perivascular
pseudorosettes. GFAP, S100, and vimentin stain positive.
Subependymomas are rare tumors that are found in adults in the 4th
or lateral ventricles. These tumors appear benign histologically and
grow slowly. Similarly, myxopapillary ependymomas are slow-growing
and are found in adults almost exclusively within the conus and filum
terminale of the spinal cord.
Imaging: Classically hypointense on T1 MRI sequences and
hyperintense on T2. Tumors enhance with gadolinium contrast. On
CT, tumors will enhance with contrast and calcifications are commonly
seen.
A
Tumors can occur throughout the entire cranial spinal axis. If the tumor is
in the posterior fossa, the most common site is the fourth ventricle and
often involves the foramen of Luschka. Supratentorial tumors also arise in
the ventricular system and spread through intraparenchymal extension.
Direct extension through the foramen magnum into the upper cervical
spinal canal is common. Subarachnoid seeding occurs in ~12% of
children.
W
History and physical: Common presenting symptoms include those
resulting from increased ICP (headaches, nausea, vomiting) due to
obstruction of CSF flow. For adults with myxopapillary ependymomas,
chronic back pain is typically reported with or without neurologic
deficits. Perform thorough neurologic exam.
Labs: CBC, CMP
Procedure/biopsy: CSF sampling with cytology (unless
contraindicated due to obstructive hydrocephalus)
Imaging: MRI of the brain and spine is essential. After resection, MRI
should be obtained <24 hours to evaluate degree of resection. CSF
cytology and MRI of the spine should be obtained ~2 weeks after
surgery to avoid false-positive result.
E G (WHO 2016)
T A
R T
D /T /T
Infratentorial Tumor
SIM: Supine, arms at side, aquaplast mask over head. For spinal
tumor or CSI, use full body Vac-Lok. Sedation with general anesthesia
may be required for children. Scan from the vertex of the skull through
coccyx.
Dose: 54-59.4 Gy in 30-33 fractions at 1.8 Gy/fx
Target: CTV margin = preop GTV + 1 cm. Consider 3-5-mm CTV to
PTV margin depending on IGRT and setup.
Technique: Proton beam therapy or intensity-modulated radiation
therapy for primary intracranial tumor. Treatment planning for CSI will
require feathering of junctions to avoid potential hot spots at field
borders (Fig. 17.1).
Figure 17.1 Representative proton beam plan for a posterior

fossa ependymoma in a 3-year-old child. 54-Gy isodose line is
represented by the white line.
Supratentorial tumor
Dose: 54-59.4 Gy in 30-33 fractions at 1.8 Gy/fx for anaplastic
tumors, if WHO grade I or II can be observed if completely resected.
Target: Same as above
Technique: Same as above
Spinal tumor
Dose: 45 Gy in 25 fractions at 1.8 Gy/fx, including two vertebral
bodies/sacral nerve roots above and below tumor. Cone down to
50.4-54 Gy if safely below cord.
Target: Same as above. May consider <3-mm PTV margins
Technique: Same as above
PTV as per institutional standards and image guidance (we do 0.3-0.5 cm)

Planning directive:
Spinal cord D max < 50 Gy
Brainstem D max < 57 Gy, V54 Gy < 10%
Chiasm D max < 54 Gy
Lt and Rt cochlea mean < 38 Gy, D max < 45 Gy
Lt and Rt eye D max < 40 Gy
Lt and Rt lens D max < 5 Gy
Lt and Rt parotid mean < 10 GyLt and Rt lacrimal gland mean < 26
Gy
S E M
Nausea/vomiting: First line Zofran → second line Compazine
Decline in IQ: More prominent in patients treated with CSI and in
children <10 years old treated with localized fields, referral to
neuropsychology and counsel parents
Growth deficiency: Rule out growth hormone deficiency. Can occur
with CSI secondary to irradiation of vertebral bodies and supporting
musculature. Counsel parents.
F -
Follow-up period is long, ~10 years as ependymomas can recur very
late following completion of treatment.
History/physical with MRI: q3-4mo for year 1 → q4-6mo for year 2 →
then q6-12mo thereafter
If CSI, check growth hormone and TSH labs at least once per year.
Consistent follow-up with neuropsychologist, especially with CSI
N T
Adjuvant radiation
St. Jude (Merchant et al. JCO 2004; Merchant et al. Lancet Oncol
2009): Prospective phase II trial evaluating whether the postoperative
irradiated volume in patients with localized childhood ependymoma
could be reduced to decrease late cognitive side effects without
compromising disease control. All patients had maximal safe surgical
resection followed by adjuvant RT. Patients ≥18 months (n = 73)
received 59.4 Gy and patients <18 months (n = 15) received 54 Gy
both to a margin of 1 cm. If patients had an STR, they were given
chemo and then reevaluated for a second surgery and adjuvant RT.
On preliminary analysis, 3-year PFS was 74% and IQ testing was
stable after 2 years. Long-term analysis demonstrated that 7-year OS
was 81%, 7-year LC was 87.3%, and 7-year EFS was 69.1%.
Barrow Neurological Institute (Rogers et al. J Neurosurg 2005):
Retrospective study evaluating if adjuvant RT is necessary for
patients with posterior fossa ependymoma after GTR. 71% of patients
had GTR. RT in 13/32 GTR and 12/13 STR. 10-Year LC: 50% for
GTR alone, 100% for GTR + RT, and 36% for STR + RT. 10-Year OS:
67% for GTR alone, 83% for GTR + RT, and 43% for STR + RT
ACNS0121 (ABSTRACT, Merchant et al. 2015): Prospective phase II
trial observing WHO grade II with supratentorial ependymoma after
microscopic GTR (stratum 1), chemotherapy with optional second
surgery prior to RT for patients with STR at the time of protocol
enrolment (stratum 2), immediate postoperative RT for patients after
near-total resection (NTR) or GTR resection (stratum 3), and WHO
grade III supratentorial or any grade infratentorial after GTR (stratum
4). 378 patients and 115 institutions participated. Median age was 5.3
years. There were 216 WHO grade II and 140 WHO grade III tumors.
Stratum 1: 5-Year event-free survival (EFS) was 61.4%. Stratum 2:
second surgery was performed in 25 of 64 patients; GTR was
achieved in 14. There was no difference in EFS comparing the 25
patients that underwent the second surgery to 39 patients that did not
(logrank test: P = .0790). Stratum 2: EFS was 39.2%. Stratum 3: EFS
was 67.3%. Stratum 4: EFS was 69.5%. Among the 281 patients
treated on stratum 3 and 4, EFS was 74.6% for WHO grade II and
60.7% for WHO grade III tumors according to central pathology
review (P = .0047).
INTRACRANIAL GERM CELL TUMOR
ETHAN BERNARD LUDMIR • ARNOLD C. PAULINO
B
Incidence/prevalence: Intracranial germ cell tumor (GCT) accounts
for 1%-2% of pediatric CNS tumors, higher in Asian/Pacific Islander
populations, including those of Asian/Pacific Islander descent living in
Western countries.
Outcomes: Modern trials report 5-year PFS for pure germinoma
>90%, for both localized and disseminated disease.
Nongerminomatous GCT (NGGCT) 5-year PFS is poorer, ~70%-80%
for localized NGGCT and ~50%-70% for disseminated NGGCT.
Demographics: Median age of diagnosis 10-12 years old, male >
female (2-3:1), as above Asians and those of Asian descent have 2-
3× higher incidence of GCT.
Risk factors: No major risk factors known
T B C
Genetics: Aberrations in KIT/RAS and/or AKT/mTOR pathways in
majority of intracranial GCTs
Pathology: Histologic division of GCT into germinoma vs NGGCT.
Germinomas are more RT sensitive and have better prognosis than
NGGCT. Approximately 65% of intracranial GCTs are germinoma
(“pure” germinoma). NGGCT includes embryonal carcinoma, yolk sac
tumor (aka endodermal sinus tumor/endodermal sinus tumor),
choriocarcinoma, teratoma, or mixed GCT. Mixed GCT may include
germinoma components, but any NGGCT component makes tumor
“mixed” and therefore treated as NGGCT (25% of NGGCT are mixed
GCT). Helpful markers for GCT: B-hCG, alpha-fetoprotein (AFP), and
placental alkaline phosphatase (PLAP). B-hCG and AFP can be
examined on IHC, as well as in serum and CSF.
aElevated AFP in serum (>10 ng/mL), in CSF, or on IHC rules out pure germinoma.
Intracranial GCT also classified as secreting vs nonsecreting depending on CSF
AFP and B-hCG levels, w/ poorer prognosis for secreting tumors.
Origin: Extragonadal GCT occurs intracranially, as well as in the

sacrococcygeal region and the retroperitoneum, among other sites.
Extragonadal GCT may arise from primordial germ cells that exhibit
aberrant or incomplete migration during embryonal development.
Location: Primary locations of intracranial GCT are the pineal gland
and suprasellar region, pineal gland more common than suprasellar
(2:1). Rare to occur at other intracranial sites. Approximately 5%-10%
of cases have both pineal and suprasellar tumors, which are known
as “bifocal” GCT.
Imaging: GCT is usually iso-/hypointense on T1, and hyperintense on
T2 (similar to MB), and like medulloblastoma shows postcontrast
enhancement. No radiographic factors reliably differentiate
germinomas from NGGCTs.
W
History and physical: Recommend baseline evaluations by
endocrinology, ophthalmology, audiology, and neuropsychology.
Consideration should be made for baseline neurocognitive studies (for
GCTs as well as other intracranial pediatric tumors). Clinical
presentation varies by primary tumor site:
Pineal tumors: increased ICP (headaches, N/V, papilledema,
lethargy/somnolence, due to obstructive hydrocephalus); ~40%
of pineal GCTs present with increased ICP. Parinaud syndrome
presents in 40%-50% of cases. This syndrome consists of
upward gaze paralysis and sluggish pupillary reflex, as well as
convergence nystagmus. This syndrome is thought to be due to
compression of superior colliculus.
Suprasellar tumors: neuroendocrinopathies/hypothalamus axis
disruption, especially diabetes insipidus, precocious/delayed
puberty, and bitemporal hemianopia (chiasm compression).
Complete a neurologic exam including cranial nerve exam +
funduscopy to evaluate papilledema.
Historical note: Decades prior, germinoma was empirically
diagnosed w/ initiation of RT. If response after ~20 Gy considered
empirical diagnosis (w/out histologic/pathologic confirmation) of
germinoma and RT continued. Not recommended in the modern
era
Differential diagnosis: Pineal tumor differential diagnosis
includes GCT (germinoma/NGGCT), glioma, pineoblastoma,
pineocytoma, PNET, ependymoma, lymphoma, and hamartoma.
Suprasellar tumor differential diagnosis includes
craniopharyngioma, Langerhans cell histiocytosis, glioma, GCT
(germinoma/NGGCT), pituitary adenoma, meningioma, and
aneurysm.
Procedures/biopsy: LP and CSF analysis, including CSF AFP and
B-hCG levels, as well as CSF cytology. CSF AFP and B-hCG are
more sensitive than serum markers. Prefer LP for markers + cytology
rather than ventricular CSF (ie, if shunt already placed for
hydrocephalus). LP for CSF analyses 10-14 days after procedure
(shunt placement, surgery). Biopsy mandatory for patients w/ normal
serum and CSF markers (AFP and B-hCG). Biopsy is only needed for
germinoma (no role for extent of resection), whereas data suggest
possible role for maximal safe resection in NGGCT.
Labs: CBC, CMP (including BUN/Cr and LFTs), serum AFP, serum B-
hCG
Imaging: MRI brain + entire spine w/ gadolinium contrast. MR spine
critical as ~10% of patients will have spinal/leptomeningeal seeding at
diagnosis.
S
M staging per modified Chang system as below used for intracranial GCTs
as well as medulloblastoma (see Medulloblastoma).
T A
Germinoma: RT alone or neoadjuvant chemotherapy → RT.
Chemotherapy-only approaches for germinomas have yielded inferior
outcomes, with >50% rates of relapse, even after CR from
chemotherapy (Balmaceda et al. JCO 1996).
NGGCT: Several approaches, but in general, maximal safe resection
→ chemotherapy (6 cycles) → possible second-look surgery (if
restaging after chemotherapy demonstrates sufficient residual tumor
to warrant second-look surgery before CSI) → consolidative RT
(including CSI)
R T T
SIM: Supine (on foam board if CSI), thermoplastic mask. Sedation
(anesthesia) may be required for younger patients.
Dose:
Generally, treat at 1.5 Gy/fx for germinoma, and 1.8 Gy/fx for
NGGCT, unless otherwise specified.
Localized germinoma: If RT alone, whole ventricle RT (WVRT) to
24 Gy → boost gross disease to 40-45 Gy.
Localized germinoma: If RT after chemotherapy, then treat per
COG ACNS1123 RT dose depending on tumor response on
repeat imaging after chemotherapy.
ACNS1123: If PR/SD after chemotherapy: 24 Gy WVRT →
12 Gy boost to primary site
ACNS1123: If CR after chemotherapy: 18 Gy WVRT → 12
Gy boost to primary site
Off protocol RT after induction chemotherapy: 21 Gy WVRT
(rather than 18 Gy) → 15 Gy boost to primary site
Bifocal germinoma: Treat as above for localized germinoma, but
boost both primaries (suprasellar and pineal). Cannot have other
tumors beyond these two sites to be classified as bifocal
Disseminated (M+) germinoma: CSI to 24-30 Gy → boost to
primary to total dose ~40-45 Gy
NGGCT: Off protocol, current standard of care is CSI to 36 Gy
and boost primary to 54 Gy. ACNS1123 is attempting to reduce
field size from CSI to WVRT, pending results.
Target:
Whole ventricular RT (WVRT): Outlined in ACNS1123 atlas
online.
WVRT includes targets: Lateral, 3rd, and 4th ventricles, as
well as suprasellar and pineal cisterns. Cover prepontine
cistern if history of 3rd ventriculostomy (ie, done previously
for obstructive hydrocephalus from tumor) or large
suprasellar tumor. WVRT target well defined using T2 MRI
fusion (or MRI simulation, if available)
Contour WV-CTV = ventricles/ventricular space, and then
expand 5 mm (depending on IGRT) to generate WV-PTV.
Tumor bed boost:
Collapsed tumor bed and gross residual disease if present
1-cm expansion from tumor bed for tumor CTV, then expand
5 mm for PTV (dependent on IGRT)
CSI:
Ensure coverage of cribriform plates, middle cranial fossae,
and thecal sac.
Technique: Similar to medulloblastoma, especially with regard to
CSI. IMRT and proton beam therapy reasonable options. See
Medulloblastoma chapter for CSI—considerations if CSI indicated.
IGRT: Daily kV
Planning directive: See Medulloblastoma chapter (Fig. 18.1).
Figure 18.1 Axial imaging showing dose distribution with whole

brain radiation (A) as part of CSI. WVRT (B) and focused
radiation of a primary target, as would be conducted in a
sequential boost (C) (Rogers Lancet Oncol 2005).
C
Carboplatin/etoposide ×4 cycles typical for induction chemotherapy
for germinoma (ACNS1123). Platinum-based chemotherapy ×6 cycles
for NGGCT. Other regimens may include bleomycin and cisplatin for
intracranial GCTs.
N T /P
Radiation for localized intracranial germinomas
Patterns of failure review (Rogers Lancet Oncol 2005). Review of

publications assessing radiation for localized intracranial germinomas
from 1989 to 2004. Analysis demonstrated higher rates of failures
(both local and spinal failures) if focal/involved field RT used for
localized germinoma rather than WVRT or WBRT.
SFOP Involved Field RT experience (Alapetite Neuro Oncol 2010).
Review of SFOP experience treating localized germinoma w/ involved
field RT. Among 10 patients with relapse after local therapy,
predominate failure patterns were periventricular (8 of 10). This
retrospective review supports the use of WVRT for germinoma pts.
SIOP CNS GCT96 (Calaminus Neuro Oncol 2013). Prospective study
with 190 pts w/ localized germinoma receiving CSI w/ tumor bed
boost vs carbo/etop ×2 cycles alternating w/ ifos/etop followed by
local RT. Study was nonrandomized. Chemotherapy and RT arm
failures were all within the ventricular system, supporting WVRT at
least; failures even w/ CR after chemotherapy. No difference in 5-year
OS but improved FPS with CSI (97% vs 88%, P = .04). Suggests
need at least WVRT even w/ CR
Treatment strategy of NGGCT
COG Phase II Trial (Goldman J Clin Oncol 2015). Nonrandomized

phase II trial of 102 pts with NGGCT treated with 6 cycles of induction
chemotherapy +/− second look surgery followed by CSI with
tumor/tumor bed boost. The 5-year EFS was 84% and OS was 93%.
Currently this strategy is the backbone for treatment of these tumors
in North America.
WILMS TUMOR
B
Incidence/prevalence: Approximately 600 cases per year in the
United States, about 7% of childhood malignancies (SEER)
Outcomes: Markedly improved survival with the addition of radiation
therapy (RT) and chemotherapy (CHT) over the last century; all-
comers Wilms tumor (WT) overall survival (OS) ~10% in the 1920s to
>90% by 2000. 4-Year OS for favorable histology (~90% of total) pts
≥90% for Stages I-III, and 85%-90% for Stages IV-V. Worse outcomes
if unfavorable histology (UH) (Stage IV UH 4-year OS ~40%).
Demographics: Median age at diagnosis is 44 months for unilateral
cases and 31 months for bilateral cases. Sex predilection higher in
girls (F:M = 1.1:1 for unilateral WT)
Risk factors: Approximately 10% WT cases have a congenital
syndrome, including WAGR (WT, Aniridia, GU malformations,
Retardation [mental]; deletion 11p13), Beckwith-Wiedemann
syndrome (hemihypertrophy, visceromegaly, macroglossia,
macrosomia, anterior abdominal wall defects; duplication 11p15), and
Denys-Drash syndrome (nephrotic syndrome, XY
pseudohermaphroditism; mutation 11p13).
T B C
Pathology/genetics: Intrinsic renal tumor derived from nephrogenic
blastemal cells, also known as nephroblastoma. 90% of WT are
favorable histology (FH), classically “triphasic” including epithelial,
blastemal, and stromal components. 10% of WT are unfavorable
histology (UH), including tumors w/ focal anaplasia (FA) or diffuse
anaplasia. UH tumors have higher rates of nodal and distant
metastasis. LOH 1p16q is poor prognostic indicator (Grundy et al.
JCO 2005). Other pediatric renal tumors (not WT family members)
include clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor
of the kidney (RTK). RTK histologically not discernable from AT/RT of
the brain (both show loss of nuclear INI1 staining).
Imaging: Radiographic differentiation of WT vs NB: WT arises within
the kidney (claw sign); rare calcifications in WT (~10%); WT rarely
crosses midline (WT occasionally “overhang” onto contralateral side)
W
History and physical: Pts typically present with painless abdominal
mass, without constitutional symptoms. Approximately 33% of WT pts
have abdominal pain, weight loss, or N/V. 25% have secondary HTN
(elevated renin). 30% present with hematuria and 10% coagulopathy.
Evaluate family history and assess for congenital syndromes,
including GU malformations, macroglossia, hemihypertrophy, aniridia,
and mental retardation.
Labs: CBC, CMP, UA, and urine catecholamines (HMA/VMA)
Procedures/biopsy: No biopsy unless unresectable or Stage V
(bilateral). North American approach is staging after surgical
resection, w/ surgical resection as first step in treatment paradigm for
most patients.
Imaging: Abdominal US w/ Doppler (assess vessel patency), usually
followed by CT chest/abdomen/pelvis, w/ contrast, as well as CXR.
Additional workup for uncommon histologies: CCSK = bone scan,
BMBx, and MRI brain (assess for brain mets); RTK = MRI brain
(assess for synchronous AT/RT)
S
Surgery: In North America, up-front radical nephrectomy and LN
sampling via transabdominal or thoracoabdominal incision, with en
bloc removal of the kidney. Inspect contralateral kidney and assess
for preoperative and intraoperative spill. Discussion between the
surgeon and radiation oncologist is crucial for site(s) of intraop spill in
particular.
T A
For FH patients
a Flank RT for all “local” Stage III FH pts; whole abdomen irradiation (WAI) indicated
if preoperative spill or diffuse intraoperative spill. Discuss with surgical team if
intraoperative spill occurred to better delineate extent/location of spill, which will
inform adjuvant treatment with flank RT vs WAI.
b Whole lung irradiation (WLI) for WT pts w/ lung mets if no radiographic complete
response on CT after 6 weeks of VAAdr (regimen DD4A; Dix et al. JCO 2018).
Generally recommend flank/abdominal RT w/in 14 days postop after nephrectomy.
However, for sequencing, can delay flank/abdominal RT for Stage IV WT pts w/ lung
mets until after 6 weeks of CHT; importance of early RT for WT pts appears to
matter in the nonmetastatic setting (Stokes et al. IJROBP 2018). This allows flank
RT/WAI to be delivered concurrently w/ WLI if needed for Stage IV pts.
For unfavorable histology and RTK patients: At least flank RT regardless

of stage (I-IV)
For CCSK: At least flank RT for Stages II-IV. No RT for Stage I if adequate
nodal sampling
R T T
SIM: Supine, Vac-Lok, most will require sedation (anesthesia)
Dose (for FH):
Flank (hemi-abdomen) RT to 10.8 Gy in 6 fx (1.8 Gy/fx).
If PA nodes involved, include PA chain in flank field from
T11-L4.
If gross residual disease >3 cm, boost additional 10.8 Gy (in
6 fx).
WAI to 10.5 Gy in 7 fx (1.5 Gy/fx).
WLI to 12 Gy in 8 fx (1.5 Gy/fx); if pt <12 mo drop 1 fx (10.5 Gy in
7 fx).
Additional dosing specifications:
Undissected (gross) LNs—19.8 Gy/11 fx
Flank RT for Stage III diffuse anaplasia or RTK I-III—19.8
Gy/11 fx
Boost gross residual lung dz 2 weeks after WLI—7.5 Gy/5 fx
Bone mets: 25.2 Gy/14 fx (30.6 Gy/17 fx if age >16 years
old)
Liver mets: Sx if local, whole liver if diffuse mets (19.8-21.6
Gy)
Brain mets: 21.6 Gy/12 fx WBRT or 30.6 Gy/17 fx if >16
years old
Target/technique (Flank RT, Fig. 19.1 below):
CTV: Preop tumor + kidney + 1 cm + entire vertebral body if block
edge touches VB w/ AP/PA techniqueTechnique: Generally AP/PA:
Sup/Inf = 1 cm expansion off disease/kidney. Med = 1 cm lateral to
whole VB (include whole VB in field, generally). Lat = body wall (no
flash)
Target/technique (WAI, Fig. 19.2 below):
CTV: As above
Technique: Generally AP/PA: Sup = 1 cm above diaphragm. Inf =
bottom of obturator foramen (therefore, more accurately this is whole
“abdominopelvic” RT, not just the abdomen). Lat = body wall (no flash)
Target/technique (WLI, Fig. 19.3):
CTV: Includes bilateral lungs, mediastinum, and pleural
recessesTechnique: AP/PA or IMRT (cardiac-sparing IMRT warrants
4D-CT simulation; see Kalapurakal et al. IJROBP 2012). If AP/PA:
Sup = 1 cm above clavicle/lung apex (flash SCV fossa). Inf = below
diaphragm. Lat = chest wall
Planning directive:
Contralateral kidney: V14.4 < 33%
Liver: V19.8 < 50%
Figure 19.1
Figure 19.2
Figure 19.3
C
Generally, vincristine/actinomycin D/Adriamycin (VAA; regimen
DD4A); with addition of cyclophosphamide/etoposide (with VAA;
regimen M) for higher-risk Stage III/IV
S E M
Acute: Skin reaction, nausea/vomiting, indigestion, diarrhea, esophagitis,
pneumonitis
Late (varies by treatment field, age, among others): Height loss,
kyphosis/lordosis/scoliosis, chronic renal insufficiency (rare <1%, unless
bilateral Wilms tumor), muscular hypoplasia, pneumonitis (4% with whole
lung irradiation), pulmonary fibrosis, infertility, malabsorption, SBO, VOD,
increased risk of cardiac morbidity, second malignancy (1%-2% at 15
years)
F -
Follow-up with imaging recommended q3mo for 2 years, then q6mo
for 2 further years. Imaging recommend alternating between CXR +
abdominal US and CT C/A/P. Most relapses occur w/in first 2 years;
some question regarding role of further imaging beyond 2 years (Brok
et al. Lancet Oncol 2018).
Long-term monitoring for late effects, which may include
echocardiography, height/growth abnormalities/bone density,
hypogonadism, chronic renal insufficiency, pulmonary function testing,
screening for second malignancies (breast, colon).
N T
NWTS 3 (D’Angio Cancer 1989). Randomized trial including 1439
patients, treatment adaptive by stage and histology. Stage II FH pts had
no difference in outcomes with no RT vs 20 Gy RT. Stage III FH pts
randomized 10 vs 20 Gy flank RT, with no difference in outcomes.
Established use of 10 Gy for flank RT
COG AREN0533 (Dix JCO 2018). Prospective trial in which 292 Stage IV
FH patients w/ CT-identified isolated lung metastases were treated w/ 6
weeks of DD4A and assessed w/ repeat CT. Those without LOH 1p/16q
with complete response on repeat CT (total 133 patients) continued DD4A
without WLI and had 4-year EFS of 79.5% and OS of 96.1%. Patients with
incomplete response or LOH 1p/16q received lWLI and four cycles of
cyclophosphamide in addition to DD4A. These patients had a 4-year EFS
of 88.5% and OS of 95.4%. Overall, there was an excellent OS observed
after omission of lung RT in select stage IV patients, although there were
more events than was expected. Additional cycles of chemo + lung RT
improved survival in high-risk stage IV patients when compared to
historical control arm (data from the prior NWTS-5 study).
NEUROBLASTOMA
AHSAN FAROOQI • ETHAN BERNARD LUDMIR • ARNOLD C.
PAULINO
B
Incidence/prevalence: Accounts for ~8% of all childhood cancers in
the United States. Approximately 650 new cases per year diagnosed
in the United States, overall 10 cases per million children (SEER data)
Outcomes: 5-Year OS for low- and intermediate-risk patients is
>90%. For high-risk neuroblastoma, the 5-year OS is between 40%
and 50%. Neuroblastoma is a rare cancer that has the potential to
spontaneously regress without any treatment.
Demographics: Most common extracranial tumor of childhood.
Median age at diagnosis is ~17 months. Most common malignancy of
infants (~50%). No sex predilection, M:F is 1.2:1
Risk factors: Majority of cases (>98%) sporadic due to chance
mutations. However, in 1%-2% of cases, neuroblastoma develops due
to a hereditary mutation in either the ALK or PHOX2B genes (Mosse
et al. Nature 2008).
T B C
Genetics: MYCN is a DNA binding transcription factor, which can
cause malignant transformation due to downstream effects. It is found
to be amplified in 25% of all neuroblastoma and is associated with
rapid progression and poor prognosis (Seeger et al. NEJM 1985;
Chan et al. Clin Can Res 1997). ATRX mutations were recently
identified in adolescents and young adults with neuroblastoma and
are associated with an indolent disease course (Cheung et al. JAMA
2012).
Pathology: Arise from primitive neural crest sympathetic ganglion
cells. Small, round, blue cell tumor of childhood (like Ewing’s,
medulloblastoma, rhabdomyosarcoma, and PNET). Shimada
pathologic classification dependent on degree of differentiation,
mitosis-karyorrhexis index, stromal component, and nodularity
(Shimada et al. Cancer 1999). Classically stains positive for
synaptophysin, chromogranin A, and neurofilaments
Imaging: X-rays may demonstrate calcifications in ~80% of
neuroblastomas (in comparison with Wilms tumors, which classically
do not have calcifications). CT of the abdomen with contrast is
typically performed, which can help identify extent of tumor and
presence or absence of regional or distant metastatic disease.
Importantly, nuclear medicine meta-iodobenzylguanidine (MIBG)
radionuclide scans can be used to identify distant sites of disease and
response to systemic therapy (Fig. 20.1).
Figure 20.1 Representative coronal, sagittal, and axial (left to
right) MIBG scans in a patient presenting with a right adrenal
neuroblastoma. The avidity can be seen in his right suprarenal
area, consistent with the primary malignancy. There were no
additional MIBG-avid sites, suggesting absence of distant
metastases.
A
May arise from any site in the sympathetic nervous system. Most
common sites are adrenal gland in the abdomen, paraspinal ganglia
along the abdomen, thorax, and head and neck.
W
History and physical: Patients typically present with an abdominal
mass with additional symptoms such as malaise, irritability, and pain.
Evaluate for Horner syndrome (meiosis, ptosis, anhidrosis) due to
involvement of the sympathetic chain on the ipsilateral affected side.
Evaluate for back pain due to possible bony involvement. Important to
do careful skin examination as metastatic disease can present with a
bluish tinge (“blueberry muffin” sign) and may be indicative of stage
4S disease. Opsoclonus-myoclonus syndrome—presenting as truncal
ataxia and/or cerebellar encephalopathy—may be seen.
Labs: CBC, CMP. Include measurement of urinary catecholamines
HVA and VMA, which are found to be elevated in >90% of patients
with stage IV disease
Procedures/biopsy: Can obtain tissue from primary site or from
gross lymph nodes. Bone marrow aspirate and biopsy are
required for appropriate staging of neuroblastoma.
Imaging: Abdominal x-rays may show calcification in up to 80%-85%
of neuroblastomas. Obtain CT of the abdomen with contrast and
MIBG nuclear medicine scan at diagnosis to determine extent of
metastatic disease. Consider MRI of the abdomen w/ and w/o
contrast if equivocal findings on CT scan.
S /G
International Neuroblastoma Staging System (INSS) (Brodeur et al.
JCO 1998)
Stage 1: Tumor removed completely during surgery, without microscopic
residual disease. Ipsilateral lymph nodes excised during surgery negative
for tumor (but nodes attached to primary tumor may be positive)
Stage 2A: Localized tumor with incomplete gross excision. Ipsilateral
lymph nodes do not contain cancer.
Stage 2B: Localized tumor with or without gross excision. Ipsilateral lymph
nodes do contain cancer.
Stage 3: Unresectable unilateral tumor extending past midline, which has
or has not spread to regional lymph nodes or other areas near the tumor
but not to other parts of the body
Stage 4: The original tumor has disseminated to distant lymph nodes,
bones, bone marrow, liver, skin, and/or other organs, except for those
listed in stage 4S, below.
Stage 4S: The original tumor is located only where it started (as in Stages
1, 2A, or 2B), and it has spread only to the skin, liver, and/or bone
marrow, in infants younger than 1 year. The spread to the bone marrow is
minimal; usually <10% of cells examined show cancer.
T A
R T T
SIM: Supine, Vac-Lok, nearly all will require anesthesia.
Dose: 21.6 Gy in 12 fractions
Target:
GTV: Define tumor bed using postinduction and chemotherapy
preoperative CT or MRI. Treat postinduction residual MIBG sites as
well (Mazloom et al. IJROBP 2014).CTV: Tumor bed + 1-1.5-cm
margin, limiting to anatomic barriers of spread (bone, etc.).PTV: 0.5-1
cm depending on institutional standards and image
guidanceConsiderations: Different than other pediatric tumors, the
GTV is not based upon the initial tumor volume. Consider shorter RT
course. Consider 4.5 Gy/3 fx regimen for palliation of liver
metastases.
Technique: IMRT typically used, especially if tumor extended past
midline. Consider AP/PA techniques if well-lateralized tumor (may
spare dose to contralateral kidney). Proton therapy can be considered
if dosimetric advantage.
IGRT: daily kV imaging
Planning directive:
Kidneys—D mean < 14.4 Gy
C
Commonly used induction and myeloablative chemotherapy regimens
include cyclophosphamide or ifosfamide, cisplatin/carboplatin, vincristine,
doxorubicin, etoposide, topotecan, and busulfan or melphalan (for stem
cell transplant).
S E M
Acute: Skin reactions, mucositis, diarrhea, and fatigue are commonly
seen. Prescribe Aquaphor for mild skin reactions; consider Silvadene if
worse.
Late: Spinal deformities are commonly seen due to RT to the bony
structures. Children may be shorter than their peers. Chronic renal
insufficiency rarely seen in survivors. Risk of secondary malignancies
about 1%-2% per decade of life
F -
Typically will resume care with medical oncologist following completion of
RT for maintenance therapy (for Stage IV patients). Follow-up with
abdominal and whole body imaging is recommended q3mo for 1 year,
q6mo for 2-4 years, and then every year.
N T
COG 3891 (Matthay et al. NEJM 1999). Randomized 539 high-risk Stage
IV or III with MYCN amplification patients to myeloablative therapy and
autologous bone marrow transplant (ABMT) with TBI vs intensive
nonmyeloablative chemotherapy. Patients underwent a second
randomization to either receive 6 cycles of adjuvant therapy with 13-
cisretinoic acid or no further therapy. 3-Year EFS are 34% (ABMT) vs 22%
(no ABMT) (P = .034) and 46% (retinoic acid) vs 29% (no retinoic acid) (P
= .027).
COG ANBL0032 (Yu et al. NEJM 2011). 226 high-risk neuroblastoma
patients who had a response to induction therapy and stem cell
transplantation were assigned to (1) standard maintenance therapy
consisting of 6 cycles of isotretinoin or (2) immunotherapy (Ch14.18 with
GM-CSF and IL-2) + 6 cycles of isotretinoin. EFS superior with
immunotherapy (66% vs 46% at 2 years, P = .01). OS superior with
immunotherapy (86% vs 75% at 2 years, P = .02).
EWING SARCOMA
B
History: Described in 1921 by James Ewing as a bone tumor
sensitive to radiation. Ewing family of tumors (EFT) includes Ewing
sarcoma (EWS) (both osseous and extraosseous), as well as
malignant small cell tumor of the chest well (Askin tumor), and
primitive neuroectodermal tumor (PNET). Osseous EWS accounts for
~85% of EFT; 8% of EFT are extraosseous EWS.
Incidence/prevalence: Approximately 200 cases per year dx in the
United States of EFT including EWS ~3% of adolescent malignancies.
Second most common pediatric malignant bone tumor after
osteosarcoma
Outcomes: 5-Year OS for localized EWS ~70% (~60% for pelvic
primaries, 80% for extremity primaries). 5-Year OS for metastatic
EWS ~30% (~40% for lung mets only).
Demographics: Median age at diagnosis is 14 years. 20%-30% of
EFT occur in ptts <10 years old, and another 20%-30% occur in pts
>20 years old. Higher incidence in M (M:F = 1.5:1 for EFT) and in
Caucasians (very uncommon among African Americans)
Risk factors: No known/established congenital syndrome associated
w/ EFT. Rare reports of EWS as a second malignancy after treatment
with chemotherapy
Prognostic factors: Better prognosis w/ extremity tumors vs axial
tumors. Larger size has worse prognosis (both those treated
definitively with surgery and RT). Also prognostic: extent of viable
tumor after neoadjuvant chemotherapy (≥5% residual viable tumor is
a poor prognostic marker) and older age. Better prognosis for fusion
of exon 7 of EWS to exon 6 of FLI
T B C
Pathology/genetics: Proposed neuroectodermal origin of EFT,
though other hypotheses exist. Histologically, EFT are small round
blue cell tumors, differentiated by expression of vimentin, c-myc, and
CD99 (CD99 being sensitive for EWS, but not specific as it is also
expressed in rhabdomyosarcoma). Most cases involve breakpoints
clustered within EWSR1 gene on chromosome 22. 80%-90% of EFT
have t(11;22), generating an EWS-FLI fusion protein, which has been
shown to function as a transcription regulator. An additional 5%-10%
of EFT have other translocations involving EWSR1, including t(21;22)
and t(7;22) and less commonly t(17;22) and t(2;22).
A
For osseous EWS, pooled data from European Intergroup Cooperative
Ewing Sarcoma Studies (EI-CESS) trials demonstrated that 54% of tumors
had primary axial skeletal sites and 42% had primary appendicular
skeletal sites (Cotterill et al. JCO 2000). Pelvic primary tumors = 25% of
osseous EWS, and femoral primary tumors = 16% of osseous EWS.
Primary location is typically diaphyseal.
W
History and physical: Patients typically present with pain and
swelling at the primary tumor site; often, minor trauma can precipitate
pain/swelling at the site, which worsens over weeks. Pain associated
with primary tumor is often worse at night and w/ exercise. Pts can
present with pathologic fracture as well. Constitutional symptoms,
including fevers and weight loss, occur in ~10%-20% of EWS pts at
presentation and can portend metastatic dz + poorer prognosis.
Imaging: Plain x-ray of primary site (“onion skin” appearance in EWS
vs “sunburst” in osteosarcoma). Contrasted MR or CT of primary site
(MRI preferred due to soft tissue delineation and involvement of
neurovascular structures, surgical planning/ considerations).
Metastatic workup outlined per guidelines (Meyer Pediatr Blood
Cancer 2008) generally includes PET/CT and radionuclide bone
scintigraphy (bone scan). Also, note that repeat imaging prior to local
therapy is recommended (usually MRI of primary site) to guide
surgical planning and/or RT volumes.
Labs: CBC, CMP (including BUN/Cr and LFTs), LDH, ESR.
Procedures/biopsy: Core needle biopsy (often CT-guided) or
incisional biopsy. Ensure surgeon is involved before biopsy, especially
for cases where limb salvage is being considered (extremity EWS
cases). At least unilateral bone marrow biopsy is recommended due
to a significant risk of bone marrow metastases from EFT as well.
S
No commonly used staging systems are present for EFT; rather the
primary categorization of EWS (osseous and extraosseous) is
localized or metastatic.
Notably, 25% of EWS pts p/w metastatic disease, most commonly in
the lungs (50%), bones (30%), and bone marrow (25%). Rare spread
(<10%) to LNs, brain, and liver. If mets to other bones, vertebral
column most often involved. Patterns of relapse mirror de novo sites
of metastatic disease, w/ lung as most common site of relapse.
T A
Conceptually, even localized EWS pts should be regarded as having
occult systemic disease.
General treatment algorithm: VDC/IE × 12 weeks → local therapy

→ VDC/IE through week 48 (~14-17 total cycles of VDC/IE)
Local therapy: Surgery (+adj RT if needed) vs definitive RT
Surgery: Favored if possible, to decrease risk of second malignancy
and often less morbidity of resection in developing child than RT.
Often, surgery is favored if limb reconstruction/sparing approach is
possible. Resectable/dispensable bones (generally amenable to
surgery): fibula (proximal), ribs, portions of hands/feet (esp small
tumors), and distal clavicle, among others. In an effort to avoid
exposing pts to both surgery and adjuvant RT, definitive surgery
should generally be pursued if complete resection is feasible.
Radiation: Concurrent non–doxorubicin-containing chemotherapy is
often delivered with RT during local therapy. Common indications for
adjuvant RT include +margin/incomplete resection (R1 or R2), >10%
viable tumor after induction chemotherapy (12 weeks of VDC/IE), or
tumor spill. Per COG AEWS0031, adequate surgical margins are >1
cm for bone and >5 mm for soft tissue. Also, for bulky tumors in
challenging sites, preop or postop RT can be utilized in conjunction
with surgery. Similarly, adjuvant hemithoracic RT can be indicated in
high-risk chest wall primary tumors (especially those w/ pleural
infiltration or intraop contamination of pleural space). Whole lung
irradiation (WLI) is generally recommended for pulmonary
metastases, especially for those with good response to initial
chemotherapy.
R T T
SIM: Dependent on primary tumor site; some pediatric patients may
require sedation (anesthesia)
Dose (primary EWS site):
Definitive RT: 55.8 Gy (lower if paraspinal EWS w/ respect to
cord tolerance)
Adjuvant RT: 55.8 Gy for gross residual, 50.4 Gy for microscopic
residual
Doses in 1.8 Gy fractions (55.8 Gy in 31 fractions, for instance)
Target (primary EWS site):
Definitive:
GTV1 = Pre-CHT bone and pre-CHT soft tissue involved
GTV2 = Pre-CHT bone and post-CHT soft tissue involved
GTV1 + 1.5 cm = CTV1
GTV2 + 1.5 cm = CTV2
CTV1 + 5 mm (generally) = PTV1 → treat to 45 Gy in 25
fractions
CTV2 + 5 mm (generally) = PTV2 → treat to additional 10.8
Gy in 6 fractions (total to 55.8 Gy/31 fx).
Adjuvant:
As per definitive, but GTV2 = postop residual/site of positive
margins
CTV2 = GTV2 + 1.5 cm
CTV2 + 5 mm (generally) = PTV2 → treat to additional 5.4
Gy if microscopic residual or additional 10.8 Gy if
macroscopic residual
Paraspinal EWS considerations:
Challenge with respect to cord tolerance. Often dose limited
to 45 Gy or 50.4 Gy for those tumors w/ proximity to cord
Technique (primary EWS site):
Proton beam therapy and intensity-modulated radiation therapy
(IMRT) are reasonable options. For certain pelvic tumors,
consideration can be given to bladder filling, if full bladder displaces
bowel from the treatment field. Daily bladder scanning may be helpful
if this is the case. For hands/feet, use bolus/compensators. Consider
bolus to scar/drain sites if adjuvant RT.
WLI/Hemithorax RT:
Dose: 15 Gy/10 fxCTV: Includes the bilateral lungs, mediastinum, and
pleural recesses for WLI. For hemithorax RT (ie, due to pleural
effusion), includes the ipsilateral lung + pleural recessTechnique:
AP/PA or IMRT (cardiac-sparing IMRT warrants 4D-CT simulation;
see Kalapurakal IJROBP 2012). If AP/PA borders are as follows:
Superior = above the clavicle/lung apex (flash SCV fossa). Inferior =
below the diaphragm. Lateral = chest wall. See Wilms Tumor chapter
for representative fields.
Planning directive constraints:
Specific constraints are largely dependent on the primary site, but in
general:
Cord D max < 45 Gy (though consideration can be given to a D
max < 50.4 Gy, depending on circumstances)
Avoid circumferential limb irradiation (see “Soft Tissue Sarcoma”
section for more information), sparing 1-2 cm strip of skin to
reduce lymphedema risk.
Extra care should be given to avoid unnecessary bladder dose
given cystitis associated w/ EWS CHT agents cyclophosphamide
and ifosfamide, which are often given concurrent w/ RT.
Avoid premature epiphyseal closure by avoiding RT to uninvolved
epiphyseal growth plates.
C
VDC/IE = Vincristine + doxorubicin + cyclophosphamide (VDC)
alternating with ifosfamide + etoposide (IE)
S E
Acute: Varies by treatment field/primary site
Late: Varies by treatment field/primary site, but in general: height loss,
premature epiphyseal closure/decreased bone growth (and therefore
skeletal asymmetry in some cases), kyphosis/lordosis/scoliosis,
fracture, cystitis, pneumonitis, pulmonary fibrosis, infertility, and
second malignancy (SMN). Note the relatively high rate of SMN for
EWS survivors, w/ CCSS report of 24% cumulative SMN risk at 35
years (Marina et al. Cancer 2017).
F -
End-treatment imaging with PET/CT at completion of chemotherapy
and MRI of primary site ~3-4 months after definitive local treatment
(Meyer Pediatr Blood Cancer 2008)
Follow-up q3mo for first 2 years, then q6mo for years 2-5, then
annually for another 5 years, and likely longer than that. Includes
H&P, labs, as well as primary + chest imaging, generally plain films
unless concerning/focal sxs present, or abnormality detected on XR
Late relapses not uncommon w/ EWS, per CCSS occurring in 13% of
5-year EWS survivors by 20 years. Site-specific monitoring for late
effects should also be pursued (relevant site-specific guidelines
available from COG).
N T
POG 8346 (Donaldson IJROBP 1998). Randomized trial including 178
children w/ EWS, 79% with localized disease. Patients who achieved a
CR/PR after induction VDC + dactinomycin and with primary tumors
involving nonexpendable bone randomized to whole-bone RT field vs
involved field RT (GTV + 2 cm). 53% LC in both RT arms, establishing
involved field RT for EWS, compared to whole-bone RT
INT-0991 (Grier NEJM 2003). Randomized trial in which 518 EFT pts were
randomized to induction VDC + dactinomycin vs VDC + dactinomycin
alternating with IE. For pts with localized EFT, alternating VDC +
dactinomycin with IE resulted in a significant improvement in 5-year OS
(72% vs 61%, P = .01) and LC (95% vs 85%, P < .001).
RHABDOMYOSARCOMA
B
Incidence/prevalence: Rhabdomyosarcoma (RMS) is the most
common pediatric soft tissue sarcoma, with ~350-400 cases per year
in the United States. Accounts for ~3%-4% of pediatric malignancies
Outcomes: Varies by primary tumor site, histology, translocation
status, and risk stratification, among others. The 5-year overall
survival (OS) by COG risk stratification: low risk = 92%, intermediate
risk = 65%, and high risk = 14%
Demographics: Male predominance; M:F = ~1.4:1. Slight racial
trends in RMS incidence: African Americans > Caucasians > Asians.
Incidence peaks at 2-6 years old (embryonal histology) and 10-14
(alveolar histology). However, 7% of RMS is in infants (<1 year old),
and 13% of RMS is in pts 15+ years old, including cases in adults.
Risk factors: Limited knowledge, w/ most RMS cases being
sporadic. RMS has been associated w/ some genetic syndromes
including Li-Fraumeni, NF-1, and Beckwith-Wiedemann.
T B C
Pathology: Small round blue cell tumor. IHC helpful to distinguish
from other small blue round cell tumors. RMS positive for muscle-
specific proteins including myoglobin, Z-band protein, myogenic
differentiation 1 (MyoD1), actin, myosin, and desmin.
Cell of origin: Hypothesized to arise from primitive mesenchymal
cells, though emerging data suggest nonmesenchymal origin may be
possible for fusion-negative RMS (Drummond et al. Cancer Cell
2018).
Histology: Multiple histologic subtypes with prognostic importance.
From the best to the worst prognosis: botryoid, spindle cell,
embryonal, alveolar, and pleomorphic/undifferentiated. Botryoid and
spindle cells are variants of embryonal histology and confer excellent
prognosis. Botryoid is common in infants and tumors of the GU tract
(ie, vaginal RMS in infants, typically botryoid histology, which has
“bunch of grapes” appearance on physical exam). Embryonal
histology displays patchy myogenin staining, with appearance similar
to embryonal skeletal muscle; RMS of head and neck enriched for
embryonal histologies (especially orbital tumors). Alveolar histology,
with a worse prognosis, occurs in older children (10+) and has diffuse
myogenin staining. Furthermore, alveolar tumors occur in more
unfavorable sites, especially the extremities, perineum, and trunk.
Approximately 50%-55% of RMS are embryonal, and ~25% are
alveolar.
Genetics: Translocations involving FOX01 on chromosome 13 have
been shown to be associated with alveolar RMS. Approximately 80%
of alveolar RMS have either PAX3-FOX01 or PAX7-FOX01 fusion
transcripts, corresponding to t(2;13) and t(1;13), respectively. Of those
w/ fusion transcripts, majority are PAX3-FOX01 fusions. PAX-FOX01
is a negative prognostic indicator (Sorenson et al. JCO 2002).
Moreover, fusion-negative alveolar RMS has comparable outcomes to
embryonal RMS (Williamson et al. JCO 2010). Therefore, there is a
trend toward fusion status for risk assignment and trial design
(including ongoing COG trials).
A
Approximately 20% GU, ~15% H&N parameningeal, ~10% orbital, ~10%
H&N nonparameningeal, ~20% extremity, and ~15% other (including
trunk, retroperitoneum)
*Parameningeal H&N includes MMNNOOPP mnemonic = Middle ear,
Mastoid, Nasal cavity, Nasopharynx, infratemporal fOssa, pterygopalatine
fOssa, Paranasal sinuses, and Parapharyngeal space
Classify primary site into favorable and unfavorable prognostic
categories:
Favorable sites: Orbit, nonparameningeal H&N, biliary,

nonprostate/nonbladder GU
Unfavorable sites: All other sites
D E
History and physical: Clinical presentation varies by primary site.
Orbital: proptosis, ophthalmoplegia. Parameningeal H&N:
nasal/aural/sinus obstruction, CN deficits, and altered mental status
(consider intracranial extension). Other H&N: painless enlarging
mass. Extremities: mass (+/− pain associated with mass), swelling.
GU: hematuria/urinary obstruction (bladder), discharge (vagina),
scrotal/inguinal enlargement (paratesticular)
Nodal metastasis rates, including at presentation, vary by primary
site/histology; highest risks of LNs involved by site are prostate,
paratesticular, and extremity tumors. H&N alveolar tumors may also
have increased risk of LN mets.
Distant mets in ~20% of RMS pts at diagnosis, usually the lung,
bone marrow, and bone. Mets within the CNS can occur in
parameningeal RMS pts w/ intracranial extension (seeding within
CSF).
Imaging: Assess primary site: MRI preferred. Assess for LN + distant
mets: PET/CT; can omit chest CT and bone scan if PET/CT
performed. Bone marrow biopsy recommended, though bilateral
BMBx not required for embryonal RMS pts and clinically node-
negative pts.
Parameningeal RMS: These tumors have high risk of extension
into the CNS (intracranial extension, as well as cranial bone
erosion and CN deficits). Therefore, for parameningeal RMS,
CSF cytology (LP) as well as MRI of the brain is needed.
Labs: CBC, CMP (including BUN/Cr and LFTs), uric acid
Procedures/biopsy: Core needle or incisional Bx. As above, for
parameningeal RMS, LP is needed for CSF cytologic analysis.
Nodal evaluation: Biopsy any suspicious LNs to confirm nodal
status. Sentinel LN biopsy indicated for extremity tumors. Males
>10 years old w/ paratesticular RMS are recommended for
ipsilateral nerve-sparing retroperitoneal LN dissection.
Miscellaneous: Sperm banking/fertility consult, as indicated
R S /S
Risk stratification guides treatment; 4-step process
1. Site: favorable vs unfavorable: See above re: dividing primary sites
into favorable vs unfavorable categories.
2. Stage: Start by site, and then determine the stage (I-IV) as below:
Favorable site: Orbit, non-PM H&N, nonbladder/prostate GU, biliary

tractUnfavorable site: PM, everything else
3. Group (extent of surgery): IRS grouping based on the extent of

surgery
4. Risk stratification: Combination of stage + group, as well as

histology (now fusion status; Pappo et al. JCO 2017). See above for
OS rates for each risk category.
Low risk: Fusion-negative: Stage 1 Group 2, Stage 2 Groups 1
and 2, and orbital Stage 1 Group 3
High risk: All Stage 4 Group 4 except fusion-negative pts <10
years old
Intermediate risk: All others
T A
Overarching Tx paradigm: maximal safe resection (or biopsy) →
chemotherapy, start RT as indicated during chemotherapy, timing
noted below
RT used as definitive local therapy for sites w/ limited options for
primary resection w/o significant morbidity, including orbital as well as
other H&N (esp parameningeal).
RT dosing, timing, and indications vary by stage/group/risk
stratification as above.
R T T
SIM: Primary site dependent; sedation (anesthesia) may be required
in children <8 years old, for both sim and treatment.
Dose: All in 1.8 Gy fractions, generally
Group I embryonal = no RT
Group I alveolar = 36 Gy to prechemo site
Group II N0 (microscopic residual after surgery) = 36 Gy to
prechemo site
Group II N1 (resected LN involvement) = 41.4 Gy to prechemo
site and nodal region
Group III nonorbital = 50.4 Gy
Group III orbital = 45 Gy (if CR after induction chemo) and 50.4
Gy (if non-CR after induction chemo)
No RT indicated for additional settings (including nonembryonal
RMS): N0 extremity RMS s/p amputation; paratesticular s/p R0
resection
RT timing: Relative to start of chemotherapy, generally by risk
stratification
Low risk = week 13 (per ARST0331)
Intermediate risk = previously week 4 (ARST0531) though
current COG ARST1431 moving this to week 13
High risk = week 20
Emergent RT should be initiated as soon as indicated, regardless
of the above.
Parameningeal RMS w/ intracranial extension conventionally
treated weeks 0-2. ARST1431 delaying RT start to week 13.
Target:
In general: GTV = prechemotherapy volume and CTV = GTV + 1
cm
PTV margin depends on site(s) being treated, IGRT utilized, etc.
Technique: Varies by treatment site, but in general proton beam
therapy and IMRT are reasonable options, w/ multiple series utilizing
both techniques across primary sites.
IGRT: Primary site dependent, usually at least daily kV-IGRT
Planning directive dose constraints: Primary site dependent
C
Commonly utilized: VAC
(vincristine/dactinomycin/cyclophosphamide), VI
(vincristine/irinotecan), and IE (ifosfamide/etoposide)
S E
Acute: Varies by treatment field/primary site
Late: Varies by treatment field/primary site. For orbital tumors, for
instance, xerophthalmia, cataracts, decreased visual acuity H&N RT
leads to dentofacial abnormalities, facial asymmetry/hypoplasia,
endocrinopathies, and neurocognitive deficits. Other late risk factors
include premature epiphyseal closure and decreased bone growth
(and therefore skeletal asymmetry), fracture, cystitis, urinary
incontinence, infertility (especially w/ cyclophosphamide), and second
malignancy (SMN).
N T /P
IRS I (Maurer Cancer 1988). Group 1 favorable histology pts: VAC vs
VAC-RT, with no difference in OS (93% vs 81%, respectively, P = .67);
therefore no RT for Group 1 favorable histology. Also showed that for
Group II/III pts, RT coverage of whole muscle vs involved fields
resulted in no difference in LC (therefore no need for whole muscle
coverage). For pts >6 years old, LR 32% for RT < 40 Gy and LR 12%
for RT > 40 Gy (P > .4); no dose response demonstrated.
IRS IV (Crist JCO 2001). Group III pts randomized to 50.4 Gy in 1.8
Gy daily fx vs hyperfractionated 59.4 Gy in 1.1 Gy BID fx. No
difference in failure-free survival or LC (P = .85 and .9, respectively),
w/ increased mucositis in hyperfractionated arm. Therefore,
conventional daily fractionation remains standard.
OSTEOSARCOMA/RETINOBLASTOMA/BRAIN
STEM GLIOMA
O
Background:
Most common pediatric bone tumor (2nd most is Ewing sarcoma
[EWS]), w/ ~400 pediatric cases per year. Bimodal distribution w/
peak in teenage years and another peak >65 years old. M > F
and African American > Caucasian
Increased risk of osteosarcoma in pts w/ history of germline RB
mutation as well as h/o RT for retinoblastoma (irrespective of
germline RB mutation presence)
Presents with local symptoms including pain, swelling, palpable
mass, and fracture. Less common for systemic symptoms at
presentation than EWS. “Sunburst” pattern on films vs “onion
skin” appearance in EWS
80% of cases in appendicular skeleton, majority of which
originate in metaphysis (distal femur > tibia)
90% of osteosarcoma pts have radiographically localized disease
at dx, but w/ symptoms alone, ~80% of pts will develop lung mets
within 12 months. Therefore, like w/ EWS, osteosarcoma is an
“occult systemic” disease.
Treatment paradigm:
Neoadjuvant chemotherapy → surgery* → adjuvant chemotherapy
(usually double doxorubicin/cisplatin)*Pathologic response to
neoadjuvant chemotherapy on surgical specimen is prognostic, with
>90% necrosis resulting in ~80% relapse-free survival.
Role of RT:
Unlike EWS, osteosarcoma is generally considered radioresistant
(variant histologies of osteosarcoma are to some extent more
radiosensitive).
Beyond palliative indications, RT may be used in the definitive
setting for inoperable pts (inoperable due to pt and/or disease
factors) or in the adjuvant setting for those with close or positive
margins.
Definitive RT, or RT after R2 resection (gross residual dz), is
thought to require high doses of RT (60-70 Gy, usually at least 66
Gy in 2 Gy fractions).
Data suggest no role for prophylactic WLI despite high risk of
lung metastases.
R (RB)
Background:
Most common primary intraocular pediatric malignancy, with ~300
cases per year. Occurs usually in infants/toddlers (~2 years
median age at dx). 95% of cases in those <5 years old
60% of Rb cases are sporadic, and 40% are heritable (germline
RB mutation). Most heritable RB mutation is via de novo germline
mutations, since <10% of RB patients have family history of RB
mutation.
Approximately 1/3 of Rb cases are bilateral, generally suggestive
of germline RB mutation. However, 15% of unilateral Rb pts have
germline mutation, so genetic testing should be considered even
in unilateral cases. Trilateral retinoblastoma cases refer to
bilateral retinoblastoma with a concordant pineoblastoma. Occurs
in 5% of patients with RB mutation
Earlier age of presentation (~1-1.5 years old) for bilateral Rb pts
and pts w/ germline RB mutation
Usually p/w leukocoria, although can p/w strabismus, nystagmus,
and others
Multiple classification systems; COG currently using the
International Classification of Intraocular Retinoblastoma system,
where the eyes are risk stratified from A through E.
A:Small tumors (3 mm), limited to the retina and not near
important structures
B: All other tumors, limited to the retina
C: Well-defined tumors with small amount of spread under the
retina or vitreous seeding
D: Large or poorly defined tumors with widespread vitreous or
subretinal seeding
E: Large tumor, extending near the front of the eye. Bleeding,
causing glaucoma, or have almost no chance the eye can be
served
Treatment paradigm:
Variable but includes both systemic therapy (usually VCE =
vincristine/carboplatin/etoposide) and focal therapies w/ the goal
of sparing the eye from enucleation if possible
Array of local treatment options available, including intra-arterial
chemotherapy, intravitreous chemotherapy, cryotherapy, laser
photocoagulation, external beam RT, and plaque brachytherapy
EBRT may be indicated in adjuvant setting after enucleation as
well, if positive margin or nodal involvement is identified;
enucleation is often indicated for advanced (very high risk =
group E) tumors, among others.
Role of EBRT and brachytherapy:
EBRT was developed as the first technique to allow globe
sparing. However, it is used less now due to concerns for second
malignancy. Roarty et al. examined bilateral Rb pts; 35% had
second malignant neoplasm after EBRT vs 6% for those who
didn’t have EBRT (Roarty et al. Ophthalmology 1988). Data
support field and dose dependence of second malignant
neoplasm incidence after RT for Rb. Second malignant neoplasm
after RT for Rb includes osteosarcoma of bones within the
treatment field around the orbit.
EBRT (usually with concurrent chemotherapy) is often indicated
in adjuvant setting after enucleation w/ +margin or +LN. Doses
36-45 Gy.
Plaque brachytherapy provides a custom-design shielded source
that decreases RT dose to bones and therefore reduces risk for
developing secondary malignant neoplasms.
Usually I-125 or Ru-106 sources for plaques, prescribing 45 Gy
to 1 mm beyond the apex of the tumor
Logistically challenging, as plaques remain in place for ~2 days in
these young children before returning to the operating room for
plaque removal. Similarly, technically challenging; therefore not
used often in the frontline setting, but rather considered in the
setting of persistent dz after other local therapies exhausted
B G
Background:
80% of pediatric brainstem gliomas arise from pons. Most pontine
tumors are diffuse intrinsic pontine gliomas (DIPGs).
Approximately 20% of pediatric brainstem gliomas = focal,
predominantly at cervicomedullary jxn (low medulla) and tectum
(upper midbrain). Usually present with CN palsies, especially
CNs VI and VII, as well as ataxia, incr ICP (H/A, N/V,
lethargy/somnolence). Pontine gliomas are primarily infiltrative,
high-grade, and aggressive and portend poor prognosis.
Nondiffuse nonpontine lesions include dorsally exophytic lesions,
usually low-grade gliomas including JPA (WHO grade I tumors).
Incidence: DIPGs usually present at 4-9 years old, ~300 cases
per year. No gender predilection for DIPG
Pathology: Emerging understanding of molecular pathogenesis of
DIPG, including high incidence of mutations in H3F3A (histone
H3 gene). Approximately 80% of DIPG in one study found to
have H3F3A mutation (Wu et al. Nat Genet 2012). These H3
K27M mutations have been identified as portending poor
prognosis. 2016 WHO classification includes “H3 K27M-mutant
diffuse midline glioma” as a diagnostic entity.
DIPG on MRI demonstrates characteristic T1-hypointense and
T2-hyperintense expansile infiltrative pattern within the pons, w/
variable rates of Gd contrast enhancement.
Treatment paradigm:
Management of peritumoral edema (steroids) and management
of hydrocephalus (shunt) as indicated. Biopsy of tumor only
indicated if atypical appearance on imaging questioning DIPG dx.
Emerging studies/protocols are demonstrating safety of biopsy of
DIPG, but outside of protocol, do not biopsy due to risks of injury
to the brainstem.
The only standard antitumor therapy is RT. Despite this, median
survival ~1 year, w/ minimal (<5%) survival at 5 years. Of note,
non-DIPG brainstem gliomas, such as dorsal exophytic brainstem
gliomas, have better prognosis (~75% 10-year OS)
Limited role for conventional chemotherapeutics, though
increasingly HDAC inhibitors/inhibitors of histone demethylation
are being utilized on the protocol.
Role of RT:
Dose: RT for DIPG involves treatment to 54 Gy in 30 fractions
(1.8 Gy/fx)
Target: Tumor volume (MRI fusion helpful) + 1-1.5 cm for CTV.
Additionally, 5 mm PTV w/ daily kV-IGRT
Technique: Photon-based RT (IMRT/VMAT) rather than proton
beam therapy, owing to theoretical considerations regarding
higher risk of brainstem injury w/ protons.
Alternative RT dose via hypofractionation, using 39 Gy at 3 Gy/fx
(13 daily fractions) or 44.8 Gy at 2.8 Gy/fx (16 daily fractions).
Matched cohort analysis (Janssens et al. IJROBP 2013)
suggested comparable outcomes with shorter treatment
time/burden. However, RCT from Egypt randomized DIPG pts to
54 Gy/30 fx vs 39 Gy/13 fx found similar results between 2 arms,
but w/ PFS differences exceeding prespecified noninferiority
assumption (PFS favoring conventional arm).
Therefore, we continue to utilize conventional fractionation at
MDACC at present.
RT usually results in response and symptom improvement in
majority (~65%-75%) of pts, but virtually all will recur 1 year after
RT.
LATE EFFECTS
B
Overview:
Late toxicity from radiotherapy, especially in pediatric pts, informs
treatment choices and risks.
Increasing concern regarding late toxicity given improved survival
of pediatric pts across disease sites over the last 50 years.
Top causes of mortality in 5-year survivors of childhood cancers
are recurrent disease (57%), secondary malignancies (SMNs;
15%), and cardiac toxicities (7%) (Mertens et al. JCO 2001).
Factors affecting late effects:
Factors may affect risk of late toxicity to different organ
systems/sites.
Host factors, including age, gender, comorbidities, ethnicity/race,
and genetic predisposition, may affect late toxicity.
Age of patient is particularly important for OARs, given differential
rates of maturation. For example, early development of brain vs
teenage development of reproductive system; conceptually, brain
more sensitive to RT during development in early childhood,
whereas gonads more sensitive to RT during puberty
Genetic effects are also important: NF1 pts after RT for optic
pathway gliomas had ~50% risk of second malignancy (Sharif et
al. JCO 2006). Similarly, increased risk for moyamoya syndrome
for NF1 pts after RT and also increased risk of cutaneous basal
cell carcinomas in field after RT in pts w/ Gorlin syndrome (see
Happle JAAD 1999). Secondary neoplasm risk in Rb pts
markedly increased if hereditary Rb vs nonhereditary after RT
(33% vs 13%; Marees et al. JNCI 2008)
Gender is also critical, as discussed below; there is evidence for
increased sensitivity for RT toxicity in females, including
neurocognitive deficits and height impairments after cranial RT
for leukemia, hypothyroidism, and secondary malignancies after
mediastinal RT for Hodgkin lymphoma (specifically breast).
Treatment parameters also influence toxicity: radiation dose,
fraction size, volume treated, concurrent chemotherapy, as well
as timing of chemotherapy and radiation; also important are other
oncotherapeutics employed, including surgery and
chemotherapy. Multiple modalities may synergize to increase the
risk of toxicity.
L E O S
CNS:
Neurocognitive effects due to brain radiation; most sensitive in
utero and then for the first few years of life. Synaptogenesis,
axonal growth, dendritic arborization, and maturation of neural
networks over these early years are thought to be central to RT
neurotoxicity in the very young.
Neurocognitive changes affected by age of RT; IQ scores for
pediatric low-grade glioma pts show more significant long-term IQ
deficits w/ younger age at RT (Merchant et al. JCO 2009).
CSI + posterior fossa boost for medulloblastoma pts is shown to
affect both verbal and nonverbal IQ (Ris et al. JCO 2001).
The above study suggested female pts are more likely to have
verbal IQ deficits after RT; possible gender sensitivity to IQ
changes in females in study w/ ALL pts s/p CSI: 50% of girls vs
14% of boys had IQ < 90 on follow-up (Waber et al. JCO 1992).
Cranial RT may also cause leukoencephalopathy, though unlikely
(<1%) in the absence of methotrexate (IV or intrathecal).
Musculoskeletal:
RT injury to bone is dependent on portion of bone treated; for
example, epiphyseal RT arrests chondrogenesis.
Skeletal effects are observed across multiple series, including
scoliosis, kyphosis/lordosis, and iliac wing hypoplasia, among
others. The most common of these (dependent on RT fields) is
scoliosis.
Height deficits after RT are also noted, dependent on both dose
and age at RT. Example is Wilms tumor pts treated w/ RT: 8-year-
old pts s/p 10 Gy had only 0.8 cm height loss, whereas 2-year-old
pts s/p 30 Gy had 7.2 cm height loss (Hogeboom et al. Med
Pediatr Oncol 2001).
Prior to puberty, if a vertebral column or growth plate cannot
avoid radiation, then it is better to treat the entire column or
growth plate to avoid asymmetric growth.
Similarly thought to have gender bias w/ female more sensitive to
RT-related height loss
Growth abnormalities d/t both direct RT to developing bones and
cranial RT (GH deficits). Short stature risk for pts s/p cranial RT >
20 Gy for ALL pts (Chow et al. J Pediatr 2007).
Second malignancy:
Secondary breast cancer ~9%-10% incidence after RT for
Hodgkin’s
Increased sensitivity for secondary breast cancer if patient is
pubescent (~12-16 years old) at RT vs younger (<12 years old;
Constine IJROBP 2008).
After RT for Hodgkin lymphoma, secondary thyroid cancer is also
observed with comparable frequency to SBC (O’Brien JCO
2010).
Secondary malignancy is risk linked closely to RT use, among
other factors (including certain chemotherapeutics such as
procarbazine, anthracycline, and etoposide); secondary sarcoma
is largely related to prior RT, and secondary GI malignancies are
similarly related to prior abdominal RT.
Differential secondary malignancy rates by primary tumor
histology (see Ewing Sarcoma chapter; high secondary
malignancy incidence for EWS). Other reports describe low
secondary malignancy risk for other lesions, including ~1%-2% at
10-15 years for Wilms tumor, ALL, and rhabdomyosarcoma.
SMN studies are challenging due to time lapse between RT,
treatment, and tumor-causing events; modeling suggests modern
techniques have decreased risk of RT-related secondary
malignancies. Emerging data suggest trend toward decreased
secondary malignancies with progressive era of treatment
(Turcotte et al. JAMA 2017).
S R L T
Delaying/omitting RT
Utilized in young children, especially <3-year-old pts w/ brain
tumors. CSI delayed to >3 years old for MB and other CNS pts.
Approach of deferring/delaying RT supported infants w/
ependymoma (Merchant et al. JCO 2004).
Hyperfractionated RT
Relying on radiobiological principles, hyperfractionation is thought
to decrease late effects, supported by a few series. Examples
include decreased fracture and muscle atrophy in Ewing sarcoma
pts w/ hyperfractionation and decreased hypothyroidism with RT
for medulloblastoma w/ hyperfractionation.
Trials across multiple disease sites, however, have found limited
to no difference w/ fractionation (IRS-IV, EWS CESS-86, MB HIT-
SIOP PNET 4).
Decreasing RT dose and volume
Decreased RT dose is successfully applied in NWTS-3, the
results of which decreased adjuvant RT dose for Stage III
favorable histology Wilms tumor pts from 20 to 10 Gy w/ addition
of doxorubicin to chemo regimen. Used additional chemotherapy
to offset decreased RT dose.
In medulloblastoma patients, ACNS0031 demonstrated that
involved field boost is equivalent to posterior fossa boost, which
translated into a significant reduction in total brain doses.
Significant RT dose reductions for Hodgkin lymphoma, previously
total nodal/subtotal nodal/mantle field RT to 36-44 Gy, now
involved field/site/nodal RT to much lower doses (20-30 Gy
generally).
May also attempt to eliminate RT for favorable subsets of pts: for
example, in COG AREN0533, elimination of WLI for Wilms tumor
pts w/ lung metastases w/ favorable chemo response. Also, see
multiple Hodgkin lymphoma trials recommending RT for pts w/
PR after chemo vs observation for pts w/ CR after chemo.
Advanced RT technologies
IMRT Example: Decreased ototoxicity in MB pts w/ IMRT vs
3DCRT (Huang et al. IJROBP 2002)
Proton beam therapy: see Proton therapy chapter, minimal exit
dose via Bragg peak particularly advantageous for certain
disease sites. Among the most notable examples, CSI, sparked
2013 debate in IJROBP whether proton beam therapy “only
ethical” approach for pediatric pts needing CSI
Despite a concern for secondary neutron
production/contamination w/ proton beam therapy, clinical data
are not suggestive of increased risk of secondary malignancies
with protons (Sethi et al. Cancer 2013).
PENTEC group, pediatric analog of the QUANTEC effort,
developing quantitative, evidence-based guidelines for RT
treatment planning and dose constraints, among others
ORAL CAVITY
GARY WALKER • ADAM SETH GARDEN
B
Incidence/prevalence: ~30 000 cases diagnosed annually in the United
States
Outcomes: 5-Year survival across all stages estimated at 67% (SEER
data)
Demographics: M > F, older age
Risk factors: Smoking, smokeless tobacco, alcohol, betel nut, and
premalignant lesions (leukoplakia 5% risk of developing cancer,
erythroplakia 50% risk)
T B C
Genetics: Majority associated with genetic alterations from external
factors
Pathology: Vast majority are SCC. Rare histologies include adenoid
cystic, adenocarcinoma, sarcoma, and melanoma.
A
Subsites: Oral tongue, mucosal lip, buccal mucosa, alveolar ridge,
retromolar trigone, floor of the mouth, hard palate
Extrinsic muscles of the tongue: Genioglossus, hyoglossus,
styloglossus, palatoglossus
Lymph node drainage (35% are cN+):
Primary drainage to Ib and IIA.
The upper lip can drain to preauricular.
The lower lip and FOM can drain to IA.
About 15% bypass II and go directly to level III-IV.
Level IV-V can be involved with advanced nodal disease.
H N L N L
The neck is divided into six LN levels (Fig. 25.1). For all the remaining chapters
in this section, please refer to the following definitions:
Figure 25.1 Diagram of LN stations of the neck. (Adapted from Edge

SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A III. eds.
AJCC cancer staging manual. 7th ed. New York, NY: Springer; 2010.
Copyright c 2010 American Joint Committee on Cancer. Reproduced
with permission of Springer in the format Book via Copyright
Clearance Center.)
Level I: Inferior to mylohyoid muscle and above the caudal border of the hyoid
bone/carotid bifurcation:
Ia (submetal): Between anterior bellies of the bilateral digastric muscles
Ib (submandibular): Posterolateral to the anterior belly of the digastric
muscle and anterior to the posterior border of the submandibular gland
Level II (internal jugular chain): Base of the skull to caudal border of hyoid
bone/carotid bifurcation. Anterior to the posterior border of SCM. Posterior to
the posterior border of the submandibular gland:
IIa: Anterior or immediately adjacent to (eg, inseparable from) the internal
jugular vein
IIb: Posterior to internal jugular vein with a fat plane separating node from
vein (otherwise considered level IIa)
Level III (internal jugular chain): Caudal border of hyoid to caudal border of
cricoid. Anterior to posterior border of SCM. Lateral to medial margin of the
common/internal carotid artery
Level IV (internal jugular chain): Caudal border of cricoid to clavicle. Anterior
to posterior border of SCM. Lateral to the medial margin of common carotid
artery
Level V (posterior triangle/spinal accessory): Posterior to SCM and anterior
to trapezius muscle:
Va: Superior half, posterior to level II and III LN levels
Vb: Inferior half, posterior to level IV LN levels
Level VI (Prelaryngeal/pretracheal/delphian node): Caudal edge of hyoid bone
to the manubrium, anterior to levels III and IV and visceral space (Fig. 25.2)
Figure 25.2 Axial CT images showing LN levels at the lower edge of

the mandible (left panel) and low neck (right panel). See color
insert. (Reprinted from Grégoire V, Levendag P, Ang KK, et al. CT-
based delineation of lymph node levels and related CTVs in the node-
negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG
consensus guidelines. Radiother Oncol. 2003;69(3): 227-236.
Copyright © 2003 Elsevier Ireland Ltd. With permission.)
W
History and physical: Assess presenting symptoms including oral cavity
function, cranial nerve deficits, otalgia, and trismus. Direct palpation and
visualization of tumor and adjacent subsites with nasolaryngoscope and/or
mirror exam useful to assess disease spread
Labs: CBC, CMP
Procedures/Biopsy: Biopsy of primary and FNA of enlarged LNs as
clinically indicated
Imaging: CT or MRI with contrast of head and neck. Consider CT of the
chest. FDG-PET/CT recommended for Stage III/IV disease
Additional consultations: Multidisciplinary evaluation with head and
neck surgical oncology, radiation oncology, medical oncology, speech,
nutrition, and dental (fluoride/extractions)
O C C S (AJCC 8
E )
T A
apT3/T4, N2/N3, PNI, level IV/V, LVSI.

R T T
Timing: Should be started within 4-6 weeks of surgery
Dose: Highest risk (close/positive margins/ECE)—63-66 Gy in 30-33
fractions
High risk (tumor bed)—60 Gy in 30 fractionsIntermediate risk (operative
bed and dissected neck)—57 Gy in 30 fractionsLow risk (elective nodal
coverage)—54 Gy in 30 fractions
Target: Tumor bed, operative bed, and draining lymphatics (levels I-IV,
level V if node positive). Consider unilateral treatment for a well-lateralized
retromolar trigone, buccal mucosa, or alveolar ridge without nodal disease.
Technique: VMAT, IMPT, and IMRT with half-beam block and matched AP
low-neck field
SIM: Supine, consider mouth opening with the tongue forward (oral
tongue), tongue lateralizing (buccal/alveolar/retromolar trigone) or ramp
(FOM) dental stent, and aquaplast mask. Wire scar. 3-mm bolus 2 cm
around the scar (Fig. 25.3)
IGRT: Daily kV with weekly CBCT or daily CBCT.
Planning directive (for conventional fractionation):
Figure 25.3 A 64-year-old with a resected pT2N2a (4.5 cm LN with
ECE) SCC of the oral tongue reconstructed with a pectoralis flap
treated with chemoRT. GTV (green), GTV-N (forest green), CTV63
(aqua), CTV60 (red), CTV57 (blue), and CTV54 (yellow) in 30
fractions. See color insert.
S
WLE and partial, hemi-, or total glossectomy
Close margin is <5 mm.
Advanced resections may need flap/graft reconstruction.
Neck dissection for node positive or DOI > 4 mm. Consider neck
dissection if is DOI 2-4 mm.
Rad neck dissection = I-V, CN XI, IJV, SCM
Mod rad neck dissection = I-V, preserve one of the following (CN XI,
IJV, SCM)
Supraomohyoid = I-III
Lateral = II-IV
Selective neck dissection = LNs based on site
C
Concurrent: High-dose cisplatin (100 mg/m2), weekly cisplatin (40
mg/m2), weekly carboplatin.
Induction: TPF (docetaxel/cisplatin/5-FU); should not be done off protocol
S E M
Nausea/vomiting: First-line Zofran (4-8 mg q8h prn) → second-line
Compazine (5-10 mg q6h prn) → ABH (lorazepam 0.34 mg,
diphenhydramine 25 mg, and haloperidol 1.5 mg) 1 capsule q6h
Anxiety: Aquaplast mask can cause anxiety; lorazepam 1 mg 30 minutes
to 1 hour before simulation or treatment
Oral infection: Candidiasis; if superficial—nystatin 500 000 units tid; if
significant—diflucan 100 mg tablet once daily. Bacterial superinfection:
tongue VERY red, send to dental for oral cultures.
Pain: Hydrocodone/acetaminophen (7.5/325) mg q6h prn and
hydromorphone 2 mg q3-6h prn (can increase frequency). If refractory,
fentanyl 12.5-25 mcg transdermal patch q72h with prn breakthrough
narcotics. If pain is recalcitrant to the above, consider a pain management
specialist.
Skin: Dermatitis: Routine moisturizer use (ie, Aquaphor, coconut oil,
Egyptian magic, NutriShield). Pruritus: Hypoallergenic soap and lotion and
hydrocortisone 1% ointment. Moist desquamation: Mepilex dressing,
Biafine cream. Crusting: consider Domeboro soaks. Infectious dermatitis:
Most likely MSSA, can be treated with Bactroban 2% ointment 3× daily for
7-10 days. If infection does not clear, consider consult to infectious
disease specialists.
Thick secretions: Baking soda rinses, diet ginger ale gargles, papaya juice
gargles, Mucinex, Robitussin, portable suction device. Scopolamine
patches and Hycodan can be tried for refractory cases.
Xerostomia: Acupuncture and Biotene spray; encourage hydration
F -
History/physical exam and CT neck: Every 3 months for 1 year → every 4
months for the 2nd year → every 6 months for the 3rd year → yearly to 5
years
Assess compliance with fluoride trays and neck range of
motion/lymphedema exercises.
N T
Adjuvant chemoRT vs RT
RTOG 95-01 (Cooper et al. NEJM 2004; Cooper et al. IJROBP 2012)—
Phase III randomized study enrolling 459 patients with oral cavity,
oropharynx, larynx, and hypopharynx cancer after complete resection.
Patients must have had the presence of high-risk features (two or more
positive lymph nodes, ECE, or SM+). Patients were randomized to RT
alone vs RT with concurrent cisplatin (100 mg/m2 given every 3 weeks).
RT 60/30 plus optional boost to 66/33 high-risk areas. At initial report, DFS
was significantly longer with concurrent chemotherapy (HR = 0.78, P =
.04). At updated follow-up, 10-year DFS was not significantly different
(19.1% vs 20.1%).
EORTC 22931 (Bernier NEJM 2004)—Phase II randomized study
enrolling 334 patients with oral cavity, oropharynx, hypopharynx, or larynx
cancer after complete resection. Patients must have been high risk by
being in one of the following risk groups: T3-4 any N with negative
margins, T1-2 N2-3, T1-2 N0-1 with high-risk features (ECE, SM+, PNI,
LVI), or oral cavity/oropharynx with LN+ at level IV or V. Patients were
randomized to adjuvant RT alone vs RT + concurrent cisplatin (100 mg/m2
given every 3 weeks). RT dose 54/27 + boost to 66 Gy high-risk areas. At
first analysis, combination chemoradiation was associated with improved
PFS (HR = 0.75, P = .04) and OS (HR = 0.7, P = .02).
EORTC 22931/RTOG 95-01 (Bernier et al. Head Neck 2005): Combined
analysis showed ECE or SM+ had an overall survival benefit with
treatment utilizing RT and concurrent cisplatin.
OROPHARYNX
JAY PAUL REDDY • ADAM SETH GARDEN
B
Incidence/prevalence: Approximately 12 000 cases annually in the
United States
Outcomes: 5-Year survival across all stages estimated at ~80% for HPV-
positive and 50% for HPV-negative
Demographics: Current incidence in men is greater than women, 3:1 for
HPV-negative and 8:1 for HPV-positive.
Risk factors: Historically linked with tobacco and alcohol abuse, but now
dramatic rise in HPV-associated OPC. Increased by 225% from 1988 to
2004 (SEER data)
T B C
Pathology: Majority are squamous cell carcinomas (>95%). Majority of
cases are HPV positive, which are associated with better prognosis.
p16/HPV testing should be performed for all OPC. Common serotypes are
16, 18, 31, and 33.
Symptoms: The most common presentation in HPV-associated OPC is
enlarging, painless neck mass. Otalgia, dysphagia, or odynophagia is
possible. HPV-associated OPC tends to present with smaller primary
disease and advanced nodal, often cystic, disease.
A
Sites: Base of the tongue, tonsil (subsites: anterior and posterior tonsillar
pillars and tonsillar fossa), soft palate, and posterior/lateral pharyngeal
wall
Borders: Circumvallate papillae (anterior), pharyngeal wall (posterior),
tonsillar fossa (lateral), soft palate (superior), vallecula (inferior)
Lymph node drainage: 80%-90% of patients are cN+:
The tonsil primarily drains to ipsilateral level IIA.
BOT drains to levels II and III bilaterally.
Bilateral RP and levels II-IV should be covered in all cases.
See Oral Cavity chapter for neck LN description (Fig. 26.1).
W
History and physical: Assess presenting symptoms including oral
function, cranial nerve deficits, speech quality, otalgia, and trismus. Direct
palpation and visualization of tumor and adjacent subsites with
nasolaryngoscope and/or mirror exam to assess disease spread
Labs: CBC, CMP
Procedures/biopsy: Biopsy of primary and FNA of enlarged LNs as
Imaging: CT or MRI with contrast of the head and neck. Consider CT
chest or chest x-ray. FDG-PET/CT recommended for Stage III/IV disease
nutrition, dental (fluoride/extractions)
O S (AJCC 8 , 2018)
Staging now depends on HPV status.
HPV-associated (p16+) OPC
Non–HPV-associated (p16−) OPC
T A
(T Stage has historically determined RT alone vs chemoRT)
aCriteria for ipsilateral RT: tonsil primary, <1 cm soft palate involvement, no BOT involvement, ipsilateral
nodal disease. Risk of contralateral neck failure 0%-3%
bGiven recent data from randomized trials, there is little evidence to support the use of induction
chemotherapy.
cRisk factors include pT3/T4, N2/N3, PNI, level IV/V, and LVSI.
R T T
Definitive radiation therapy
Dose:
aFinish in 6 weeks (DAHANCA, eg, 6 fx/wk).
Target:
General: CTVHD includes GTV + 8-mm margin, CTVID includes high-
risk mucosal and nodal volumes, and CTVED includes uninvolved
regions at risk for microscopic spread.
Tonsil: CTVHD includes the entire tonsillar fossa from maxillary
tuberosity to superior to hyoid. CTVED typically begins at pterygoid
plates. Typically includes GP sulcus and parapharyngeal space
BOT: CTVHD inferior from soft palate to vallecula (if involved) with
coverage of the entire hyoid. Anterior extent typically includes
posterior 2 cm of tongue.
Nodal: CTVED routinely covers RP nodes (from the jugular foramen to
C2) and levels II-IV on uninvolved side of the neck. Cover ipsilateral
Ib and V on involved side of the neck
Technique: VMAT, IMRT with half-beam block and matched AP low-neck
field, or IMPT in experienced centers.
SIM: Supine, aquaplast mask covering the head and shoulders, mouth-
opening, tongue-depressing stent (for BOT/soft palate), isocenter at or
below the cricoid. Pull straps for shoulder retraction. If the patient had
neck dissection, wire scars and place 3-mm bolus on top of wired scars.
Patient should be reminded not to swallow during simulation as this
distorts anatomy.
Post-op
Target/Dose: Region of resected gross disease: 60 Gy in 2 Gy
fractions (high dose) and 66 Gy in 2 Gy fractions for positive margins
Operative bed: 57 Gy (intermediate dose)
Nondissected at risk regions including nondissected at risk nodal
levels: 54 Gy (low dose)
Technique: IMRT or VMAT. Scanning beam proton therapy can be used in
capable centers.
SIM: See Oral Cavity section.
IGRT
Daily kV imaging with weekly CBCT or daily CBCT
Planning directive
See Oral Cavity chapter.
Special circumstances
Indications for boosting stoma with post-op XRT: (1) Emergency
tracheostomy was performed, (2) subglottic extension of disease, and (3)
anterior soft tissue extension.
Indications for neck dissection after definitive XRT or chemoRT:
Persistent neck disease.
Transoral robotic surgery (TORS): Increasingly common minimally
invasive surgical technique utilizing robot arms controlled remotely to
remove lesions in the tonsil, BOT, and soft palate. Neck dissection may
also be performed during the same procedure.
PORT indications: Positive margin, ECE, pT3/4, PNI, multiple nodes,
N3, and LVI
However, the above factors do not necessarily account for the overall
good prognosis of HPV+ patients. This area is evolving.
Ipsilateral treatment: Consider for T1-2 tumors limited to the tonsillar
fossa with N0-1 (N2b per AJCC 7) ipsilateral neck involvement.
Chemotherapy, side effect management, and follow-up
See Larynx chapter.
N T
HPV status as a positive prognostic marker in oropharynx patients
RTOG 0129 (Ang et al. NEJM 2010): Phase III randomized study of 743
patients with stage III/IV oral cavity, oropharynx, hypopharynx, or larynx
cancer randomized to two arms: Arm 1, accelerated fractionation (72
Gy/42 fx in 6 weeks), vs Arm 2, standard fractionation (70 Gy/35 fx). Both
arms were given with concurrent high-dose cisplatin. No difference in
overall survival and toxicity between arms. Post hoc analysis of this trial
found that among oropharynx patients, 3-year OS was 82.4% in HPV+ vs
57.1% in HPV−. RPA was used to risk-stratify patients (with 3-year OS as
endpoint) into low (p16+ and <10-year PY, 94%), intermediate (p16+ and
>10 PY, or p16− and <10 PY, 67%), and high (p16− and >10 PY, 42%) risk
groups based on HPV status, pack-year smoking history, T stage, and N
stage.
Accelerated fractionation
RTOG 00-22 (Eisbruch et al. IJROBP 2010): Single-arm study assessing

feasibility of modest acceleration in early-stage OPC (T1/2 N0/1) by
treating to 66 Gy/30 fx. 2-Year LRF 9%. Acceptable toxicity, frequent grade
≥2 toxicities were salivary (67%), mucosa (24%), esophagus (19%), skin
(12%), and osteoradionecrosis (6%).
RTOG 90-03 (Fu et al. IJROBP 2000; Beitler IJROBP 2014): A
randomized four-arm randomized clinical trial of 1113 stage III-IV OPC,
oral cavity, hypopharynx, and larynx cancer. Arms were Arm 1, standard fx
(70 Gy/35 fx); Arm 2, hyperfractionated (81.6 Gy/68 fx [1.2 Gy bid]); Arm
3, accelerated fractionation with split course (67.2 Gy/42 fx [1.6 Gy bid])
with a 2-week break; and Arm 4, accelerated fx with concomitant boost (54
Gy/30 fx + 18 Gy/12 fx bid boost to a total of 72 Gy). All arms did not
receive concurrent chemotherapy. 2-Year LRC: Arm 1 46% vs Arm 2 54%
vs Arm 3 47% vs Arm 4 54%. At 5 years, only the comparison of Arm 1 vs
Arm 2 was significant for locoregional control (HR = 0.79, P = .05) and OS
(HR = 0.81, P = .05).
DAHANCA 6/7 (Overgaard et al. Lancet 2003): Two randomized trials
enrolling 1485 patients. DAHANCA 6 randomized patients with glottic
tumors and DAHANCA 7 randomized patients with OC and pharynx
cancer. In both studies, patients were randomized to either 5 or 6 fx/wk. All
patients received concurrent nimorazole. Six fractions a week improved
local control (5-year LRC: 60% vs 70%, P = .0005) and disease-specific
survival (5-year DSS: 73% vs 66%, P = .01). No OS difference
Concurrent cetuximab
Bonner trial (Bonner et al., Lancet Oncology 2010; Bonner et al., NEJM
2006): A randomized two-arm study enrolling 424 patients with stage III/IV
OPC, hypopharynx, or larynx cancer. Patients were randomized to
radiation + cetuximab vs radiation alone. Patients were randomized to RT
+ cetuximab exhibit significantly better OS (5 years: 46% vs 36%, P =
.018). Benefit associated with development of grade 2 cetuximab-
associated rash (HR = 0.49, P = .002)
Figure 26.1 Sites of the oropharynx.

SINONASAL AND NASOPHARYNX
SHANE MESKO • ADAM SETH GARDEN
B
Nasopharynx
Incidence/prevalence: 86 000 cases, with 55 000 deaths annually
worldwide. Marked geographic variation: incidence 0.5-2 per 100 000 in
the United States and Western Europe vs endemic regions at 25 per 100
000. Estimated 3000-4000 cases per year in the United States annually
Outcomes: 5-Year survival estimated 38%-72% (Stage I-IV) (SEER data)
Demographics: Median age 55, endemic to Southern China, common in
N. Africa and Middle East
Risk factors: Endemic regions: Male sex (RR 2-3), EBV, and preserved
and smoked foods; nonendemic: smoking and alcohol
Sinonasal
Incidence/prevalence: Incidence 0.56 per 100 000, estimated 2000
cases per year in the US annually, nasal cavity and maxillary sinus most
common
Outcomes: 5-Year survival estimated 35%-63% (Stage I-IV) (SEER data)
Demographics: Median age 50-60; higher frequency of cases in Japan
and South Africa
Risk factors: Male sex, environmental/occupational exposures (eg, wood
dusts, glues, adhesives), smoking, HPV, retinoblastoma
T B C
Nasopharynx
Pathology:
Keratinizing (WHO I): most common sporadic form (25% US, 2%
endemic)
Nonkeratinizing differentiated (WHO II): (12% US, 3% endemic)
Nonkeratinizing undifferentiated (WHO III): commonly associated with
endemic disease and has favorable prognosis (63% US, 95%
endemic)
Sinonasal
Pathology: Squamous cell (36%-58%) is most common, but
adenocarcinoma (12%-15%), melanoma (6%-8%), adenoid cystic
carcinoma (6%), olfactory neuroblastoma (3%-6%), and sinonasal
undifferentiated carcinoma (SNUC) (3%) are also seen.
A
Nasopharynx
Anterior border: Nasal cavity posterior to choana
Lateral border: Torus tubarius, pharyngeal recess (fossa of Rosenmüller)
Superior border: Clivus
Posterior border: Clivus/occipital bone, C1/C2 vertebral bodies
Inferior border: soft palate
Lymph node drainage:
RP nodes
Jugular chain (levels II-IV)
Spinal accessory nodes (level V)
See Oral Cavity chapter for neck LN description.
Local invasion:
Lateral tumors can occlude the eustachian tube (causing hearing
loss). Tumors that extend beyond the nasopharynx laterally can
invade the masticator space.
Inferior extension can invade the oropharynx.
Anterior extension can invade the nasal cavity.
Superior extension can invade the base of the skull (clivus). Further
extension can invade the sphenoid sinus. Intracranial extension can
occur through either the clivus or adjacent foramina. Foramen
lacerum provides easy access to intracranial invasion. Foramen ovale
and rotundum can lead to V3 and V2 deficits and are a conduit to the
cavernous sinus where the abducens nerve (VI) and less commonly
III can be involved. Very advanced cases can either push or invade
the temporal lobe.
Posterior extension can invade the prevertebral muscles and
eventually adjacent bones (inferior clivus, C1). Further extension
through the bone can impinge on the brainstem, or the adjacent
posterior cranial nerves (IX-XII) that emerge from the lateral aspects
of the brainstem.
Sinonasal
Includes the nasal cavity and the paranasal sinuses (maxillary, ethmoid,
sphenoid, and frontal)
The nasal cavity:
Anterior border: Limen nasi and nasal vestibule
Posterior border: Choana
Lateral border: Maxillary sinus
Inferior border: Hard palate of the oral cavity
Superior: Frontal sinus and cribriform plate
The borders of the sinuses are complex. The main point is that they all
abut the orbit and also are in close proximity to the brain.
Nasal vestibule: Submandibular, facial, preauricular, can be bilateral
Nasal cavity and ethmoid sinuses: Retropharyngeal and levels I-II
Maxillary sinus drains to levels I-II; tumors with premaxillary space or
skin involvement can drain to buccal and facial nodes.
Local invasion:
Orbital structures, bones of the hard palate, nasal meatus, cribriform
plate, dura, brain, clivus, and middle cranial fossa
W
History and physical: Assess presenting symptoms including cranial
nerve dysfunction. Direct visualization of tumor and adjacent subsites with
nasolaryngoscope.
Labs: CBC and CMP; consider EBV virus titers pre and post therapy.
Imaging: CT with contrast of the head and neck/skull base to evaluate
bony invasion and LN involvement. MRI with contrast of the head and
neck/skull base to evaluate soft tissue component and cranial nerve
involvement. Consider CT of the chest. FDG-PET/CT is recommended for
Stage III/IV disease.
neck surgical oncology, radiation oncology, medical oncology, nutrition,
and dental (fluoride/extractions). Consider ophthalmologic and endocrine
evaluation.
N C S (AJCC 8
E )
T A
Nasopharynx
S C S (AJCC 8 E )
T A
Sinonasal: ethmoid sinus and nasal cavity
aIndications for post-op chemoRT: positive margins, intracranial extension, ENE

bFor select T1N0 tumors centrally located, low grade, and with negative margins
Consider systemic therapy for all patients with sinonasal undifferentiated

carcinoma (SNUC), small cell neuroendocrine carcinoma (SNEC), or small cell
tumors.
Sinonasal-Maxillary Sinus
aIndications for post-op RT: PNI, positive margins, intracranial extension, adenoid cystic histology, ENE,
T3/4 disease
bFor positive margins, if feasible. Follow with RT ± chemo
cAdd neck dissection for any node-positive disease
Consider systemic therapy for all patients with sinonasal undifferentiated carcinoma
(SNUC), small cell neuroendocrine carcinoma (SNEC), or small cell tumors.
R T T
Dose/target:
Nasopharynx (Definitive, Fig. 27.1)
Gross disease ( CTVHD ):
Dose: 70 Gy in 33-35 fractions, daily
Target: GTV (tumor + involved nodes) + 5-8 mm margin (margins
may be tighter if GTV abuts critical neural structures)
Intermediate risk (CTV ID ):
Dose: 59.4-63 Gy in 33-35 fractions
Target nasopharynx: Entire nasopharynx, RP nodes, clivus
(anterior 1/2 if uninvolved, entire clivus if involved), pterygoid
fossa, parapharyngeal space, sphenoid sinus (inferior 1/2 if
uninvolved, entire if involved or cavernous sinus disease),
posterior 1/3 of maxillary sinus and nasal cavity, cavernous sinus
in locally advanced disease, and skull base (rotundum, ovale,
lacerum).
Target neck (excludes neck covered by CTVHD): In the positive
neck, cover the remaining neck level in the axial plane not
covered in CTVHD and 2 cm cranially and caudally.
Low risk (CTV ED ):
Dose: 54-56 Gy in 33-35 fractions
Target (excludes neck covered by CTVHD and CTVID): In the N0,
neck levels II-IV should be covered. In the involved neck levels
Ib-V; the bilateral RPs should be covered.
PTV expansion: 3-5 mm depending on the setup and IGRT
Sinonasal
PTV expansion: 3-5 mm depending on setup
Technique: IMRT with 6-MV photons is preferred; option to consider
matched low-neck field of 40 Gy in 20 fractions with larynx block, followed
by 10 Gy in 5 fractions with full midline block, however IMRT/VMAT plans
with larynx avoidance may achieve excellent dosimetric results.
Start post-op cases within 6 weeks of surgery.
SIM: Supine, thermoplastic mask, shoulder pull straps. Mouth-opening
tongue-depressing stent (with space to fill cavities in maxillary sinus
cancers, may optimize position to displace tissues that don’t need
treatment, posterior head cradle, isocenter at arytenoids). Consider adding
MR simulation, and/or fuse previous MRI imaging.
IGRT: Daily kV imaging, cone beam CT
Planning directive (for conventional fractionation)
Brainstem: General goal <45 Gy; proximity of targets may require higher
dose and constraint can be set at 54 Gy
Spinal cord: Max 45 Gy
Parotids: Mean < 26 Gy
Mandible: Less than prescribed dose to CTVHD
Brachial plexus: <66 Gy if treating adjacent disease; otherwise max < 60
max
Larynx: Mean < 30 Gy or ALARA
Esophagus: Mean < 30 Gy
Oral cavity: <40 Gy
Optic nerves/chiasm: <54 Gy
Figure 27.1 Definitive chemoradiation planning showing treatment
IMRT treating to 70 Gy to CTVHD and 59.4 Gy to CTVID. A 3D
conformal field is treating 45 Gy to the low neck.
C
Nasopharynx
Concurrent: Cisplatin 30-40 mg/m2 weekly or 100 mg/m2 on days 1, 22,
and 43 (cumulative cisplatin dose goal 200 mg/m2); carboplatin can be
used in patients who cannot tolerate or have contraindication to cisplatin.
Adjuvant: Cisplatin 80 mg/m2 weekly + 5-FU 1000 mg/m2 q4wk × three
cycles
Induction: No defined standard of care; possible regimens include
Docetaxel + cisplatin ± 5-FU
Cisplatin + 5-FU
Cisplatin + epirubicin + paclitaxel
Sinonasal
Concurrent: Cisplatin 30-40 mg/m2 weekly or 100 mg/m2 on days 1, 22,
and 43 (cumulative cisplatin dose goal 200 mg/m2); carboplatin can be
used in patients who cannot tolerate or have contraindication to cisplatin.
Can consider cetuximab
S E M
F -
First posttreatment follow-up at 8 weeks with MRI and/or CT imaging.
Consider PET/CT at 12 weeks if suspicion for persistent disease or lack of
response.
Consider neck dissection for PET-positive lymph nodes with >1 cm of
residual primary disease.
History/physical with nasopharyngoscopy: Every 3-4 months for years 1-3
→ every 6 months for years 4-5
Thyroid function tests every 6 months
Can consider EBV titer monitoring if initially positive pretreatment for
nasopharyngeal
Consider longer-term follow-up for esthesioneuroblastoma as recurrence
can occur >15 years after primary treatment.
N T
Nasopharynx
Benefit of chemoRT over RT alone
Intergroup-0099 (Al-Sarraf et al. JCO 1998): Phase III randomized study of

147 stage III-IV nasopharyngeal cancer patients randomized to definitive
RT vs concurrent cisplatin/RT+ adjuvant cisplatin. The total dose was 70
Gy in 1.8-2 Gy/fx, 66 Gy for involved nodes, and 50 Gy for elective nodes.
3-Year PFS of 24% vs 69% (P < .001) and OS of 46% vs 78% (P = .005)
in favor of chemoRT
Singapore phase II (Wee et al. JCO 2005): Phase II randomized study
randomizing 221 stage III-IV nasopharyngeal cancer patients to definitive
RT vs concurrent cisplatin/RT+ adjuvant cisplatin. Found improved 2-year
OS (78% vs 85%; HR = 0.51, P = .0061) and DFS and DM favoring
chemoRT arm. Confirmed the results of Intergroup-0099 in an endemic
(Asian) population
MAC-NPC meta-analysis (Blanchard et al. Lancet Oncol 2015): 19 trials
and 4806 patients. Found improved overall survival and progression-free
survival with addition of concomitant chemotherapy over RT alone—10-
year OS benefit of 9.9% and 10-year PFS benefit of 9.5%. There was no
OS benefit observed for induction or adjuvant chemotherapy alone.
Benefit of IMRT for nasopharynx cancer
Kam et al. JCO 2007: Randomized 60 patients with T1-2bN0-1M0

nasopharynx cancer to either IMRT or 2DCRT. Patients were treated to 66
Gy in 33 fractions to gross tumor and 60-54 Gy to the node-negative
regions. At 1 year after RT, patients in the IMRT arm had lower rates of
xerostomia (39.3% vs 82.1%, P = .001).
Pow et al. IJROBP 2006: Randomized 51 patients with T2N0-1M0
nasopharynx cancer to IMRT vs conventional RT. IMRT significantly
improves quality of life (P < .001). Most significant improvement in
xerostomia-related symptoms at 12 months for IMRT group.
Induction chemotherapy
GORTEC NPC 2006 (Huang et al. Eur J Cancer 2015): 10-Year outcome
of 408 patients with locoregionally advanced nasopharyngeal carcinoma
randomized to induction chemotherapy (carboplatin + floxuridine) followed
by either chemoRT (carboplatin) or RT alone. No significant differences in
OS (induction chemo 50.4% vs no induction chemo 48.8%, P = .71),
locoregional failure (induction chemo 79% vs no induction chemo 82.5%,
P = .41), or distant failure-free survival (induction chemo 67.7% vs no
induction chemo 66.1%, P = .90).
Sun et al. Lancet Oncol 2016: Phase III multicenter trial randomized 480
patients with locally advanced nasopharyngeal cancer to induction TPF
(cisplatin, fluorouracil, docetaxel) + chemoRT (cisplatin) vs chemoRT
alone. 3-Year failure-free survival favored the induction group (80% vs
72% P = .034).
Cao et al. Eur J Cancer 2017: Phase III multicenter trial randomized 476
patients with locoregionally advanced NPC to induction (cisplatin,
fluorouracil) + chemoRT (cisplatin) vs chemoRT alone. 3-Year DFS (82%
vs 74%, P = .028) and DMFS (86% vs 82%, P = .056) favored the
induction arm. However, OS (88.2% vs 88.5%, P = .815) and locoregional
relapse-free survival (94.3% vs 90.8%, P = .430) showed no difference.
There was a significant (P < .001) increase in grade 3-4 toxicity in the
induction arm.
Adjuvant chemotherapy
Chen et al. Eur J Cancer 2017: Long-term update of phase III multicenter
randomized trial with 251 patients with locoregional advanced NPC.
Patients were randomized to chemoRT (cisplatin) vs chemoRT + adjuvant
chemo (cisplatin, fluorouracil). There was no significant difference in 5-
year failure-free survival (adjuvant 75% vs no adjuvant 71%, P = .45) or
late grade 3 or 4 toxicity (adjuvant 27% vs no adjuvant 21%, P = .14).
LARYNX AND HYPOPHARYNX
COURTNEY POLLARD III • JACK PHAN
B
Incidence/prevalence: Approximately 13 400 laryngeal cancers and
~2500 hypopharyngeal cancers annually in the United States
Outcomes: 5-Year survival across all stages estimated at ~60% for larynx
and 30% for hypopharynx (SEER data).
Demographics: Majority of patients are male and associated with
advanced age (>60).
Risk factors: Larynx cancer—smoking is associated with the vast majority
of cases; in nonsmokers, GERD is associated with larynx cancer.
Hypopharyngeal cancer—in addition to smoking, alcohol abuse, chronic
voice strain, vitamin C and iron deficiencies (Plummer-Vinson syndrome),
and prior head and neck malignancy particularly if the patient received
prior head and neck radiation.
T B C
Pathology: Majority are squamous cell carcinomas (>95%). Minority of
cases are HPV positive but clinical implications are not established.
p16/HPV testing should be considered for all supraglottic cancers and
hypopharyngeal cancers, particularly those arising in nonsmokers. In
larynx cancer, invasive cancer can progress from leukoplakia or
erythroplakia (premalignant lesions).
Symptoms: Hoarseness, sore throat, dysphagia, odynophagia, globus
sensation in the throat, referred otalgia from branch of cranial nerve X
(Arnold nerve), and asymptomatic neck mass
A
The larynx consists of three sites each with multiple subsites (Fig. 28.1):
Supraglottis (suprahyoid and infrahyoid epiglottis, aryepiglottic folds,
arytenoids, false vocal folds, and ventricles)
Glottis (true vocal cords including anterior/posterior commissures, 5
mm inferior to free margin of true cords)
Subglottis (lower boundary of the glottis to the inferior aspect of the
cricoid cartilage). Site incidence: Glottis (65%-70%) > supraglottis
(25%-30%) > subglottis (1%)
The hypopharynx consists of the pyriform sinuses, the postcricoid area,
and the posterior pharyngeal wall (3 Ps). Site incidence: Pyriform sinus
(75%) > posterior pharyngeal wall (20%) > postcricoid (5%) (Fig. 28.1)
Figure 28.1 Larynx and hypopharynx structures. AC, anterior

commissure; AE, aryepiglottic; FC, false cord; IH, infrahyoid; PC,
posterior commissure; SH, suprahyoid; TVC, true vocal cord.
(Adapted from
http://www.laryngologysurgery.com/examinationendoscopy.html.
Reprinted by permission from Dr. Rahmat Omar.)
W
History and physical: Assess presenting symptoms; assess including
voice quality, swallow function, breathing, and ability to protect airway.
Visualization of tumor and adjacent subsites with nasolaryngoscope
and/or mirror exam to assess disease spread. Consider videostroboscopy.
Palpate the thyroid to evaluate for pain as it may be indicative of cartilage
invasion.
Labs: CBC, CMP
Imaging: MRI with contrast or CT with contrast and thin-angled cuts
through the larynx. Evaluation of cartilage invasion and infiltration of
adjacent subsites. Consider CT of the chest. FDG-PET/CT recommended
for stage III/IV disease
neck surgical oncology, radiation oncology, medical oncology,
speech/swallow (swallowing exercise regime), nutrition, and dental
(fluoride/extractions)
L H S (AJCC 8
E , 2018)
The different sites of the larynx have different T staging.
Glottis
Supraglottis
Subglottis
Hypopharynx
Larynx/Hypopharynx NM Staging
Larynx/Hypopharynx Group Staging

Note: TisN0M0 is group stage 0.
L T A
H T A
R T T
Early stage glottic
Dose: T1: 63 Gy in 28 fractions at 2.25 Gy/fx.
T2: 70 Gy in 35 fractions at 2 Gy/fx or 65.25 in 2.25 Gy/fx; consider
hyperfractionation (79 Gy at 1.2 bid) or mild acceleration (bid once per
week to complete treatment in 6 weeks)
Factors that influence local control (especially T2): (1) fraction size 2.25
Gy > 2 >> 1.8 Gy (Le et al. IJROBP 1997), (2) overall treatment time ≤43
days (Le et al. IJROBP 1997), and (3) altered fractionation increases local
control ~10% in T2N0 disease (Trotti et al. IJROBP 2014; DAHANCA—
Overgaard et al. Lancet 2003).
Target: T1: Entire glottic larynx, anteriorly flash 1 cm, posteriorly cover to
anterior edge of vertebral bodies, superiorly cover to top of thyroid
cartilage, and inferiorly cover to bottom of cricoid cartilage (Fig. 28.2)
T2: Same as T1 with adjustments superiorly and/or inferiorly if T2 based
on supraglottic or subglottic extension. Typically with conventional
techniques field border 2 cm above or below GTV
Technique: 3DCRT: right and left opposed laterals, can consider 3 beam
(0, 70, 290 degrees) IMRT for carotid sparing in experienced centers
(Rosenthal et al. IJROBP 2010).
SIM: Supine w/ neck hyperextended, aquaplast mask covering the head
and shoulders, isocenter in midlarynx. Pull straps for shoulder retraction.
Consider thin bolus for patients with anterior disease. Patient should be
reminded not to swallow during simulation or treatment as this can cause
distortion of anatomy.
Figure 28.2 Classic early-stage glottic fields. Smaller box represents
T1 lateral field. Larger box represents T2 lateral field.
A S G ,S ,
S , H
Dose:
Primary tumor and involved nodes: 70 Gy in 33-35 fractions (high dose,
CTVHD) (Fig. 28.4)
High-risk regions (involved nodal level and disease adjacent
mucosa): 60-63 Gy (intermediate dose, CTVID)
Subclinical disease (at-risk nodal levels): 50 Gy in 25 fractions, 54 Gy
in 30 fractions, or 57 Gy in 33 fractions (low dose, CTVED)
Target: Primary tumor with 8 mm to 1 cm CTV margin and involved nodes
receive high dose (CTVHD). Adjacent at-risk tissue, involved nodal levels,
and 1 nodal level above and below involved nodal levels receive
intermediate-risk subclinical dose (CTVID). Uninvolved at-risk nodal levels
receive low-risk subclinical dose (CTVED).
experienced centers.
SIM: Same as for early larynx
L N D
Supraglottic cancers most commonly spread to levels II, III, and IV LNs.
Glottic cancers have almost no LN drainage, so LNs are not covered for
stage I disease and rarely in stage II disease. Subglottic cancers can
involve level VI nodes (Fig. 28.3).
Hypopharyngeal cancers are richly drained by lymphatics and ~75% have
nodal involvement at diagnosis. Levels II, III, VI, and V and RP LNs are
most commonly involved and should be covered when planning XRT. Will
often cover level IV as well.
Figure 28.3 Lymph node involvement of laryngeal cancer based on
site. (Top: Reprinted from Garrett CG, Ossoff RH. Hoarseness. Med
Clin N Am. 1999;83(1):115-123. Copyright © 1999 Elsevier. With
permission. Bottom: Reproduced with permission from Koch WM,
Machtay M, Best S. Treatment of early (stage I and II) head and neck
cancer: The larynx. In: UpToDate, Post TW (Ed), UpToDate, Waltham,
MA. (Accessed on [Date].) Copyright © 2019 UpToDate, Inc. For more
information visit www.uptodate.com.)
Figure 28.4 Representative VMAT treatment plan of patient with

hypopharyngeal cancer involving structures of the larynx including
epiglottis. Note extensive elective LN coverage. Inner RT field shows
high-risk dose (CTVHD) treated to 70 Gy and intermediate-dose CTV
(CTVID) treated to 63 Gy. The outer RT field shows low-dose CTV
treated to 57 Gy.
P -O
Target/dose: Region of resected gross disease: 60 Gy in 2 Gy fractions
(high dose, CTVHD), 66 Gy in 2 Gy fractions for positive margins
Operative bed of primary and LNs: 57 Gy (intermediate dose, CTVID)
Nondissected at-risk regions including nondissected at-risk nodal
levels: 54 Gy (low dose, CTVED). The stoma is typically included in this
volume.
Note: if stoma or tracheostomy is made emergently through tumor, then
this is included in the CTVHD.
capable centers.
SIM: Same as above. Wiring scars helps define the operative bed.
Especially if there was neck disease with ECE, consider bolus for scars,
and also consider bolus for stoma if at increased risk due to disease
proximity.
IGRT: Daily kV Imaging
S C
Indications for neck dissection after definitive XRT or CRT: Persistent
neck disease. Avoid treatment of brachial plexus to doses >66 Gy. If nodal
disease is adjacent to brachial plexus, consider treating disease to 60-64
Gy with a planned nodal dissection.
S
Endoscopic resection: For early-stage tumors—done either via a transoral
laser microsurgery (TLM) technique or transoral robotic surgery (TORS)
technique. Preserves the larynx. Compared to RT, results in equivalent
oncologic outcomes but voice outcomes may not be as good as RT
(controversial)
Total Laryngectomy: Resection of the entire larynx including all three
substructures (supraglottis, glottis, subglottis) and creation of a stoma to
provide a method for the patient to breathe. Requires total thyroidectomy.
Typically can receive primary closure
Pharyngolaryngectomy: Resection of the entire larynx including all three
substructures (supraglottis, glottis, subglottis) and partial resection of the
soft tissues of the pharynx. Performed for bulky hypopharyngeal cancers,
used sparingly secondary to morbidity. Requires creation of a stoma, total
thyroidectomy, and typically requires a flap resection of pharyngeal
structures
C
Concurrent: IV cisplatin 100 mg/m2 every 3 weeks (days 1, 22, and 43) of
RT OR weekly IV cisplatin at a dose of 40 mg/m2. If the patient cannot
tolerate cisplatin secondary to toxicity, weekly carboplatin or cetuximab
can be considered.
Neoadjuvant: Most common regimen is TPF (docetaxel, cisplatin, 5-
flourauracil). Consists of docetaxel at a dose of 75 mg/m2, administered as
a 1-hour infusion on day 1; followed by cisplatin at a dose of 75 mg/m2,
administered as a 1-hour infusion on day 1; and fluorouracil at a dose of
750 mg/m2, administered by continuous infusion on days 1 to 5
(Vermorken et al. NEJM 2007). Can give up to 4 cycles every 3 weeks.
Primarily used for downstaging, NO survival advantages.
Adjuvant: No role.
S E M
F -
General—History/physical with nasolaryngoscopy, TSH, T4, BUN, Cr, CT,
or MRI (use the same imaging as pretreatment): q3mo at year 1 → q4mo
at year 2 → q6mo at years 3-5 → annually after year 5. PET/CT as
baseline posttherapy evaluation ~12 weeks posttreatment, particularly in
the node-positive patient treated definitively
Can consider stopping imaging after year 2 as this is the highest-risk time
period for recurrence; imaging can be saved for clinical symptoms or
suspicious PE findings. Annual CXR—screening for metastases and
second primary.
For early-stage glottic cancers, imaging is not needed; just use
videostroboscopy and regular follow-up with MD.
If PEG tube is placed, follow up with speech pathology and nutrition.
N T
Feasibility of larynx preservation with induction chemotherapy followed
by RT
VA Larynx Trial (Wolf et al. NEJM 1991; Hong et al. Cancer Res 1993):
Phase III randomized controlled trial randomizing 332 ≥ stage III laryngeal
cancer patients to total laryngectomy + post-op RT vs sequential RT:
Induction chemo (cis/5-FU) followed by RT. At 2 years, OS was the same
(68%) with overall larynx preservation rate of 64% in the chemoRT arm.
Decreased DM in the chemoRT arm (11% vs 17%, P = .016) but with
higher rates of local recurrence at the primary site (12% vs 2%, P =
.0005). 5-year follow-up showed no OS difference and persistent larynx
preservation benefits.
Larynx preservation superior with chemoRT
RTOG 91-11 (Forastiere et al. NEJM 2003; updates JCO 2006 and 2013):
Phase III randomized of 547 patients with stage III cancers of the glottis
and supraglottis. Patients were randomized to 3 arms: Arm (1) Induction
chemo (cis/5-FU) followed by XRT (or laryngectomy if poor response plus
adjuvant RT to 50-70 Gy depending on surgical margin status), Arm (2)
concurrent cisplatin and RT, and Arm (3) RT alone (70 Gy in 35 fractions).
Elective neck and SCV received 50 Gy in 25 fractions. Both induction and
concurrent chemoRT regimens improved laryngectomy-free survival over
XRT alone, HR 0.75, P = .02 and .78, P = .03, respectively. No OS
difference between the three arms. Larynx preservation rate was improved
with concurrent chemoRT arm vs the induction arm (HR 0.58, P = .005).
Larynx preservation was similar between the induction chemoRT arm and
XRT alone arm.
SALIVARY GLAND NEOPLASMS
CHRISTOPHER WILKE • BRIAN J. DEEGAN
B
Incidence/Prevalence: Malignant salivary gland tumors account for ~5%
of all H&N malignancies. Annual incidence is ~1 per 100 000 (SEER).
Peak incidence occurs during the sixth decade of life.
Outcomes: 5-Year survival across all stages and sites is estimated at
70%.
Risk factors: Prior radiation, smoking (Warthin tumor), male sex, solvent
exposure
T
Genetics: t(11;19)(q21;p13) translocation creates a fusion oncogene
(CRTC1-MAML2), which is associated with the development of
mucoepidermoid carcinomas (Tonon et al. Nat Genet 2003). t(6;9)
translocations produce the MYB-NFIB fusion protein commonly observed
in many adenoid cystic carcinomas (Persson et al. Proc Natl Acad Sci
USA 2009).
Pathology: Most tumors (~70%) arise in the parotid gland; however, a
majority (70%-80%) of all parotid tumors are benign. In contrast, tumors of
the minor salivary glands are most likely malignant. Mucoepidermoid
carcinoma (MEC) is the most common malignant histology followed by
adenoid cystic (ACC), acinic cell and adenocarcinomas. MEC varies from
low to high grade. Although ACC exhibit different grades, histologic
subtypes substitute for grade with cribriform and tubular being low grade
while solid type is considered high grade. Acinic cell carcinoma is almost
always low grade. Adenocarcinoma is often a catchall descriptor and
includes low-grade polymorphous adenocarcinoma and salivary duct
carcinoma. The latter is a very aggressive high-grade tumor and in recent
years is identified separately. Mixed malignant tumors (MMT) most
commonly have components resembling benign pleomorphic adenomas
but despite this are often high grade.
A
The parotid gland abuts the posterior mandibular ramus and is separated
into the superficial and deep lobes by the plane of the facial nerve.
The facial nerve arises from the base of the pons, traverses through the
temporal bone, and exits the skull base at the stylomastoid foramen.
The submandibular gland is located within the submandibular triangle and
is bounded superiorly by the lower border of the mandible and inferiorly by
the anterior belly of the digastric muscle. The hypoglossal nerve traverses
inferior to the gland, and the lingual nerve (a branch of V3) traverses over
the gland. Either can be involved by cancer, particularly if the cancer is
neurotropic.
Lymph node involvement is less common compared with other H&N sites,
particularly for well-differentiated cancers. Primary drainage is to the
periparotid nodes (for parotid primaries) and ipsilateral neck (primarily
levels I and II). See Oral Cavity chapter for neck LN description.
W
History and physical: Head and neck evaluation with special attention to
cranial nerve deficits. Direct palpation and visualization of tumor and
possibly with nasolaryngoscope and/or mirror exam to assess disease
spread. Major salivary gland masses may represent a lymph node
metastasis from a separate primary site, specifically cutaneous squamous
cell carcinoma of the skin; thus, consider a skin examination of the head
and neck.
Labs: CBC, CMP
Imaging: CT or MRI with contrast of the head/neck. MRI useful for
evaluation of nerve invasion and soft tissue component. CT useful for
evaluation of bone invasion. Consider CT of the chest. Ultrasound can
also be of value for superficial tumors of the parotid or submandibular
glands.
neck surgical oncology, radiation oncology, medical oncology, nutrition,
and dental (fluoride/extractions).
M (AJCC 8
)
Major salivary gland defined as parotid, submandibular, or sublingual gland
M (AJCC 8
)
Tumors arising in minor salivary glands are staged the same as a head and
neck squamous cell carcinoma arising from the same anatomical location. For
example, a minor salivary gland cancer arising from the tonsil region would be
staged as an oropharynx cancer.
S
Surgical management is preferred with definitive radiotherapy reserved for
patients who are not operative candidates or those with unresectable
tumors.
Patients with cN+ typically are treated with a planned neck dissection.
While there is no consensus regarding the role of an elective neck
dissection in all clinically N0 patients, it is generally recommended for
those with high-grade histologies felt to be at highest risk of occult nodal
disease.
C
While the use of platinum agents is often extrapolated from other H&N
sites, there is a lack of prospective data for use in salivary gland tumors
(currently under investigation on RTOG 1008).
Retrospective series have failed to demonstrate a survival benefit with
adjuvant chemoradiotherapy vs radiotherapy alone in these patients
(Amini et al. JAMA Otolaryngol Head Neck Surg 2016).
I
Extraglandular extension
High-grade histology
Close or positive surgical margins
Perineural invasion
Lymph node metastases
Recurrent disease
C
As a general rule of thumb, it is useful to use the contralateral intact gland as a

reference in all patients. All borders listed below are contingent on tumor
extent.
M
( )
Dose: High risk (CTVHD): 60 Gy in 30 fractions at 2 Gy/fx (Fig. 29.1)
*High-risk areas for residual disease (ECE, +margin) can be boosted to 66
Gy.
Intermediate risk (CTVID): 57 Gy (1.9 Gy/fx)
Low risk/elective dose (CTVED): 54 Gy (1.8 Gy/fx)
Target:
CTVHD: Primary and nodal tumor bed with 8- to 10-mm expansion
CTVID: Remaining operative bed not included in CTVHD
CTVED: Ipsilateral neck levels II-IV in N0 patients with high-grade tumors,
coverage of at-risk perineural tracks
Technique: IMRT or IMPT
SIM: Supine with head extended. Thermoplastic mask extending to the
shoulders for immobilization. A tongue-lateralizing oral stent can help
displace the tongue away from the target volume. Scan vertex to the
carina.
IGRT: Daily 2D kV orthogonal imaging or cone beam CT
Dose constraints (at 2 Gy/fx):
Contralateral parotid: Mean < 10 Gy
Oral cavity: Mean < 30 Gy
Larynx: Mean < 30 Gy
Brachial plexus: Max < 66 Gy
Optic nerves and chiasm: Max < 54 Gy. Can go to Max < 60 Gy if
necessary; (ex PNS salivary gland cancer abutting optic structure)
Cochlea: Max < 35 Gy; soft constraint if have to cover facial nerve through
temporal bone
Mandible: Max less than prescription dose for CTVHD
Figure 29.1 Adjuvant treatment for an early-stage adenoid cystic
carcinoma of the left parotid gland with perineural invasion. Maroon,
CTVHD 60 Gy.
S E M
F -
Posttreatment clinical assessment at 4-6 weeks → if response/no
recurrence, then PET/CT at 3 months
History/physical with imaging: Every 3 months for 2 years → then every 6
months for 3 years → annual clinical exam thereafter
TSH every 6-12 months if the neck was treated
Dental evaluation every 6-12 months
Audiology and speech/swallow assessment as needed
N
Retrospective series assessing risk factors and radiation doses
Dutch Cooperative Group (Terhaard et al. IJROBP 2005): Retrospective

analysis of 498 patients with salivary gland tumors treated with surgery
followed by adjuvant radiotherapy or observation. Radiotherapy improved
10-year local control for T3/T4 tumors (84% vs 18%, P < .001), close
margins (95% vs 55%, P = .003), incomplete resection (82% vs 44%, P <
.001), bone invasion (86% vs 54%, P = .04), and perineural invasion (88%
vs 60%, P = .01). For pN+ patients, adjuvant radiotherapy improved 5-year
locoregional control (83% vs 57%, P = .04).
UCSF (Chen et al. IJROBP 2007): Retrospective study of 251 patients
with cN0 carcinomas of the salivary gland treated with surgery and
adjuvant radiotherapy. 52% received elective nodal irradiation. 10-Year
nodal relapse-free survival was significantly improved with elective nodal
irradiation (26% vs 0%, P = .0001). Histologies associated with the highest
rate of nodal relapse included squamous cell carcinoma (67%),
undifferentiated carcinoma (50%), adenocarcinoma (34%), and
mucoepidermoid carcinoma (29%). No nodal failures occurred with
omission of elective neck radiotherapy in adenoid cystic or acinic cell
histologies.
MD Anderson (Garden et al. IJROBP 1995): Retrospective analysis of 198
patients with adenoid cystic carcinomas of the head and neck who
received adjuvant radiotherapy. 10-Year local control rates worse with
positive margins vs close/negative margin (77% vs 93%, P = .006) and
worse with named nerve involvement vs named nerve not involved (80%
vs 88%, P = .02); both positive margins and named nerve involvement vs
one feature vs none (70% vs 83% vs 93%, P = .002). Improved local
control with doses ≥56 Gy in patients with positive margins (88% vs 40%,
P = .006). Recommended doses of 60 Gy to the tumor bed with boost to
66 Gy for patients with positive margins.
Prospective trial demonstrating the benefit of neutron-based radiation
RTOG-MRC Neutron Trial (Laramore et al. IJROBP 1993): Two-arm

prospective randomized phase III trial comparing fast neutron radiotherapy
to conventional photon and/or electron radiotherapy for inoperable or
recurrent malignant salivary gland tumors. Neutron dose was 16.5-22 Gy
in 12 fractions. Conventional RT dose was 55 Gy/4 weeks or 70 Gy/7.5
weeks. Trial stopped after accrual of 32 patients due to significantly
improved local control in neutron arm. Significantly improved 10-year local
control with neutrons (56% vs 17%, P = .009); however, no difference in
OS (15% vs 25%, P = .5)
THYROID CANCER
GARY WALKER • JEENA VARGHESE • ADAM SETH GARDEN
B
Incidence/prevalence: Approximately 56 000 cases diagnosed annually
in the United States
Outcomes: 5-Year survival for well differentiated across all stages
estimated at 98% (SEER data). 5-Year survival for anaplastic histology is
<5%.
Demographics: F > M, 63% are age 35-65
Risk factors: Family history, diet low in iodine, history of goiter, radiation
exposure (diagnostic tests, previous cancer treatment, and nuclear
fallouts), genetics (Cowden’s, MEN2 for medullary), nodules (4% are
malignant)
T
Genetics: Papillary and follicular thyroid cancer associated with defects in
the gene PRKAR1A, familial adenomatous polyposis (FAP), Cowden
disease, Carney complex, and familial nonmedullary thyroid carcinoma.
Medullary thyroid cancer can be familial, either as part of the multiple
endocrine neoplasia type 2 (MEN2) or isolated familial medullary thyroid
cancer syndrome. Anaplastic thyroid cancers appear to arise from
differentiated cancers.
Pathology: Differentiated histologies: Papillary (85%) and follicular (11%)
Derived from neuroendocrine C cells: Medullary (2%)Undifferentiated
histology: Anaplastic (ATC) (1%)Other pathologies of the thyroid include
primary thyroid lymphomas.
A
The thyroid is deep to sternohyoid muscle. Consists of two lobes and
isthmus
Lymph node drainage (35% are cN+)
Prelaryngeal (level VI, delphian)
Pretracheal/paratracheal nodes/mediastinal
Levels II-IV
W
History and physical: Assess presenting symptoms including symptoms
of hyper/hypothyroidism. Direct palpation and visualization of the thyroid
and vocal cords with nasolaryngoscope when advanced
Labs: CBC, CMP, TSH, free T4/T3, T4/T3
Procedures/biopsy: US-guided FNA of primary and enlarged LNs as
Imaging: Ultrasound, 123I thyroid uptake and scan, CT or MRI of the neck
with contrast for locally advanced, PET/CT for anaplastic histology
neck surgical oncology, endocrinology, nuclear medicine, radiation
oncology, medical oncology, speech (evaluation of vocal cord mobility),
T C S (AJCC 8 )
T
a Ref: Haugen et al. Thyroid 2016.
NCCN, National Comprehensive Cancer Network; ATA, American Thyroid Association;

BTA, British Thyroid Association; ESMO, European Society of Medical Oncology.
E R T T
Timing: Should be started within 4-6 weeks of surgery
Dose: Highest risk (close/positive margins/ECE)—63-66 Gy in 30-33
fractions (FIg. 30.1)
High risk (tumor bed)—60 Gy in 30 fractions
Intermediate risk (operative bed)—57 Gy in 30 fractions
Low risk—54 Gy in 30 fractions
Target: The principal target is the central compartment (hyoid to top
of aortic arch and between the carotids). This typically includes the
tumor bed, operative bed, draining lymphatics (levels VI, III-V),
paratracheal (consider level II, only if significant nodal disease with ECE),
tracheal esophageal groove.
Technique: VMAT, IMRT, and IMPT in experienced centers
SIM: Supine, Aquaplast mask. Wire scar. 3-mm bolus 2 cm around scar
IGRT: Daily kV with weekly CBCT or daily CBCT
Figure 30.1 A 74-year-old with four previous resections for papillary

thyroid cancer. Following surgery, he was found to have a 3-cm right
level II node with ECE, 2/10 level right level III nodes up to 2 cm, as
well as a right tracheal sidewall mass resected with SM+. Contours
shown are GTV-LN (green), CTV63 (purple), CTV60 (red), CTV57
(blue), and CTV54 (yellow). Treatment was delivered utilizing
simultaneous integrated boost in 30 fractions. See color insert.
S
Total thyroidectomy or ipsilateral thyroid lobectomy with central neck
dissection
Neck dissection for node positive
Radical neck dissection = I-V, CNXI, IJV, SCM
Modified radical neck dissection = I-V, preserve one of the above
Supraomohyoid = I-III
Lateral = II-IV
Selective neck dissection = LNs based on site
C
Limited role for traditional chemotherapy
TKIs: Lenvatinib, vandetanib, cabozantinib, pazopanib, sorafenib
Anaplastic thyroid cancer: RTOG 0912 is looking at
paclitaxel/pazopanib with radiation; other targeted agents are heavily
investigated. Some ATC can exhibit BRAF mutation, which can be
targeted similar to melanoma with vemurafenib.
S
F -
History/physical exam and ultrasound or CT of the neck: Every 3-6 months
for 3 years → yearly to 5 years. Maintain follow-up with endocrinologist to
evaluate thyroid supplementation and target TSH levels.
Assess compliance with fluoride trays (if applicable) and
neck/lymphedema exercises.
UNKNOWN HEAD AND NECK PRIMARY
HOUDA BAHIG • ADAM SETH GARDEN
B
Definition: Metastatic disease in the lymph nodes of the neck for which
complete workup failed to determine primary tumor origin—diagnosis of
exclusion
Incidence/prevalence: Accounts for 1%-4% of all head and neck
cancers. The incidence of cervical node from unknown primary (CUP) has
diminished significantly with advances in diagnostic imaging and surgical
techniques.
Outcomes: With aggressive radiation approaches, the 5-year overall
survival rate is between 80% and 90%; mucosal emergence occurs in
<10%, and the most common site of recurrence is distant (20%).
Risk factors: Since CUP is often from undetected oropharyngeal cancer,
HPV association is common. Other risk factors include those common for
head and neck cancer in general.
T B C
Pathology: Derived from FNA or core biopsy. Open biopsy is discouraged
because of risk of tumor spillage.
Most common histology is squamous cell carcinoma (75%), of which HPV
(HPV-DNA via PCR and/or p16 on IHC) association is identified in up to
75% of patients. EBV association may also be detected.
HPV+: Likely oropharynx or nasopharynx primary
EBV+: Likely nasopharynx primary
HPV−/EBV−: Head and neck primary including all head and neck
subsites in addition to skin primary
Adenocarcinoma histology is most likely associated with subclavicular
primary origin (eg, esophageal or lung cancer), after salivary gland or
thyroid primary tumors are excluded. Consider thyroglobulin, TTF1,
calcitonin, and PAX8 IHC for undifferentiated carcinoma or
adenocarcinoma.
Other histologies include undifferentiated, lymphoma, melanoma, and
sarcoma.
A
Most likely occult primary origin is the tonsil or base of the tongue.
Upper cervical nodes (levels II, III, and V) are likely from HNC primary
origin.
Consider subclavicular primary origin (lung, gastrointestinal, breast) for
lower cervical (Ievels IV and V) and supraclavicular nodes—associated
with worse prognosis. Consider skin or salivary gland primary origin for
parotid nodes.
The presence of a level II cystic metastasis is a hallmark of HPV-related
SCC.
Level III metastasis without involvement of level II suggests larynx or
hypopharynx primary origin.
See Oral Cavity chapter for discussion of LN levels.
W
History and physical: The oral cavity, entire pharynx, larynx, and skin,
should be carefully examined utilizing palpation and
nasopharyngolaryngoscopy.
Labs: CBC, CMP
Procedures/biopsy: FNA or core biopsy of enlarged LN(s). Evaluation of
histology with appropriate stains. For the most common histology
(squamous), assess HPV status (PCR and/or p16 on IHC) and EBV
staining. Exam under anesthesia with panendoscopy, including palatine
tonsillectomy, random mucosal biopsies, and biopsy of suspicious sites.
Consider bronchoscopy and EGD especially for low LNs (levels IV and V).
Imaging: FDG-PET/CT detects occult primary in 25% of cases and should
be done before EUA with panendoscopy. CT and/or MRI of the head and
neck, CT of the chest (>T0N2b). CT of the chest, abdomen, and pelvis for
lower cervical nodes (levels IV-V)
U P S (AJCC 8 E )
As per AJCC 8th edition, EBV-related cervical adenopathy is staged using
nasopharynx cancer staging and HPV-related cervical adenopathy is staged
using the HPV-mediated oropharynx cancer staging. HPV-unrelated and EBV-
unrelated cervical adenopathy are staged as follows:
Clinical ENE(+): invasion of the skin, infiltration of musculature, dense tethering

or fixation of adjacent structures, or invasion (with dysfunction) of cranial nerve,
brachial plexus, sympathetic trunk, or phrenic nerve.
Pathologic ENE detected on histopathologic examination is designed as ENE

mi (microscopic ENE ≤ 2 mm) or ENE ma (major ENE > 2 mm).
T A
a Favored in patients with open biopsy (violated neck)

R T T
Target:
Dose (Fig. 31.1):

Figure 31.1 Target volumes for CUP with metastasis to left LN
levels II-III, showing CTVHD (red),CTVID (blue), and CTVED
(yellow). See color insert.
Technique: IMRT, IMPT
SIM: Supine position, arms in shoulder straps to lower shoulders from
treatment field, thermoplastic head and neck mask, wire and 3-mm bolus
on surgical scar (if LN dissection or excisional biopsy)
IGRT: Daily kV imaging +/− weekly 3D imaging
Planning directive:
Ensure each PTV coverage by prescription dose with the goal of V100% >
95%, V95% > 99%, V105% < 10%, D max < 120%
OAR dose should respect the following constraints:
C
The chemotherapy regimen is extrapolated from data from head and neck
cancers with detectable primary.
Concurrent: Single-agent cisplatin, carboplatin, or cetuximab

Neoadjuvant: Docetaxel, cisplatin, and 5-FU
S E M
F -
CT of the neck at 8 weeks posttreatment +/− PET/CT at 12 weeks. Failure
to achieve complete response mandates neck dissection.
H&P exam with fiberoptic and skin examination q2-4 mo for years 1-2,
q6mo for years 3-5, and q12mo thereafter. Further follow-up imaging as
TSH q6-12 mo. Annual low-dose chest CT or CXR for patients with
smoking history; smoking cessation counseling as indicated
N T
Surgery alone
Mayo Clinic (Coster et al. IJROBP 1992). Retrospective study of 24

patients with unilateral CUP treated by dissection or excisional biopsy;
58% N1 disease; 33% ECE. Primary developed in 4%; neck recurrence in
25%; all but 1 neck recurrence had ECE. Both N1 patients who recurred
had ECE. 5-Year OS is 66%. Surgery alone may be sufficient in pN1 and
no ECE; consider adjuvant RT if pN2+ or ECE
Radiation
Danish (Grau et al. Radiother Oncol 2000). National survey of 277 pts
with CUP treated with definitive therapy; 81% treated with bilateral neck +
mucosal RT (nasopharynx, hypopharynx, oropharynx, and larynx), 10%
treated with ipsilateral RT, 9% with surgery alone. Mucosal primary
emergence rate was 19% (50% in lung/esophagus). Emergence of
primary was significantly higher with surgery alone vs with RT (54% vs
15%, P < .0001). Relative risk of locoregional recurrence was 1.9 for
ipsilateral RT vs bilateral + mucosal RT.
MD Anderson (Kamal et al. Cancer 2018). Retrospective analysis of 260
pts treated with IMRT to bilateral neck + mucosa. 5-Year OS, regional
control, and DMFS were 84%, 91%, and 95%, respectively. 7% had
chronic radiation-associated dysphagia. No obvious benefit of adding
chemotherapy
Beth Israel (Hu et al. Oral Oncol 2017). 60 patients treated with bilateral
neck RT + oropharynx mucosa; 82% had neck dissection, 55% received
IMRT, and 62% had concurrent chemoradiotherapy. 5-Year regional
control, distant metastasis, and overall survival were 90%, 20%, and 79%,
respectively. 5-Year primary emergence rate was 10% overall and 3% in
nonoropharynx site.
Unilateral vs bilateral radiation
Princess Margaret (Weir et al. Radiother Oncol 1995). Retrospective

analysis of 144 patients with CUP (85 pts irradiated to involved node
region vs 59 pts irradiated to bilateral neck + mucosal sites). 5-Year OS is
41%; trend toward improved survival for treatment of both potential
primary sites and nodes (P = .07), but no difference in both OS and CSS
after adjusting for extent of nodal disease. RT of involved node alone may
be adequate in selected patients.
Loyola (Reddy et al. IJROBP 1997). Retrospective analysis of 52 patients
(36 pts bilateral neck RT + mucosal sites vs 16 pts unilateral neck RT).
Control of contralateral neck: 86% for bilateral RT vs 56% with unilateral
RT (P = .03); mucosal primary emergence 8% for bilateral RT vs 44% for
unilateral RT (P = .0005). Similar 5-year OS. Bilateral RT + mucosal
irradiation is superior for preventing contralateral recurrence and mucosal
emergence.
EARLY-STAGE NSCLC
SHERVIN ‘SEAN’ SHIRVANI • ERIC D. BROOKS • JOE Y.
CHANG
B
Incidence/prevalence: The second most common diagnosed cancer
and leading cause of cancer death among men and women in the
United States.
Outcomes: 5-Year survival estimated at 54% for localized disease,
26% for regional nodal involvement, and 4% for distant disease
(SEER). NOTE: 5-Year survival often worse for patients treated with
SABR compared with surgery; most patients treated with SABR are
medically inoperable and expected to have shorter life expectancy
due to greater comorbidities (selection bias). Recent pooled
randomized data show SABR yields equivalent or better OS
compared with lobectomy and nodal dissection in medically operable
patents (STARS/ROSEL trials).
Risk factors: Smoking, radon, ionizing radiation, asbestos,
chromium, male sex, family history, acquired lung disease (ie,
interstitial pulmonary fibrosis), and other occupational exposures
(silica, arsenic, beryllium, coal).
Prognostic factors: Stage, performance status, weight loss,
molecular mutations.
T B C
Genetic markers: Higher percentage of clinically relevant mutations
that are targetable are found in adenocarcinomas. These include
EGFR (~20% of adeno cases), ALK (~5%), KRAS, ROS-1 (~2%),
BRAF, MET, RET, and PDL-1.
Pathology: Majority are adenocarcinomas (40% of lung
malignancies), then squamous cell carcinomas (30%). Rarer
histologies include large cell (15%), neuroendocrine, bronchoalveolar
(arising from type II pneumocytes), and carcinoid.
A
Right lung: 3 lobes (upper, middle, lower) and 2 fissures (major,
minor)
Left lung: 2 lobes (upper, lower) and 1 fissure (major)
Drainage most commonly to ipsi hilar/mediastinal nodes.
Hematogenous spread common.
Lymph node names (numeric classifications) (Fig. 32.1):
Supraclavicular: Low cervical, supraclavicular, and sternal notch (LN
station 1) Superior mediastinal: Upper paratracheal (2R/L),
prevascular (3a), retrotracheal (3p), and lower paratracheal (4R/L)
Aortic: Subaortic (5) and para-aortic (6) Inferior mediastinal:
Subcarinal (7), paraesophageal (8), and pulmonary ligament (9) N1:
Hilar (10), interlobar (11), lobar (12), segmental (13), and
subsegmental (14)
Pancoast tumor (syndrome): Superior sulcus tumor associated with
shoulder pain, Horner syndrome (ipsilateral ptosis, miosis,
anhidrosis), and atrophy of hand muscles
Early-stage (T1-3N0) tumors are divided into central and peripheral
lesions. The central zone is defined as the region within 2 cm of the
proximal bronchial tree (Fig. 32.2) (which extends from the trachea to
the lobar bronchi and other central structures [esophagus, heart,
pericardium, great vessels, vertebral body]). Peripheral lesions are
beyond this 2-cm zone. Distinction is important for risk of lymph node
spread and treatment planning.
Figure 32.1 Diagram illustrating mediastinal and thoracic lymph
node stations. (Adapted from Edge SB, Byrd DR, Compton CC,
Fritz AG, Greene FL, Trotti A III. eds. AJCC cancer staging
manual. 7th ed. New York, NY: Springer; 2010. Copyright © 2010
American Joint Committee on Cancer. Reproduced with
permission of Springer in the format Book via Copyright Clearance
Center.)
Figure 32.2 Central zone figure. (Reprinted from Chang JY,
Bezjak A, Mornex F, et al. Stereotactic ablative radiotherapy for
centrally located early stage non-small-cell lung cancer: what we
have learned. J Thorac Oncol. 2015;10(4):577-585. Copyright ©
2015 International Association for the Study of Lung Cancer. With
permission.)
W
History and physical: Typically present with cough, shortness of
breath, hemoptysis, weight loss, and/or incidental mass on chest x-
ray/CT.
Screening: Annual low-dose CT scan recommended for pts aged 55-
74 with ≥30 pack-year smoking history and cessation <15 years ago
(NLST NEJM 2011).
Labs: CBC, CMP
Procedures/biopsy: Consider CT-guided biopsy if able to obtain
tissue of primary. Not necessary if pathology more easily obtained by
sampling suspicious nodes during mediastinal staging. Selective
sampling of hila/mediastinum (eg, mediastinoscopy, EBUS) is
recommended for higher-risk characteristics including central tumors,
radiographic suspicion of adenopathy, or ≥T2a tumors but should be
considered for all tumors. Pulmonary function testing to evaluate
surgical candidacy and to provide baseline.
Imaging: CT of the chest w/ contrast and PET/CT to rule out
regional/distant disease for all patients. Brain MRI for all ≥T2a tumors
(optional for T1b) or neurologic symptoms. Consider MRI of the
shoulder for superior sulcus tumors and octreotide scans if with
carcinoid histology.
NSCLC S (AJCC 8 )
T A
R T T
(S A R ,
C S B R
T )
SIM: Supine with Vac-Lok device and arms above the head. Four-
dimensional imaging required. If tumor moves more than 10 mm,
consider breath-hold technique or gating if patient is able to hold
breath. Scan from base of the skull to top of the kidneys to
encompass lung volume across the entire respiratory cycle.
Dose: Goal is BED > 100 (Onishi et al. showed this is required for
optimal local control).
50 Gy to PTV in 4 fractions (peripheral)
70 Gy to PTV in 10 fractions (central that cannot be safely treated
with 50 Gy in 4 fractions, or peripheral lesion abutting the chest wall
where 50 Gy in 4 fractions could lead to chest wall injury/pain).
Note: For large-volume PTV in central regions, consider SIB (70 Gy to
iGTV, 50 Gy to PTV in 10 fractions).
Target: iGTV: Tumor across all phases of respiratory cycle (contour
on MIP) or, when used, across all breath-hold trials.
PTV: iGTV + 5 mm.
Technique: 3DCRT, IMRT/VMAT. 6-10 MV photons with
heterogeneity correction.
IGRT: Daily cone beam CT with respiratory management.
Peripheral tumor planning directive (for 50 Gy in 4 fractions):
Chest wall: V30 ≤ 30 cc
Skin: V30 ≤ 50 cc
Vessels: V40 ≤ 1 cc, D max ≤ 56 Gy
Trachea: V35 ≤ 1 cc, D max ≤ 38 Gy
Bronchial tree: V35 ≤ 1 cc, D max ≤ 38 Gy
Brachial plexus: V30 ≤ 0.2 cc, D max ≤ 35 Gy
Esophagus: V30 ≤ 1 cc, D max ≤ 35 Gy
Heart/pericardium: V40 ≤ 1 cc, V20 ≤ 5 cc, D max ≤ 45 Gy
Spinal cord: V20 ≤ 1 cc, D max ≤ 25 Gy
Ipsilateral lung: iMLD ≤ 10 Gy, iV10 ≤ 35%, iV20 ≤ 25%, iV30 ≤ 15%
Total lung: MLD ≤ 6 Gy, V5 ≤ 5%, V10 ≤ 17%, V20 ≤ 12%, V30 ≤ 7%
Central tumor planning directive (for 70 Gy in 10 fractions):
Chest wall/skin: V50 ≤ 60 cc, D max ≤ 82 Gy
Vessels: V50 ≤ 1 cc, D max ≤ 75 Gy
Trachea: V40 ≤ 1 cc, D max ≤ 60 Gy
Bronchial tree: V50 ≤ 1 cc, D max ≤ 60 Gy
Brachial plexus: V50 ≤ 0.2 cc, D max ≤ 55 Gy
Esophagus: V40 ≤ 1 cc, D max ≤ 50 Gy
Heart/pericardium: V45 ≤ 1 cc, D max ≤ 60 Gy
Spinal cord: V35 ≤ 1 cc, D max ≤ 40 Gy
Total lung: MLD ≤ 9 Gy, V40 ≤ 7%
S E M
Esophagitis: Magic mouthwash (viscous lidocaine, Benadryl,
nystatin), glutamine supplement (eg, Helios), aloe products, and
narcotic elixir second line.
Chest wall pain: OTC analgesics (eg, Tylenol, NSAIDs) or neuropathic
agents (select agent based on pain etiology—radicular/neurogenic,
myositis/muscular), narcotics second line.
Pneumonitis: For symptomatic patients (shortness of breath,
reduction in O2 on pulse oxygenation), consider oral steroid taper
(typically prednisone starting at 1 mg/kg daily for 2-3 weeks with
taper). Bactrim prophylaxis for PCP pneumonia and antacid
prophylaxis for gastric ulcers.
F -U
CT of the chest with contrast q3mo for years 1-2, q6mo for years 3-5,
and annually thereafter.
PET for suspicious CT findings (establish postradiation changes vs
recurrence).
Biopsy for imaging findings consistent with recurrence.
N L
Stereotactic body radiation therapy—single arm
RTOG 0236 (Timmerman et al. JAMA 2010, update ASTRO abstract

2014): 55 patients with inoperable, stage I NSCLC. Peripheral only.
54 Gy in 3 fractions (heterogeneity corrected) over 1.5-2 weeks. 3-
Year LC 98%, LRC 87%, DFS 48%, and OS 54%. 17% grade 3 or
higher toxicity (4% grade 4 or higher). At 5 years, LC is 98%, LRC
62%, and OS 40%. Importantly, EBUS was not required prior to
treatment on this trial.
RTOG 0813 (Bezjak et al. ASTRO abstract 2015 and 2016): Phase
I/II trial of 120 patients with inoperable, central (within 2 cm of
tracheal/bronchia tree or adjacent to mediastinal/pericardial pleura),
stage I NSCLC. 50-60 Gy in 5 fractions. Treatment was given every
other day for 1.5 to 2 weeks. Less than 10% dose-limiting treatment
toxicity observed but several treatment-related deaths were reported.
Final results for oncologic outcomes are pending; however, 7/33
patients treated to 11.5 Gy or 12 Gy/fx had grade 3+ toxicity.
Phase II SABR Study (Sun et al. Cancer 2017): 65 patients,
inoperable, stage I, median of 7.2-year follow-up. 7-Year local
recurrence was 8.1% and regional recurrence 13.6%. 7-Year PFS
was 38.2%, and OS was 47.5%. 4.6% of patients experienced grade
3 or greater events. No grade 4 or 5 events.
RTOG 0915. Single fraction SBRT randomized phase II (Videtic et al.
IJROBP 2015). 94 patients, medically inoperable treated to either 34
Gy/1 fx or 48 Gy/4 fx. Adverse event rate between single fraction and
multiple fraction regimens similar (10.1% vs 13.3%), along with local
control at 1 year (97% vs 92.7%).
Comparison of SBRT vs surgery
STARS/ROSEL Combined Analysis (Chang et al. Lancet Oncol

2015). Unplanned pooled analysis of two randomized controlled trials
comparing SBRT and lobectomy. 58 patients randomized. SBRT arm
had similar 3-year relapse-free survival (86% vs 80%, P = .54) and
improved overall survival (95% vs 79%, HR 0.14, P = .037). Lower
grade 3+ event rates with SBRT vs surgery (10% vs 44%). Further
studies are warranted to compare these treatment strategies.
STAGE III NSCLC
STEPHEN GRANT • ERIC D. BROOKS • DANIEL GOMEZ
B
Incidence/prevalence: Stage III NSCLC accounts for ~1/3 of all
NSCLC cases.
Outcomes: 5-Year OS for stage III is highly variable and dependent
on numerous factors including performance status and comorbidities,
estimated to be between 5% and 35% (IIIA, 30%; IIIB, 10%-15%).
Demographics and risk factors: See Early Stage NSCLC chapter.
T B C
See Early Stage NSCLC chapter.
A
W
T A (S III)
aIncludes patients with multiple N2 stations, N3, bulky/invasive LN, lobectomy not feasible, med
inoperable
bPACIFIC trial: ↑ PFS with durvalumab (anti–PD-L1) compared to placebo following chemoRT
R T T
Simulation:
Supine, upper body cradle, arms above head, and wedge below
knee. A 4DCT preferred. Consider breath-hold if tumor moves >1
cm. Optional fusion with PET
Dose:
Definitive (able to tolerate chemotherapy): 60 Gy in 30
fractions with concurrent chemotherapy
Consider simultaneous integrated boost to GTV to 66 Gy.
PORT: 50.4 Gy in 28 fractions or 50 Gy in 25 fractions
Increase dose for areas of concern (60-66 Gy for positive
margins).Add concurrent chemo for gross residual dx.Add
sequential chemo for N2 disease.
Neoadjuvant: 45 Gy in 1.8 Gy/fx > surgery if operable or
completion to 60-66 Gy radiation if inoperable
RT alone (if unable to tolerate chemotherapy): 45 Gy in 15
fractions to PTV and SIB to 52.5-60 Gy in 15 fractions to GTV.
Superior sulcus tumors:
Neoadjuvant: 45 Gy in 1.8 Gy/fx > surgery if operable or
completion to 60-66 Gy radiation if inoperableAdjuvant: Consider
Hyper FX regimen (60 Gy in 1.2 Gy/fx bid) to minimize late
radiation effects and reduce risk of brachial plexopathy (Gomez
et al. Cancer 2012).
Target:
Definitive/neoadjuvant:
CTV: GTV contoured on MIP + 8 mm, edited out of the bone and
heart, and includes involved nodal stations and, if dose
constraints met, ipsilateral hilum (no other elective nodal
irradiation except ipsilateral hilum if staging adequate)
PTV: CTV + 5 mm if daily kV or CTV + 3 mm if daily CBCT
Technique:
IMRT/VMAT or protons
IGRT:
Daily kV imaging and weekly CBCT
Planning directive (for daily fractionation):
Spinal cord: D max < 45 Gy
Total lung: MLD < 20 Gy, V20 < 35%, V10 < 45%, and V5 < 60%
Heart: V30Gy < 45%, mean < 26 Gy
Esophagus: D max < 80 Gy, V70 < 20%, V50 < 40%, and mean < 34
Gy
Kidney (bilateral): V20Gy < 32%
Liver: V30Gy < 40%, mean liver <30Gy
Brachial plexus: D max < 66 Gy
S
Surgical resection alone is not sufficient treatment for locally
advanced NSCLC.
Standard surgery is lobectomy with mediastinal lymph node
dissection.
Other options depending on the extent of disease include
pneumonectomy, segmentectomy, and sleeve resection
S T
Most commonly given alone in the preoperative setting or concurrent
with radiation
Concurrent chemo:
Cisplatin and etoposide
Cisplatin and vinblastine
Carboplatin and pemetrexed
Cisplatin and pemetrexed
Carboplatin and paclitaxel
Neoadjuvant and adjuvant chemo:
Multiple platinum-based combinations including cisplatin with
etoposide, paclitaxel, pemetrexed, and vincristine
If patient can’t tolerate cisplatin, consider carboplatin and
paclitaxel.
Immunotherapy
Adjuvant durvalumab for at least 1 year (if no progression of
disease after definitive chemoradiation).
S E M
F -U
History/physical and CT: Every 3 months for 2 years → annually for 3
years
Postradiation toxicity
Esophagitis peaks 1-2 weeks after radiation therapy and then
resolves weeks-monthsRadiation pneumonitis: Occurs 6 weeks to 1
year following RT with symptoms of dyspnea, cough, and fatigue.
Inflammatory changes within RT field on imaging. Treat with high-
dose steroid taper.Esophageal stricture/fistula (months-years)Long-
term dyspnea/fibrosis (months-years)Brachial plexopathy for apical
tumors (years)
N L T
Evidence supporting trimodality therapy
INT 0139 (Albain et al. Lancet 2009): Phase III randomized study of
429 operable stage IIIA (N2) patients randomized to surgery
(pneumonectomy or lobectomy) vs no surgery following neoadjuvant
chemoradiation. All patients received adjuvant cisplatin/etoposide. RT
in the surgery arm was 45 Gy/25 fx. Those randomized to no surgery
received definitive chemoRT to a total of 61 Gy. Median PFS
improved in surgical arm (12.8 vs 10.5 months, P = .017), but not 5-
year OS (27% surgery vs 20% chemoRT, P = .10). Unplanned
subgroup analysis showed that pneumonectomy was associated with
high mortality risk but that lobectomy was associated with improved
OS compared to patients randomized to no surgery.
SWOG 9416 (Rusch et al. JCO 2007): Phase II single-arm study of
110 superior sulcus tumor patients with T3-4N0-1. Patients received
45 Gy with concurrent cisplatin/etoposide → surgical resection →
adjuvant cisplatin/etoposide × 2 cycles. 83 patients underwent
complete resection and pathologic complete response seen in 61
patients. 5-Year survival was 44% for all patients and 54% after
complete resection.
Postoperative radiation (PORT)
PORT Meta-analysis Trialists Group (Lancet 1998). Included 2128

patients who were treated on 9 randomized controlled trial between
1966 and 1994. OS was found to be worse in those who received
PORT with an HR of 1.21 (P = .001).
Adjuvant Navelbine International Trialist Association (ANITA)
Trial. (Douillard et al. IJROBP 2008). Retrospective analysis of a
prospective adjuvant chemotherapy trial where patients were
randomized to surgery +/− chemo. PORT was recommended for pN+
patients but not mandated. 238/840 patients (28%) received PORT to
45-60 Gy. In univariate analysis among all patients, PORT deleterious
on OS, but survival benefit was seen in pN2 patients regardless of
whether chemotherapy was given.
Evidence supporting definitive chemoradiation approach
EORTC 08941 (van Meerbeeck et al. JNCI 2007): Phase III

prospective randomized trial of 579 operable stage III patients
randomizing to induction chemotherapy followed by either surgery or
radiation (60-62.5 Gy total). PORT allowed in surgical arm if positive
margins (40% of patients received PORT on surgical arm). 5-Year OS
(resection, 15.7%; and RT, 14%) and PFS were not significantly
different between arms. Radiation was associated with less morbidity.
RTOG 9410 (Curran et al. JNCI 2011): Three-arm prospective
randomized trial of 610 patients with inoperable stage II-IIIB NSCLC.
The three arms were the following: arm 1, induction chemotherapy
followed by radiation (vinblastine/cisplatin → 63 Gy in 34 fractions in
1.8 Gy × 25 fractions and then 2 Gy × 9 fractions); arm 2, standard
daily chemoradiation (cisplatin/vinblastine and 63 Gy in 34 fractions);
and arm 3, concurrent bid high-dose chemoradiation
(cisplatin/etoposide and 69.6 Gy in 58 fractions bid). Acute toxicity
was worse in the bid chemoradiation arm, specifically acute
esophagitis grade 3-4: arm 1, 4%; arm 2, 23%; and arm 3, 42% (P <
.001). However, OS was moderately improved with chemoradiation
arms compared to sequential treatment: arm 1, 14.6 months; arm 2,
17 months; and arm 3, 15.6 months.
NSCLC Collaborative Group Meta-Analysis (Auperin et al. JCO
2010). Combined data from six eligible RCTs of locally advanced
NSCLC, total of 1205 patients. Concurrent chemoRT found to be
associated with absolute survival benefit of 4.5% at 5 years (P =
.004).
Benefit with adjuvant immunotherapy after chemoradiation
PACIFIC (Antonia et al. NEJM 2017): Phase III randomized trial of

713 patients with stage III unresectable NSCLC randomized after
completion of definitive chemoradiation to adjuvant durvalumab for 1
year (anti–PD-L1 immunotherapy) or observation. PFS was higher
with adjuvant durvalumab (16.8 vs 5.6 months, HR = 0.52, P < .001).
Time to distant metastasis or death was also better with durvalumab
(23.2 vs 14.6 months, P < .001). Grade 3-4 toxicity was not increased
with durvalumab (29.9% vs 26.1% placebo). Patients with and without
PD-L1 expression benefited.
Dose escalation for definitive chemoradiation leads to worse
outcomes
RTOG 0617 (Bradley et al. Lancet Oncol 2015): Phase III 2 × 2

randomized trial of stage IIIA-B to dose-escalated chemoradiation (60
vs 74 Gy with carboplatin/paclitaxel). Patients then were randomized
for the second time to receive adjuvant cetuximab or nothing. The trial
was closed early due to futility. OS was worse in the 74 Gy group (1
year: 80% vs 69.8%, P = .004) and adding cetuximab did not improve
survival. Reason for the poorer survival in the high-dose group was
possibly worse heart dose (no DVH restraints required). Secondary
analysis demonstrates correlation of increased heart V40Gy with
worse survival (Chun et al. JCO 2017).
SMALL CELL LUNG CANCER
ALEXANDER AUGUSTYN • ERIC D. BROOKS • DANIEL
GOMEZ
B
Incidence/prevalence: ~30 000 cases of SCLC per year in the
United States (15% of all lung cancer diagnoses). About 1/3 are
diagnosed with limited stage disease.
Outcomes: 5-Year survival for stage I, II, III, and IV disease is 31%,
19%, 8%, and 2%, respectively.
Demographics: Average age of diagnosis is 70. Highest incidence in
white male smokers
Risk factors: Smoking is the biggest risk factor (>90% of patients are
heavy smokers). Increasing age, asbestos, and radon gas exposure
are also risk factors.
T B C
Genetics: TCGA genomic profiling of 110 SCLCs identified loss of
TP53 and RB1 in nearly all cases. 25% of patients exhibited
inactivating NOTCH pathway mutations. Targetable mutations in
EGFR, ALK, K-RAS, and ROS-1 not seen in SCLC
Pathology: Malignant epithelial tumor of small round blue cells of
neuroendocrine origin (Fig. 34.1) and scant cytoplasm. Necrosis often
extensively seen in pathologic specimens with high mitotic count.
SCLC is grouped into two variants: small cell carcinoma and
combined small cell carcinoma, which include SCLC cells and any
histologic subtype of NSCLC. On pathology, positive staining seen for
synaptophysin, chromogranin A, IGF-1, and CD56 and typically
negative for TTF1 and keratin (which are positive in NSCLC)
Imaging: Enhance significantly on contrasted CT and highly PET-avid
as well (Fig.34.1). Typically presents centrally as opposed to
peripherally
Figure 34.1 Representative CT (left) and PET (middle) images
obtained from a patient presenting with cough/weight loss. The
LUL mass and L hilar LNs were biopsied with pathology returning
as SCLC. Note the small, round blue cells with scant cytoplasm
and large nuclei which is classic for SCLC (right image).
W
History and physical: High frequency of bulky mediastinal
lymphadenopathy leads to shortness of breath, hoarse voice,
dysphagia, and/or superior vena cava syndrome. Evaluate for
neurologic symptoms, paraneoplastic syndromes, and bone pain.
Labs: CBC, CMP, LFTs, and LDH. SCLC is the most common solid
malignancy associated with paraneoplastic syndromes: Syndrome of
inappropriate antidiuretic hormone SIADH seen in 11%-15% of
patients. Ectopic Cushing syndrome (5%) and Lambert-Eaton
syndrome (1%-3%) are also observed.
Procedures/biopsy: Bronchoscopy +/− FNA with biopsy if central,
CT-guided, or thoracentesis for peripheral lesions. If cT1-T2N0
disease with no evidence of distant metastases, consider mediastinal
staging.
Imaging: CT of the chest with contrast and PET/CT done for staging
(identifying distant metastases, distinguishing between limited stage
and extensive stage). MRI of the brain w/ contrast performed on all
patients as the brain is a sanctuary site with respect to chemotherapy
and frequently the first site of failure in patients with SCLC
A
See Early NSCLC section.
S C L C S (AJCC
8 )
(Same as NSCLC; however, use of historical “limited” and “extensive”
stage definitions is frequently made)
VA L C S G S
Historical definitions:
Limited stage: Intrathoracic disease that can be encompassed
within a reasonable radiation field, excluding those with pleural or
pericardial effusions. However, applicability of these definitions to
modern techniques is questionable. Overall, “limited” = localized;
“extensive” = metastatic
Extensive stage: All others
T A
C T G
LS-SCLC:Acceptable regimens for limited stage disease (maximum
4-6 cycles)
Cisplatin or carboplatin with etoposideDuring concurrent
chemoradiation, cisplatin/etoposide is recommended.
ES-SCLC:Acceptable regimens for extensive stage disease
(maximum 4-6 cycles)
Cisplatin or carboplatin with etoposide
R T T
SIM: 4DCT, supine, both arms abducted holding T-bar, upper Vac-
Lok, wingboard, and knee wedge. Consider breath-hold technique if
motion is >1 cm on 4D CT scan (Fig. 34.2).
Dose: Limited stage: 45 Gy in 30 fractions twice a day (at least 6
hours apart) at 1.5 Gy/fx (preferred MDACC approach).
If bid fractionation is not feasible, acceptable alternative is 1.8-2.0
Gy/d to a dose of 60-70 Gy. Radiation should be delivered
concurrently with chemotherapy, ideally beginning during cycle 1.
Extensive stage: 30 Gy in 10 fractions or 45 Gy in 15 fractions daily.
Target: Paradigm similar to NSCLC. GTV defined by most recent
PET/CT. If chemo is given first, can limit GTV to postchemo tumor
volume. Use prechemo PET/CT involved LN stations. Historically,
elective nodal radiation was used, but it is omitted in current trials as
rate of nodal failure is low when using PET/CT for staging.
Margins: 5- to 10-mm CTV, 5-mm PTV expansion for daily CBCT.
Technique: IMRT (Fig. 34.3)
IGRT: For free breathing treatment setup, daily kV imaging, and
weekly CBCT For breath-hold treatment setup, CBCT before each
fraction
Planning directive (either daily or BID fractionation)
Ensure coverage of PTV by >95% of prescription dose
Spinal cord D max < 36 Gy (bid), <45 Gy (daily).
Mean lung dose <20 Gy, V20 < 35%, V10 < 45%, and V5 < 60%
Heart V30 < 45 Gy, mean heart dose <26 Gy
Esophagus D max < 80 Gy, V70 < 20%, V50 < 40%, mean dose <34
Gy
Kidney (bilateral) V20 < 32%
Liver V30 < 40%, mean liver dose <30 Gy
Brachial plexus D max < 50.6 Gy (bid), <3 cc, >44.5 Gy (bid), D max <
66 Gy (daily)
Chest wall V40 < 150 cc (bid) (Figs. 34.2 and 34.3)
Figure 34.2 Typical SCLC/NSCLC simulation setup showing a
patient positioned supine with a wingboard, upper Vac-Lok device,
both hands gripping a T-bar. Opaque markers mounted on a box
are taped to the patient’s abdomen to assess breathing.
Figure 34.3 Limited stage SCLC IMRT plan. 45 Gy isodose line

showed in blue surrounding PTV (sky blue color wash), CTV (tan),
and GTV (red). Note sparing of contralateral lung. See color
insert.
P C I (PCI)
IndicationFor limited stage, PCI should be discussed for patients with
a partial or complete response following chemoRT, as it decreases
the risk of developing brain metastasis by about 50% and improves
OS based on clinical studies. Restage after completion of chemoRT
and if no progression (local or distant) then consider starting PCI 6-12
weeks after chemoRT completion.
For extensive stage, a thorough discussion should take place in
context of conflicting data (Takahashi et al. Lancet Oncol 2017;
Slotman et al. NEJM 2017). Patients should be informed that it will
reduce the risk of developing subsequent brain metastases with
questionable OS benefit.
midbrain.
Dose: 25 Gy in 10 fractions
Target: Whole brain, ensure coverage of cribriform plate and inferior
edge should extend to C1/C2 vertebral bodies.
Technique: 3DCRT. Beam arrangement typically opposed laterals or
right and left anterior obliques (gantry angled to 85 and 275 degrees)
to spare lens exposure due to beam divergence.
IGRT: Usually no image guidance, setup to marks only. Consider daily
MV or kV imaging.
S
High local recurrence rates (35%-50%) suggest that surgery may offer
benefit in local control.
Surgical resection generally only recommended for patients with a
solitary pulmonary nodule, no evidence of local/regional
lymphadenopathy, no distant metastatic disease, and no
contraindications to surgery. Lobectomy preferred
The survival of patients undergoing surgery for pathologic stage I, II,
and III disease was 48%, 39%, and 15% at 5 years.
No randomized trials exist for adjuvant therapy; however, most
patients receive adjuvant chemotherapy and adjuvant radiation for
those found to have pathologic N1 or N2 disease.
S E M
Nausea: Zofran, Compazine, Reglan, low-dose dexamethasone,
Haldol, IV fluids
Pneumonitis: For symptomatic patients (eg, shortness of breath, drop
in pO2), consider oral steroid taper (typically prednisone starting at 1
mg/kg daily for 2-3 weeks, remember Bactrim prophylaxis for PCP
pneumonia and antacid prophylaxis for ulcers)
nystatin), glutamine supplement (eg, Helios), aloe products, narcotic
elixir second line
Dermatitis: Aquaphor or other moisturizing cream, gel sheets
Chest wall pain: Analgesics, physical therapy
Neurocognitive side effects of PCI: Memantine 20 mg bid (start 20 mg
daily ×1-2 weeks and then increase) to reduce risk of late
neurocognitive side effects in patients with >6 months expected
survival
F -U
History/physical and CT: Every 3 months for 2 years → annually for 3
years.
Postradiation toxicity
Esophagitis peaks 1-2 weeks after radiation therapy and then
resolves weeks-monthsRadiation pneumonitis: Occurs 6 weeks to 1
year following RT with symptoms of dyspnea, cough, and fatigue.
Inflammatory changes within RT field on imaging. Treat with high-
dose steroid taper.Esophageal stricture/fistula (months-years)Long-
term dyspnea/fibrosis (months-years)Brachial plexopathy for apical
tumors (years)
N T
Chemoradiation vs chemotherapy alone
RT Meta-analysis (Pignon et al. NEJM 1992): Meta-analysis

evaluated 13 trials with 2140 patients comparing chemo vs chemoRT
and identified a 5% increase in 3-year overall survival with chemoRT
(8.9 → 14.3%; P = .001). Local control improved from 16% to 34%. A
trend was seen toward a larger reduction in mortality among younger
patients (<55 years). Chemotherapy was predominately
cyclophosphamide or doxorubicin based, not cisplatin + etoposide,
which is standard of care.
Daily vs twice daily thoracic radiation in limited stage disease
INT 0096 (Turrisi et al. NEJM 1998): Evaluated biologic advantage of

bid treatment based on empiric data that the dose-response curve for
SCLC lacks a shoulder. Prospective randomized phase III trial
comparing daily vs twice daily concurrent chemoRT. Patients with
limited stage disease were randomized to daily thoracic RT to 45 Gy
in 1.8-Gy fractions over 5 weeks vs thoracic RT to 45 Gy in 1.5-Gy
fractions BID. All patients receiving concurrent cis/etoposide. PCI was
offered to those with a complete response after 12 weeks. OS at 5
years was improved by 10% with bid fractionation (16% vs 26%, P =
.04), along with decreased rate of local failure in bid arm (36% vs
52%, P = .06). However, there was increased incidence of grade 3
esophagitis in bid fractionation arm (27% vs 11%, P < .001).
CONVERT Trial (Faivre-Finn et al. Lancet Oncol 2017). Randomized
547 limited stage SCLC patients to either BID chemoRT (45 Gy/30 fx)
or daily chemoRT (66 Gy/33 fx). Primary endpoint was 2-year OS and
was found to be nonsignificant (56% BID vs 51% daily, P = .14).
Toxicities were similar aside from increased grade 4 neutropenia in
BID group (49% vs 38%, P = .05). Grade 3 esophagitis nonsignificant
between both arms (19% in both)
Role of consolidative chemoRT in extensive stage disease

Yugoslavia trial (Jeremic et al. JCO 1999): Phase III trial enrolled 210
patients treated w/ 3 cycles of cisplatin/etoposide. Pts w/ distant CR +
local CR/PR randomized to RT (54 Gy in 36 fractions over 18 days)
with concurrent carboplatin/etoposide followed by 2 more cycles of PE
vs no radiation and 4 additional cycles of cisplatin/etoposide. PCI
done for all patients with distant CR. Median survival improved in
chemoRT consolidation arm (17 vs 11 months, P = .041).
Netherlands trial (Slotman et al. Lancet 2015): Phase III study
randomizing 498 ES-SCLC patients who had any response to
cisplatin/etoposide to thoracic RT and PCI vs PCI alone. All patients
received 4-6 cycles of cisplatin/etoposide. Thoracic RT was started
within 7 weeks of chemotherapy to a dose of 30 Gy in 10 fraction
targeting the postchemo GTV with a 15-mm margin. For those who
received prechemoradiation, the involved hilar and mediastinal nodes
were included. OS was improved at 2 years in thoracic RT arm (13%
vs 3%, P = .004). Consolidative thoracic RT improved 6-month PFS
(24% vs 7%, P = .001) and resulted in 50% reduction in intrathoracic
recurrences.
Evidence for prophylactic cranial irradiation in SCLC
PCI Meta-Analysis (Auperin et al. NEJM 1999). A total of 987 patients

included from seven RCTs who received PCI vs no PCI in SCLC
patients who achieved complete response to therapy (12%-17% had
ES-SCLC). 3-Year OS was 21% vs 15% in favor of PCI (P = .01). 3-
Year local control in the brain was 33% for PCI arm vs 59% in no PCI
arm (P < .001). Larger RT doses (8, 24-25, 30, 36-40 Gy) led to
greater decrease in risk of mets, but no impact on survival.
EORTC 08993-22993 (Slotman et al. NEJM 2007). Phase III RCT of
PCI vs no PCI in ES-SCLC with any response to platinum-based
therapy. PCI doses ranged from 20 to 30 Gy in 10 fractions. 1-Year
OS found to be improved with PCI (27.1% vs 13.3%, P = .003) with
reduced incidence of brain mets (14.6% vs 40.4%, P < .001).
Japanese Trial (Takahashi et al. Lancet 2017). Phase III RCT of PCI
vs no PCI in ES-SCLC patients with any response to platinum-based
doublet chemotherapy. PCI dose 25 Gy/10 fx. At 1 year, PCI reduces
incidence of brain mets (32.9% PCI vs 59% no PCI, P < .0001),
without improvement in median survival (11.6 months PCI vs 13.7
months no PCI, P = .094). Importantly, unlike the EORTC 08993-
22993 study, patients received MRI for upfront staging. Close MRI
surveillance was performed (q3mo) on all pts.
THYMOMA AND THYMIC CARCINOMA
SAMANTHA M. BUSZEK • ERIC D. BROOKS • QUYNH-NHU
NGUYEN
B
Incidence/prevalence: Rare, ~0.15/100 000, the most common
neoplasm of the anterior mediastinum
Outcomes: 5-Year OS by Masaoka stage: stage I, 95%; stage II,
90%; stage III, 60%; and stage IV, 11%-50%. Thymic carcinoma,
20%-30%
Demographics: Median age 40-60 years; equal in males and
females
Risk factors: May be related to autoimmune disorders including
myasthenia gravis. No other known etiologic risk factors
T B C
Pathology: Histologic subtypes include benign, medullary, and
spindle cell, mixed; moderately malignant, lymphocyte-rich,
lymphocytic, predominantly cortical, organoid, cortical, epithelial,
atypical, squamoid, and well-differentiated thymic carcinoma; and
highly malignant, thymic carcinoma (<1% of thymic tumors).
A
Thymus originates from thymic epithelial cells (third pharyngeal pouch);
involved in processing and maturation of T lymphocytes to recognize
foreign Ag from self-Ag
Thymomas: 1%-2% lymph node metastasis rate and 1% distant

metastasis (mostly to the lung)
Thymic carcinomas: 30% lymph node metastasis rate and 12%
distant metastasis (lung, bone, liver)
Lymph node drainage to the lower cervical, internal mammary, and
hilar nodes
Differential of mediastinal mass
Anterior: Thymoma, thymic carcinoma, carcinoid, germ cell tumor,
lymphoma, and goiterMiddle: Cysts > lymphomas, teratomas >
sarcomas, and granulomaPosterior: Neurogenic tumors (PNET,
schwannomas, neurofibroma, neuroblastoma, ganglioneuroma) and
pheochromocytoma
W S
History and physical: 1/3 asymptomatic (incidental), 1/3 myasthenia
gravis, and 1/3 thoracic symptoms (cough, SOB, CP, SVC). Ask for B
symptoms (rule out lymphoma). Thymoma diagnosed clinically if
mediastinal mass + symptoms of myasthenia, red cell aplasia, or
hypogammaglobulinemia
Labs: LDH, ESR, and AFP/HCG (rule out germ cell tumor).
Paraneoplastic syndromes include myasthenia gravis (35%-50%),
due to autoAb to postsynaptic AChR; symptoms, easy fatigability,
double vision, and ptosis; diagnosis, Tensilon test (edrophonium);
treatment, AChE inhibitors (pyridostigmine) or thymectomy. May also
present with red cell aplasia (5%), immune deficiency syndromes (ie,
hypogammaglobulinemia, 5%), autoimmune disorders (collagen
vascular, dermatologic, endocrine), and other malignancies
(lymphomas, GI/breast carcinoma, Kaposi sarcoma)
Imaging/procedures: CT of the chest with contrast preferred. MRI
optional. PET/CT if lymphoma or thymic carcinoma suspected, PFTs.
If thymoma is suspected, straight to surgery (avoid biopsy if
resectable to avoid seeding)
N T T C
S (AJCC 8 )
T A a
Prognosis: associated with completeness of resection

If myasthenia gravis, signs and symptoms should be controlled
medically before surgery
aWith new AJCC staging, these recommendations may change.

R T T
SIM: 4DCT, supine, upper Vac-Lok device. Consider breath-hold if
tumor moves >1 cm.
Dose: Unresectable: 60-70 Gy (45-50 Gy to PTV and 60-70 Gy SIB to
GTV)
PORT: R0 resection = 45-50 Gy; R1 resection = 54 Gy; R2 resection
= 60-70 Gy
Target: GTV: grossly visible tumor/tumor bed (clips can be useful if
placed)
CTV: Entire pretreatment superior-inferior extent of disease,
posttreatment lateral extent (respect anatomic boundaries and follow
pleural spaces)PTV: 0.5-1 cm based on IGRT
Technique: IMRT or VMAT
C
Induction: Can downstage if unresectable
First line: Cytoxan/adriamycin/cisplatin (CAP) +/− prednisone
Adjuvant: Thymoma with gross residual disease or thymic carcinoma

with R1-R2 resection
Possible chemotherapy regimens includeVP-16/ifosfamide/cisplatin
(VIP)Cisplatin/VP-16
(EP)Carboplatin/paclitaxelCisplatin/adriamycin/vincristine/Cytoxan
(ADOC)
S E
F -U
History/physical q3-12mo + annual CT of the chest for life (late
recurrences can occur for >10 years)
N L
Adjuvant radiation therapy after surgical resection
Peking 1999 (Zhang Chin Med J (Engl) 1999): 29 patients

randomized trial (stage I, age <65). Surgery vs surgery → adjuvant
RT. RT AP and/or two anterior oblique wedge fields. Lymphocytic
predominant, 50 Gy/25 fx; epithelial/mixed, 60 Gy/30 fx. Outcome: no
recurrence or mets in either group; 10-year OS surgery 92% vs
surgery + RT 88% (NS). Conclusion: Adj RT not necessary for stage I
thymoma
ITMIG 2016 (Rimner et al. JCO 2016): 1263 patients with stage II-III
thymoma and R0 resection were analyzed from a retrospective
database consisting of patients from 39 centers (international). Those
who received PORT after R0 resection were compared to those who
did not receive PORT. Patients who received PORT had significantly
longer 10-year OS (86% vs 79%, P = .002). However, patients
receiving PORT were younger, more likely to have myasthenia gravis,
had more stage III disease, were male, had larger tumors, had
malignant thymomas, and were less likely to receive chemotherapy.
Recurrence-free survival was not affected by giving PORT. As such,
selection bias must be taken into account for possibilities in survival
benefit; however, PORT remained a significant factor on multivariate
analysis and for both Stage II and III thymoma. As such, this provides
evidence and support for PORT in stage II-III completely resected
thymoma.
MESOTHELIOMA
NIKHIL G. THAKER • ERIC D. BROOKS
B
Incidence/prevalence: Approximately 3000 cases diagnosed
annually in the United States. Overall incidence in decline in the
United States due to less asbestos exposure.
Outcomes: Median survival is ~12 months (range 4-20 months). MS
8 months sarcomatoid, 19 months epithelioid, and 13 months mixed
subtype. Stage I MS = 20 months, Stage II MS = 19 months, Stage III
MS = 16 months, Stage IV MS = 11 months (Rusch et al. J Thorac
Oncol 2012)
Demographics: Peak incidence in fifth to seventh decades.
Risk factors: 70%-80% related to asbestos exposure (commonly
found in insulation, ship building, construction work, and brake pads
and therefore 90% male predominance). Rod/needle (amphibole)
greater risk factor than serpentine (chrysotile). Latency is 20-40 years
due to chronic pleural irritation leading to malignant transformation.
Smoking + asbestos increases risk.
T B C
Genetics: Four distinct molecular subtypes: sarcomatoid, epithelioid,
biphasic-epithelioid (biphasic-E), and biphasic-sarcomatoid (biphasic-
S) based on RNA-seq. Mutations in BAP1, NF2, TP53, SETD2,
DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51. Loss of tumor
suppressor genes p14, p16, and NF-2. Alterations in Hippo, mTOR,
histone methylation, RNA helicase, and p53 signaling pathways
Pathology: Sarcomatoid (15%-25%), epithelioid (40%-60%, best
prognosis), and mixed subtypes (25%-35%). May be confused with
adenocarcinoma (IHC or electron micro required to differentiate).
Imaging: Appears as a pleural thickening, possibly with pleural
plaques, calcifications, involvement of interlobar fissures on x-ray and
CT imaging
A
Mesothelium is a membrane composed of simple squamous
epithelium, which forms the lining of pleura (thoracic cavity),
mediastinum, pericardium, peritoneum, tunica vaginalis testis, and
tunica serosa uteri.
The inner lining of the pleura is the visceral pleura and outer lining is
the parietal pleura. Parietal pleura includes the mediastinal and
diaphragmatic pleura.
Pleura extends from SCV fossa (thoracic inlet) superiorly to the
insertion of the diaphragm inferiorly.
Mesothelioma spreads by direct extension and seeding into the
pleural space, through the chest wall, into the mediastinum, to the
peritoneum, and to the lymph nodes. It has a tendency to grow along
tracks of biopsies or chest tubes. Lymph node drainage:
Peribronchial, internal mammary nodes (IMN), hilar, and ipsi and
contralateral mediastinum
Spreads to level 8 (lower paraesophageal), level 9 (pulmonary
ligament), and diaphragmatic nodes more frequently than NSCLC
Axillary and/or supraclav (SCV) nodes at risk if with chest wall
involvement
W
History and physical: Ask about asbestos exposure. Evaluate
performance status. Typically present with weight loss and respiratory
symptoms
Labs: CBC, CMP, and PFTs
Procedures/biopsy: Historically, biopsy is done via thoracentesis,
but if VATS is being done, obtain biopsy at that time. Perform
pulmonary function tests to evaluate operability. VATS to r/o c/l or
peritoneal dz. Mediastinoscopy to r/o N2/N3 disease. Renal scan prior
to RT
Imaging: CT of the chest/abdomen with contrast for pleural effusions
or calcified pleural plaques. Chest MRI with contrast and PET/CT
scan optional and typically done to determine chest wall/diaphragm
invasion.
M P M S
(AJCC 8 )
T A
S
Surgical resection possible in only a minority of patients with T1-3N0-
1
Extrapleural pneumonectomy (EPP) provides the greatest
cytoreduction and includes the en bloc resection of the parietal and
visceral pleura, lung, pericardium, and ipsilateral diaphragm.
Mediastinal lymph node sampling of at least three stations is
recommended. Graft is placed in the region of the diaphragm.
Pleurectomy and decortication (P/D) is the complete removal of the
pleura, and all gross tumor +/− en bloc resection of the pericardium
and/or diaphragm with reconstruction, P/D can be considered for
patients with more extensive disease (greater nodal burden, more
invasive disease) or medically high risk. Allows expansion of the ipsi
lung and reduces recurrent pleural effusions
Pleurodesis with talc can be palliative.
R T T
SIM: Supine, arms up, with a wingboard, upper body Vac-Lok device,
and T-bar. 4DCT scan. Wire scar/drain sites. Consider 5-mm bolus (3
cm) around the scar/drain sites. Scan from thoracic inlet (beg. of ribs
around T1) through below the ribs (at least L2 or as inferiorly as
possible). If PD or biopsy only, get quantitative perfusion scan to
assess lung function (FEV1 [% contribution contralateral lung] should
be >30% predicted).
Dose: 45-50.4 Gy in 28 fractions at 1.8 Gy/fx, consider SIB to gross
disease, positive margin, and PET-avid regions to 60 Gy (2.4 Gy/fx) to
increase the likelihood of local control.
Palliation: Several possible regimens, including 45 Gy in 15 fractions,
30 Gy in 10 fractions, or 20 Gy in 5 fractions. ≥4 Gy for skin
nodules/pain from chest wall invasion
Prophylactic: 7 Gy × 3 to drain sites (Boutin et al. Chest 1995 and
NCCN), although may not reduce rate of seeding (Clive et al. Lancet
Oncol 2016), not done routinely at MDACC
Target: Ipsilateral hemithoracic pleural surfaces, including the
parietal/visceral pleura, diaphragm, and involved nodal stations (Fig.
36.1). Modify contours to include scars and drains with ~2.5 cm
margin. Approach center of the sternum anteromedially and
approach/abut the spinal canal posteromedially. Include the
diaphragm crus/insertion (~L2) inferiorly. Utilize surgical clips, scars,
and drain sites. High-risk areas for contouring misses: costophrenic,
costodiaphragmatic, anteromedial pleural reflection, and
cardiophrenic angles. If treatment after P/D or biopsy alone, consider
1 cm outside chest wall, 0.6 cm into lung parenchyma (+/− inclusion
of fissures) with “donut” technique.
Technique: IMRT/VMAT (Fig. 36.2)
IGRT: Daily kV imaging with once or twice weekly CBCT up to daily
CBCT (depending on setup stability)
Planning directive (for 45 Gy in 25 fractions sp EPP and with
optional boost to 54-60 Gy for R1/R2 resection AND hemithoracic
RT on protocol sp P/D):
Target: V95% or D95% of the PTV is 45 Gy; D99%-100% of CTV gets
45 Gy.
Contralateral lung: MLD < 8 Gy, V20 < 7%
Liver: V30 < 50%, Mean < 30 Gy
Contralateral kidney: V15 < 20%
Ipsilateral kidney: V20 < 33% (compromise coverage if necessary
based on renal scan results)
Stomach: Mean < 30 Gy
Esophagus: V55Gy < 70%, V60Gy < 30%, Mean < 34Gy
Heart: V40Gy < 70%, V45Gy < 30, V30Gy < 45%, Mean < 26Gy%
Spinal cord: D max < 50 Gy, V45Gy < 10%
Major vessels: 5 cc < 70 Gy, 10 cc < 60 Gy
Brachial plexus: D max < 60 Gy, 1 cc < 50 Gy, 10 cc < 40 Gy
Figure 36.1 IMRT/VMAT contours for right-sided mesothelioma.
For palliative cases, utilize standard lung constraints (see NSCLC

sections).
Figure 36.2 IMRT/VMAT plan for right-sided mesothelioma.
C
Agents: Cisplatin and pemetrexed +/− bevacizumab
S E M
Haldol, IV fluids
Pneumonitis: For symptomatic patients (eg, shortness of breath, drop
in pO2), consider oral steroid taper (typically prednisone starting at 1
mg/kg daily).
nystatin), glutamine supplement (eg, Helios), aloe products, narcotic
elixir second line
Dermatitis: Aquaphor or other moisturizing cream, gel sheets
Chest wall pain: Analgesics, physical therapy
F -U
CT of the chest/abdomen/pelvis: at 6 weeks, then q3mo for 2 years
and then q6-12mo thereafter. PET/CT scan can also be used at 3
months and then PRN for suspicious findings on CT imaging.
N L
EPP +/− hemithoracic RT
SAKK Trial (Lancet Oncol 2015). Questioned whether hemithoracic

RT improves outcomes following EPP and chemo in mesothelioma in
a randomized trial (phase II). Fifty-four patients received neoadjuvant
cisplatin and pemetrexed followed by EPP and were eligible for
randomization to hemithoracic RT vs observation. RT provided no
LRR benefit, OS benefit, and added toxicity and detracted from
baseline QOL compared to observation. However, this included
unfavorable histologies (eg, sarcomatoid)—although this was only 4%
of the population—and the trial was likely not powered enough to
detect meaningful differences. However, the study results suggest
that the role of radiation needs to be discussed thoroughly with
patients and evaluated with further protocols moving forward. The
rationale for continued use of RT in the EPP setting comes from
retrospective studies showing reasonable outcomes with
multidisciplinary management.
Intensity-modulated radiation therapy s/p EPP
Harvard (Allen et al. IJROBP 2006). 13 patients treated with IMRT to

54 Gy. Most also received heated intraoperative cisplatin. 46% fatal
pneumonitis. Beams passing through contralateral lung. Pulmonary
death: MLD 15.2 Gy, V20 17.6%. No pulmonary death: MLD 12.9 Gy,
V20 10.9%
MD Anderson (Rice et al. IJROBP 2007). 63 patients s/p EPP, Stages
III-IV. IMRT to 45-50 Gy. MS: 14.2 months. LRR 13%, DM 54% (only
7 received chemo). Pulmonary death: 9.5%. Pulmonary death: MLD
10.2 Gy, V20 9.8%. No pulmonary death: MLD 7.6 Gy, V20 3.6%.
Recommended constraints: MLD < 8.5 Gy, V20 < 7%
MD Anderson (Gomez et al. J Thorac Oncol 2013). 86 patients s/p
EPP and adjuvant IMRT (45-50 Gy). Median OS 14.7 months. Grade
5 pulmonary toxicity, n = 5. Grade 3+ toxicity: skin 17%, lung 12%,
heart 2.3%, and GI 16%. LRR 16%, DM 59%
Intensity-modulated radiation therapy s/p P/D

MD Anderson (Chance et al. IJROBP 2015). Hemithoracic IMRT post
P/D vs post EPP. Retrospective. 48 patients (24 each group). Nearly
all had neoadjuvant chemotherapy. Epithelioid and sarcomatoid/mixed
histologies (~75% epithelioid). P/D IMRT associated with improved
OS 28.4 vs 14.2 months, improved PFS 16.4 vs 8.2 months
MSKCC (Gupta et al. IJROBP 2005). 125 patients s/p P/D followed by
RT. Median dose 42.5 Gy. MS 13.5 months, 2-year OS 23%. LC 42%.
RT dose <40 Gy, nonepithelioid, left-sided disease, and use of implant
worse. 12 pts with pneumonitis, 8 pts with pericarditis, and 2 pts died
from grade 5 toxicity.
Chemotherapy
University of Chicago (Vogelzang et al. JCO 2003). Randomized

phase III trial. 456 pts, unresectable disease. Pemetrexed/cisplatin vs
cisplatin alone. Response rate: 41% vs 17%. TTP 6 vs 4 months. OS
12 vs 9 months
ESOPHAGEAL CANCER
LISA SINGER • ERIC D. BROOKS • DANIEL GOMEZ
B
Incidence/prevalence: The seventh leading cause of cancer death in
men in the United States; 16 940 cases diagnosed each year (15 690
estimated deaths); lifetime risk 0.5%
Outcomes: 5-Year survival for local, regional, and distant disease
42.9%, 23.4%, and 4.6%, respectively (SEER)
Demographics: More common in men; squamous cell carcinoma
prevalent in developing nations (>90%). Adenocarcinoma more
common in developed countries including the United States (~70%
cases). Typically diagnosed between ages 50 and 70. Men account
for 80% of the diagnoses.
Risk factors: Squamous cell carcinoma risks include tobacco,
smoking, alcohol, asbestos, and possibly HPV. Adenocarcinoma risks
include obesity, hiatal hernia, elevated BMI, and Barrett
esophagus/GERD.
T B C
Genetics: HER-2 (25% of adenocarcinomas+), COX-2, EGFR
overexpression; TP53 mutations common
Pathology: Squamous cell carcinoma or adenocarcinoma; Barrett
esophagus is replacement of squamous with columnar epithelium and
is associated with progression to adenocarcinoma.
A
The esophagus extends from the pharynx to the stomach, the trachea
anteriorly.
Total length of the esophagus estimated to be 25 cm.
Cardia marks the junction of the stomach and esophagus.
Locations of esophageal tumors and lymph node drainage
summarized below.
W
History and physical: Typically present with progressive dysphagia,
weight loss, and/or worsening heartburn
Screening: Indicated for patients with documented Barrett esophagus
(usually via biannual EGDs) (Fig. 37.1). Risk of development to
esophageal cancer is 0.1%-0.4% per year.
Labs: CBC and CMP. Consider HER-2 tested for adenocarcinoma if
metastatic.
Procedures/biopsy: EGD and EUS +/− FNA (most sensitive for
nodal staging). Consider bronchoscopy to rule out tracheal invasion of
tumors located above the carina.
Imaging: CT of the chest/abdomen/pelvis with contrast and PET/CT
to rule out regional/distant disease for all patients
Figure 37.1 Image taken from surveillance upper endoscopy of a

63-year-old male with long-standing history of Barrett esophagus.
Note the ulcerated mucosal lesion, which was biopsied and
consistent with superficially invasive esophageal adenocarcinoma.
E TNM C S (AJCC
8 )
S S (AJCC 8 )
T A
a Note: Postoperative chemoradiation only recommended for ≥pN1+ if adenocarcinoma histology,

observation recommended for ≥pN1+ squamous cell histology.
R T T
SIM: NPO ×3 hours. Supine, arms up if tumor below carina (arms
down if tumor above carina), immobilization device, iso at carina; scan
from the mandible through stomach and celiac axis. Consider oral
contrast to delineate tumor and head and neck mask for cervical
primaries. 4DCT for GEJ tumors to account for movement.
Dose: 50.4 Gy in 1.8 Gy/fx with concurrent chemotherapy
Consider 66-70 Gy boost to GTV only for definitively treated
squamous tumors.
Target: GTV = PET/CT + primary and nodal disease at EGD/EUS
CTV = 3-4 cm mucosal margin superiorly/inferiorly and 1 cm radial
margin, trimmed from surrounding structures (Fig. 37.2)PTV = 5 mm
margin with daily kV imaging
Technique: IMRT and proton therapy (under investigation)
IGRT: Daily kV imaging, consider weekly CBCT
PTV: 50.4 Gy in 28 fractions
GTV (squamous undergoing definitive treatment): 66.6 Gy in 37
fractions (sequential boost)
Esophagus minus GTV: D max < 70 Gy, V50 < 50%
Heart V30 < 45%, mean < 26 Gy
Total lung mean dose <20 Gy; V5 < 65%, V10 < 45%, V20 < 25%
Liver minus GTV: Mean dose <32 Gy, V20 < 50%, V30 < 30%
Kidney V20 < 33% each kidney
Stomach D max < 54 Gy
Figure 37.2 Representative cross-sectional image illustrating
typical contours for an esophageal adenocarcinoma patient. GTV,
CTV, and PTV contours showed in orange, red, and pink,
respectively. See color insert.
S
Approaches to esophagectomy:
Transhiatal esophagectomy: Upper midline laparotomy and L
neck incision; often uses gastric pull-through approach for
cervical anastomosis; usually avoids thoracotomy
Transthoracic esophagectomy, Ivor-Lewis approach: R
thoracotomy of the abdomen and upper abdominal laparotomy
incisions allow for direct visualization of thoracic esophagus but
limit length of proximal esophagus that can be removed.
Transthoracic esophagectomy, modified Ivor-Lewis approach: L
thoracoabdominal incision only with anastomosis in L chest
Conduits: Following esophagectomy. Connection between the
remaining esophagus and stomach, colon, or jejunum
Lymph node dissection: Should include at least 15 LNs if no preop
chemoRT
C
Concurrent with RT, preoperative or definitive:
Paclitaxel/carboplatin or 5-FU/cisplatin, or 5-FU/oxaliplatin
Adjuvant: Capecitabine or oxaliplatin
Perioperative (thoracic adenocarcinoma or GEJ): 5-FU/cisplatin,
ECF (epirubicin, cisplatin, 5-FU)
RT S E M
Haldol, and IV fluids
nystatin), glutamine supplement (eg, Helios), aloe products, and
narcotic elixir second line.
Thrush: Nystatin swish/swallow, fluconazole
Weight loss: Nutrition consult/diet modifications, opiates if needed;
may require feeding tube
Leukopenias due to chemotherapy: Weekly labs with
transfusion/Neupogen PRN
Pneumonitis: ~6 weeks to 1 year after RT and may present with
cough, dyspnea, and fever. Prescribe steroid taper (60 mg for 2-3
weeks with taper) and/or NSAIDs. Patient may even require O2.
Late effects: Tracheoesophageal fistula (5%-10%) if esophageal
tumor invades trachea; presents as choking with PO intake, coughing,
or recurrent pneumonias; treatment may involve stent or surgery (Ke
et al. J Thorac Dis 2015). RT induced pericarditis and coronary artery
disease in long-term survivors.
F -U (P NCCN)
History/physical: Every 3-6 months for 1-2 years → every 6-12
months for 3-5 years
CT of the chest/abdomen with contrast: Every 4-6 months for the first
year and every 6-9 months for the next 2 years
EGD: Every 3-6 months × 2 years and then 6-12 months in definitive
chemoRT or early-stage surgical patients
N L
Outcomes with definitive chemoradiation
RTOG 85-01 (Herskovic et al. NEJM 1992; Cooper et al. JAMA 1999):
Phase III trial randomizing 129 patients with cT1-3, N0-N1, M0
squamous cell carcinoma, or adenocarcinoma of the esophagus to
RT alone (50 Gy + 14 Gy boost) vs chemoRT (30 Gy + 20 Gy boost
with 5FU and cisplatin); 5-year OS 0% vs 27% in RT alone vs
chemoRT. No significant differences in late effects but acute toxicity
worse in chemoRT arm
INT-0123/RTOG 94-05 (Minsky et al. JCO 2002): Phase III trial
randomizing patients to 50 Gy or high-dose (65 Gy) chemoRT with
concurrent 5FU and cisplatin; trial stopped due to interim analysis
demonstrating equivalent 2-year OS and LR with decreased
treatment-related death in standard vs high-dose arms (2% vs 10%).
Neoadjuvant chemoradiation improves overall survival
CROSS Trial (van Hagen et al. NEJM 2012; Shapiro et al. Lancet
Oncol 2015): Phase III trial randomizing patients with resectable
squamous cell or adenocarcinomas of the esophagus or GEJ to
surgery alone or pre-op chemoRT (41.4 Gy/23 fx with
carboplatin/paclitaxel) followed by surgery. 366 patients randomized.
Median OS improved with preop chemoRT (49.4 vs 24 months, P =
.003). Furthermore, R0 resection rates improved with chemoRT (92%
vs 69%, P < .001). pCR rate 29% overall (49% for SCC and 23% for
adenocarcinoma)
COLORECTAL CANCER
AHSAN FAROOQI • CHAD TANG • PRAJNAN DAS
B
Incidence/prevalence: The third most common diagnosed cancer
and third leading cause of death among men and women in the
United States. Approximately 39 220 cases are diagnosed annually in
the United States.
Outcomes: 5-Year survival across all stages estimated at 67%
(SEER data)
Demographics: Lifetime risk 1 in 20 (5%). Highest incidence in
Western countries
Risk factors: Increasing age, familial syndromes (FAP, HNPCC,
Peutz-Jeghers syndrome, juvenile polyposis), personal or family
history of polyps, obesity, sedentary lifestyle, EtOH consumption,
tobacco use, inflammatory bowel disease, low-fiber diet, and Western
diet
T B C
Genetics: TCGA genomic profiling identified ~16% of colorectal
cancers hypermutated. Frequent mutations in APC, TP53, SMAD4,
PIK3CA, and KRAS (Cancer Genome Atlas Network Nature 2012).
Four consensus molecular subtypes proposed include CMS1
(hypermutated microsatellite unstable, 14%), CMS2 (epithelial with
marked WNT and MYC signaling, 37%), CMS3 (epithelial and
metabolically dysregulated, 13%), and CMS4 (mesenchymal, 23%)
(Guinney et al. Nature Med 2015).
Pathology: Majority adenocarcinomas (>90%). Minority
neuroendocrine, mesenchymal tumors or lymphomas. IHC testing for
mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6)
commonly conducted and predictive of response to immunotherapy
(Le et al. Science 2017). Consider testing for BRAF and KRAS
mutations.
Imaging: MRI accurate tool for local staging and for assessment of
pelvic lymphadenopathy. Tumors typically visualized on high-
resolution T2-weighted sequences, with increased signal on DWI
sequence. Endorectal US can help distinguish between T1 and T2
tumors.
A
Rectum: Begins at the rectosigmoid junction at the level of S3.Total
length of the rectum estimated to be between 12 and 15 cm.
Squamous mucosa ends at the dentate line (~2 cm from anal verge).
Internal anal sphincter ends 2 cm superior to dentate line (~4 cm from
anal verge).
Colon: Cecum is the junction between the small and large intestines
(intraperitoneal) → ascending colon (retroperitoneal) → transverse
colon (intraperitoneal) → descending colon (retroperitoneal) →
sigmoid colon (intraperitoneal).
Upper half rectum: Superior hemorrhoidal → IMA → para-aortic
Lower half rectum: Inferior + middle hemorrhoidal → internal iliac,
obturator presacral nodes
Involvement of anal canal: Superficial inguinal nodes
Invading anterior structures (prostate, bladder, vagina) →
external iliac
W
History and physical: DRE for all patients and pelvic exam in
women
Labs: CBC, CMP, CEA
Procedures/biopsy: Colonoscopy with biopsy of primary(ies)
Imaging: Contrast-enhanced CTs of the chest/abdomen/pelvis
(important to image the liver) for all patients. MRI of the pelvis w/
contrast typically done as well (if available). Contrast-enhanced
PET/CT is not routinely indicated.
C R C S (AJCC
8 )
T A R C
Treatment for colon cancer is surgical + adjuvant chemo without

routine use of adjuvant RT. Local control benefit of adjuvant RT was
seen in T4 tumors invading adjoining structures, associated with
perforation or fistula, or in the setting of residual disease (Willett et al.
Cancer J Sci Am 1999). However, this was not confirmed when tested in
the phase III Int 0130 trial comparing adjuvant chemo to chemo+RT
(Martenson et al. JCO 2004) in T4 or T3N+ patients. Consider RT to
metastatic sites if oligometastatic with good PS.
R T T R
C
SIM: Prone on a bellyboard, Vac-Lok device, comfortably full bladder,
and marker on anal verge (wire perineal scars if post-op). Scan from
mid lumbar spine to middle femur, isocenter midline at top of femoral
heads.
Dose: 45 Gy in 25 fractions at 1.8 Gy/fx → cone-down boost to 50.4
Gy in 1.8 Gy/fx
Recurrent after prior RT: 39 Gy in 1.5 Gy/fx bidShort course: 25 Gy at
5 Gy/fx
Target: Pre-op: GTV, mesorectum, internal iliac, obturator, presacral
nodes
Post-op: Tumor bed, anastomosis, mesorectum, internal iliac,
obturator, presacral nodes
Considerations: If T4 disease (invasion into anterior structures including

the bladder, vagina, prostate), cover external iliac nodes. If locally
advanced or recurrent, consider intraoperative radiation therapy (10-15
Gy, electrons, or HDR brachytherapy)
Technique: 3DCRT: 3-field PA and opposed laterals, use IMRT for

short-course radiation (Fig. 38.1).
Figure 38.1 Standard PA and lateral fields.
IGRT: Weekly kV imaging
Ensure coverage of GTV by 50.4 Gy isodose line
Femoral heads V45 < 20%
Bowel “bag” V45 < 195 cc
Bladder V50 < 30%
S
Transanal excision (TAE): Sphincter-preserving, full-thickness local
excision with adequate margin. Consider for low-lying (<10 cm) T1N0
lesions <30% circumferential involvement, <3 cm in size, clear
margins, low-intermediate grade, and no LVI. Consider post-op
chemoRT or radical surgery if path shows high-risk features, staging
is upgraded, or there are inadequate margins.
Low anterior resection (LAR): Sphincter-preserving total mesorectal
excision (TME). Dissection and anastomosis below peritoneal
reflection with ligation of superior and middle hemorrhoidal arteries.
Adequate LN dissection removes ≥12 LNs.
Abdominoperineal resection (APR): Total mesorectal excision (TME)
with complete removal of the rectum and anal canal and permanent
colostomy. Adequate LN dissection removes ≥12 LNs.
C
Concurrent: Capecitabine (825 mg/m2 bid, 5 days a week) or
continuous infusion 5-FU (225 mg/m2/d)
Adjuvant/neoadjuvant: FOLFOX (folinic acid, oxaliplatin, 5-FU), or
capecitabine, or CAPOX (capecitabine + oxaliplatin)
S E M
Nausea: First-line Zofran (8 mg q8h PRN) → second-line Compazine
(10 mg q6h prn) → ABH (lorazepam 0.34 mg, diphenhydramine 25
mg, and haloperidol 1.5 mg) 1 capsule q6h
Diarrhea: First-line Imodium titrating to a max of 8 pills/day → second-
line alternating Lomotil 2 pills and Imodium 2 pills every 3 hours
Cystitis: Urgency/frequency and dysuria. UA to r/o UTI. Treat if
positive.
Skin care: First-line sitz baths, Aquaphor, and Domeboro powder →
second-line Silvadene cream and hydrogel dressings (Cool Magic)
Proctitis: Diarrhea/abdominal pain. first-line alternating Lomotil and
Imodium (as above) → second-line steroid enemas.
Hand and foot syndrome: Redness, swelling, and pain in the hand
and foot. Consult with medical oncology about reducing concurrent
capecitabine dose.
F -
History/physical and CEA: Every 3-4 months for 3 years → every 6
months for 2 years
CT of the chest/abdomen/pelvis: Every year
Colonoscopy: At years 1 and 3 and every 5 years thereafter
Vaginal dilators for women
N T
Neoadjuvant chemoradiation
German rectal trial (Sauer et al. NEJM 2004; Sauer et al. JCO 2012):
Two-arm prospective randomized phase III trial comparing patients
undergoing neoadjuvant chemoRT followed by surgery vs surgery
followed by adjuvant chemoradiation. Both groups received adjuvant
chemotherapy with bolus 5-FU. No OS survival difference but 10-year
local recurrence is 7.1% vs 10.1% (P = .048, HR 0.60) favoring
neoadjuvant approach. Grade 3-4 acute toxicities reduced (27% vs
40%, P = .001) along with grade 3-4 long-term toxicities (14% vs
24%, P = .01) in neoadjuvant-treated patients. Increased sphincter
preservation among unfavorable patients in neoadjuvant group
NSABP R-04 trial (O’Connell et al. JCO 2014; Allegra et al. JNCI
2015): Four-arm prospective randomized phase III trial comparing
concurrent infusional 5-FU vs capecitabine, vs 5-FU + oxaliplatin, vs
capecitabine + oxaliplatin. No significant difference in pathologic
complete response, locoregional control, and overall survival.
Increased diarrhea with oxaliplatin
Short-course (SC) radiation
Dutch Trial (Kapiteijn et al. NEJM 2001; van Gijn et al. Lancet Oncol
2011): Two-arm prospective randomized phase III trial comparing SC
+ surgery (TME required) vs surgery alone. SC consisted of 25 Gy in
5 fractions given over 1 week. Surgery could include APR, LAR, or
Hartmann procedure. 10-Year local recurrence improved with
neoadjuvant SC (5% vs 11%, P < .0001).
Polish Trial (Bujko et al. Ann Oncol 2016): cT3-T4 patients
randomized prospective phase III trial comparing neoadjuvant SC RT
followed by 3 cycles of FOLFOX4 to neoadjuvant long-course
chemoRT to 50.4 Gy/28 fx combined with concurrent bolus 5-FU and
leucovorin. Primary endpoint was R0 resection rate (77% SC vs 71%
long course, P = .07). 3-Year OS favoring SC (73% vs 65%, P =
.0046)
TROG 01.04 (Ngan et al. JCO 2012): Two-arm randomized phase III
trial comparing SC followed by surgery and adjuvant chemotherapy to
long course chemoRT followed by surgery and adjuvant
chemotherapy. Trial was powered to detect a 3-year local recurrence
rate of 15% for SC and 5% for long course. At 3 years, local
recurrence was not significantly different between the arms (7.5% SC
vs 4.4% long course, P = .24).
ANAL CANCER
EMMA B. HOLLIDAY
B
Incidence/prevalence: Very rare; it makes up only 1% of all GI
malignancies, but the incidence is increasing. 8200 new cases
diagnosed in 2017 leading to 1100 deaths
Outcomes: 5-Year survival for T2-T4; M0 was 71%-78% (RTOG
9811).
By stage (Gunderson et al. IJROBP 2013):
Risk factors: Female gender, older age (most 50-60+), and

increased number of sexual partners, receptive anal intercourse,
smoking, immunosuppression (including HIV)
T B C
HPV association: 80%-90% of anal cancers are HPV+; HPV16 is
present in 70% of tumors. HPV+ anal cancers have a better
prognosis. HPV vaccination has been shown to decrease the
incidence of premalignant anal lesions in men who have sex with men
(Lawton et al. Sex Transm Infect 2013), but there has been no
evidence of benefit for widespread cancer/premalignancy screening
programs (Leeds et al. World J Gastrointest Surg 2016).
Pathology: ~90% squamous cell carcinoma and ~10%
adenocarcinoma (have much worse prognosis and typically treated
with rectal cancer paradigm of neoadj chemoRT → APR)
Imaging: Primary anal tumors are not typically well visualized on
cross-sectional imaging. So anoscopy is very important.
A
The anal region includes the anal canal (3-5 cm from the anal verge)
and the anal margin (5-6-cm radius of perianal skin around the anal
verge). Dentate line represents separation between columnar and
squamous epithelium and occurs ~2 cm into the anus
Anal margin: Superficial inguinal nodes
Anal canal below the dentate line: Superficial inguinal nodes
Anal canal above the dentate line: Anorectal, perirectal,
paravertebral nodes → internal iliac nodes
Invasion into anterior structures (prostate, bladder, vagina):
External iliac nodes
W
History and physical: DRE and inguinal nodal exams for all patients
Labs: CBC, CMP, LFTs, HIV testing, Pap smear/cervical screening for
all females if they are not up to date. PSA and prostate cancer
screening for all males
Procedures/biopsy: Anoscopy with biopsy of primary
Imaging: Contrast-enhanced CTs of the chest and abdomen for
systemic staging and a CT or an MRI recommended for pelvis. We
favor a contrast-enhanced PET/CT for both locoregional and systemic
staging, and pelvic MRI reserved for patients with bulky T3 or T4
disease for whom better visualization of the tissue planes is desired.
A C S (AJCC 8 )
T A
R T T
SIM: Supine, frog-legged position, and custom immobilization device
for the lower body. Place radiopaque BB at the anal verge to help
delineate tumor during treatment planning, place wire around any
perianal extension, and consider bolus. Consider full bladder to
displace small bowel. Use vaginal dilator for women to displace the
anterior vaginal wall. Use scrotal shelf for men to minimize skin
toxicity. Position and immobilize penis midline.
RTOG0529 dose:
MDACC dose:
a The tumor, involved LNs, and elective nodal volume are treated
using one IMRT plan with a simultaneous integrated boost technique.
The number of fractions should be determined by the largest of either
the primary tumor or the involved LN. For example, a T2 tumor with a
1.5-cm inguinal node would be treated in 27 fractions. The primary
tumor would receive 54 Gy, the inguinal node would receive 50 Gy,
and the elective nodal volume would receive 45 Gy.
Target: CTVp (primary) = anal GTV + 1 cm
CTVn (involved nodes) = nodal GTV + 5 mm
CTVe (elective nodal volume) = Should extend at least 2 cm inferior to
anal GTV and include the entire mesorectum to the pelvic floor. Nodal
areas include inguinal, perirectal, presacral, internal, and external
iliacs to the level of the bifurcation of the common iliacs (~L5/S1)
PTV margin with daily kV IGRT is 5 mm from CTV.
Technique: IMRT
Target delineation:
Primary and nodes:
Utilize information from physical exam, CT, PET/CT or MRI, and
endoscopy reports to delineate the GTVp and GTVn.
Elective nodal volume:

In the low pelvis, the CTVe should extend inferiorly at least 2 cm
below GTVp (may include perianal skin).
Should include the entire mesorectum to the pelvic floor.
+/− extension into ischiorectal fossa (RTOG atlas states only extend a
few mm beyond levators if no ischiorectal fossa involvement;
Australasian atlas includes the entire ischiorectal fossa.)
The inguinal nodal area should be covered from the inguinal ligament
superiorly to the lesser trochanter inferiorly. The lateral border is the
iliopsoas (I), the medial border is the adductor longus (AL) and
pectineus (P), the posterior border is the I and P, and the anterior
border is the sartorius (S).
In the mid pelvis, the CTVe should extend to the lateral pelvic
sidewall (muscle or bone). There should be an extension of ~1 cm
into the bladder and cover the posterior internal obturator vessels.
In the high pelvis, the perirectal coverage should extend to the
rectosigmoid junction. The superior border of CTVe should extend to
where the common iliacs bifurcate into internal and external iliacs
(~L5/S1). The internal, external, and presacral nodal basins should be
covered. A margin of ~7 mm in soft tissue around the external iliac
vessels should be added excluding muscle and bone.
Resources:
RTOG Atlas (used for RTOG 0529):
https://www.rtog.org/CoreLab/ContouringAtlases/Anorectal.aspx
Australasian GI Trials Group Atlas: Ng et al. Int J Radiat Oncol Biol
Phys 2012.
Inguinal Nodal Atlas: Kim et al. Pract Radiat Oncol 2012.
IGRT: daily kV imaging and/or daily CBCT to ensure consistent

bladder filling and soft tissue alignment
Planning directive:
Ensure coverage of GTV by prescription Gy isodose line.
Small bowel V50 < 10 cc, D max < 54 Gy
Bowel bag V45 < 195 cc (Kavanaugh et al. Int J Radiat Oncol Biol
Phys 2010)
Bladder V50 < 30%
Genitalia V30 < 20%, V20 < 67%
Figure 39.1 RTOG Atlas (used for RTOG 0529)
https://www.rtog.org/CoreLab/ContouringAtlases/Anorectal.aspx.
See color insert. (Australasian GI Trials Group Atlas: Ng et al.,
Int J Radiat Oncol Biol Phys , 2012.; Inguinal Nodal Atlas: Kim
et al., Pract Rad Onc , 2012.)
C
Concurrent:
Most widely accepted regimen: Continuous-infusion 5-FU 1000
mg/m2/d IV days 1-4 and 29-32. Mitomycin C 10 mg/m2 IV bolus
days 1 and 29 or Mitomycin C 12 mg/m2 (capped at 20 mg) on
day 1
MDACC preferred regimen: Weekly bolus cisplatin 20 mg/m2
and continuous-infusion 5-FU 300 mg/m2 administered Monday-
Friday on the days of radiation (NCCN cat 2B recommendation)
Other NCCN-listed regimens: Capecitabine 825 mg/m2 PO bid,
Monday-Friday on the days of radiation. Mitomycin C 10 mg/m2
days 1 and 29 or mitomycin C 12 mg/m2 IV bolus on day 1.
S E M
Nausea: First-line Zofran (8 mg q8h prn) → second-line Compazine
line alternating Lomotil 2 pills and Imodium 2 pills every 3 hours
positive. If negative, consider Pyridium OTC or prescription for
dysuria.
Dermatitis—Grades 1-2: sitz baths, Aquaphor, and Domeboro powder
→ Grades 2-3: Silvadene cream and hydrogel dressings (Cool Magic)
→ Grade 4: treatment break and surgical consult
Proctitis/anal pain: treat diarrhea and dermatitis as above. Consider
topical lidocaine, steroid suppositories, or steroid enemas. Many
patients require opiate pain medications.
F -
Skin and toxicity check at 6 weeks posttreatment with a DRE
First restaging at 12 weeks posttreatment includes DRE, anoscopy,
and CT of the chest/abdomen/pelvis. If disease is persistent,
reevaluate in 4 weeks and continue monitoring until complete clinical
response (CR). If no complete CR by 6 months, consider biopsy.
*It is important not to biopsy prematurely as only 52% of patients on
ACT II achieved a complete CR by 11 weeks from the start of
treatment, but 72% of the patients who didn’t achieve a complete CR
by 11 weeks had achieved a complete CR by 26 weeks.
Once complete CR achieved, DRE q3mo, anoscopy q6mo, and CT of
the chest/abdomen/pelvis annually if initially T3, T4, or N+ disease
If biopsy-proven locally recurrent disease, perform systemic restaging
and proceed to salvage abdominoperineal resection +/− inguinal
nodal dissection. If metastatic disease is found, treat with cisplatin/5-
FU systemic therapy or enroll on a clinical trial.
N T
chemoRT vs RT alone
UKCCCR ACT I (Northover et al. Br J Cancer 2010): 577 patients with

T2-T4M0 anal squamous cell carcinoma randomized to either RT or
chemoRT with 5-FU/MMC. RT included 45 Gy in 20-25 fractions
followed by reassessment at 6 weeks. If >50% response, boost with
15 Gy or 25 Gy Ir-192. If <50%, proceed to APR. Trend toward
improved overall survival (OS) (33% vs 28% at 12 years, P = .12), but
significantly improved local control (LC) (66% vs 41% at 12 years, P <
.0001), colostomy-free survival (CFS) (30% vs 20% at 12 years, P =
.004), and disease-free survival (DFS) (30% vs 18% at 12 years, P =
.004)
EORTC (Bartelink et al. JCO 1997): 103 patients with T3-T4 and N1-
N3 anal squamous cell carcinoma randomized to either RT or
chemoRT with 5-FU/MMC. RT included 45 Gy in 25 fractions followed
by reassessment at 6 weeks. If CR, boost 15 Gy; if PR, boost 20 Gy;
if no response, proceed to APR. No difference in 5-year OS or DFS,
but 5-year LC and CFS were improved with chemoRT (68% vs 50%,
P = .02 and 68% vs 40%, P = .002, respectively).
Optimal concurrent chemoRT regimen
RTOG 9811 (Gunderson et al. JCO 2012): 649 patients with T2-T4
and M0 anal squamous cell carcinoma randomized to either
chemoRT with 5-FU/MMC or induction cis/5-FU ×2 → chemoRT with
cis/5-FU. RT included 45 Gy in 25 fractions followed by a 10-14 Gy
boost for T3/T4 or N+ disease or residual T2 disease after the first 45
Gy. No difference in LC or CFS, but DFS and OS were better in the 5-
FU/MMC arm (68% vs 58%, P = .006, and 78% vs 71%, P = .026,
respectively).
UKCCCR ACT II (James et al. Lancet Oncol 2013): 940 patients with
M0 anal squamous cell carcinoma randomized in a 2 × 2 design to
chemoRT with either 5FU/MMC or cis/5-FU and +/− maintenance
cis/5-FU. RT included 50.4 Gy in 28 fractions. LC at 26 weeks was no
different. 3-Year CFS, DFS, and OS were all no different. Only 44% of
patients randomized to maintenance chemo completed it. G3
hematologic toxicity was 16% with cis/5FU compared with 26% with
5-FU/MMC.
Induction chemotherapy and additional RT boost
ACCORD 03 (Peiffert et al. JCO 2012): 307 patients with M0

squamous cell carcinoma >4 cm or N+ randomized in a 2 × 2 design
to +/− neoadj cis/5FU followed by chemoRT with cis/5-FU followed by
either a 15 Gy boost or a 20-25 Gy boost. RT included 45 Gy in 25
fractions followed by reassessment at 3 weeks. If any clinical
response was seen, the boost was given according to the
fractionation arm. If no response, the patient was taken off trial and
given an APR. There was no difference in 5-year LC, OS, CFS
(primary endpoint), or DFS among all arms.
PANCREATIC CANCER
SHALINI MONINGI • LAUREN ELIZABETH COLBERT •
PRAJNAN DAS
B
Incidence/prevalence: The 12th most commonly diagnosed cancer
and the 4th most common cause of cancer death. Estimated ~50 000
new cases diagnosed per year in the United States
Outcomes: The 5-year survival is 8%.
Demographics: Lifetime risk is 1 in 65. Slightly higher incidence in
males vs females (1.25:1). More common in developed nations.
Typically diagnosed between ages 50 and 70 years
Risk factors: Increasing age, familial-associated genetic changes
(p16 and BRCA2), obesity, ETOH consumption, chronic pancreatitis,
diabetes, red meat, tobacco use, exposure to 2-naphthylamine and
benzidine
T B C
Genetics: The most common mutated oncogenes in PCA include
KRAS, CDKN2A, TP53, and SMAD4.
Pathology: Majority are ductal adenocarcinomas (80%). Other less
common subtypes include mucinous cystadenocarcinoma, acinar cell
carcinoma, and adenosquamous carcinoma.
Imaging: Predominately hypointense compared with a normal
pancreas on CT scans with contrast. Hypointense on T1-weighted
MRI. Associated imaging findings include pancreatic duct dilatation,
abrupt changes in duct caliber, and parenchymal atrophy distal to the
lesion.
A
The pancreas is divided into the head, neck, body, and tail.
Retroperitoneal structure, with pancreatic duct merging with the
common bile duct to drain into the second portion of the duodenum at
the ampulla of Vater.
The pancreas is next to numerous critical GI structures including the
duodenum, jejunum, stomach, spleen, liver/gallbladder, and both the
celiac and SMA axes, which makes treatment difficult.
Lymphatic drainage is to peripancreatic, celiac, SMA, porta hepatis,
and para-aortic lymph nodes.
Bony landmarks:
Celiac artery at the level of T12SMA at the level of L1Pancreas is
seen at the level of L1-L2.
W
History and physical: Examination focusing on abdominal symptoms
including bloating, abdominal pain, and history of pancreatitis.
Evaluation of systemic symptoms including jaundice, weight loss, and
back pain.
Labs: CBC, CMP, LFTs, and CA19-9
Procedures/biopsy: Endoscopic ultrasound with biopsy if able.
Consider endoscopic evaluation with endoscopic retrograde
cholangiopancreatography (ERCP) or percutaneous transhepatic
cholangiography (PTC) for evaluation and biopsy. If jaundice,
consider stent placement. If resectable, consider staging laparoscopy
in high-risk patients.
Imaging: CT of the chest and abdomen with contrast, pancreas
protocol (early arterial, pancreatic, and portal venous phase)
P C S (AJCC 8
)
D R (K JA
C S 2008)
TVI, tumor-vessel interface.

T S
aStereotactic body radiation therapy (SBRT) is contraindicated when significant bowel (duodenum)
invasion.
R T T
Conventional RT
SIM:
Supine, wingboard, T-bar, Vac-Lok, and Iso at T-12 right of midline.
Scan from carina to iliac crest. IV contrast
Dose: Pre-op: Capecitabine + 50-50.4 Gy, 1.8-2 Gy/fx
Post-op: Capecitabine + 50-50.4 Gy, 1.8-2 Gy/fx
Target: Pre-op: Tumor, involved nodes, celiac, SMA, +/− porta
hepatis (for pancreatic head only)
Post-op: Tumor bed, celiac, SMA, porta hepatis (for pancreatic head
only), para-aortics (Goodman et al. IJROBP 2012)
Locally advanced: Tumor, involved nodes, celiac, SMA
Technique: 3D or IMRT
SBRT
SIM:
Arms extended overhead, upper Vac-Lok, T-bar, and wingboard. IV
contrast, breath-hold scans. Patient is NPO 3 hours prior to SIM and
treatment. Fiducials
Dose:
33-36 Gy in 5 fractions (Fig. 40.1)
Target:
GTV and tumor-vessel interface (TVI)
Technique:
6× photons delivered by VMAT
aAdapted from Alliance trial A021501 contouring guidelines.
IGRT :
Daily cone beam CT and kV.
Respiratory motion management, for example, breath hold
We strongly recommend implanting fiducials for SBRT cases.
Planning Directive (for SBRT) and Conventional RT:
Figure 40.1 Representative cross-sectional axial, sagittal, and
coronal images (L→R) from a SBRT treatment plan for locally
advanced pancreatic cancer. The white isodose line represents 36
Gy encompassing the red color wash, which delineates PTV3
(tumor-vessel interface minus PRV). The sky-blue isodose line
represents 25 Gy, which is encompassing the yellow contour that
represents PTV1 (gross tumor + TVI + 3 mm). This patient had
fiducials placed, which was used daily for image guidance along
with CBCT. See color insert.
S
Pancreaticoduodenectomy (Whipple procedure):
En bloc removal of the distal stomach, 1st and 2nd position of the
duodenum, head of the pancreas, common bile duct, and the
gallbladderAnastomoses:
Pancreas to jejunum
Gallbladder to jejunum
Stomach to jejunum
C
Concurrent with standard dose RT: Capecitabine
Neoadjuvant: FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan,
and oxaliplatin) or gemcitabine and nab-paclitaxel
Metastatic: FOLFIRINOX or gemcitabine and nab-paclitaxel
S E M
Nausea: First-line Zofran (8 mg q8h prn) → second-line Compazine
line alternating Lomotil 2 pills and Imodium 2 pills every 3 hours.
Patients will be evaluated and receive CREON (pancrelipase) prior to
initiation of therapy.
Fatigue: Supportive care
Chronic side effects: Ulcer formation, bowel perforation, and bowel
stenosis. Refer to GI specialists.
F -
History/physical and CT of the abdomen and chest: Every 3 months
N T
Resected pancreatic cancer
ESPAC 1 Trial (Lancet 2001): Prospective trial that randomized 541

patients with resected pancreatic cancer to observation,
chemotherapy alone (5-FU), chemoradiation alone (40 Gy split course
given in two 20 Gy increments), or chemoradiation followed by
additional chemotherapy. There was no benefit to chemoRT (HR 1.18,
P = .24), but median survival improved with adjuvant chemotherapy
(19.7 months vs 14 months, P = .0005). There are many criticisms of
the trial design including lack of central QA and selection bias.
CONKO-001 Trial ( JAMA 2007, 2013): Prospective randomized trial
of 354 patients with either N0 or N1 disease s/p R0-R1 resection.
Patients were randomized to observation or adjuvant therapy with 6
cycles of gemcitabine. Results showed a 5-year OS benefit with
adjuvant gemcitabine (21% vs 9%, P = .01), which was maintained at
10-year follow-up update (12.2% vs 7.7%, P = .01).
ESPAC 4 Trial (Lancet 2017): Prospective randomized trial of 451
patients with gross total resection of T1-4N0-N1M0 pancreatic tumors.
Randomized to receive either adjuvant gemcitabine or adjuvant
gemcitabine and capecitabine. Improved overall survival with
gemcitabine + capecitabine (median survival 28 months vs 25.5
months, P = .032).
Locally advanced pancreatic cancer
LAP 07 Trial ( JAMA 2016): Prospective randomized trial of 442

patients with locally advanced unresectable pancreatic
adenocarcinoma. 2 × 2 randomization, first between gemcitabine and
gemcitabine with erlotinib. For those without progression, they were
again randomized to receiving additional chemotherapy with or
without RT (54 Gy and capecitabine at 1600 mg/m2/d). Of 269
patients with no progression after 4 months, median survival is
equivalent between the chemo and chemo+RT arms. However, there
was a local control benefit with additional of chemoRT (32% vs 46%,
P = .03).
Phase II SBRT (Herman Cancer 2015): Evaluated 49 patients with
locally advanced PCA. All patients received 6.6 Gy ×5 SBRT following
gemcitabine. Median OS was 13.9 months with 1 year freedom from
local progression of 78%.
GASTRIC CANCER
LAUREN ELIZABETH COLBERT • PRAJNAN DAS
B
Incidence/prevalence: 22 000 new cases in the United States
annually. More common in East Asia (Japan, China, Korea) relative to
the United States
(SEER data)
Demographics: 35% gastric fundus, 25% gastric body, 40%
distal/antrum
Risk factors: HNPCC, Li-Fraumeni, E-cadherin alteration (CDH1),
Bloom syndrome (BLM/RECQL3), BRCA1/BRCA2, xeroderma
pigmentosum, Cowden (PTEN), GERD/gastritis/Barrett esophagus,
pernicious anemia, diet high in salted meats and nitrates and low in
fruits and vegetables, smoking
T B C
Genetics: 60% have p53 loss and should have HER2 overexpression
seen in 22% of patients on ToGA trial (Bang et al. Lancet 2010); other
subtypes include EBV+, microsatellite instability (MSI)+, genomically
stable (GS), and chromosomal instability (CIN) (TCGA 2014). Many
are associated with H. pylori and EBV; others have CDH1 mutation or
mismatch repair w/ MLH1 silencing (CIMP phenotype).
Pathology (Lauren histologic classification):
Intestinal subtype: Male predominant; arises from precursor
lesions; better prognosis, more localized; EBV, MSI, or CIN
subtype; arises in GEJ/cardia
Diffuse subtype: Female predominant; no precursor lesions;
worse prognosis, more invasive; GS subtype; locations diffuse
A
From cranial to caudal: Esophagus → GE junction → cardia → fundus
→ body → antrum/pyloric antrum → pylorus → duodenum (Fig. 41.1)
Siewert classification: Type I—5-1 cm proximal (above) to GEJ, Type
II—Epicenter of tumor located between 1 cm proximal and 2 cm distal
of GEJ, Type III—2-5 cm distal to GEJ
Fundus/cardia → perigastric, celiac, left gastric, splenic, hepatic
Body → Perigastric, celiac, left gastric, splenic, hepatic,
sub-/suprapyloric, pancreaticoduodenal
Antrum/pylorus → perigastric, celiac, left gastric, hepatic,
sub-/suprapyloric, pancreaticoduodenal
Vascular supply (from celiac artery)
Left gastric: Lesser curvature
Right gastric: Lesser curvature/inferior stomach
Right gastroepiploic: Greater curvature
Left gastroepiploic: Upper greater curvature
Short gastric arteries: Fundus/proximal stomach
Figure 41.1 Anatomy of the stomach. (Reproduced with

permission from Mansfield PF. Clinical features, diagnosis, and
staging of gastric cancer. In: UpToDate, Post TW (Ed), UpToDate,
Waltham, MA. (Accessed on [Date].) Copyright © 2019 UpToDate,
Inc. For more information visit www.uptodate.com.)
W
History and physical: Standard H&P with evaluation of left-sided
supraclavicular lymph nodal station (Virchow node)
Labs: CBC, CMP
Procedures/biopsy: Esophagogastroduodenoscopy (EGD) with
biopsies (>6 preferred) along with endoscopic ultrasound (EUS)
(depth of tumor + LN involvement; ~85%-90% accurate; nodal Sn/Sp
are ~83%/67%). Nutritional assessment/counseling. Consider Her2-
neu testing if metastatic disease documented/suspected. Need
laparoscopy evaluation particularly if T4 or undergoing neoadjuvant
therapy (20%-30% of pts with >T1 tumors and negative imaging +
peritoneal implants)
Imaging: Recommend CT of the chest, abdomen, and pelvis with IV
and oral contrast. NCCN recommends PET/CT if there is no evidence
of M1 disease (false negative ~40% of the time, particularly in diffuse
subtype).
G C S (AJCC 8 )
T A
R T T
Preoperative
SIM:
Supine, arms up, upper Vac-Lok, 3 hours NPO, +/−4DCT, scan
carina to pelvic brim, Iso@T12
Dose:
45 Gy in 25 fractions at 1.8 Gy/fx
Target:
GTV: based on EGD/CT/PET + 3 cm mucosal expansion = mucosal
target volume (MTV) (Fig. 41.2)
CTV = MTV + involved nodes + elective nodes + 1 cm
PTV = CTV + 0.5 cm
Elective Nodes
Technique: IMRT
Figure 41.2 Representative axial, sagittal, and coronal cross-

sectional images (L → R) illustrating a typical IMRT treatment plan
for preoperative radiation for gastric adenocarcinoma. The 45-Gy
isodose line is shown in blue, which encompasses the MTV (red
line), involved and elective nodes, with a 1-cm expansion. This
patient’s primary tumor was located at the GEJ extending 4 cm
into the cardia. See color insert.
Adjuvant/post-op
Dose: 45 Gy in 25 fractions at 1.8 Gy/fx, consider boost if R1/R2
resection
Target: Draw tumor bed using pre-op imaging, op report, and
pathology. Same nodal regions as pre-op, cover anastomosis (may be
high in the thorax), cover gastric remnant.
Technique: IMRT
Cord Max < 45 Gy
Lung: V20 < 25%, V10 < 45%, V5 < 65%, MLD < 20 Gy
Heart: V30 < 25%, ALARA
Kidney: Each kidney V20 < 33%, mean < 18 Gy
Liver: V30 < 30%, V20 < 50%, mean < 25 Gy
S
For distal tumors (body/antrum) → subtotal gastrectomy; proximal →
total gastrectomy
D1 Dissection—removes involved proximal or distal or entire stomach
+ perigastric LNs
D2 Dissection—D1 + celiac, L gastric, hepatic, splenic, splenic hilum
(celiac + branches)
D3 Dissection—D2 + PA +/− porta hepatis
Billroth I anastomosis (end-to-end gastrojejunal w/ gastric resection
margin) or Billroth II (end-to-side anastomosis, gastric resection
margin NOT used)
C
Concurrent pre-op: Infusional 5-FU based (+/− oxaliplatin) OR
paclitaxel/carboplatin
Concurrent post-op: 5-FU alone (infusional or capecitabine)
Perioperative/postoperative: 5-FU + cisplatin OR fluoropyrimidine +
oxaliplatin OR epirubicin, cisplatin + 5-FU
S E M
Nausea: Use PPI, first-line Zofran (8 mg q8h prn) → second-line
Compazine (10 mg q6h prn) → ABH (lorazepam 0.34 mg,
diphenhydramine 25 mg, and haloperidol 1.5 mg) 1 capsule q6h
Anorexia: Maintain hydration, IVF if necessary, dietary counseling
including protein heavy intake
Skin care: Aquaphor
Hand and foot syndrome: Redness, swelling, and pain in hand and
foot. Consult with medical oncology about reducing concurrent
capecitabine dose.
F -
History/physical: Every 3-6 months for 2 years → every 6-12 months
for 5 years
EGD: As clinically indicated
CT C/A/P w/ contrast (or PET/CT): Every 6-12 months for 2 years and
then annually
N T
Post-op chemoRT
Intergroup 0116 (Macdonald NEJM 2001; Smalley JCO 2012): Two-

arm randomized b/w surgery vs surgery + post-op chemoRT (5-FU/LV
×1 before, 2 during, 2 after). Included Stage IB-IV, R0 resection, PS ≤
2, and maintaining 1500 kcal/day diet. Mostly D0 and D1 dissections
(10% D2). Improved median OS with post-op chemoRT: 39 months vs
27 months (P = .0046) and 3-year RFS 48% vs 31% (P < .001).
Subgroup analysis showed lack of benefit in women with diffuse
subtype.
CRITICS (Dikken BMC Cancer 2011; Verheij ASCO abstract 2016):
Prospective randomized trial of 788 patients from Netherlands,
Denmark, and Sweden. Patients had Stage IB-IV gastric cancer and
received neoadjuvant chemo ECC/EOC ×3 + gastrectomy/D1
dissection → post-op chemo (3× ECC/EOC) vs post-op chemoRT (45
Gy/25 fx + cape/cis) → 5-year OS similar (41.3% chemoRT vs 40.9%
CHT, P = .99), heme toxicity higher in CHT arm vs chemoRT (44% vs
34%, P = .01).
ARTIST (Lee JCO 2012; Park JCO 2015): Prospective randomized
trial of 458 patients with Stage IB-IV gastric cancer following D2
dissection. Patients randomized to receive post-op chemo (cape/cis
×6) vs post-op chemo + chemoRT (cape/cis ×2 → RT 45Gy/cape →
cape/cis ×2). Median OS similar between arms; however local
recurrence lower with RT (13% vs 7%, P = .003). Subgroup analysis
showed improved DFS in node+ patients with chemoRT (76% vs
72%, P = .04) or those with intestinal subtype (94% vs 83%, P = .01).
Pre-op chemoRT
CROSS trial (van Hagen NEJM 2012; Shapiro Lancet Oncol 2015):
Two-arm randomized esophageal + GE junction (75% adeno, 23%
SCC) T1-T3, N0-N1 to surgery alone vs pre-op chemoRT + surgery
(41.4 Gy w/ carbo/tax). Median OS 49 months (chemoRT) vs 24
months (sx), higher for SCC but both groups benefit. R0 resection
rate 92% (chemoRT) vs 69% (sx alone).
RTOG 9904 (Ajani JCO 2006): Phase II trial of 49 total patients with
localized gastric adenocarcinoma. A negative laparoscopic evaluation
was required. Patients received 2 cycles of induction 5-FU,
leucovorin, and cisplatin followed by concurrent chemoRT (with
infusional 5-FU and weekly paclitaxel). Resection was attempted
following completion of neoadjuvant therapy. pCR and R0 resection
rates were 26% and 77%, respectively. Patients with pCR had
improved survival at 1 year (82% vs 69%). D2 performed in 50% of
patients.
Periop chemo
MAGIC (Cunningham NEJM 2006): Prospective randomized trial of

503 patients with gastric/GEJ cancer ≥ Stage II randomized to surgery
alone vs periop chemo + surgery (pre-op ECF ×3 and post-op ECF
×3). 5-Year OS 36% (chemo + sx) vs 23% (sx alone), P = .009, with
0% pCR rate.
FFCD (Ychou JCO 2011): Prospective randomized trial of 224
patients with GEJ + gastric/GEJ cancer, ≥Stage II → sx alone vs
periop chemo + sx (5-FU/cis ×2-3 pre-op and ×3-4 post-op). 5-Year
OS improved with chemotherapy 38% vs 24% (P = .02) along with
DFS 34% vs 19% (P = .003). Overall 38% grade 3-4 toxicity in
chemotherapy + sx arm, with 3% pCR rate
Post-op chemo
CLASSIC (Bang Lancet 2012; Noh Lancet Oncol 2014): Prospective

randomized trial of 1035 patients with Stage II-IIIB gastric, required
D2 dissection. Randomized between surgery alone vs surgery + post-
op chemo (cape/oxali ×6 months). Improved 5-year DFS with chemo
68% vs 53% (P < .0001) and 5-year OS 78% vs 69% (P = .0015)
HEPATOBILIARY CANCER
LAUREN ELIZABETH COLBERT • PRAJNAN DAS
H C (HCC)
Incidence/prevalence: Fifth most common cancer worldwide, third
leading cause of cancer mortality. Screening programs are effective—
those w/ risk factors should be screened with US and AFP q6-12mo.
Risk factors: Cirrhosis from any cause, including hepatitis (B > C;
accounts for 75% of cases), alcoholic, autoimmune, and NASH-
related
Evaluation/workup: Need to know Child-Pugh score (albumin, total
bili, INR, ascites, encephalopathy); imaging w/ triphasic CT or MRI;
hepatitis serologies; labs including AFP and LFTs
T A HCC
C L T
C
Incidence/prevalence: 10% intrahepatic, 60% perihilar, 30% distal.
Extrahepatic includes perihilar and distal. The second most common
primary hepatobiliary malignancy after HCC. Estimated 6000 cases
per year in the United States
Risk factors: Anything causing chronic inflammation of the
gallbladder or gallbladder tracts: Primary sclerosing cholangitis, liver
flukes, chronic calculi
Evaluation/workup: Triphasic CT or MRI with contrast. MRCP or
ERCP (particularly if obstruction, need stenting), CA19-9, AFP, CEA,
and LFTs. Evaluate for resectability (hepatic duct involvement,
encasement of portal vein, stage III-IV disease, late-stage cirrhosis,
medically unfit for surgery are all reasons to pursue alternate
treatment options).
T A
C
A
The liver has eight independent segments.
The middle hepatic vein divides the liver into right and left lobes.
The portal vein divides the liver into upper and lower segments.
Dual blood supply by portal vein and hepatic artery
R T T
HCC/C
SIM: NPO for 3 hours, with IV contrast, 5-6 repeat deep inspiration
breath-hold scans for reproducibility; start scans 30 seconds after IV
contrast administration to get variable contrast phases
Dose: Depends on tumor location, size, and anatomy; goal BED > 80
if possible. SBRT (50 Gy in 4-5 fractions), dose-escalated
hypofractionated IMRT (60-67.5 Gy in 15 fractions) or standard
fractionation (54-50.4 Gy in 28 fractions). Consider lower doses for
post-op cases with R0 resection. Need >5 mm from GI mucosa.
Preserve >700-800 cc functional liver
Target: Tumor defined on liver protocol CT/MRI and breath-hold
scans from simulation to accommodate respiratory movement;
contour GI mucosal avoidance structure based on anatomic
movement + 5 mm
If extrahepatic cholangiocarcinoma, consider elective treatment of
portal and celiac vein LN basins to 45 Gy in 25 fractions.
Technique: IMRT, SBRT, or protons; use daily CT on rails or fiducials
with CBCT for cases with escalated dose/SBRT
Constraints:
N T
SWOG 0809 (Ben-Josef JCO 2015): Phase II trial of 79 patients with
extrahepatic cholangiocarcinoma or gallbladder cancer s/p radical
resection. Patients received four cycles of IV gemcitabine and
capecitabine, followed by chemoRT with capecitabine (54-59.4 Gy to
tumor bed, 45 Gy to regional lymphatics). 2-Year OS 65%, including 67%
and 60% in R0 and R1 patients, respectively. Grade 3 side effects were
observed in 52% and grade 4 in 11%. Overall survival was higher than
expected with this regimen (predicted to be ~45% for this population using
historical data).
GENERAL BREAST CANCER
AMY C. MORENO • WENDY WOODWARD
B
Incidence/prevalence: See other breast cancer chapters.
Outcomes: See other breast cancer chapters.
Risk factors: Increasing age, personal or family history of breast
cancer, genetic mutations (BRCA1/2, p53 [Li-Fraumeni], PTEN
[Cowden], STK11 [Peutz-Jeghers], ATM [ataxia-telangiectasia]),
prior chest radiotherapy, estrogen exposure (obesity, hormone
therapy/contraceptive use, early menarche, late menopause,
nulliparity), alcohol consumption
B C S G
American Cancer Society: Annual mammogram (MMG) ages
45-54, biennial MMG beginning at age 55
U.S. Preventive Task Force: Biennial screening MMG from ages
50 to 74. Recommends against breast self-examination
High-risk patients: BRCA carriers/untested 1° relatives: age 25-
30 or 10 years earlier than affected 1° relative; women with 1°
relative with premenopausal BCA or women with lifetime risk of
BCA ≥ 20%
Breast MR imaging: Not required for screening, useful for
women with dense breasts
T B C
Genetics: BRCA1: 60%-80% lifetime risk of breast cancer and
40% risk for ovarian cancer
BRCA2: 40%-50% lifetime risk of BCA and 10%-20% risk for
ovarian cancer. Genetic counseling recommended if high-risk
features present for hereditary breast cancer
Pathology: See other breast cancers.
Imaging: See other breast cancers.
A
Field borders are not to rigidly supercede volume-based target
definitions edited for patient- and tumor-specific factors.
Breast anatomic breast borders: Inferior border of clavicular

head or 2nd anterior rib (superior) and loss of apparent breast
parenchyma or 6th anterior rib (inferior), midaxillary line (lateral),
and sternum-rib junction (medial). Breast contouring should
include all of the glandular breast tissue and the clinically
apparent breast mound.
Regional nodal borders (normal volumes are described in the
RTOG atlas and should be considered a starting place and edited
for clinical risk):
Axillary: level 1 (inferior and lateral to pectoralis minor), level
2 (subpectoral and constrained by pectoralis minor, includes
Rotter nodes), and level 3 (medial and superior to pectoralis
minor, should always be contoured if targeted and should be
entirely within the SCV field when treating with 3D)
Internal mammary: superior aspect of medial 1st rib
(superior) to superior aspect of 4th rib (inferior). IM nodes
should be contoured if targeted.
Supraclavicular: cricoid (superior), inferior border of
clavicular head (inferior). Medial border should cover the
volume even if it includes the trachea.
B C S (AJCC 8
)
Abbreviations: Ipsi, ipsilateral; IM, internal mammary; ITCs, isolated tumor
cells.
S T
Preference at our institution is for neoadjuvant chemotherapy (NAC) if
the decision to give chemotherapy is known. NAC is the first option in
a patient who wants BCS but cannot proceed due to tumor size.
a Choice of hormone therapy, chemotherapy, or Herceptin-based chemotherapy is unclear

and depends on discussion of factors including patient preference, age, and pathology
factors (size, grade, margin, etc.).
b if Oncotype DX score <18, then no chemotherapy; score 18-30, then unclear; score >30,
then chemotherapy.
Chemotherapy (for Her2−): AC (Adriamycin, cyclophosphamide)

×4, ddAC (dose-dense AC, administered twice for every 4-week
cycle) ×4, or FAC (fluorouracil, Adriamycin, and
cyclophosphamide) ×4 → paclitaxel q1wk ×12
Herceptin-based chemotherapy (for Her2+): THP (paclitaxel,
Herceptin, pertuzumab) ×6, then consider ddAC q2wk ×4
pre-/postop → maintenance Herceptin q3wk (total 1 year)
Alternate Her2+ regimen: TCHP (paclitaxel, carboplatin,
Herceptin, pertuzumab) ×6 → maintenance trastuzumab q3wk
(total 1 year)
Hormone therapy: tamoxifen or aromatase inhibitor for 5-10 years
DUCTAL CARCINOMA IN SITU (DCIS)
AMY C. MORENO • WENDY WOODWARD
B
Incidence/prevalence: Approximately 70 000 cases diagnosed
annually in the United States. DCIS accounts for 15%-30% of all
detected breast cancer.
Outcomes: Mortality from DCIS is very low. 20-Year breast
cancer–specific mortality is 3.3% (Narod et al. JAMA Oncol
2015).
Risk factors: See General Breast Cancer chapter.
T B C
Genetics: See General Breast Cancer chapter.
Pathology: Subtypes of DCIS include comedonecrosis and
noncomedo (cribriform, papillary, medullary, and solid type).
Imaging: On mammogram, characteristically appears as linear or
granular calcifications. May underestimate size by 1-2 cm. On
ultrasound, typically presents as hypoechoic mass with ductal
extension. On MRI, regional branching or linear enhancement is
seen on T1.
W
History and physical: Including bilateral breast examination and
axilla palpation. Consider genetics evaluation.
Labs: β-HCG (if premenopausal)
Procedures/biopsy: Core needle biopsy of suspicious breast
lesions, pathology staining of biopsy for ER/PR status. Two
commercially available genomic tests may further refine risk
estimates: DCISionRT and Oncotype DX.
Imaging: Bilateral diagnostic mammogram (MMG), breast ±
regional LN basin ultrasound, consider MRI for dense breasts.
T A
a If ER/PR+
R T T WBI
SIM: Supine, upper Vac-Lok device, ipsilateral arm
abducted/externally rotated over the head. Use slant board (5-15
degrees) to make breasts fall downward but balance with degree
of inframammary fold (can worsen skin reactions). Consider
wiring surgical scar and treatment borders, inspiration breath-
hold for left-sided tumors to reduce heart/lung doses, and prone
simulation for larger BMI and/or pendulous breasts.
Dose: 40.05 Gy in 15 fx → boost to 10-16 Gy* in 2 Gy/fx or 42.5
Gy in 16 fx if a boost was intended but not feasible (eg,
complicated surgical bed)
Target: Clinical breast mound including all glandular breast
tissue (Fig. 44.1)
Considerations: Boost doses: *10 Gy for negative SM, 14 Gy for
close SM, and 16 Gy for positive SM (reexcision preferred but if
not possible [ie, positive SM at fascia] give higher boost dose)
Technique: Opposed lateral tangents and appositional electron
field for boost
IGRT: Weekly MV imaging once setup is stable

Planning directive for WBI:
Breast: V98 ≥ 100%, V100 > 90%
Entire breast/CW covered by 98% isodose line (IDL)
Entire tumor bed covered by 100% IDL
Boost target covered by 90% IDL
Heart: V5 ≤ 40% (≤50% for left-sided tumors)
Expected mean heart dose for left intact breast with no IMC
< 1 Gy
Total lung: V20 < 35%
V40 < 20%
Evaluate each beam separately for adequate coverage
Avoid 106% hot spots, consider using wedges or field-in-
fields
S T
Chemotherapy not part of management for DCIS
Consider endocrine therapy for 5 years for estrogen receptor
(ER)-positive DCIS.
Tamoxifen 20 mg PO daily for premenopausal women
Aromatase inhibitors (anastrozole, letrozole) for pre- or
S D P
I
Breast-conserving surgery (BCS) or lumpectomy: Removal of
tumor and surrounding area of breast tissue to ensure negative
margins
Total or skin-sparing mastectomy: Complete removal of the
breast ± overlying skin
Sentinel lymph node biopsy (SLNB): Not indicated in DCIS.
May be offered if high risk for occult invasive disease and if
mastectomy is planned. Blue dye and/or radioactive tracer is
injected into the ipsilateral breast to help locate typically 1-3
sentinel nodes for removal
Pathology report: Review ER/PR status, tumor grade, tumor
size, extent (multifocal?), surgical margin status (either positive,
close [0-1.9 mm], or negative [≥2 mm])
S E M
Skin care: Aquaphor → Cool Magic → Mepilex dressings
F -
History and physical: Every 6-12 months ×5 years, then annually
Bilateral diagnostic mammogram: Every year
N T
WBI after lumpectomy results in ~50% reduction in ipsilateral
breast recurrence
NSABP B17/B24 (Wapnir et al. JNCI 2011): BCS vs BCS + WBI,

margins negative (50 Gy in 25 fractions, 9% received boost). 15-
Year ipsilateral breast tumor recurrence reduced with BCS + WBI
(IBTR; DCIS or invasive): 19% vs 9% (HR 0.48, P < .001). No
difference in OS or CSS
EORTC 10853 (Donker et al. JCO 2013): BCS vs BCS + WBI (50
Gy in 25 fractions, 5% received boost). 15-Year IBTR reduced
with BCS + WBI: 30% vs 17% (HR 0.52, P < .001). No difference
in OS or CSS
SweDCIS (Warnberg et al. JCO 2014): BCS vs BCS + WBI (48-
50 Gy total dose, boost not recommended). 20-Year IBTR risk
reduced with BCS + WBI: 32% vs 20%. No difference in OS or
CSS
EBCTCG DCIS meta-analysis (Correa et al. JNCI 2010): RT
after BCS decreases any IBTR by ~50% (28.1% w/o RT vs
12.9% w/ RT). Proportional reduction in ipsilateral breast events
greater in older vs younger women (≥50 vs <50). RT reduced
absolute 10-year risk of IBTR by 15% regardless of patient age,
extent of BCS, use of TAM, margin status, tumor grade, or size
Tamoxifen after lumpectomy further reduces ipsilateral breast

recurrence
UK/ANZ (Cuzick et al. Lancet Oncol 2011): 2 × 2 comparing BCS

± WBI ± tamoxifen (TAM) given 20 mg PO daily for 5 years. 10-
Year IBTR reduced with WBI: 19% vs 7% (HR 0.32, P < .001).
10-Year IBTR reduced with TAM: 20% vs 16% (HR 0.68, P = .04)
NSABP B17/B24 (Wapnir et al. JNCI 2011): BCS + WBI vs BCS
+ WBI + tamoxifen. 15-Year contralateral breast tumor
occurrence reduced with BCS + WBI + tamoxifen (IBTR): 11% vs
7% (HR 0.68, P = .023). No difference in OS or CSS
Omission of RT after BCS for good-risk DCIS
ECOG 5194 (Solin et al. JCO 2015): BCS vs BCS + WBI (31%
received TAM) in “low-risk” patients: grade 1-2 DCIS measuring
≤2.5 cm or high-grade DCIS measuring ≤1 cm, all required
normal post-op MMG and margins ≥3 mm. High-grade patients
had unacceptable 25% 12-year IBTR (13% invasive) compared
with lower/intermediate-grade patients who had an acceptable
14% IBTR (8% invasive).
Additional conclusion: High-grade DCIS is a poor prognostic
factor for radiation omission.
RTOG 9804 (McCormick et al. JCO 2015): BCS vs BCS + WBI in
“low-risk” patients. Grade 1-2 DCIS ≤ 2.5 cm with margins ≥3
mm. TAM 20 mg PO daily given in both arms (69% overall
compliance). 7-Year local failure rate reduced with BCS + WBI:
6.7% vs 0.9%, but 6.7% was deemed an acceptable risk. Grade
1-2 toxicities were lower in observation arm: 76% vs 30%.
Hypofractionated whole breast radiation is safe for DCIS
MDACC randomized clinical trial (Shaitelman et al. JAMA

Oncol 2015): 287 women age ≥40 with stage 0-II BCA (22%
DCIS) randomized to HF-WBI (42.56 Gy/16 fx + boost) vs CF-
WBI (50 Gy/25 fx + boost) after BCS. Decreased acute grade 2
toxicity with HF-WBI (47% vs 78%; P < .001) and improved QOL
and less fatigue with HF-WBI vs CF-WBI
Figure 44.1 CT-based XRT planning images and DRR of the
left lateral tangent beam. Contours: Maroon, tumor bed.
Isodose lines on CT images: White, 98% IDL.
EARLY-STAGE BREAST CANCER (ESBC)
JAY PAUL REDDY • WENDY WOODWARD
B
Definition: Stage I/II patients (T1/2 N0/1mic/1)—T3N0 (stage
IIB) is included in LABC chapter.
Incidence/prevalence: Most commonly diagnosed cancer
among women and second leading cause of death in the United
States. Approximately 250 000 new cases of invasive breast
cancer (BCA) annually and 40 000 deaths annually. Lifetime risk
is 1 in 8 (12%).
Outcomes: 5-Year survival ~90%
Screening guidelines: See General Breast Cancer chapter.
T B C
Pathology: Majority invasive ductal carcinoma (~90%).
Remaining 10% is invasive lobular carcinoma, which is bilateral
in up to 30% of cases. Pathologic evaluation for tumor grade,
size, extent (multifocal?), surgical margin (SM) status (either
positive, close [0-1.9 mm], or negative [≥2 mm]). IHC testing for
ER (≥1% threshold), PR, Her2 (IHC: 3+ on ≥10% breast tissue
threshold, if Her2+ utilize FISH testing and test if ratio > 2.0), and
Ki-67
Molecular subtypes (incidence and receptor-based
surrogates):
Luminal A–like (70%): grades 1-2, high ER+/PR+, Her2−,
low Ki-67
Luminal B–like (10%): grade 3, low ER+/PR+, +/−Her2+,
high Ki-67
Her2-like (10%): grade 3, ER/PR−/+, Her2+, high Ki-67
Basal-like (10%): grade 3, triple negative (TNBC), BRCA1
associated. Basal-like further subclassed.
Note: gene expression and receptor subtypes not perfectly

correlated.
Multigene panels and signature scores: Routinely utilize
recurrence scores including Oncotype DX DCIS recurrence
score. Retrospective analyses of the NSABP data suggest that
recurrence score is prognostic for LRR in node-negative and
node-positive ER+ patients (Paik et al. NEJM 2004).
Imaging: MMG, linear or granular microcalcifications, masses,
skin thickening, nipple retraction, or distortions. Ultrasound,
hypoechoic mass with irregular margins and ductal extension ±
infiltration of surrounding tissue. MRI, regional branching, mass,
or linear enhancement on T1
Anatomy: See General Breast Cancer chapter.
W
History and physical: Including bilateral breast examination and
axilla palpation. Consider genetics evaluation.
Labs: β-HCG (if premenopausal), for stage IIB add CBC and
LFTs
Procedures/biopsy: Core needle biopsy of suspicious breast
lesions, pathologic staining of biopsy for ER/PR status and Her2
expression. Consider obtaining Oncotype DX score if indicated.
Imaging: Bilateral diagnostic MMG, breast and regional LN basin
ultrasound. Consider MRI for dense breasts, suspected
multicentric/multifocal disease, occult primary, or chest wall
invasion. If abnormal LFTs, or symptoms, bone scan and/or CT of
the chest, abdomen, and pelvis.
T A
Overall treatment: Both adjuvant and neoadjuvant chemotherapy are
equally valid, consider neoadjuvant if patient desires BCS but cannot
due to size of primary disease. Institutional preference is for
neoadjuvant approach.
Adjuvant systemic therapy approach: Mastectomy/BCS + SLNB ±
ALND → systemic therapy (if any) → radiation → completion
hormone/Herceptin therapy (if any)
Neoadjuvant systemic therapy approach: Systemic therapy (if any)
→ mastectomy/BCS + SLNB ± ALND → radiation → completion
hormone/Herceptin therapy (if any)
Radiation options
Whole breast irradiation (WBI): See DCIS chapter. In a patient

with involvement of 1-2 LNs identified on SLNB and who did not
have an ALND, consider contouring level I-II LNs and modifying
WBI tangents to encompass.
WBI + regional nodal irradiation (RNI): See LABC chapter.
Postmastectomy radiation therapy (PMRT): Chest wall
radiation and RNI, see LABC chapter.
Accelerated partial breast irradiation (APBI): If patient meets
eligibility criteria
a Consider radiation omission (CALGB9343): age ≥70, tumor size ≤3 cm, N0, margin >2
mm, ER+, and willing to undergo hormone therapy.
b Patients with LN+ SLNB and no ALND w/ significant risk factors
(http://www3.mdanderson.org/app/medcalc/bc_nomogram2), consider modifying tangents to
include level 1 and 2 LNs (high tangents).
c Consider WBI + RNI/PMRT in patients meeting the following criteria:
pN1 and ≥1 of the following: Age ≤40 and upfront surgery, ≥3 LN+ and
upfront surgery, cT3N1, ER− and upfront surgery, age <50 and Oncotype
DX RS >18, ER− and upfront surgery, and ypN+
p1-2 LN+, age >40, ER+ and ≥2 of the following: Luminal B (Ki-67 >20%
or Her 2+), grade 3, LVSI, Oncotype DX RS > 18
pN0/pN0(i+)/pN1mic and ≥3 of the following: Age ≤40, >1 LN with
micromet (0.21-2 mm), T3, central/medial tumor, ER−, grade 3, LVSI, Ki-
67 >20% Oncotype DX RS > 18
d Consider WBI + RNI/PMRT in patients with ≥cT3N1 or <cT3N1 and ≥1 of the following
criteria: Premenopausal, TNBC, greater initial clinical tumor burden, residual tumor in the
breast.
e Consider omission of RNI/PMRT in patients who are ypT0N0 as part of a clinical trial.
APBI S C (N0( +/ −)
T O )
a Unsuitable pathology factors: Size 2.1-3 cm, T2, margins <2 mm, limited/focal LVSI, ER−,
clinically unifocal with size 2.1-3 cm, invasive lobular histology, pure DCIS ≤ 3 cm if criteria
for “suitable” not fully met, extensive invasive component ≤3 cm
ASTRO Consensus Guidelines, Adapted from Correa et al. Pract Radiat Oncol
2017.
R T T
For WBI, see DCIS chapter. For chest wall + RNI, see LABC chapter.
R T T
APBI
Dose: 38.5 Gy in 10 fractions bid photon-based EBRT (Fig. 45.1)
34 Gy(RBE) in 10 fractions bid proton-based EBRT (special
planning considerations described elsewhere, Strom et al. Pract
Radiol Oncol 2015)
Alternative: Using minitangents to treat with APBI per UK
IMPORT Low Regimen also acceptable (40.05 Gy/15 fx)
Target: (based on NSABP B-39)
CTV: Surgical cavity + 15 mm; but limited to 5 mm from skin
and excludes chest wall/pectoralis muscles
PTV: CTV + 10 mm
PTV_Eval: PTV but limited to 5 mm from skin and excludes
chest wall/pectoralis muscles
Technique: 3DCRT: multiple noncoplanar beams
SIM: Supine, upper Vac-Lok device, ipsilateral arm
abducted/externally rotated over the head, head turned slightly
away (open neck). Use 5- to 15-degree slant board if breast
intact or to minimize SCV lung dose. Wire surgical scar. Deep
inspiration breath-hold for left-sided tumors to reduce heart/lung
doses
Figure 45.1 External beam APBI volumes. (From NSABP B-
39.)
P D APBI
PTV_EVAL: ≥90% receives >90% of Rx
Uninvolved ipsi breast: <35% receives 100% of Rx
<60% receives <60% of Rx
Contralateral breast: <3% of Rx dose
Ipsilateral lung: <15% of volume receives ≤30% of Rx
Contralateral lung: <15% of volume receives ≤5% of Rx
Heart (right breast target): <5% receives ≤5% of Rx
Heart (left breast target): <40% receives ≤5% of Rx
Thyroid: D max is ≤3% of Rx
IGRT (EBRT APBI)
kV every treatment, align to clips
S E M /F -
Skin care: Aquaphor → Cool Magic → Mepilex dressings
Fatigue: Encourage exercise and adequate daily protein intake,
good sleep hygiene → referral to fatigue clinic
Lymphedema: Referral to physical therapy for education and
sleeve fitting → plastic surgery options include LN transfer and
lymphatic bypass
S T
See LABC chapter.
S D
Breast-conserving surgery (BCS) or lumpectomy: Removal of
tumor and surrounding area of breast tissue to ensure negative
margins
Total or skin-sparing mastectomy: Complete removal of the
breast ± overlying skin
Sentinel lymph node biopsy (SLNB): Conducted in all cLN−
patients. Blue dye and/or radioactive tracer injected into the
ipsilateral breast to locate one to three sentinel nodes for removal
Axillary lymph node dissection (ALND): Conducted in all
patients with invasive disease if cLN+ or cLN− and SLNB+.
Adequate if 10 LNs dissected from axillary levels 1-2. Consider
extended level 3 or level 2 Rotter node (intrapectoral) dissection
if disease identified in these areas. Consider omitting ALND for
cLN− and SLNB+ if T1-2 and 1-2 sLN+ when doing lumpectomy
and no neoadjuvant therapy (Guiliano et al. JAMA 2011).
N T
Radiation after BCS improves local control and breast cancer
deaths
EBCTCG meta-analysis (Lancet 2011): RT after BCS decreases

any first recurrence at 10 years from 35% to 19.3% (P < .001),
reduces 15-year risk of BCA death from 25.2% to 21.4% (P <
.001).
Lumpectomy boost after whole breast radiation
EORTC Boost Trial (Bartelink et al. Lancet Oncol 2015): 50 Gy

in 25 fractions WBI vs 50 Gy in 25 fractions + 16 Gy boost.
Median f/u 17-year IBTR 16.4% vs 12% (P < .001). No difference
in OS or DMFS.
Omission of RT after BCS is acceptable in low-risk breast cancer

patients
CALGB 9343 (Hughes et al. JCO 2013): Low-risk early breast

cancer patients (age ≥70 years, T1 N0, ER+). BCS + observation
vs BCS + WBI 45 Gy/25 fx + 14 Gy boost → tamoxifen (TAM) ≥5
years. 10-Year LRFS lower with WBI 98% vs 90% LRFS (P <
.001). However, the risk of locoregional failure was deemed
acceptable with observation.
PRIME II (Kunkler et al. Lancet Oncol 2015): Low-risk early
breast cancer patients (age ≥65 years, HR+, T1/2 [≤3 cm], N0,
grade 3 or LVSI [not both], margins ≥1 mm). BCS + observation
vs BCS + WBI 40-50 Gy in 15-25 fractions → hormone ≥5 years.
5-Year IBTR lower with WBI, 1.3% vs 4.1% IBTR (P < .001). No
difference in OS
Hypofractionation has equivalent efficacy and at least as good

cosmesis as conventional fractionated radiation
Canada (Whelan et al. N Engl J Med 2010): HF-WBI (42.56
Gy/16 fx) vs CF-WBI (50 Gy/25 fx) in patients with T1/2 N0,
margin-negative disease. No boost. 10-Year LR 6.7% vs 6.2%
(NS). No difference in OS or DFS. Excellent/good cosmesis in
70% vs 71% (NS)
UK START (Haviland et al. Lancet Oncol 2013): Combination of
two RCTs, START A and B. HF-WBI (multiple regimens: 40 Gy/15
fx, 41.6 Gy/13 fx, and 39 Gy/13 fx) vs CF-WBI (50 Gy/25 fx) in
patients with pT1-3a N0-1, margin-negative disease. 10-Year LR
4%-6% vs 5%-7% (NS). No difference in OS or DFS. Better long-
term cosmesis in 40 Gy vs 50 Gy arm (START B)
MDACC (Shaitelman et al. JAMA Oncol 2015): HF-WBI (42.56
Gy/16 fx + 10-12.5 Gy/4-5 fx boost) vs CF-WBI (50 Gy/25 fx +
10-14 Gy/5-7 fx boost) in patients with Tis-2 N0-1a disease.
Significantly less physician-reported acute toxicity on HF-WBI
arm (dermatitis, 36% vs 69%; pruritus, 54% vs 81%; pain, 55%
vs 74%; hyperpigmentation, 9% vs 20%; fatigue, 9% vs 17%)
Accelerated partial breast irradiation is associated with good

efficacy and cosmesis
GEC-ESTRO (Strnad et al. Lancet 2015): Interstitial

brachytherapy (32 Gy/8 fx or 30.3 Gy/7 fx bid) vs CF-WBI (50-
50.4 Gy/25-28 fx + 10 Gy/5 fx boost) in patients with T1/2 N0 (≤3
cm), margin-negative disease. 5-Year IBTR 1.4% vs 0.9% (NS).
RAPID (Olivotto et al. JCO 2013): External APBI (38.5 Gy/10 fx
bid) vs WBI (50 Gy/25 fx or 42.56 Gy/16 fx optional 10 Gy boost)
in patients with T1/2 N0 (≤3 cm). Increased fibrosis and worse
cosmesis in APBI arm at 3 years
IMPORT LOW (Coles et al. Lancet 2017): Reduced dose WBI
(36 Gy/15 fx with 40 Gy to partial breast) vs PBI (40 Gy/15 fx) vs
WBI (40 Gy/15 fx) in patients with pT1-2 (≤3 cm) N0-1, margin ≥
2 mm disease. 5-Year LR: 0.2% (reduced dose) vs 0.5% (APBI)
vs 1.1% (WBI) (NS). Similar to improved cosmesis with APBI and
reduced dose compared with WBI
Axillary LN dissection can be omitted in select patients with
positive SLNB
ACOSOG Z11 (Guiliano et al. JAMA 2017): BCS → SLNB +/−

ALND in patients with T1/2, cN0, 1 or 2 SN+. 10-Year OS 86.3%
vs 83.6% (NS). 10-Year DFS 80.2% vs 78.2% (NS). 46% of SN+
were micromets, and 27.4% of patients treated with ALND had
additional positive nodes beyond SLNB.
ACOSOG Z11 radiation field analysis (Jagsi et al. JCO 2014):
Post hoc analysis of 28.5% evaluable RT records. Of these, 50%
received high tangents and 20% had separate regional nodal
field.
Regional nodal irradiation (RNI) associated with similar axillary

control compared with LN dissection in low-risk patients
AMAROS (Rutgers et al. Lancet Oncol 2014): BCS → SLND. If

SN+ → axillary RT vs ALND in patients with T1/2 disease. 5-Year
axillary recurrence 1.2% vs 0.4%. 5-Year OS 94% vs 94%. 5-
Year DFS 87% vs 83%.
Regional nodal irradiation (RNI) associated with improved

efficacy in high-risk patients
NCIC MA.20 (Whelan et al. NEJM 2015): 1832 pts with high-risk
(primary >5 cm or >2 cm and <10 ALN removed and either grade
3 histology, ER−, or LVIS) pN0 or pN1-3 s/p BCS + adjuv chemo
→ WBI vs WBI + RNI. RNI included IMC, SCV, and axillary
coverage. Improved 10-year DFS with RNI (82% vs 77%, P =
.01). No difference in OS between arms (82.8% vs 81.8%, P =
.38). Increased rates of grade 2+ acute pneumonitis (1.2% vs
0.2%, P = .01) and lymphedema (8.4% vs 4.5%, P = .001)
observed in RNI group
Inclusion of IM nodes in comprehensive PMRT fields may

improve efficacy
EORTC 22922/10925 (Poortmans et al. NEJM 2015): 4004 pts
with axillary LAD (~55%) or medial tumors s/p BCS or MRM
randomized to PMRT +/− IMC/medial SCV RT. IMC/median SCV
RT associated with lower DFS (72.1% vs 69.1%, P = .04) and
DMFS (78% vs 75%, P = .02) at 10 years, trend toward higher
OS (82.3% vs 80.7%, P = .056). No increased toxicities reported
LOCALLY ADVANCED BREAST CANCER
(LABC)
JENNIFER LOGAN • WENDY WOODWARD
B
Definition: Includes stage III patients (T3N1, N2-3, T4) but can
also include stage IIB (T3N0) pts. IBC patients are a subset of
LABC (see separate Inflammatory/Recurrent Breast Cancer
chapter). Stage IV patients are not included.
Incidence/prevalence: LABC accounts for 8%-15% of all
detected breast cancers in the United States, with decreased
rates in regions of increased screening. Impoverished or minority
communities can experience higher rates of LABC and increased
mortality.
Outcomes: 5-Year survival rates for stage IIIA and IIIB breast
cancers are 52% and 48%, with median survival for stage III at
4.9 years (SEER data).
T B C
Pathology: See ESBC chapter. Predominant histologies include
infiltrating ductal and lobular carcinoma. More favorable
histologies, such as tubular or medullary carcinoma, are less
common in LABC.
Genetics and molecular subtypes: See ESBC and General
Breast Cancer chapter.
A /W /S /T
A
See ESBC and DCIS chapters.
R T T
C B /C W
I
Sim: Supine, upper Vac-Lok device, ipsilateral arm
abducted/externally rotated over the head, head turned slightly
away (open neck). Use 5- to 15-degree slant board if breast
intact or to minimize SCV lung dose. Wire surgical scar and
treatment borders (optional). Deep inspiration breath-hold for left-
sided tumors to reduce heart/lung doses. Aquaplast masks are
appropriate for patients who need supraclavicular nodal boosts or
who will be treated with protons.
Dose: 50 Gy in 25 fractions → boost to 10-16 Gy in 2 Gy/fx
Target: Entire breast/chest wall and regional nodes (SCV, IMC,
undissected cN+)
Considerations: Boost doses: 10 Gy for negative SM; 14 Gy for
<2 mm SM; 16 Gy for positive SM (reexcision preferred but if not
possible [ie, positive SM at fascia] give higher boost dose). If
gross or residual nodes, consider 10 Gy boost with a 2-cm CTV
margin. Postmastectomy, utilizing 3-mm bolus every other day for
2 weeks and then PRN to achieve a brisk skin reaction.
Technique: Multi-isocenter technique utilizing photon-based
tangent fields matched to AP oblique SCV field and appositional
electron IMC field
IGRT/P D
IGRT: Weekly MV once setup is stable
Planning directive considerations for comprehensive
breast/chest wall
Evaluate each beam separately for adequate coverage

Entire breast/CW covered by 98% isodose line (IDL)
All nodal CTV covered by >90% IDL
Evaluate cold triangle between IMC and tangents
Continuous coverage of 35 Gy line, most notably at IMC and
tangent interface
Boost target covered by 90% IDL
Dose constraints
S E M /F -
Same as ESBC chapter.
S T
See General Breast Cancer chapter.
N T
Neoadjuvant chemotherapy improves outcomes in LABC
NSABP B-18 (Fisher et al. JCO 1997): Randomized 1523

operable pts to presurgery AC vs postsurgery AC. In preoperative
arm, breast tumor size reduced in 80% and nodal reduction in
89%. 73% clinical CR and 44% of those had clinical CR. 12%
more lumpectomies performed with pre-op AC. No difference in
OS or DFS. OS and DFS trend favoring pre-op AC in women <50
years old (P = .06, P = .09)
NSABP B-27 (Rastogi et al. JCO 2008): Randomized 1567 pts to
pre-op AC, pre-op AC + Taxotere, or pre-op AC with post-op
Taxotere. Pre-op AC + Taxotere showed increased pCR (26% vs
13%, P < .001). No difference in DFS or OS
Improved outcomes with PMRT
Premenopausal Danish Trial (DBCG 82b) (Overgaard et al.

NEJM 1997): Randomized 1708 premenopausal pts with T3/T4
or axillary N+ s/p MRM + ALND to CMF chemo vs CMF + PMRT
to 50 Gy/25 fx or 48 Gy/22 fx. PMRT included CW, scar, and
regional LN (SCV/ICV/IMC). PMRT improved 10-year DFS from
34% to 48%, 10-year OS from 45% to 54%, and LRR 9% vs 32%
(all P < .001).
Postmenopausal Danish Trial (DBCG 82c) (Overgaard et al.
Lancet 1999): Randomized 1375 postmenopausal women <70
years old with T3/T4 or axillary N+ disease s/p MRM + ALND to
tamoxifen alone vs tamoxifen + PMRT to 50 Gy/25 fx or 48 Gy/22
fx. PMRT improved 10-year DFS from 24% to 36% (P < .001)
and 10-year OS 36% to 45% (P = .03).
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG
RT meta-analysis) (Clarke et al. Lancet 2005; update McGale et
al. Lancet 2014): 78 randomized trials of 42 000 women.
Subgroups analyzed: N0 s/p BCS, adjuvant RT reduced 5-year
LR (22.9% → 6.7%) and 15-year breast cancer mortality (BCM)
(31.2% → 26.1%). N+ s/p BCS, adjuvant RT reduced 5-year LR
(41.1% → 11%) and 15-year BCM (55%→ 47.9%). N0 s/p MRM,
PMRT reduced 5-year LR (6.3% → 2.3%) but increased 15-year
BCM (27.7% → 31.3%). N+ s/p MRM, PMRT reduced 5-year LR
(22.8% → 5.8%) and 15-year BCM (60.1% → 54.7%). Tamoxifen
use for 5 years reduced LR risk by ~50% in ER+ pts. 2014
updates showed no benefit to PMRT in N0 MRM pts but
confirmed significant reduction in LR and BCM in pts with 1-3 and
≥4 positive axillary LN.
INFLAMMATORY/RECURRENT BREAST
CANCER
JENNIFER LOGAN • WENDY WOODWARD
B
Definition: Inflammatory breast cancer (IBC) is primarily a
clinical diagnosis requiring (1) rapid onset of breast erythema,
edema, and/or peau d’orange with or without a palpable mass or
skin thickening, (2) <6-month duration of symptoms, (3) erythema
occupying at least 1/3 of the breast, and (4) pathologic
confirmation of invasive carcinoma. Note: Erythema not
classically “red” in all skin tones, and pathologic evidence of
lymphatic involvement not required
Incidence/prevalence: IBC accounts for 1%-4% of all detected
breast cancer with ~70% presenting with regional disease and
30% with metastatic disease.
Outcomes: Lower than non-IBC. Best reported outcomes with
trimodality treatment. Retrospective series suggest presence of
dermal lymphatic invasion, lack of breast-feeding, obesity, and
triple-negative subtype are negative prognostic indicators.
Risk factors: Bimodal incidence by age. IBC tends to be
diagnosed at younger ages with increased prevalence in African
American/Hispanic vs white women and is associated with
obesity. Pregnancy is not protective. No difference in BRCA
status or family history compared to non-IBC.
T B C
Pathology: Although all subtypes present, there is higher
incidence of ER/PR− and Her2 +/− than non-IBC. Luminal A not
associated with clearly favorable prognosis. Commonly, dermal
lymphatic invasion or tumor emboli are noted in the involved skin
but are not required for diagnosis. Emboli-clogged dermal
lymphatics are purported cause of erythema and swelling.
Molecular/biologic features: 90% express RhoC (van Golen et
al. Cancer Res 2000). All E-cadherin positive. IBC tumors can
demonstrate increased angiogenic properties such as increased
mRNA expression of VEGF and VEGFR, as well as several
cytokines (IFN-γ, IL-1, IL-12, bFGF, FGF-2, IL-6, and IL-8). Role
for tumor-promoting stromal macrophages demonstrated
W
See General Breast Cancer chapter.
Imaging modifications: Bilateral breast and bilateral nodal imaging
required (contralateral nodes involved in 10%). CT of the
chest/abdomen/pelvis/neck or PET/CT. Prechemo cross-sectional
imaging of involved regional nodes and including the neck helpful in
RT planning. Upfront medical photography. Mammogram can be
negative except for skin thickening.
T A
An aggressive trimodality approach is optimal.
Algorithm: Neoadjuvant chemotherapy ± Her2-targeted therapy

→ non–skin-sparing MRM → PMRT → completion hormone
therapy × 5-10 years and/or completion Her2-targeted therapy ×
1 year
R T T
C C W (CW)
I
Dose:
If pCR to neoadjuvant systemic and age > 45 years old: 50 Gy/25
fx + 16 Gy/8 fx boost (QD)
If <pCR to neoadjuvant systemic or age ≤ 45 years old: 51 Gy/34
fx + 15 Gy/10 fx boost (bid)
Target/technique/SIM: Same as PMRT techniques listed in
LABC chapter. Critical to use upfront imaging and photographics
to increase field size and cover all disease prior to neoadjuvant
chemotherapy
S T
See General Breast Cancer chapter for systemic therapy
regimens. IBC patients are treated primarily with neoadjuvant
systemic therapy.
Minimal response or progressive disease with neoadjuvant
systemic therapy → follow closely and perform MRM before the
window of operability is lost given morbidity of local failure.
Consider pre-op radiotherapy if margin-negative surgery is
unlikely.
S O P
Non–skin-sparing modified radical mastectomy (MRM):
Complete removal of the breast, overlying skin, and axillary levels
I-II. SLNB not effective in IBC. Cannot place tissue expander due
to non–skin-sparing procedure
Pathology report: Review ER/PR/Her2 status, tumor grade,
tumor size, extent (multifocal?), surgical margin status (either
positive, close [0-1.9 mm], or negative [≥2 mm]), extent of
response to chemotherapy, presence of dermal lymphatic
invasion/tumor emboli
N S (A R
S I )
Dose escalation/patient selection in IBC
Bristol et al. IJROBP 2008 (MDACC): 256 M0 IBC pts treated

with trimodality therapy. 192 completed treatment. Demonstrated
pts with unknown/close/+ margins, <pCR to NAC, or age < 45
years benefited from dose escalation of PMRT from 60 to 66 Gy.
For those that completed all treatment: 5-year LRC 84% vs 51%,
5-year DMFS 47% vs 20%, and 5-year OS 51% vs 24% (all P <
.001).
Rosso et al. Ann Surg Oncol 2017 (MDACC): Prospective
study with 114 nonmetastatic IBC pts receiving trimodality
treatment: AC ± carboplatin (for TNBC) ± Her2-directed therapy
(for HER2+) → Taxol → MRM → PMRT to >60 Gy → ± hormone
therapy. 2-Year LRR 3.2% and 5-year OS 69.1%. Improved DFS
in Her2+, clinical stage IIIB, complete or partial radiologic
response to NAC, pCR, and lower initial nodal burden.
Aggressive local therapy in metastatic IBC
Akay et al. Cancer 2014 (MDACC): 172 stage IV IBC pts. 55%
of pts with oligomet IBC. 46% of pts underwent curative primary
tumor resection (93% MRM). PMRT involved 51 Gy/34 fx bid +
15 Gy/10 fx CW boost. 5-Year OS 29% and 5-year DPFS 17%.
MVA showed improved OS with response to chemotherapy (HR
0.49, P = .005) and surgery + PMRT (HR 0.9, P = .0001).
R B C
Background
Definition: Recurrences can be local (ipsilateral breast/tumor

bed), regional (in nearby lymph nodes), or distant. Contralateral
breast disease is not considered recurrent.
Outcomes: Dependent on type/timing, 5-year OS 50% (any
recurrence) vs 70% (CW only)
Workup: Similar workup to IBC workup, important to note
previous therapies received. Depending on site and timing of
recurrence, repeat biopsies are likely. Multidisciplinary evaluation
is essential.
Surgical options and systemic therapy
Dependent on multidisciplinary evaluation and prior therapies

received
Trimodality treatment preferred when possible (Aebi et al. Lancet
Oncol 2014)
Treatment algorithm
aCareful review of prior records, consideration of reirradiation in extenuating circumstances

in which safety may not be compromised.
Considerations for prior RT

General principles: Prior dose recall is 50% at 10 years; flap
placement can reduce volume of previously irradiated tissue. If
adequate dose for tumor control cannot be given safely, the risk-
benefit ratio favors no treatment.
If indications for local recurrence are high and other therapies not
feasible, reirradiation may be considered. Greater consideration for
radiation techniques that limit reirradiation of ribs and other normal
structures (eg, electrons/protons).
Radiation treatment technique for recurrent breast cancer
Rationale: Recurrent disease in the setting of prior therapy as

opposed to persistent or inadequately treated disease has had
time and pressure to increase resistance. As such, an empiric
10% dose escalation is recommended.
Dose: 54 Gy in 27 fraction → boost of 12 Gy/6 fx (empiric 10%
dose escalation)
Target/technique/SIM for locoregional recurrence is similar to
PMRT techniques in LABC chapter.
PROSTATE CANCER (DEFINITIVE)
DARIO PASALIC • GEOFFREY V. MARTIN • SEUNGTAEK CHOI
B
Incidence/prevalence: Third most common cancer with 160 000 new
cases of prostate cancer per year with 27 000 deaths in the United
States in 2017. Most prevalent cancer in men in the United States
with lifetime risk estimated to be ~15%
Outcomes: Prostate cancer–specific survival at 10 years with
treatment is 99% for low risk (Hamdy et al. NEJM 2016), 95% for
intermediate risk (Pisansky et al. JCO 2015), and 84% for high risk
(Nguyen et al. Cancer 2013).
Demographics: African American men present with more advanced
disease and have shorter progression-free survival than Caucasian
counterparts (Chornokur et al. Prostate 2011).
Risk factors: Advanced age, African American race, family history,
smoking
T B C
Genetics: 5%-10% familial (Bratt et al. J Urol 2002). RR of 2.5 and
3.5 in patients with 1 and 2 first-degree relative(s), respectively (Johns
and Houlston BJU Int 2003). Associated with BRCA2 mutations, and
increased risk in patients with Lynch syndrome and Fanconi anemia.
Pathology: Majority acinar adenocarcinoma (~95%), but more high-
risk variants include sarcomatoid, ductal, squamous, small cell,
urothelial (Humphrey Histopathology 2011)
Imaging: 1.5 T (with endorectal coil) or 3 T (with/without endorectal
coil) multiparametric MRI with contrast: T2 hypointense (Fig. 48.1),
contrast enhancing, and DWI restricted.
Anatomy: Prostate bordered by bladder/bladder neck (superiorly),
fascia of urogenital diaphragm (inferiorly), attached to pubic
symphysis by puboprostatic ligament (anteriorly), separated from
rectum by Denonvilliers fascia and attached to the rectum near the
prostate apex via the recto-urethralis muscle (posteriorly), and levator
ani muscles (laterally)
Prostatic lymph node drainage
First echelon: Periprostatic, obturator
Second echelon: External iliac, internal iliac, presacral,
presciatic
Third echelon (M1a): Common iliac, inguinal, retroperitoneal
Figure 48.1 Representative MRI T2 sequence identifies dominant
lesion appearing as T2 hypointense on axial (left) and coronal
(right) cross-sectional images (white arrows). (Images acquired
from Medscape.com.)
W
History and physical: Specific attention to PSA screening history,
history of urologic procedures including TURPs, AUA score, SHIM
score, history of IBD (ulcerative colitis and Crohn’s), collagen vascular
disease, and colonoscopy. Digital rectal exam (DRE)
Labs: PSA, testosterone. If treating with hormone therapy: CBC, LFTs
Procedures/biopsy: 10-12 core US-guided biopsy. MRI-guided
biopsy if discordant finding between MRI, DRE, and/or US-guided
biopsy.
Imaging: MRI of the pelvis/prostate >6 weeks after biopsy. Tc-99m
bone scan (positive in 49.5% T3-T4 and 29.9% Gleason ≥ 8) for high
risk or Gl 4+3 and PSA > 10. Consider baseline DEXA scan prior to
start of long-term ADT and colonoscopy prior to start of RT.
*Imaging (MRI, CT scan, etc.) can only be used to evaluate LN
staging and is not used to evaluate primary staging.
P C S (AJCC 8
)
a Nonregional LNs refer to common iliacs and superior and inguinals and inferior.
b Unless noted, pathologic stage is the same as clinical stage.
c ISUP, International Society of Urological Pathology.
T A
R T T
SIM:
Fiducial marker placement (2 carbon for proton; 3 gold for photon)
prior to simulation; head first, supine, lower extremity immobilization
(Fig. 48.2), bladder full, empty rectum (milk of magnesia day before
and enema day of SIM). Endorectal balloon if proton simulation or if
sigmoid/small bowel close to radiation field. Isocenter in middle of the
prostate
Figure 48.2 Standard setup at simulation for definitive EBRT for

prostate cancer. We typically immobilize lower extremity with
Medtec© device.
Dose: 78 Gy in 39 fractions (all eligible intact prostate EBRT patients)
72 Gy in 30 fractions or 60 Gy in 20 fractions (low-intermediate-risk
patients, small/medium prostate, AUA < 15, and no recent TURP)
46 Gy in 23 fractions to pelvic LN, boost radiographically enlarged LN
to 54-60 Gy
44 Gy in 22 fractions followed by brachytherapy boost
Pd-103 to 90 GyI-125 to 110 Gy
Target: Prostate only (low risk)
Prostate, proximal 1.5-2 cm of seminal vesicles (intermediate risk)
Prostate, full seminal vesicles, ± pelvic lymph nodes (high risk)
Technique: IMRT/VMAT; consider protons
IGRT: Bladder volume scan prior to each treatment, treat if bladder
volume is within 20% of simulation
Daily kV imaging with alignment to intraprostatic fiducials
Consider CBCT if fiducial is not available or if anticipated problems
with setup.
Planning directive (for conventional fractionation at 2 Gy/day):
PTV V100 ≥ 98%
Rectum V80, 70, 60, 40 Gy ≤ 3, 20, 40, 60, respectively (do not have
V30 line encompass the entire rectum on a single axial slice)
Bladder V70Gy ≤ 20% (allow up to ≤30%)
Femoral heads V45Gy ≤ 10%; V50Gy ≤ 5%; D max < 55 Gy
Small bowel D max < 50-54 Gy
Sigmoid D max < 60 Gy
Planning directive (for 72 Gy in 30 hypofraction regimen):
PTV V100 ≥ 98%
Rectum 70, 60, 35 Gy ≤ 5, 20, 60, respectively
Bladder V60 ≤ 20%, respectively
Femoral heads V50Gy ≤ 5%; V45Gy ≤ 10%; D max < 55 Gy
Small bowel D max < 50 Gy
Sigmoid D max < 54 Gy
S
Radical prostatectomy either open or minimally invasive, generally
robotic. Robotic surgery associated with lower blood loss and
decreased hospital stays. Oftentimes combined with pelvic lymph
node dissection, especially for some low-risk and all
intermediate/high-risk patients.
C /H T
Androgen deprivation therapy: Neoadjuvant/concurrent/adjuvant
lupron with 14-30-day course of Casodex. Practice at MDACC
includes 6 months with unfavorable intermediate-risk patients
receiving EBRT, 24 months in high-risk patients with EBRT and 12
months with EBRT + brachytherapy boost. ADT duration may vary
based on response, tolerance, and patient factors.
Abiraterone: Concurrent/adjuvant treatment reasonable to consider
for high-risk or LN+ patients, refer to medical oncology for patients
with highly unfavorable disease (James et al. NEJM 2017). Given with
prednisone 5 mg daily
Docetaxel: More evidence is needed; consider referral to medical
oncology for patients with highly unfavorable disease (Vale et al.
Lancet Oncol 2016)
S E M
Obstruction: Decreased flow/hesitancy/frequency. 1st-line tamsulosin
(0.4 mg 30 minutes after dinner up to 2 tablets per evening) → 2nd-
line terazosin (1 mg 30 minutes after dinner, can titrate up to 10 mg as
tolerated)
Overactivity: Urgency/frequency. 1st-line ibuprofen (400 mg 2 tablets
bid prn; avoid in kidney disease) → oxybutynin (5 mg 2-4 times per
day)
Cystitis: Urgency/frequency + dysuria. UA + urine culture to r/o UTI.
Treat if positive. If negative, 1st-line ibuprofen (400 mg 2 tablets bid
prn; avoid in kidney disease) → 2nd-line Pyridium (100-200 mg tid
after meals; short course, turns urine orange; avoid in kidney disease)
Diarrhea: 1st diet modification (low residue, lower fiber, and low dairy)
→ 2nd-line Imodium titrating to a max of 8 pills/day → 3rd-line
alternating Lomotil 2 pills and Imodium 2 pills every 3 hours
Proctitis: Rectal pain. 1st-line cortisone suppository → 2nd-line steroid
enemas.
F -U
History and PSA (get testosterone if on ADT): Every 3-6 months for 2
years then every 6-12 months until year 5, annually thereafter
Consider DRE every 12 months.
Minimize instrumentation (eg, colonoscopy, cystoscopy) in first 2
years.
N T —L R
Treatment options
PROTECT (Hamdy et al. NEJM 2016): Established the role of active

surveillance. RCT comparing active surveillance, prostatectomy, or
EBRT + ADT in early stage prostate cancer. Most patients Gleason 6
(76%) and T1c (76%). RT was to 74 Gy and patients received 3-6
months of ADT. Median follow-up of 10 years. Treatment with RP or
EBRT improved DFS (9% compared to 23% in AS arm), but no
difference in prostate cancer–specific survival (99%) and OS (88%) at
10 years. 53% of AS patients received definitive treatment during
study period.
PROTECT QOL (Donovan et al. NEJM 2016): QOL surveys for
patients on PROTECT trial with 6-year follow-up. Radical
prostatectomy associated with worse sexual and incontinence.
Radiation associated with worse urinary urgency and bowel
symptoms
N T —I R
Combination ADT + EBRT
RTOG 94-08 (Jones et al. NEJM 2011): Established the role of

neoadjuvant ADT in intermediate-risk prostate cancer. RCT
comparing EBRT + ADT vs EBRT alone in 1979 patients. Inclusion
criteria were T1-T2b, PSA < 20, and 60% Gleason 6 and 27%
Gleason 7. RT was 66.6 Gy to prostate, 46.8 Gy to pelvis with 4
months of ADT. Median follow-up of 9.1 years. Treatment with ADT +
EBRT improved 10-year OS by 5% (62% with ADT, 57% without), and
10-year disease-specific mortality (4% with ADT, 8% without ADT).
Harvard (D’Amico et al. JAMA 2008): Established the role of adjuvant
ADT in intermediate-risk prostate cancer. RCT comparing EBRT +
ADT vs EBRT alone in 206 patients. Inclusion criteria was T1-T2b on
exam with at least one unfavorable feature of GS ≥ 7, PSA > 10, or
T3 on MRI. RT was 70 Gy to prostate only with 6 months of ADT.
Median follow-up of 7.6 years. Treatment with ADT + EBRT improved
8-year OS by 13% (74% with ADT, 61% without), and disease-specific
mortality (4% with ADT, 13% without ADT).
N T —H R
EBRT + ADT
SPCG-7 (Widmark et al. Lancet 2009): Established the role of RT.

Randomized, multicenter to RT + ADT vs ADT-alone. Enrolled cT1b-
T2 and grade 2-3, or cT3; 40% with PSA ≥ 20; 19% grade 3; 78% T3.
RT was to 70 Gy and patients received 3 months of leuprorelin +
flutamide followed by indefinite flutamide. Median follow-up of 7.6
years. RT improved 10-year biochemical-free survival (74.1% vs
25.3%; p < .001), disease-specific survival (88.1% vs 76.1%; p <
.001), and overall survival (70.4% vs 60%; p = .004).
RTOG 8610 (Roach et al. JCO 2008): Established the role of
neoadjuvant ADT. Randomized phase III trial to RT alone vs RT +
neoadjuvant ADT 2 months before RT and concurrent with RT.
Enrolled patients with bulky T2-4 tumors +/− lymph node involvement.
RT was 65-70 Gy to the prostate and 44-46 Gy to the lymph nodes.
Median follow-up 12.5 years. Neoadjuvant ADT improved prostate
cancer–specific mortality (23% vs 36%; p = .01) and distant
metastases (35% vs 47%; p = .006).
EORTC 22863 (Bolla et al. Lancet 2002): Established the role of
concurrent long-term ADT. Randomized to RT-alone vs RT +
concurrent ADT for 3 years. Enrolled patients with T3-4 or T1-2 with
Gleason ≥ 7. RT was 70 Gy with whole pelvis to 50 Gy. Median follow-
up of 9 years. Three-year ADT improved 5-year overall survival (78%
vs 62%; p = .0002) and disease-specific survival (94% vs 79%; p =
.0001).
RTOG 9202 (Horwitz et al. JCO 2008): Confirmed that long-term ADT
is better than short-term ADT. Randomized to RT + neoadjuvant ADT
for 4 months vs additional 24 months. Enrolled patients with cT2c-T4,
PSA < 150. RT was 65-70 Gy (45 Gy to whole pelvis). Median follow-
up of 11.3 years. Long-term ADT improved 10-year disease-specific
survival (89% vs 84%; p = .004) and distant metastases (15% vs
23%; p < .0001).
Note: All of the above ADT + EBRT studies were done prior to the era
of dose escalation to 78 Gy in 2 Gy/day fractions; therefore there is some
question as to the impact of hormones with a higher dose.
EBRT + brachytherapy boost + ADT
ASCENDE-RT (Morris et al. IJROBP 2017): Randomized, multicenter

trial that treated patients with EBRT alone vs EBRT + LDR
brachytherapy boost. Enrolled intermediate and high-risk patients
(~69%); T1c-T3a disease; all patients received 12 months ADT (8
months neoadjuvant ADT). RT was 46 Gy in 23 fractions for all
patients, followed by boost to 78 Gy in EBRT alone vs I-125
brachytherapy boost with minimal peripheral dose of 115 Gy. Median
follow-up of 6.5 years. EBRT + brachytherapy boost improved
biochemical progression-free survival at 7 years (86% vs 75%; p <
.001).
EBRT to lymph nodes
RTOG 9413 (Roach et al. JCO 2003; update Lawton et al. IJROBP
2007): Phase III randomized 2 × 2 factorial design—whole-pelvis RT
(WPRT) to 50.4 Gy vs prostate-only RT to 70.2 Gy in 1.8 Gy fractions
and neoadjuvant ADT vs adjuvant ADT for 4 months. Included those
with PSA < 100 and LN-positive risk >15%; excluded surgical staging.
Majority of patients were unfavorable intermediate risk or high risk
(>T2c, PSA < 30, GS > 7); all RT was 4-field 3DCRT. Median follow-
up of 7 years. No significant difference in PFS between neoadjuvant
ADT vs adjuvant ADT or WPRT vs prostate only RT. Criticisms
include low hormone therapy duration and RT doses by today’s
standards, as well as a complex interaction between RT field size and
ADT.
GETUG-01 (Pommier et al. JCO 2007; IJROBP 2016): Randomized,
multicenter trial of prostate RT to 66-70 Gy +/− pelvis to 46 Gy.
Inclusion criteria of T1b-T3c, N0M0 with normal bone scan and pelvic
CT, surgical staging not allowed. Approximately 50% of patients had
<15% risk of lymph node positive disease. Majority of patients (~80%)
were high risk and received 4-8 months of neoadjuvant ADT; all RT
was 4-field 3D CRT. Median follow-up 11.4 years. No significant
difference in PFS or OS between the arms. Criticisms include low
hormone therapy duration and RT doses by today’s standards, as well
as small pelvic field volume.
PROSTATE CANCER (ADJUVANT/SALVAGE)
DARIO PASALIC • GEOFFREY V. MARTIN • SEUNGTAEK CHOI
B ,T B ,
C
See Definitive Prostate Cancer chapter.
W PSA R
History and physical: AUA score, SHIM score, IBD (ulcerative colitis
and Crohn’s), collagen vascular disease, and colonoscopy (within 3-5
years). Initial stage. Type and date of surgery, PSA measurements
after surgery. Digital rectal exam. Delay post-op RT until urinary
function maximized/stabilized to ≤1 pad/day (typically ≥3 months from
the date of surgery).
Labs: PSA, testosterone. If treating with hormone therapy: CBC
Procedures/biopsy: Consider image-guided biopsy if nodule is
palpated or visible on imaging.
Imaging: MRI of the pelvis/prostate. Tc-99m bone scan. CT chest and
abdomen with contrast. Consider advanced PET imaging modalities.
Anatomy:
Prostate fossa: Top of pubic symphysis (superiorly), 1 cm below
vesicourethral anastomosis (inferiorly), bladder wall or posterior
edge of pubic bone (anteriorly), anterior rectal wall (posteriorly),
and pelvic floor muscles/fascia (laterally)
SV fossa: Top of the prostate fossa (inferiorly), posterior wall of
the bladder (anteriorly) to the anterior rectum wall (posteriorly) up
to the remnants of the vas deferens (superiorly)
Prostatic lymph node drainage
First echelon: Periprostatic, obturator
Second echelon: External iliac, internal iliac, presacral,
presciatic
Third echelon (M1a): Common iliac, inguinal, retroperitoneal
P C S (AJCC 8
)
See Definitive Prostate Cancer chapter.
T A
a Factors favoring ADT use include negative margins, Gleason ≥ 8, and short time to PSA
recurrence.
R T T
SIM:
Lower extremity immobilization, bladder full, empty rectum (milk of
magnesia day before and enema day of SIM), +/− endorectal balloon.
Isocenter in the middle of prostate fossa
Dose: SIB 66 Gy in 33 fractions to the prostate fossa (post-op
adjuvant). Consider 59.4 Gy in 33 fractions to SV fossa (if pSV−).
SIB 70 Gy in 35 fractions to the prostate fossa (post-op salvage).
Consider 63 Gy in 35 fractions to SV fossa (if pSV−).Pelvic LN
radiation to 46 Gy in 23 fractions. Consider boosting gross LNs to 54-
60 Gy.Consider boosting gross disease in the fossa to 72-74 Gy in 35
fractions.
Target: Prostate fossa and SV fossa ± pelvic lymph nodes
Technique: IMRT/VMAT
Figure 49.1 Sagittal and axial views showing an RT plan treating the
prostate fossa to 70 Gy (blue colorwash) and SV fossa (yellow
colorwash) to 63 Gy. See color insert.
IGRT: Daily kV imaging with alignment to bone. Consider CBCT if

anticipated problems with setup.
PTV: V100 ≥ 98%
Rectum: V70Gy < 20%, V60Gy < 40%, V40Gy < 60%, respectively
(do not have V30 line encompass the entire rectum on a single axial
slice)
Bladder: V70Gy ≤ 20%
Femoral heads: V45Gy ≤ 10%; V50Gy ≤ 5%; D max < 55 Gy
Small bowel: D max < 50-54 Gy
Sigmoid: D max < 60 Gy
C /H T
Androgen deprivation therapy: Neoadjuvant/concurrent/adjuvant
lupron. Consider 4-6 months for early salvage (0.2 ≥ PSA ≥ 0.5), 6
months for salvage (PSA ≥ 0.5) and ≥12 months for pLN+ disease.
Can consider RT without ADT for early salvage PSA < 0.5 especially
if positive surgical margin.
S E M
See Definitive Prostate chapter.
F -U
History and PSA (get testosterone if on ADT): Every 3-6 months for 2
years, then every 6-12 months until year 5, annually thereafter
Consider DRE every 12 months.
Minimize instrumentation (eg, colonoscopy, cystoscopy) in first 2
years.
N S
Advantage of adjuvant radiation over salvage radiation
Multi-institutional (Hwang et al. JAMA Oncol 2018): Multi-institutional

retrospective review in patients with pT3 and/or + margins. Propensity
score matching to compare adjuvant (n = 366; PSA < 0.1) vs salvage
(n = 366; 0.1 ≥ PSA ≥ 0.5). Adjuvant radiation associated with
statistically significant improvement in freedom from biochemical
failure (12-year: 69% vs 43%, p < .001), freedom from distant
metastases (12-year: 95% vs 85%, p < .03), and overall survival (12-
year: 91% vs 79%, p = .01). Sensitivity analysis demonstrated that
decreased risk of biochemical failure with adjuvant radiation remained
significant unless >56% of patients in adjuvant group were cured by
surgery alone.
Benefit of adjuvant/salvage radiation after prostatectomy
SWOG 8794 (Thompson et al. J Urol 2009): Phase III trial

randomizing 425 patients with pT3 disease (ECE or SV involvement)
with or without positive surgical margins after prostatectomy to
adjuvant EBRT 60-64 Gy vs observation. Enrolled patients were 79%
adjuvant (PSA undetectable) and 31% salvage (PSA detectable).
Treatment with adjuvant radiation improved metastasis-free survival
(median: 14.7 vs 12.9 months, p = .016). Overall survival also
improved in adjuvant radiation arm (total deaths: 52% vs 41%, p =
.023).
ARO 96-02/AUO 09/95 (Wiegel et al. J Urol 2014): Phase III trial
randomizing 388 pT3-4N0 (ECE or SVI involvement) with or without
positive surgical margins after prostatectomy to adjuvant EBRT 60 Gy
vs observation. All patients were treated adjuvant (PSA undetectable).
Adjuvant radiation resulted in significantly better PFS (10 years: 35%
vs 56%, p < .001). No significant improvement in metastases-free
survival or overall survival
EORTC 22911 (Bolla et al. Lancet 2012): Phase III trial randomizing
1005 patients with pT3 (ECE or SVI) or + surgical margins after
prostatectomy to adjuvant EBRT 60 Gy (50 Gy followed by 10 Gy
conedown boost) vs observation. Enrolled patients were 70%
adjuvant (PSA undetectable) and 30% salvage (PSA detectable).
Treatment with adjuvant radiation improved biochemical-free survival
(10 years: 61% vs 41%, p < .001). Metastasis free and overall survival
not different between arms. Any grade late adverse effects more
common in EBRT arm (10 years: 71% vs 60%)
Benefit of hormone therapy with salvage radiation
RTOG 9601 (Shipley et al. NEJM 2017): Phase III trial randomizing
760 patients to ADT for 2 years + salvage EBRT after prostatectomy,
vs EBRT alone. Inclusion in study was post-op PSA > 0.2, pN0, M0.
RT was 64.8 Gy, and ADT was 150-mg bicalutamide daily for 24
months. Median follow-up of 13 years. At 12-year follow-up, treatment
with ADT reduced metastases (cumulative incidence: 14.5% vs 23%,
p = .005) and prostate cancer death (cumulative incidence: 5.8% vs
13.4%, p < .001). Overall survival also improved in ADT arm (10
years: 76% vs 71%, p = .04). Gynecomastia significantly increased
with ADT (cumulative incidence: 70% vs 11%, p < .001).
GETUG-AFU-16 (Carrie et al. Lancet Oncol 2016): Phase III trial
randomizing 743 patients. to ADT + salvage EBRT after
prostatectomy, vs EBRT alone. Inclusion in study was post-op PSA ≥
0.2 but <2, pN0, M0. RT was 66 Gy, and ADT was goserelin for 6
months. Median follow-up of 5.2 years. Treatment with ADT improved
PFS (5 years: 80% vs 62%, p < .0001) but no difference in OS (5
years: 96% vs 95%)
BLADDER CANCER
RACHIT KUMAR • CHAD TANG
B
Incidence/prevalence: Fourth most common diagnosed cancer in
men and 11th in women in the United States. Approximately 81,000
cases will be diagnosed in 2018 in the United States, with almost 19
000 deaths predicted. Approximately 25% of cases would be muscle
invasive.
Risk factors: Tobacco use (urothelial type), industrial exposures
(aromatic amines, hair dyes, arsenic), Schistosoma infection, and
indwelling catheter use (squamous cell type)
T B C
Genetics: Papillary tumors are frequently seen to have mutations in
FGFR3, and nonpapillary tumors often have mutated TP53 and RB1.
Pathology: Majority urothelial carcinomas (>90%). Minority
squamous cell carcinomas and small cell carcinomas. Consider
testing for PD-L1 based on recent data demonstrating the efficacy of
immunotherapeutic agents in the metastatic setting. Common
presentation with synchronous primary in the upper urinary tract
(ureter and renal pelvis)
Imaging: Direct visualization with cystoscopy and exam under
anesthesia often required to assess location and stage. CT urogram
can demonstrate three-dimensional lesions. Bladder MRI appearance
is T1 hypointense (bladder wall is medium in intensity) and T2
intense.
Anatomy:
Situated anterior to the rectum; in men superior to the prostate, in
women both superior and anterior to the vagina/uterus
Urothelial lining is in the bladder, as well as in the upper GU tract
up to the renal pelvis and inferiorly to the urethra. This
contributes to the risk of “field cancerization effect” in which the
entire GU tract may be subject to the same neoplastic effect seen
in the bladder tissue. This necessitates assessment of the entire
GU epithelium when bladder cancer is identified.
Internal iliac, external iliac, and obturator nodes
W
History and physical: History of exposure including aniline dyes,
smoking, and bladder parasites. Symptoms including hematuria,
bladder cramping, and dysuria
Labs: CBC and basic chemistry panel including alkaline
phosphatase.
Procedures/biopsy: Bimanual exam under anesthesia for staging
and transurethral resection of bladder tumor (TURBT).
Imaging: While direct visualization using cystoscopy with
transurethral resection is required for diagnosis, urine cytology may
often initially detect the disease. The extent of disease in the
abdomen/pelvis is best established with CT or MRI, though the upper
tract may be imaged using an IV pyelogram or retrograde
ureteroscopy. Metastatic disease to the chest is generally evaluated
with a chest x-ray or CT chest, and a bone scan/PET scan is often
used in patients with muscle-invasive disease.
Figure 50.1 Representative CT urogram cross-sectional image
from a bladder cancer patient. Mild thickening at the posterior wall
of the bladder (arrow) represents the primary tumor.
B C S (AJCC 8
)
a Note that major change in staging from AJCC 7th to 8th edition is shift from node-positive
disease from Stage IV (7th edition) to Stage III (8th edition).
T A
Figure 50.2 IMRT bladder conservation radiation plan treating to

45 Gy (blue isodose line) in 25 fractions to LNs and whole bladder
followed by a sequential boost to the bladder resection cavity to
64.8 Gy (red isodose line) in 26 fractions. See color insert.
R T T
SIM: Supine, arms on chest. When treating with a bladder boost, two
simulations are needed—whole pelvic and whole bladder fields are
treated with an empty bladder, and boost fields utilize a full bladder.
Empty bowel
Dose (acceptable regimes):
Whole pelvis to 45-50.4 Gy in 25-28 fractions at 1.8 Gy/fx →
Bladder tumor boost to 60-65 Gy in 1.8-2.0 Gy/fx
64 Gy in 32 fractions to whole bladder
55 Gy in 20 fractions to whole bladder
Target: Whole pelvis CTV fields: Bladder, prostate, internal iliac,
external iliac, obturator, and presacral nodes
LN PTV: LN CTV + 0.7 cm setup margin
Bladder PTV: Bladder + 1.5 cm PTV setup margin
Include prostatic urethra for men.
Boost target: Initial TURBT area or known bladder tumor with 2-cm
mucosal margin
Considerations: Midcourse cystoscopy to evaluate response is
optional and is normally conducted between the initial pelvic RT field
and initiation of radiation boost.
Technique: 3DCRT or IMRT; IMRT may be necessary to help reduce
small bowel dose.
IGRT: Daily US bladder + daily kV or CBCT at least weekly + daily kV,

consider more frequent CBCT if difficulty with bladder filling.
Planning directive (for 1.8-2 Gy/day fractionation):
Small bowel V50 < 10 cc, D max < 54 Gy
Bowel “bag” V45 < 195 cc
S
Transurethral resection of bladder tumor (TURBT):
Cystoscopically guided tumor resection with the goal of resecting all
visible tumor with negative margins. Random biopsies should be
performed to identify multifocal disease or carcinoma in situ. Ideally,
the surgeon should perform a thorough mapping of the bladder to
assist in radiation planning.
Cystectomy: Resection of the bladder and prostate. If ileal conduit
(neobladder) is created, surgeon should ensure that urethral margin is
negative.
Lymphadenectomy: Surgeons should perform bilateral pelvic
lymphadenectomy at the same as an surgery with the goal of disease
cure. Completion of a pelvic lymphadenectomy (specifically external
iliac, internal iliac, and obturator lymph nodes) has demonstrated
improvements in disease-specific survival and pelvic recurrence risk.
C
Concurrent: Cisplatin weekly (30-40 mg/m2) or every 3 weeks (100
mg/m2). Alternatively, 5FU and MMC can be utilized. Acceptable
single agents include 5FU, cisplatin, or gemcitabine.
Adjuvant/neoadjuvant: Multiagent cisplatin-based chemotherapy
should be utilized, most frequently. Regimes generally feature
gemcitabine and cisplatin.
S E M
Nausea: 1st-line Zofran (8 mg q8h prn) → 2nd-line Compazine (10
mg q6h prn) → ABH (lorazepam 0.34 mg, diphenhydramine 25 mg,
and haloperidol 1.5 mg) 1 capsule q6h
Diarrhea: 1st-line Imodium titrating to a max of 8 pills/day → 2nd-line
alternating Lomotil 2 pills and Imodium 2 pills every 3 hours
positive. Hyoscyamine (0.125 mg q4-6h prn, do not take more than 12
pills in a day)
Obstruction: Decreased flow/hesitancy/frequency. 1st-line
Tamsulosin (0.4 mg 30 minutes after dinner up to 2 tablets per
evening) → 2nd-line Terazosin (1 mg 30 minutes after dinner, can
titrate up to 10 mg as tolerated)
Proctitis: Diarrhea/abdominal pain. 1st-line alternating Lomotil and
Imodium (as above) → 2nd-line steroid enemas.
F -U
History/physical with urine cytology and cystoscopy every 3 months ×
1 year, then every 6 months × 2 years, then annually
CT abdomen/pelvis every 6-12 months for 2-3 years, then annually
Vaginal dilators for women
N P
Improvement in survival with neoadjuvant chemotherapy prior to
cystectomy
SWOG8710: Phase III trial randomizing 317 patients with muscle-

invasive bladder cancer to radical cystectomy or neoadjuvant
chemotherapy followed by radical cystectomy. Chemotherapy was
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).
Neoadjuvant chemotherapy associated with a trend in OS
improvement (median: 46 vs 77 months, p = .06) and with significantly
higher rate of no residual disease (38% vs 15%, p < .001).
Improvement in bladder preservation outcomes with concurrent

chemo
BC2001: Phase III trial 2:2 randomization of 360 patients with muscle-
invasive bladder cancer to (1) definitive radiation + concurrent
chemotherapy or radiation alone and (2) whole bladder or reduced
high-dose volume radiation therapy (RHDVRT). Radiation dose was
either 55 Gy in 20 fractions or 64 Gy in 32 fractions. Concurrent
chemotherapy was 5FU and MMC.
Chemoradiation vs radiation alone (James et al. NEJM 2013):
Chemoradiation improved locoregional DFS (2 years: 67% vs
54%, p = .03). No significant difference in OS (5 years: 48% vs
35%, p = .16). Grade 3-4 adverse events more common with
chemoradiation during treatment (36% vs 27.5%, p = .07).
Whole bladder vs RHDVRT (Huddart IJROBP 2013): No
difference in overall survival (38% vs 44%) or locoregional failure
(61% vs 64%). No difference in bladder capacity reduction or
grade 3-4 toxicities.
Retrospective review of outcomes and toxicities with bladder

preservation
MGH long-term outcomes-bladder preservation (Giacolone Eur

Urol 2017): Retrospective review of 472 patients with T2-4 bladder
cancer treated with bladder preservation from 1986 to 2013 with a
median FU of 7.21 years. Risk of salvage cystectomy at 5 years was
29%. 5-Year OS was 57%, and DSS with bladder intact was 66%.
Pooled analysis of RTOG bladder-preservation trials (Mak JCO
2014): Retrospective review of 468 patients with muscle-invasive
bladder cancer included on five prospective phase II RTOG trials
(8802, 9506, 9706, 9906, and 0233). The 5- and 10-year OS rates
were 57% and 36%, respectively, and 5- and 10-year DSS were 71%
and 65%, respectively.
Late pelvic toxicities related to bladder-preservation trials
(Efstathiou JCO 2009): Compiled toxicity related to RTOG bladder-
sparing trials: 8903, 9506, 9706, 9906 after a median follow-up of 5.4
years. Late grade 3 pelvic toxicities: 7%, late grade 3 GU toxicities:
5.7%, and late grade 3+ GI toxicities: 1.9%. There were no late grade
4 or 5 toxicities noted.
TESTICULAR CANCER
GEOFFREY V. MARTIN • SEUNGTAEK CHOI
B
Incidence/prevalence: 8000-9000 new cases of testicular cancer per
year. Incidence of testicular germ cell tumors increasing in the past
two decades. Overall 1% of tumors in males
Outcomes: 5-Year survival in patients with testicular cancer is 98%.
Demographics: Most common solid malignancy in males between
ages 15 and 35
Risk factors: Family history, cryptorchidism, testicular dysgenesis,
Klinefelter syndrome
T B C
Pathology: 95% of testicular tumors are germ cell tumors (GCTs),
classified as seminoma or nonseminoma. Nonseminomatous tumors
consist of varied histologies including embryonal, choriocarcinoma,
yolk sac, tumor, and teratomas. Non-GCTs include lymphoma and sex
cord–stromal tumors.
Serum markers:
Seminomas: Mild elevation of β-HCG can be observed (~100
IU/L). Alpha-fetoprotein rarely elevated. LDH may be elevated
and is associated with prognosis but is a nonspecific marker.
Nonseminomatous tumors: Moderate to extreme elevation of
β-HCG observed (>10 000 IU/L) in 10%-20% of early-stage
tumors and 40% of late-stage tumors. Moderate to extreme
elevation of alpha-fetoprotein (>10 000 ng/mL), often associated
with a yolk sac component. LDH may be elevated and is
associated with prognosis but is a nonspecific marker.
Imaging: Hypoechoic mass on testicular transscrotal ultrasound
W
History and physical: History and examination including testicular.
Discussion of sperm banking.
Labs: AFP, β-HCG, LDH, chemistry panel, and CBC. Repeat AFP, β-
HCG, and LDH after orchiectomy for staging purposes
Procedures/biopsy: Radical inguinal orchiectomy, consider inguinal
biopsy of contralateral testes if indicated. Note: Avoid transscrotal
procedures as this may alter lymphatic drainage.
Imaging: Testicular ultrasound, CT abdomen/pelvis, chest imaging
(chest x-ray or CT of chest)
Anatomy:
Testicle surrounded by fibrous tunica layer (tunica vaginalis: outer
layer, tunica albuginea: inner layer). Each testicle divided into
lobules with multiple seminiferous tubules. Seminiferous tubules
drain into the rete testis, which is attached to the spermatic cord
via epididymis, which empties into the vas deferens and then the
urethra at the prostate. Blood-testis barrier established by tight
junctions between Sertoli cells
Testicle/scrotum lymph node drainage
Testes: Retroperitoneal/para-aortic nodes
Scrotum: Inguinal lymph nodes
T C S (AJCC 8
)
T A —P S
All algorithms describe treatment after an initial radical inguinal
orchiectomy, preferably a high ligation of the spermatic cord.
T A —N
All algorithms describe treatment after an initial radical inguinal
orchiectomy, preferably a high ligation of the spermatic cord.
R T T —
S
SIM: Head first, supine, Med-Tec lower extremities, clamshell
contralateral testis
Dose: 20 Gy in 10 fractions to at-risk lymphatics (para-aortic,
ipsilateral iliacs) in stage I-II seminoma
30 Gy in 15 fractions for stage IIA seminoma to gross nodes
36 Gy in 18 fractions for stage IIB seminoma to gross nodes
Target: Para-aortic lymph nodes in all patients being treated (Fig.
51.1)
Add ipsilateral iliac lymph nodes (common, internal, external) for
“dogleg” field in stage II
Boost gross nodes with 2-cm margin to block edge for stage II (Fig.
51.2)
Technique: AP/PA with photons or single PA beam with protons
IGRT: Weekly MV ports, consider daily kV as needed.
Planning directive:
Kidney V20 < 33%
S
Transinguinal orchiectomy with high ligation of spermatic cord is
therapeutic, establishes diagnosis, and establishes T stage.
Nerve-sparing retroperitoneal lymph node dissection used in
treatment of some stage IIB or higher seminoma patients and in
select nonseminoma tumors.
C
BEP: Etoposide 100 mg/m2, cisplatin 20 mg/m2, bleomycin 30 units
every 21 days
EP: Etoposide 100 mg/m2, cisplatin 20 mg/m2 every 21 days
VIP: Etoposide 75 mg/m2, cisplatin 20 mg/m2, ifosfamide 1200 mg/m2
every 21 days with mesna 240 mg/m2 prior to ifosfamide
S E M
Nausea: For prophylaxis, 4-8 mg PO 1-2 hours prior to each fraction
of RT. For treatment, 8 mg po q8h until 1-2 days after RT completion
F -U
After definitive treatment with adjuvant radiation, chemotherapy,
and/or LN dissection
History and physical: Every 6 months for years 1-2, then yearly
CT of chest/abdomen/pelvis with contrast yearly for 1-3 years after
treatment, then as indicated. Can substitute CT of abdomen/pelvis
with chest x-ray
For nonseminoma, obtain serum markers on the same schedule as
history/physical exams.
Active surveillance after orchiectomy without adjuvant therapy
History and physical: Every 2 months for year 1, every 3 months for
year 2, and every 4-6 months for years 3-5. Annually after year 5
CT of chest/abdomen/pelvis with contrast every 4-6 months for years
1-2 and every 6-12 months for years 3-4. Annually thereafter. Can
substitute CT of abdomen/pelvis with chest x-ray
For nonseminoma, obtain serum markers on the same schedule as
history/physical exams.
N T —S
Stage I seminoma
MRC TE19/EORTC 30982 (Oliver et al. JCO 2011): Established the

noninferiority of adjuvant carboplatin compared to adjuvant
radiotherapy in stage I seminoma. Total of 1477 stage I patients
randomized to single-dose carboplatin (AUC 7 ×1 dose) or
radiotherapy to 20 Gy. Most patients (87%) received para-aortic field
only. Overall relapse-free survival was the same between arms at
95%-96% at 5 years. Contralateral seminoma was more common in
radiotherapy-only arm (5-year incidence: 1.2% vs 0.2%, p = .03).
MRC TE10 (Mead et al. JNCI 2011): Established para-aortic only field
as equivalent to dogleg. Total of 478 stage I patients randomized to
the para-aortic vs dogleg field. Radiation dose was 30 Gy in 15
fractions. No difference in 5-year recurrence-free survival (96% in
both arms). Only four pelvic relapses in para-aortic arm, no pelvic
relapses in dogleg arm.
MRC TE18 (Mead et al. JNCI 2011): Established the dose of radiation
in stage I seminoma. Total of 1094 patients randomized to 20 Gy in 10
fractions vs 30 Gy in 15 fractions para-aortic fields (included dogleg
for prior inguinopelvic or scrotal surgery). No difference in 5-year
recurrence-free survival (for 20 and 30 Gy: 95% and 97%). All but one
relapse occurred within 3 years of treatment.
Figure 51.1 Example para-aortic radiation plan utilized to treat
stage I patients (Wilder et al. IJROBP 2012).
Figure 51.2 Example para-aortic and ipsilateral iliac LN field for a
stage II seminoma showing the initial field (left panel) and
subsequent sequential nodal boost (right panel) (Wilder et al.
IJROBP 2012).
PENILE CANCER
SHALINI MONINGI • CURTIS A. PETTAWAY • KAREN
ELIZABETH HOFFMAN
B
Incidence/prevalence: Rare cancer, 0.4%-0.6% of all malignant
neoplasms in men
Outcomes: 5-Year survival is 50%.
Demographics: Higher incidence in Asia, Africa, and South America.
Most commonly seen in ages between 50 and 70 years
Risk factors: Increasing age, phimosis, balanitis, chronic
inflammation, penile trauma, lack of neonatal circumcision, lichen
sclerosus, STDs (particularly HPV types 16 and 18 and HIV), and
tobacco use
T B C
Genetics: Overall about 50% associated with HPV infection, but this
varies with histology; oncogenic HPV types (ie, 16, 18, others) result
in E6 and E7 suppression of p53 and Rb, respectively.
Pathology: Majority are squamous cell carcinomas (95%).
Anatomy
Penile shaft: Consists of skin, subepithelial tissues, corpus
cavernosum, and corpora spongiosum, which surrounds the urethra
Head of penis (glans penis): Primarily consists of an expansion of
the corpora spongiosum. Urethral meatus located at the tip. The
corona is the proximal rounded surface, which is the junction between
the penile shaft and glans.
Lymph node drainage: Superficial inguinal nodes → Deep inguinal
nodes → External/internal iliac nodes
W
History and physical: Exposure history and examination of the penis
and inguinal LNs
Labs: CBC and chemistry panel including calcium
Procedures/biopsy: Punch, excisional, or incisional biopsy of
primary lesion. Percutaneous LN biopsy of palpated LNs. If planning
for definitive radiation (eg, brachytherapy or external beam),
circumcision should always precede RT to prevent radiation-related
complications.
Imaging: If palpable inguinal adenopathy then CT or MRI of abdomen
and pelvis to evaluate pelvic/inguinal LNs. If no palpable adenopathy
routinely CT or MRI utilized for ≥T1b primary tumor, obese patients,
and those with prior inguinal surgery
P C S (AJCC 8 )
T P
Most patients are treated with partial or complete penectomy. Limited
excisions and laser ablation are appropriate for lower-stage lesions to
accomplish organ preservation.
Surgery
Penile organ-sparing approaches:
Wide local excision (WLE): Consider for Tis, Ta, T1, and select
T2 lesions involving the distal glans penis only.
Mohs surgery: An alternative to WLE in some select patient
cases
Glansectomy: Consider in patients with glans-only tumors; clinical
Ta, T1, and select T2 tumors.
Penectomy: Partial or total penectomy. Partial penectomy is sufficient
for most tumors as they arise distally. Consider total penectomy for
large tumors when the remaining phallus would not provide sufficient
length to stand and void.
Radiation therapy for the primary penile tumor may also permit organ
preservation.
Interstitial brachytherapy
Indication: Tumor ≤4 cm, no deep shaft invasion (<1 cm), ideally
confined to the glans, but minor extension across the coronal sulcus
is acceptable.
Dose: PDR/LDR: 60 Gy over 5 days, ~50 cGy/hour
HDR: 3 Gy bid ×5 days
Toxicity: Meatal stenosis (8%-25%; especially >50 Gy); tissue
necrosis (<20%)
Definitive external beam RT
Indication: T1-2N0
Dose: Shaft: 45-50 Gy
10-20 Gy boost to primary disease + 2 cm margin
Consider concurrent cisplatin-containing regime.
Target: GTV, penile shaft
Technique: 6 MV photons utilized for larger lesions to treat the full
thickness. Electrons can be considered for superficial lesions.
SIM: Arms on chest holding a bar, frog leg, lower Vac-Loc, rice, wax,
or lucite block technique to provide full bolus to penile skin surface
(Fig. 52.1). Reproducible setup can be challenging.
Figure 52.1 Simulation setup for a man receiving primary external

beam radiation therapy for penile cancer. Setup shows Vac-Loc
device immobilization into a frog-leg position. Rice bolus utilized to
ensure dose coverage to the penis surface.
R L N M
No palpable or visible nodes pTstage ≥T1b: Dynamic sentinel lymph
node biopsy or superficial inguinal dissection.
Biopsy proven nodal disease(mobile <4 cm): Complete ipsilateral
inguinal node dissection and modified contralateral dissection →
pelvic lymph node dissection for extranodal metastasis, or >2 inguinal
node metastases or bilateral positive inguinal nodes.
Among patients with bulky inguinal metastases, inguinal and pelvic
lymph node dissection, chemotherapy, and radiotherapy may be
indicated. External beam RT can be used as neoadjuvant treatment to
downsize unresectable LNs, definitive treatment instead of LN
dissection, as adjuvant treatment after LN dissection for patients at
high risk of recurrence, or as palliative treatment. The optimal
integration of chemotherapy, chemoradiation, and surgery is being
studied in the ongoing International Penile Advanced Cancer Trial
(InPACT; NCT02305654).
External beam RT for LN management
SIM: Arms on chest holding a bar, frog leg, and lower Vac-Loc.
Consider bolus for superficial LN coverage in thin men.
Indication: Adjuvant radiation considered for N3 disease, ≥3 LNs
involved, bilateral positive nodes or ECE
Dose: 60-70 Gy to gross nodes or sites of ECE
45-50.4 Gy to at-risk inguinal/pelvic node basins and the prepubic fat
(Fig. 52.2)
Concurrent chemotherapy preferred utilizing a cisplatin-containing
regime
Technique: 6× photons delivered by VMAT
Figure 52.2 Example of neoadjuvant treatment of inguinal LNs

and prepubic fat.
F -U
History/physical: Every 3 months for years 1-2, every 6-12 months for
years 3-5, and yearly after year 5. CT or MRI of the abdomen/pelvis
for LN+ and CT or x-ray chest for N2-3 disease.
N D
Outcomes after definitive organ preservation surgery for invasive
penile cancer
Philippou et al. J Urol 2012: Reported on 179 patients having

undergone a variety of organ-sparing procedures, including
glansectomy, excisions, and distal corporectomy. With a mean follow-
up of 43 months, the incidence of local, regional, or distant recurrence
was 8.9% (16 patients), 10.6%(19 patients), and 5% (9 patients),
respectively. The 5-year overall local recurrence-free survival rate was
86.3%. It is important to note that local relapse did not affect disease-
specific survival as patients who recurred could often be salvaged
with additional local therapy.
Outcomes after definitive external beam radiation
Lausanne (Ozsahin et al. IJROBP 2006): Retrospective review of 60

patients treated with surgery ± postoperative RT or definitive RT.
Among patients treated with penile preservation therapy, the 5- and
10-year rates of surviving with an intact penis were 43% and 26%,
respectively. Locoregional relapse occurred in 56% treated with
organ-sparing technique. No difference in survival between
treatments
Outcomes after definitive brachytherapy
Princess Margaret (Crook et al. World J Urol 2009): Retrospective

review of 67 patients with T1-T3 penile cancer who were treated with
definitive EBRT or brachytherapy. Local control rate was 87%, and 5-
year penile preservation rate was 88%. Ten-year OS was 59%, and
cause-specific survival was 83.6%. Late soft tissue necrosis and
urethral stenosis rates were 12% and 9%, respectively.
Adjuvant lymph node radiation
MDACC (Reddy et al. BJU Int 2017): Retrospective review of 182

patients who underwent lymph node dissection for penile squamous
cell carcinoma. On multivariate analysis, clinical N3 (HR = 3.53, P =
.001), ≥3 pathologically involved lymph nodes (HR = 3.78, P < .001)
and ECE (HR = 3.32, P < .001) associated with worse recurrence-free
survival. These data suggest that patients with these pathologic
features may benefit from adjuvant therapies including
chemoradiation. This is being prospectively evaluated in the ongoing
International Penile Advanced Cancer Trial (InPACT; NCT02305654).
CERVICAL CANCER
SHANE R. STECKLEIN • PATRICIA J. EIFEL
B
Incidence/prevalence: Uncommon in developed countries, and
incidence continues to decrease. Third most common gynecologic
cancer in the United States (12 578 diagnoses, 4115 deaths in 2014
[CDC]). 80% of cases occur in developing countries; 3rd most
common cancer and 2nd most frequent cause of cancer-related death
in women worldwide
Outcomes: 5-Year survival across all stages is estimated at 67%
(SEER data).
Demographics: Lifetime risk 1 in 167 (0.6%). In the United States,
incidence in Hispanic and African-American women is higher than that
in non-Hispanic white women.
Risk factors: Infection with high-risk human papillomavirus (HPV;
virotypes 16, 18, 31, 33), immunosuppression, smoking, multiparity,
early age at coitarche, multiple sexual partners.
T
Pathology: 75%-80% are squamous carcinomas, and about 20% are
adenocarcinomas; rare subtypes include neuroendocrine (small cell,
large cell, low-grade carcinoidlike). Nearly all squamous and
adenocarcinomas are positive for HPV DNA and stain positively for
p16; neuroendocrine cancers are positive for CD56, chromogranin A,
synaptophysin.
Imaging: PET-CT most accurate for detection of nodal metastasis.
MRI pelvis useful for establishing extent of primary cervical disease;
tumor best visualized on T2-weighted images with intravaginal gel
(Fig. 53.1). Lung and liver are the most common sites of metastatic
disease.
Figure 53.1 MRI T2 sequence in sagittal axis for a patient with a

newly diagnosed 3-cm cervical adenocarcinoma of the anterior lip.
Note the hyperintense signal in the vagina indicating presence of
intravaginal gel, which allows for improved contrast and detection
of cervical tissue.
A
Cervix is located at the caudal portion of the uterus. Composed of
muscle covered by stratified squamous epithelium (ectocervix) or
simple columnar epithelium (endocervix).
Length of endocervical canal is ~2 cm.
External iliac → common iliac → para-aortic
Obturator and internal iliac → common iliac → para-aortic
Presacral → para-aortic
Tumors that involve the uterine fundus can spread directly to the
para-aortic lymph nodes via lymphatics along the gonadal veins.
Inguinal lymph nodes, if tumor involves distal 1/3 of vagina
Perirectal lymph nodes, if tumor invades the rectovaginal septum,
cul-de-sac, or rectum
W
History and physical: Presentation may include postcoital bleeding,
irregular or heavy vaginal bleeding, vaginal discharge, and lower back
or pelvic pain. May be asymptomatic and detected during routine
gynecologic examination. Conduct complete pelvic examination
including bimanual examination and placement of fiducial markers at
caudal extent of vaginal disease.
Screening: Women aged 21-65 should be screened with
(Papanicolau [“Pap”] smear) every year. Consider lengthening
screening interval to every 5 years with combination Pap smear and
HPV testing for women aged ≥30 (USPTF grade A recommendation).
Labs: CBC, CMP, and LFTs. Consider HIV testing and pregnancy
test.
Procedures/biopsy: Cervical biopsy and cone biopsy as indicated.
For advanced stages (stage ≥IB2), consider examination under
anesthesia, cystoscopy, and/or proctoscopy as indicated.
Imaging: PET/CT. Pelvic MRI with intravaginal water-based gel.
Chest imaging with chest x-ray or CT chest
C C S (FIGO 2009)
Note: FIGO cervical cancer staging is based on clinical examination and
does not include most advanced imaging modalities or any surgical
findings. It allows the following diagnostic tests to determine stage:
physical examination, colposcopy, endocervical curettage, cystoscopy,
proctoscopy, intravenous urography, or CT/MRI to evaluate for urinary
tract obstruction only. Plain chest radiograph and skeletal radiograph to
evaluate for metastases.
T
aMotivated women with tumors ≤2 cm may be a candidate for fertility-sparing approaches, which
include cone biopsy (stages IA1 and IA2) ± LN dissection or radical trachelectomy (stage IB1) ±
LN dissection.
Indications for postoperative chemoradiotherapy (Peters criteria

[GOG 109]):
Positive margin, positive nodes, positive parametria
Indications for postoperative radiotherapy (simplified Sedlis
criteria [GOG 92]):
At least two of three: Tumor size >4 cm, deep (>1/3) cervical
stromal invasion, LVSI
R T T
SIM: Supine, lower Vac-Lok (add upper Vac-Lok if treating extended
fields), arms on chest (above head if treating extended fields). If
treating with IMRT acquire scans with full and empty bladder. Scan
from midlumbar spine to midfemur (extend scan superiorly to T10 if
treating extended fields). Place isocenter midline, midplane, ~2 cm
superior to femoral heads.
Dose:
Overall goal is HR-CTV D90 to ≥87 Gy (EQD2) (EMBRACE),
gross lymph nodes and parametrial involvement to ≥60 Gy
(EQD2), and subclinical nodal volumes to 43-45 Gy (EQD2).
External beam: 45 Gy in 25 fractions at 1.8 Gy/fx (consider 43.2
Gy in 24 fractions at 1.8 Gy/fx for clinically node-negative
patients). Boost grossly involved lymph nodes and parametrial
disease using sequential or simultaneous integrated boost.
Brachytherapy:
HDR: 6 Gy × 5 fractions (EQD2, α/β=10 = 40 Gy)
LDR/PDR: Generally ~18-22 Gy × 2 fractions, respecting
normal tissue constraints
Details regarding brachytherapy doses and volumes. See
Brachytherapy chapter.
Targets:
Definitive radiotherapy
External beam: Uterus and cervix (generate uterocervix ITV),
uterosacral and cardinal ligaments, parametria, obturator,
internal iliac, external iliac, presacral, common iliac, ± para-
aortic lymph nodes.
Brachytherapy: HR-CTV, defined as the entire cervix and any
gross disease at the time of applicator placement; also any
vagina or uterine body initially involved with disease
Postoperative radiotherapy
External beam: Vaginal cuff ITV, remnants of the parametria,
obturator, internal iliac, external iliac, presacral, common
iliac, ± para-aortic lymph nodes (Fig. 53.2)
Brachytherapy (if indicated): Vaginal cuff and target proximal
~2 cm of the vagina
Considerations: If tumor involves distal 1/3 of the vagina, cover

inguinal lymph nodes. If disease invades posteriorly into the
rectovaginal septum, cul-de-sac, or rectum, cover the perirectal lymph
nodes.
Technique: 4-field 3DCRT (AP/PA and opposed laterals). Use IMRT
in posthysterectomy setting or if covering inguinal or para-aortic lymph
nodes.
IGRT: Weekly kV imaging for 3DCRT, daily kV imaging for IMRT

Dose constraints (external beam only)
Bladder V45 Gy < 50%
Rectum V45 Gy < 80%
Kidney (each) V20 < 33%, V15 < 50%
Small bowel V40 < 30%
Duodenum V55 < 15 cc, V60 < 2 cc
Spinal cord <45 Gy max
Dose constraints (brachytherapy; doses include external beam
contribution)
HR CTV D90% > 87 Gy
Bladder D2cc < 80 Gy
Sigmoid D2cc < 75 Gy
Rectum D2cc < 70 Gy
Figure 53.2 Aqua blue contour line in coronal (left) and sagittal
(right) planes representing target lymph nodes in a postoperative
cervical cancer case that was treated with IMRT. Note the vaginal
ITV in turquoise. See color insert. (Adapted from Eifel and Klopp.
Gynecologic Radiation Oncology, a practical guide . Wolters
Kluwer, 2016.)
C
Concurrent: Cisplatin (40 mg/m2 once weekly) for 5-6 cycles
S E M
Diarrhea: Imodium titrating to a maximum of 8 pills/day; schedule
Imodium if diarrhea persists on prn dosing → may consider
alternating Lomotil and Imodium or recommending 1-2 pills before
meals and at bedtime → 3rd-line tincture of opium. Rule out other
causes of diarrhea, especially if presentation is early (eg, Clostridium
difficile).
Cystitis: UA with culture and sensitivity to rule out UTI. Treat if
positive. Pyridium for noninfectious radiation cystitis
Nausea: 1st-line Zofran (8 mg q8h prn) → 2nd-line Compazine (10
mg q6h prn) → 3rd-line Emend (aprepitant) → 4th-line ABH
(lorazepam 0.34 mg, diphenhydramine 25 mg, and haloperidol 1.5
mg) 1 capsule q6h.
F -
H&P 1 month after completing radiotherapy, PET-CT 3 months
thereafter. Interval H&P every 3-6 months for 2 years, every 6-12
months for 3-5 years, and then annually
Cervical/vaginal cytology as recommended for detection of lower
genital tract neoplasia
Imaging of para-aortic nodes for patients with positive pelvic nodes
who were treated with pelvic RT may be performed to detect
salvageable para-aortic recurrences. Additional imaging can be
performed based on symptoms or examination findings suggestive of
recurrence.
Vaginal dilators or intercourse 2-3 times per week starting 2-3 weeks
after completing radiotherapy to mitigate vaginal stenosis.
N
Surgery vs Radiotherapy
Milan (Landoni et al. Lancet 1997): 343 stage IB-IIA patients

randomized to radical hysterectomy vs definitive radiotherapy.
Improved 5-year PFS (66% vs 47%, p = .02) and OS (70% vs 59%, p
= .05) in surgery arm for adenocarcinoma, but no difference in PFS
(76% vs 78%) or OS (84% vs 88%) for squamous cell carcinoma.
63% of surgery patients received adjuvant radiotherapy for high-risk
features. Toxicity (mainly urinary) 28% for surgery vs 12% for
radiotherapy (p = .0004).
Concurrent chemoradiation
RTOG 90-01 (Morris et al. NEJM 1999; Eifel et al. JCO 2004): Stage
IIB-IVA patients comparing extended-field radiation therapy (EFRT) vs
pelvic radiotherapy with concurrent cisplatin and 5-fluorouracil (CRT).
51% reduction in disease recurrence with CRT. 8-Year OS 67% for
CRT vs 41% for EFRT (p < .0001). Additional contemporary
chemoradiation trials include GOG-120 (Rose et al. NEJM 1999),
GOG-123 (Keys et al. NEJM 1999), GOG-85 (Whitney et al. JCO
1999), SWOG 87-97 (Peters et al. JCO 2000), and NCIC (Pearcey et
al. JCO 2002).
IMRT for posthysterectomy radiotherapy
NRG-RTOG 12-03 (Klopp et al. JCO 2018): Randomized trial of

patients with cervical or endometrial cancer with an indication for
postoperative radiotherapy comparing 3D CRT vs IMRT. Significant
reduction in acute (5 week) bowel and urinary toxicity and improved
quality of life and sense of physical well-being with IMRT. At the end
of radiation, IMRT was associated with significantly less diarrhea
(52% vs 34%, p = .01) and less use of antidiarrheal medications (20%
vs 8%, p = .04).
Additional guidance: Eifel PJ, Klopp AH. Gynecologic Radiation

Oncology: A Practical Guide . Wolters Kluwer; 2016.
Figure 53.3 Standard AP (left panel) and lateral (right panel)
fields. The imaging shows the contoured uterocervix ITV (grey),
and nodal CTV (black).
ENDOMETRIAL CANCER
BHAVANA S. VANGARA CHAPMAN • ANN H. KLOPP
B
Incidence/prevalence: Most common gynecologic cancer in
developed countries (53 028 diagnoses and 9727 deaths in the
United States in 2014 [CDC]), second most common gynecologic
cancer in developing countries, and second most common cause of
gynecologic cancer deaths; overall incidence is increasing
Outcomes: 5-Year survival across all endometrial histologies and
stages is estimated at 81% (SEER).
Demographics: Lifetime risk 2.8%. Generally, postmenopausal
women of 55-85 years old, Caucasian > African American, but African
American women have higher mortality rates than other racial groups.
Risk factors: Unopposed estrogen (obesity, PCOS, nulliparity, early
menarche, late menopause, tamoxifen), Lynch syndrome (consider
genetic testing if <50 years old with family history of colorectal cancer
+/− endometrial cancer)
T
Pathology/genetics:
Endometrial:
Type 1: Endometrioid (75%-80%), mucinous (1%-5%);
genomic perturbations in PTEN, KRAS, PIK3CA, PAX2, and
CTNNB1 (β-catenin). May be associated with microsatellite
instability (MSI)
Type 2: Nonendometrioid (10%-15%); serous, clear cell,
carcinosarcoma (previously malignant mixed müllerian tumor
[MMMT]), squamous cell, and undifferentiated); genomic
perturbations in TP53, ERBB2 (HER2), CDKN2A (p16), and
CDH1 (E-cadherin) and may overexpress EGFR or HER2
Uterine sarcoma (5%): Leiomyosarcoma, endometrial stromal
sarcoma, and adenosarcoma
Imaging: Typical presentation of early-stage disease is a thickened
endometrium.
A
1-2 cm muscular uterine wall composed of inner endometrium
(epithelial origin), myometrium (mesenchymal origin), and outer
serosa (mesenchymal origin)
Cranial to caudal: Fundus is the dome superior to the fallopian tubes;
body; and internal os is the constriction in the middle of the uterus
above the cervix
Determining uterine position and degree of flexion is important when
sounding for intracavitary brachytherapy.
Endometrium has few lymphatics, but subserosa has rich
lymphatics, so depth of invasion (DOI) is related to nodal
metastases (GOG 33, Creasman et al. Cancer 1987).
Fundus can drain directly to para-aortics via lymphatics along
gonadal vessels and inguinal nodes via round ligament.
Fundus and upper body: Hypogastric route
Junctional interiliac nodes → common iliac → para-aortic
Middle and lower body, internal os: Lateral route to parametrial
LNs, then
External iliac → common iliac → para-aortic
Obturator and internal iliac → common iliac → para-aortic
Presacral → para-aortic
W
History and physical: Presentation includes vaginal bleeding
(classically postmenopause), pelvic pain, and/or dyspareunia. May be
asymptomatic and detected during routine gynecologic exam.
Conduct complete pelvic examination including bimanual examination
and rectovaginal exam.
Labs: CBC, CMP, CA125, and LFTs. Consider pregnancy test.
Procedures/biopsy: Endometrial sampling/biopsy under
hysteroscopy, and consider dilation and curettage if unable to obtain
adequate biopsy. Patients are surgically staged via hysterectomy.
Imaging: Preoperative CXR only for early-stage, low-grade
endometrioid endometrial cancer; CT C/A/P or PET-CT if FIGO G3,
high-risk histology/sarcoma, or suspect extrauterine disease; MRI
pelvis if gross cervical or vaginal involvement
G
Note: FIGO uterine cancer staging relies on evaluation of the surgical
pathology.
a Includes carcinosarcoma.
T
a Consider risk factors: Age >60 years, DOI, LVSI, large tumor, lower uterine involvement, cervical
glandular involvement; EBRT for inadequate LND or >20% risk on Mayo Clinic nomogram (Alhilli
et al. Gyn Oncol 2013).
b May require interstitial brachytherapy if patient had thick or extensive disease at presentation.
VBT, vaginal brachytherapy; WPRT, whole pelvic radiation therapy; EFRT, extended-
field radiation therapy.
O T C
Extensive cervical involvement: Pre-op WPRT/EFRT + ICRT →
surgery vs radical hysterectomy if negative margins can be achieved.
Vaginal involvement: Pre-op WPRT/EFRT + intracavitary
brachytherapy (ICRT) → surgery vs definitive chemoRT. If distal
vaginal involved, need to include inguinal nodes.
Adnexal involvement: Chemotherapy with RT recommended based
on relative risk factors for local recurrence.
Inoperable: WPRT/EFRT + ICRT (like cervical cancer with HR-CTV
including endometrial target) with consideration of chemotherapy
Uterine sarcoma: Generally simple hysterectomy and BSO, consider
ovarian preservation in young patients with early-stage disease; role
of chemotherapy and radiation is limited.
Other unfavorable histologies (eg, serous carcinoma): Consider
the addition of concurrent chemotherapy and adjuvant chemotherapy
if not otherwise planned due to stage.
R T T
SIM: Supine, arms on chest holding A-bar (above head holding T-bar
for EFRT), lower Vac-Lok (add upper Vac-Lok for EFRT), legs
straight. Scan full and empty bladder to identify an ITV, from T12 to
midfemur (from T10 for EFRT). Isocenter midline, midplane, ~2 cm
superior to femoral heads
Dose (Fig. 54.1):
EBRT: 45-50.4 Gy in 25-28 fractions at 1.8 Gy/fx. Boost grossly
involved lymph nodes to 60-66 Gy. 40 Gy in 2 Gy/fx for patients
receiving EBRT without chemotherapy.
HDR VBT for prophylaxis: 6 Gy × 5 fractions prescribed to the
vaginal surface (EQD2, α/β=10 = 40 Gy) for VBT alone, 5 Gy × 2
fractions (EQD2, α/β=10 = 12.5 Gy) with WPRT/EFRT to 45 Gy
Targets:
Postoperative radiotherapy
EBRT: Vaginal cuff ITV generated with full and empty
bladder; nodal CTV including common iliac, external iliac,
and internal iliac (hypogastric and obturator), presacral if
cervical involvement ± para-aortic nodes
If disease involves distal 1/3 of the vagina, cover medial
inguinal lymph nodes.
If disease invades posteriorly to rectovaginal septum,
cul-de-sac, or rectum, cover the perirectal lymph nodes.
For significant rectal gas on sim scan, extend vaginal
ITV to cover rectum.
VBT: Vaginal cuff and proximal ~2 cm of the vagina
See Brachytherapy Chapter for more details regarding
brachytherapy.
Technique: IMRT (Fig. 54.1) (NRG-RTOG 1203; Klopp et al.
unpublished).
IGRT: Weekly CBCT or CT-on-rails, daily kV imaging
Dose constraints:
a Cumulative EQD 2 , including EBRT.
Figure 54.1 Extended-field IMRT (EFRT) plan. Blue isodose line

representing 50.4 Gy is seen covering nodal CTV and vaginal ITV
(red colorwash). See color insert.
C
Concurrent: Cisplatin (40 mg/m2 once weekly) for 5-6 cycles.
Consider weekly paclitaxel for serous carcinoma (50 mg/m2 once
weekly).
Adjuvant: Carboplatin (AUC 5-6 mg · min/mL) and paclitaxel (175
mg/m2) for 3-4 cycles
S E M
See Cervical Cancer chapter
F -
Physical examination, CT A/P, and CXR q3mo for 2 years, q6mo for 3
years, then annually thereafter
Vaginal dilators or intercourse 2-3 times per week starting 2-3 weeks
after completing radiotherapy to mitigate vaginal stenosis
N
Observation vs WPRT: PORTEC 1* (Creutzberg Lancet 2000;
Creutzberg IJROBP 2011): Randomized 714 patients with stage IB (G2-3)
and IC (G1-2) endometrial cancer s/p TAH/BSO and no LND randomized
to observation vs WPRT (46 Gy/23 fx). 15-Year LRR rates were 6% vs
16% in the WPRT and observation arms, respectively (p < .0001). 15-Year
OS was not significantly different between groups.
WPRT vs VBT: PORTEC 2* (Nout Lancet 2010): Noninferiority RCT
with 427 stage I-IIA high-intermediate-risk endometrial cancer s/p TAH-
BSO randomized to WPRT (46 Gy/23 fx) vs VBT. 5-Year vaginal
recurrence was not different between groups (p = .74). No difference in
LRR (vaginal and/or pelvic recurrence), distant metastases, OS, or DFS
between arms. G1-2 gastrointestinal toxicity was lower in the VBT group at
the completion of RT (13% vs 54%).
Whole abdominal radiation therapy (WART) vs chemotherapy:
GOG 122* (Randall et al. JCO 2006): RCT with 396 patients with stage III-
IV endometrial carcinoma s/p TAH/BSO randomized to WART (30 Gy/10
fx + 15 Gy boost) vs doxorubicin/cisplatin × 7 cycles + cisplatin × 1 cycle.
Improved 5-year PFS (50% vs 38%, p = .007) and OS (55% vs 42%, p =
.004) in the chemotherapy arm. G3-4 hematologic toxicities worse with
chemotherapy arm (88% vs 14%). Criticisms include stage-adjusted
statistical analysis and inclusion of patients with gross residual disease
treated to insufficient doses.
Concurrent chemoradiation + chemotherapy: RTOG 9708* (Greven
et al. Gyn Oncol 2006): Phase II study with 46 G2-3 endometrial cancer
with high-risk features s/p TAH/BSO who underwent concurrent
chemoradiation (45 Gy/25 fx with cisplatin) + VBT + cisplatin/paclitaxel
after completion of RT. 4-Year pelvic, regional, and distant recurrence
rates were 2%, 2%, and 19%, respectively. 4-Year OS and DFS rates were
85% and 81%, respectively. G3 and G4 toxicities occurred in 16% and 5%
of the cohort, respectively.
Chemotherapy vs chemoradiation: NSGO-EC-9501/EORTC-55991
and MaNGO ILIADE-III* (Hogberg et al. Eur J Cancer 2010): Pooled
analysis of two RCTs of 540 patients with stage I-III endometrial cancer
with high-risk features s/p TAH/BSO ± LND randomized to adjuvant RT ±
sequential chemotherapy. In combined analysis, 5-year PFS was
improved in the chemoradiation arm (78% vs 69%, p = .009) and OS
trended toward significance.
Radiation vs concurrent chemoradiation: PORTEC-3 (de Boer et al.
Lancet Oncol 2018): RCT of 686 patients with IA-IIIC endometrial cancer
with high-risk features s/p TAH or TLH ± BSO ± LND randomized to WPRT
(48.6 Gy/27 fx) ± VBT vs concurrent WPRT and cisplatin ± VBT +
concurrent carboplatin + adjuvant carboplatin/paclitaxel. Improvement with
addition of chemotherapy in 5-year failure-free survival (76% vs 69%, p =
.022). No difference in 5-year OS between groups (82% vs 77%, p = .11).
Grade 3 or worse adverse events occurred in 60% of patients receiving
chemoradiation vs 12% who received radiation (p < .001).
WPRT vs VBT + chemotherapy: GOG 249 (Randall et al. ASTRO
abstract 2017): Phase III RCT of 601 patients with high-risk early-stage I-II
endometrial, serous, or clear cell endometrial cancer s/p TAH or TLH ±
BSO ± LND who underwent WPRT ± VBT vs VBT + chemotherapy.
Preliminary results showed no difference in recurrence-free survival,
distant failure, or OS. Acute and late toxicities and pelvic/PA-nodal failure
rates were greater in the VBT + chemotherapy arm.
Uterine sarcoma and carcinosarcoma—observation vs RT:
EORTC 55874* (Reed et al. Eur J Cancer 2008): Phase III RCT of 224
patients with stage I-II high-grade uterine sarcoma and carcinosarcoma
s/p TAH/BSO randomized to observation vs WPRT 50.4 Gy/28 fx. LRR
was reduced in the adjuvant RT arm (22% vs 40%, p = .004) but PFS and
OS were no different. On subtype analysis, RT improved LC in
carcinosarcomas, but not in leiomyosarcomas.
*Studies used 1988 FIGO staging
Additional guidance: Eifel PJ, Klopp AH. Gynecologic Radiation
Oncology: A Practical Guide. Wolters Kluwer; 2016.
VAGINAL CANCER
SHANE R. STECKLEIN • ANUJA JHINGRAN
B
Incidence/prevalence: Least common of all gynecologic cancers
(<3000 vaginal cancers diagnosed each year in the United States)
Outcomes: 5-Year survival across all stages is estimated at
60%-70% (SEER data).
Risk factors: Infection with high-risk human papillomavirus (HPV;
detected in 75% of vaginal cancers), immunosuppression, early age
at coitarche, multiple sexual partners, smoking, increasing age
T
Pathology: 80%-90% of all vaginal cancers are squamous.
Adenocarcinomas classically associated with in utero exposure to
diethylstilbestrol (DES), but DES-associated adenocarcinomas are
now exceedingly rare. Vaginal adenocarcinoma associated with
higher risk of in-field failure and higher risk of distant metastasis.
Other rare subtypes include neuroendocrine cancers and melanoma.
A
The average vaginal length is 7-10 cm. Most vaginal cancers arise in
the upper vagina.
Proximal vaginal cancers share the same pattern of spread as
cervical cancers:
External iliac → common iliac → paraaortic
Obturator and internal iliac → common iliac → paraaortic
Presacral → paraaortic
Distal vaginal cancers may spread through the inguinal lymph
nodes similar to vulvar cancers.
Invasion of the rectovaginal septum, cul-de-sac, or rectum
warrants coverage of the perirectal lymph nodes.
W
History and physical: Presentation includes postcoital bleeding,
irregular or heavy vaginal bleeding, vaginal discharge, pelvic pain,
painful/frequent urination.
Labs: CBC, CMP. Consider pregnancy test.
Procedures/biopsy: Lesion biopsy. Examination under anesthesia
(EUA) with fiducial placement is critical prior to initiating treatment to
delineate extent and location of initial disease to facilitate boost
planning.
Imaging: CT abdomen and pelvis and PET-CT (most sensitive) to
evaluate for inguinal, pelvic, and paraaortic lymphadenopathy. The
vagina is poorly visualized on CT; pelvic MRI with intravaginal gel is
the modality of choice for imaging the primary tumor.
V C S (FIGO 2012)
Note: FIGO vaginal cancer staging is based on clinical exam, which does
not include many imaging modalities or surgical findings. It allows the
following diagnostic tests to determine stage: physical exam, proctoscopy,
and cystoscopy. Plain chest radiograph and skeletal radiograph to
evaluate for metastases.
T
R T T
SIM: Supine, frog-leg (if treating inguinal lymph nodes), lower Vac-Lok
(add upper Vac-Lok if treating extended fields), arms on chest (above
head if treating extended fields). Acquire scans with full and empty
bladder. Scan from mid–lumbar spine to mid-femur (extend scan
superiorly to T10 if treating extended fields). Place isocenter mid-line,
mid-plane, ~2 cm superior to femoral heads.
Dose: If feasible, goal is to treat the tumor with 1- to 2-cm margin to a
cumulative dose of 75-90 Gy (EQD2) using a combination of external
beam radiotherapy and interstitial (or intracavitary if original tumor
was <7 mm thick) brachytherapy. For some apical lesions where
brachytherapy cannot be used, external beam boost to cumulative
dose of ~66 Gy may be employed.
Targets: Vagina and paravaginal tissues (ITV), with at least 3-cm
distal margin on gross disease, obturator, internal iliac, external iliac,
presacral, common iliac, ± inguinal, ± paraaortic lymph nodes.
Technique: IMRT/VMAT, to reduce dose to the central pelvis
C
Concurrent: Cisplatin (40 mg/m2 once weekly) for 5-6 cycles; use is
extrapolated from cervical cancer data.
S E M
Dermatitis: Aquaphor for radiation dermatitis, hydrogel for areas of
moist desquamation. Important to encourage hygiene early in
treatment course to prevent bacterial and fungal infection; Domeboro
Sitz bath 2-3 times daily. If erythema and pain are out of proportion to
expected dermatitis, suspect fungal overgrowth and treat empirically
with fluconazole.
Diarrhea: 1st line Imodium titrating to a max of 8 pills/day; schedule
Imodium if refractory on prn dosing → 2nd line alternating Lomotil 2
pills and Imodium 2 pills every 3 hours → 3rd line tincture of opium
Cystitis: UA with culture and sensitivity to rule out UTI. Treat if
positive. Pyridium for noninfectious radiation cystitis
Nausea: 1st line Zofran (8 mg q8h prn) → 2nd line Compazine (10 mg
q6h prn) → 3rd line Emend (aprepitant) → 4th line ABH (lorazepam
0.34 mg, diphenhydramine 25 mg, and haloperidol 1.5 mg) 1 capsule
q6h
F -
Vaginal dilators or intercourse 2-3 times per week after the vagina has
healed to mitigate vaginal stenosis
Interval H&P every 3-6 months for 2 years, then every 6-12 months
for 3-5 years, then annually
Cervical/vaginal cytology as recommended for detection of lower
genital tract neoplasia
Imaging based on symptoms or examination findings suggestive of
recurrence
N
NCDB analysis (Rajagopalan et al. PRO 2015): Health research
database with 1530 women. Concerning decline in utilization of
brachytherapy boost for vaginal cancer, decreasing from 87.7% in 2004 to
68.6% in 2011. Corresponding increase in IMRT external beam boost.
MDACC experience with vaginal SCC (Frank et al. IJROBP 2005):
Retrospective review of 193 patients with vaginal squamous cell
carcinoma treated with definitive radiation. Excellent outcomes using
external beam radiotherapy and brachytherapy with 5-year disease-
specific survival 85% (stage I), 78% (stage II), and 58% (stage III-IVA).
Low rate of 5-year major complications: 4% (stage I), 9% (stage II), and
21% (stage III-IVA)
MDACC experience with vaginal adenocarcinoma (non-DES
associated) (Frank et al. Gynecol Oncol 2007): Retrospective review of
26 patients with non–DES-associated vaginal adenocarcinoma treated
with external beam followed by brachytherapy (77%) or external beam
alone (23%). 5-Year survival 34% for adenocarcinoma compared to 58%
for SCC. Adenocarcinoma associated with worse pelvic control and higher
risk of distant metastasis.
Additional guidance: Eifel and Klopp. Gynecologic Radiation Oncology:
A Practical Guide. Wolters Kluwer; 2016.
VULVAR CANCER
SHANE R. STECKLEIN • ANUJA JHINGRAN
B
Incidence/prevalence: <6000 vulvar cancers diagnosed each year in
the United States
(SEER data)
Risk factors: Prior infection with high-risk human papillomavirus
(HPV; detected in 50% of vulvar cancers), immunosuppression,
smoking, increasing age, chronic inflammation (eg, lichen sclerosis).
T
Pathology: 90% of all vulvar cancers are squamous.
Adenocarcinoma accounts for the majority of the remaining epithelial
neoplasms. Other rare subtypes include neuroendocrine cancers and
melanoma.
A
Vulvar cancers can arise from the prepuce, clitoris, labia majora, labia
minora, urethral opening, Bartholin and Skene glands (more likely to
be adenocarcinoma), or perineum.
Inguinal → external iliac → common iliac → paraaortic
Locally advanced tumors that involve the anus, rectum, or
rectovaginal septum may also spread through the internal iliac,
presacral, and perirectal lymph nodes.
W
History and physical: Presentation includes vulvar bleeding,
pruritus, discharge, dysuria, vulvar mass, or pain.
Labs: CBC, CMP. Consider pregnancy test.
Procedures/biopsy: Lesion biopsy and/or radical local excision.
Imaging: CT abdomen and pelvis and PET-CT (most sensitive) to
evaluate for inguinal, pelvic, and paraaortic lymphadenopathy. The
vulva is poorly visualized on CT; pelvic MRI is the modality of choice
for imaging the primary tumor.
V C S (FIGO 2012)
Note: FIGO vulvar cancer staging is a hybrid of a clinical and surgical
staging approach, which includes physical examination, imaging studies,
and evaluation of the surgical pathology.
T
R T T
SIM: Supine, frog-leg, lower Vac-Lok (add upper Vac-Lok if treating
extended fields), arms on chest (above head if treating extended
fields). Scan from mid–lumbar spine to mid-femur (extend scan
superiorly to T10 if treating extended fields). Place isocenter mid-line,
mid-plane, ~2 cm superior to femoral heads.
Dose prescribed to volume at risk:
Adjuvant treatment:
Definitive treatment:
Initial external beam treatment: 45 Gy in 25 fractions at 1.8 Gy/fx

(consider simultaneous integrated boost to gross disease and/or high-
risk clinical target volume(s) to 50-52.5 Gy).Boosts: Sequentially
boost gross disease and/or high-risk clinical target volume(s) to target
dose(s) using external beam treatment at 1.8-2.0 Gy/fx.
Targets:
Adjuvant treatment:
For close/positive margins: Vulva and tumor bed with at least
2 cm of vagina proximal to operative bed.
For positive nodes: Inguinofemoral and pelvic* nodes ±
paraaortic lymph nodes.
Definitive treatment:
Vulva, inguinofemoral and pelvic* nodes (see below) ±
paraaortic lymph nodes.
*For negative inguinal lymph nodes, nodal target should extend to the
bottom of the sacroiliac (SI) joint or the bifurcation of the common
iliac; for positive inguinal lymph nodes but negative pelvic lymph
nodes, nodal target should extend to the mid-SI joint; for positive
pelvic lymph nodes, upper field border is the aortic bifurcation. For
patients with common iliac nodes, the low paraaortic nodes can be
treated. If definitive radiotherapy is considered for patients with
positive paraaortic nodes, the entire paraaortic nodal CTV should be
treated.
Technique: IMRT/VMAT, to reduce dose to the central pelvis and
mons pubis. TLDs at first fraction(s) to ensure adequate dose (Fig.
56.1)
Dose constraints (external beam)
Bladder V45 Gy < 50%
Rectum V45 Gy < 80%
Kidney (each) V20 < 33%, V15 < 50%
Small bowel V40 < 30%
Duodenum V55 < 15 cc, V60 < 2 cc
Spinal cord <45 Gy max
Figure 56.1 Representative treatment plan illustrating coverage of
classical CTV (red colorwash) and PTV (purple colorwash)
volumes for a vulvar cancer patient undergoing IMRT. See color
insert. (Adapted from Eifel and Klopp, Gynecologic Radiation
Oncology: A Practical Guide.)
C
Concurrent: Cisplatin (40 mg/m2 once weekly) for 5-6 cycles,
extrapolated from cervical cancer data.
S E M
See Vaginal Cancer chapter.
F -
Vaginal dilators or intercourse 2-3 times per week after the vulva has
healed to mitigate vaginal stenosis.
Interval H&P every 3-6 months for 2 years, then every 6-12 months
for 3-5 years, then annually. Cervical/vaginal cytology as
recommended for detection of lower genital tract neoplasia.
Imaging based on symptoms or examination findings suggestive of
recurrence.
N
Adjuvant radiotherapy for positive inguinal lymph nodes: GOG-37
(Homesley Obstet Gynecol 1986): Randomized trial of 114 patients with
positive groin nodes after radical vulvectomy and bilateral inguinofemoral
lymphadenectomy randomized to pelvic node resection or adjuvant groin
radiotherapy to 45-50 Gy in 5-6.5 weeks. 2-Year overall survival 68% for
radiotherapy group vs 54% for pelvic node resection group (p = .03)
Groin dissection vs radiotherapy for N0-N1 patients: GOG-88
(Stehman et al. IJROBP 1992): Randomized trial of 58 (prematurely
closed) patients with clinically N0-N1 vulvar squamous cell carcinoma
randomized to groin dissection or groin radiotherapy to 50 Gy in 25
fractions prescribed to 3 cm below skin. Groin relapse observed in 18.5%
of radiotherapy patients vs 0% in dissection patients (p = .03). Numerous
criticism of this trial including preliminary closure of trial and inadequate
depth of prescribed dose.
Sentinel lymph node (SLN) metastasis size and risk of additional
non-SLNs: GROINSS-V (Oonk et al. Lancet Oncol 2010): 403 patients
with T1-T4 (<4 cm) vulvar SCC underwent SLN biopsy followed by
inguinofemoral lymphadenectomy if SLN was positive. Disease identified
in 135 (33%) of patients, of which 115 (85%) underwent
lymphadenectomy. Risk of non-SLN metastasis increased with increasing
size of SLN metastasis. All patients with SLN metastasis should have
additional groin treatment. Prognosis significantly worse in patients with
SLN metastasis >2 mm (69.5% vs 94.4%, p = .001)
Contouring atlas: RTOG (Gaffney et al. IJROBP 2016): Consensus
guidelines for contouring and treatment of vulvar cancer.
Additional guidance: Eifel and Klopp, Gynecologic Radiation Oncology:
A Practical Guide. Wolters Kluwer; 2016.
OVARIAN CANCER
SHANE R. STECKLEIN • LILIE L. LIN
B
Incidence/prevalence: 2nd most common gynecologic cancer and
5th most common cause of cancer-related death in women in the
United States (22 440 diagnoses, 14 080 deaths in expected in 2017
[ACS]).
(SEER data)
Demographics: Lifetime risk 1 in 77 (1.3%)
Risk factors: Age; family history of breast, ovarian, or colorectal
cancers; familial cancer syndromes (hereditary breast and ovarian
cancer syndrome, PTEN hamartoma syndrome, hereditary
nonpolyposis colorectal cancer, Peutz-Jeghers syndrome) obesity;
nulliparity; or first pregnancy after age 35
T
Pathology: Epithelial ovarian cancers (EOC) constitute 85%-90% of
all ovarian cancers and include primary malignancies of the fallopian
tube and primary peritoneal cancer. Type I ovarian cancers include
low-grade serous, endometrioid, and mucinous subtypes and often
exhibit mutations in KRAS, BRAF, or PTEN (Singer et al. JNCI 2015).
Type II ovarian cancers are predominately high-grade serous
carcinoma (70% of all ovarian cancers), which are associated with
TP53 mutation (Ahmed et al. J Pathol 2010), but also include
undifferentiated carcinomas and carcinosarcomas. 10%-15% of
ovarian tumors are borderline tumors or germ cell tumors.
Genetics: Inherited deleterious mutations in BRCA1 and BRCA2
result in ~40% and 15% lifetime risks of ovarian cancer, respectively.
Overall, 18%-24% of ovarian cancer patients carry inherited mutations
in BRCA1, BRCA2, BARD1, BRIP1, CHEK2, MRE11A, MSH2, MSH6,
NBN, PALB2, PMS2, RAD50, RAD51C, RAD51D, or TP53 (Walsh et
al. PNAS 2011; Norquist et al. JAMA Oncol 2016). Tumors with
mutations in BRCA or other homologous recombination pathway
genes are hypersensitive to platinum-based chemotherapy and
poly(ADP)ribose polymerase (PARP) inhibitors.
A
Ovaries lie near the uterine horns at the opening of the fallopian tubes
and are connected to the lateral surface of the uterus via the utero-
ovarian ligament.
Lymphatic drainage from the ovaries and fallopian tubes primarily
follows the gonadal vessels, and first echelon drainage is the
paraaortic and aortocaval nodes. Rarely, ovarian cancers can drain
along the round ligament to the inguinal lymph nodes.
Intraperitoneal dissemination is the primary mechanism of ovarian
cancer spread.
W
History and physical: Presentation includes bloating, pelvic or
abdominal pain, early satiety, and urinary frequency. Genetic risk
evaluation for all patients
Labs: CBC, CMP, LFTs, CA125. Consider pregnancy test.
Procedures/biopsy: Biopsy and/or peritoneal cytology as needed
Imaging: Ultrasound, CT or MRI abdomen/pelvis, and/or PET. Chest
x-ray or CT chest to evaluate lungs
O C S (FIGO 2014)
T
C
Adjuvant platinum/taxane chemotherapy is employed for all high-
grade ovarian cancers. Patients with stage I disease get 3-6 cycles,
while 6 cycles are recommended for patients with stage II-IV disease.
Neoadjuvant chemotherapy may be used in patients with bulky or
unresectable disease.
Intraperitoneal chemotherapy is often recommended for patients with
stage II-IV disease who have undergone optimal debulking surgery.
At relapse, major determinant of response to additional therapy and
outcome is interval between last platinum chemotherapy and disease
recurrence.
>6 months = Platinum sensitive, consider additional platinum-
based chemotherapy.
≤6 months = Platinum resistant, move to second-line
chemotherapy (docetaxel, etoposide, gemcitabine, liposomal
doxorubicin [Doxil], topotecan ± bevacizumab).
R T T
Radiotherapy is seldom used in the 1st-line treatment of ovarian
cancer.
Prior studies of whole abdominal radiotherapy (WART) showed some
efficacy in the curative treatment of ovarian cancer; due to toxicity,
technical challenges, and subsequent improvements in
chemotherapy, WART has not been widely adopted.
The major use of radiotherapy for ovarian cancer is in palliation of
recurrent or metastatic disease.
Definitive radiotherapy is warranted in select patients with confined
postchemotherapy local or nodal recurrences. Radiotherapy may be
particularly effective in patients with clear cell (Hoskins et al. JCO
2012), mucinous, or endometrioid histology. It is less effective and
rarely used for borderline or low-grade serous tumors.
GTV should be treated to 60-66 Gy(EQD2).
CTV that includes regions of possible adjacent soft tissue
infiltration and adjacent regional lymph nodes should be treated
to 45-50 Gy(EQD2).
3DCRT or IMRT may be used, depending on location, anatomy,
and proximity of critical structures.
N
WART vs pelvic radiotherapy and chemotherapy: Princess Margaret
(Dembo et al. Cancer Treat Rep 1979): Prospective trial randomizing 231
patients with stage IB-III ovarian cancer treated postoperatively with
WART vs pelvic radiotherapy and chlorambucil chemotherapy.
Recurrence-free survival was 64% in the WART group vs 40% in the
pelvic radiotherapy and chlorambucil group.
Benefit of radiotherapy in clear cell ovarian cancer: British
Columbia Cancer Agency (Hoskins et al. JCO 2012): Retrospective review
of 241 patients with stage I or II clear cell ovarian cancer receiving
adjuvant chemotherapy or chemoradiotherapy (WART). On subset
analysis, postoperative radiation improved 5-year DFS in patients with
stage IC (excluding rupture alone) and stage II disease by 20%.
Radiotherapy for locoregionally recurrent ovarian cancer: MD
Anderson (Brown et al. Gynecol Oncol 2013): Retrospective review of 102
patients with localized nodal and extranodal recurrences treated with
definitive involved-field radiotherapy (IFRT) to ≥45 Gy. 5-Year in-field
disease control was 71%. RT is associated with excellent local control,
protracted disease-free intervals, and cures in appropriately selected
patients.
SOFT TISSUE SARCOMA
KAITLIN CHRISTOPHERSON • B. ASHLEIGH GUADAGNOLO
B
Incidence/prevalence: Heterogeneous group of solid tumors of
mesenchymal cell origin. Rare, 12,000 cases diagnosed annually in
the United States. Account for 1% of adult cancers. Relatively high
rates of distant failure
Outcomes: Disease-specific survival ~60% at 10 years. Prognostic
factors for survival: grade, size, site, LN involvement, age (older
worse). Prognostic factors for local recurrence: positive margin,
locally recurrent disease, head and neck location, retroperitoneal
location, older age
Demographics: Median age at diagnosis is 45-55 years.
Risk factors: Can be associated with genetic syndromes like Li-
Fraumeni, tuberous sclerosis, FAP, NF type 1. Prior exposure to
ionizing radiation. Majority of cases have no clear predisposing
exposure. Injuries have not been associated with an increased risk for
developing sarcomas.
T B C
Histologic subtypes: Over 20 major categories of STS with >60
histologic subtypes. Most common histologies include undifferentiated
pleomorphic sarcoma (UPS), liposarcoma, synovial sarcoma, and
leiomyosarcoma.
Pathology: Core biopsy is ideal. Excisional biopsy should be
avoided. Important for expert sarcoma pathology review due to rarity
and diversity of tumors. Grade is prognostic for DM and OS. Look for
signature translocations (ie, synovial sarcoma t(X;18) SS18-
SSX1/SSX2, or myxoid liposarcoma t(12;16)). MDM2 amplification in
well-differentiated liposarcoma and dedifferentiated liposarcoma is
used to distinguish from benign adipose tumors and poorly
differentiated sarcomas (which are negative for amplification).
Imaging: Mixed appearances. Generally on MRI: T1 tumor is
isointense, T2 tumor is hyperintense.
A
Can occur anywhere, most common location lower extremity ≫ upper
extremity = superficial trunk = retroperitoneal > head and neck
LN involvement in <5% of all cases. More common (15%) in “CARE”
tumors, clear cell, (cutaneous) angiosarcoma, rhabdomyosarcoma,
and epithelioid sarcoma
W
History and physical: Focus on personal/family history of cancer;
refer to genetics when appropriate.
Procedures/biopsy: Core needle or incisional biopsy
Imaging: MRI with gadolinium for primary extremity and superficial
trunk lesions. CT with contrast for head and neck and retroperitoneal
primaries. CT chest for staging. For retroperitoneal sites, obtain
renal perfusion scan to assess differential renal function prior to RT or
surgery.
S T S C C S
(AJCC 8 )
T A
R T T
SIM: Depending on anatomic location. Supine position preferred,
prone may be needed. For post-op cases, wire the scar or the entire
field to help with target delineation. Do not specifically target drain
sites.
Lower extremity: Vac-Lok for involved extremity. CT scan done feet
first. Can elevate noninvolved leg to isolate if neededUpper
extremity: Upper Vac-Lok. Arm position depends on location of
primary. May need bolusDistal extremities: Can consider custom
cushion +/− aquaplast mask to help with immobilizationHead and
Neck: Prior to SIM, consider dental evaluation/need for stent.
Aquaplast mask
Dose: Pre-op: 50 Gy at 2 Gy/fx
Post-op: 60 Gy at 2 Gy/fx for R0 resection, with field size reduction
after 50 Gy. Boost to 64-68 Gy for positive margin.(Despite higher
boost dose, LR is higher for R1/2 resection; in other words, higher
radiation dose does not make up for lack of R0 resection.)
Considerations: If IMRT preferable for postoperative cases, can also
consider a simultaneous-integrated boost technique where GTV
(post-op bed) treated to 59.92 Gy in 28 fractions (2.14 Gy/fx) and CTV
50.4 cGy in 28 fractions (1.8 Gy/fx). See Figure 58.1.
Target: Pre-op: GTV + 4 cm longitudinally sup/inf along fascial
planes and 1.5 cm radially to yield CTV (Haas et al. IJROBP 2012).
Post-op: Virtual GTV = Post-op bedCTV50 as above (4 cm sup/inf,
1.5 cm radially off of vGTV)Cone down to CTV60-68 (vGTV + 2 cm
sup/inf, 1.5 cm radially).
Considerations: CTV expansions can be increased in areas of
difficult surgical access or for superficial spreading histologies. CTVs
can be trimmed/carved out of bone if not involved. Do not cover
elective nodes for any histology other than alveolar
rhabdomyosarcoma in select cases. PTV expansions typically 0.5-1
cm depending on daily imaging techniques
Technique: 3DCRT: We prefer 3D planning in extremities. Consider
parallel opposed fields (with nondivergent deep border to spare
bone/joint). Other beam arrangements (wedge-pair, obliques, etc.)
may be used as well. Asymmetric beam weighting can be used if
tumor is not centrally located.
IMRT: Consider more conformal radiation techniques for proximal
lower extremities, thoracic, pelvic, retroperitoneal, head and neck
sites (Fig. 58.1).
IGRT: Related to modality used and site of body.

Daily kV typically used. (For 3D planning: consider rotating collimator
parallel with long bone for set-up and kV alignment.)
Spare 1-cm strip of limb circumference/skin
Avoid treating entire limb circumference >45 Gy
Avoid treating entire femur circumference to ≥50 Gy
Spare ½ cross section of weight-bearing bone; V40 < 64%
Block part of the joint cavity; V45 < 50%
Avoid >45 Gy to 50% of major tendons (ie, patellar/Achilles)
S
Mainstay of treatment for soft tissue sarcomas
Wide local excision with goal of widely negative margin (goal = 2-cm
normal tissue around tumor, unless tumor abuts natural barrier to
spread like bone, nerve).
In unirradiated patients with R1 or R2 resection, consider additional
surgery or re-excision prior to RT or pre-op RT to 50 Gy followed by
re-excision.
C
Controversial, as studies have failed to show OS benefit
We consider neoadjuvant chemotherapy for patients with high-grade,
large (>5 cm) tumors. Neoadjuvant chemotherapy is preferred over
adjuvant as due to a 20%-30% response rate to chemotherapy, thus
intact measurable disease is important. Typically assess response
following 2-4 cycles.
Standard starting chemotherapy regimen involves
Adriamycin/ifosfamide for most STS. Other agents commonly used
include doxorubicin, gemcitabine, and docetaxel. Targeted therapy
with pazopanib (TKI) and trabectedin (targets FUS-CHOP
transcription) can be considered as both are FDA approved for
advanced STS cases. Can also consider enrolling on trials with other
targeted agents (MDM2 inhibitors, immunotherapy)
S E M
Skin care: First-line emollients. Can add Domeboro soaks thereafter.
If having further grade 2+ skin toxicity, consider Mepilex. For grade 3
dermatitis, consider Silvadene cream (on weekends or after RT has
been completed entirely). Have a low threshold for considering
infection/antibiotics in setting of fungating tumors.
L R
In a radiation-naive patient with local recurrence of STS, treat with
preoperative radiation (50 Gy) followed by surgery if feasible.
Generally avoid reirradiation, as complications following reirradiation
have been reported as high as 80% and reirradiation has not been
shown to improve local control for tumors that have been previously
irradiated.
N P
Limb-sparing surgery (LSS) + RT results in similar OS and DFS
Rosenberg et al. Ann Surg 1982: Prospective RCT, (2:1) LSS + post-
op RT vs amputation. All points received post-op chemo with
Adriamycin and Cytoxan followed by high-dose MTX. RT dose 45-50
Gy between joints, shrinking field boost to 60-70 Gy. Local failure 15%
(LSS + RT) vs 0% (amputation) (P = .06). OS and DFS for LSS + RT
83%/71% vs amputation 88%/78% (P = NS). Conclusion: LSS + RT
effective for most points. R1 resection increases risk of LR.
Preoperative radiation results in less long-term fibrosis than

postoperative radiation
O’Sullivan et al. Lancet 2002: 2-Arm prospective RCT. 190 patients

randomized to pre-op RT 50 Gy in 2 Gy fractions, (plus post-op boost
16-20 Gy if + surgical margin), vs post-op RT 50 Gy, with cone down
to 66-70 Gy. Primary endpoint wound complications (≤120 days post-
op) higher in pre-op (35% vs 17%, P = .01). No difference in LC, PFS,
DM. + Surgical margin predicts LF. Size and grade prognostic for RFS
and OS.
Davis et al. Radiother Oncol 2005: Analyzed 129 patients from
O’Sullivan trial (above). Analysis of function 2 years after treatment.
Grade 2+ fibrosis was lower in pre-op arm 31% vs post-op arm 48%
(P = .07). Edema and joint stiffness also less in pre-op 18% vs 23%
(NS). On multivariate analysis, field size was a significant predictor for
fibrosis and stiffness. No significant difference in function reported by
points or MDs. Conclusion: Post-op RT tends to result in more
fibrosis.
Consensus papers
RT for extremity STS (Haas et al. Int J Radiat Oncol Biol Phys 2012).
Review of data in regard to RT for extremity STS and the implications
for local control, survival, and complications. Pre- and postoperative
RT discussed with consensus recommendations for target volumes.
Treatment guidelines for preoperative RT for retroperitoneal sarcoma
(Baldini et al. Int J Radiat Oncol Biol Phys 2015). Expert panel of 15
academic radiation oncologists and systematic review of published
data regarding pre-op RT for RPS. Role of RT for RPS is not
established. Awaiting EORTC STRASS trial. Outlines patient selection
and recommended volumes from available data
Figure 58.1 Representative sagittal and coronal (L → R) images

of an IMRT treatment plan for a 40-year-old male being treated
with adjuvant RT following R0 resection of a grade III PNET of the
left lower extremity. Using IMRT in this case allowed for reduced
dose to the left femoral head/proximal femur. The red isodose line
represents 59.92 Gy (covering GTV) and blue represents 50.40
Gy (covering CTV). See color insert.
MELANOMA
KAITLIN CHRISTOPHERSON • B. ASHLEIGH GUADAGNOLO
B
Incidence/prevalence: Aggressive skin cancer. Accounts for 1% of
all skin cancers in the United States. Incidence is ~87 000 new cases
annually, with 10 000 deaths annually. Incidence increasing over past
three decades
Outcomes: 5-Year survival for localized melanomas varies with
depth/thickness but can be upward of 90% for lesions with <1 mm
depth. With presence of regional adenopathy, survival at 5 years is
60%. With the presence of DM, survival at 5 years is ~10%-20%.
Demographics: Median age at diagnosis is 60. Caucasians ≫
Hispanics > African Americans. For patients <50 years old, more
common in women. For patients >50 years old, more common in men
Risk factors: Ultraviolet (UV) exposure, family history, history of
multiple atypical moles or dysplastic nevi. Increased risk among
immunocompromised patients. History of Xeroderma pigmentosum
T B C
Histologic subtypes: Superficial spreading (70% of cases, arise
from pigmented dysplastic nevus), lentigo maligna, nodular, acral
lentiginous, and desmoplastic (more likely to be neurotropic, may be
amelanotic)
Pathology: Cell of origin is melanocyte. Pathology report should
include: Breslow thickness, ulceration, primary tumor mitotic rate,
resection margins, microsatellitosis, Clark level, and presence of
desmoplasia. Molecular genetic testing should be considered to test
for BRAF mutational status if nodal or metastatic involvement at
presentation, or clinical trial is considered.
Imaging: Stage 0-II routine imaging not recommended unless there
are focal symptoms. Stage III (SNLB+), consider baseline CT C/A/P.
Stage III (cN+, in-transit mets, or microsatellitosis), at minimum CT of
primary body compartment. Consider brain MRI and PET/CT for stage
IIIC-IV.
A
Can occur anywhere on skin, predominantly on sun exposed areas.
Most common locations in males are the back followed by head/neck.
Most common locations in females are the extremities and trunk.
W
History and physical: Focused and complete skin examination of the
skin and regional lymph nodes w/ assessment of melanoma risk
factors
Procedures/biopsy: Optimally, an excisional biopsy is preferred for
any suspicious, pigmented lesion with 1-3 mm negative margins.
Consider full-thickness punch biopsy if in difficult area (distal digit,
face, palms) vs excisional biopsy. Avoid shave biopsies as they give
no information on depth.
Imaging/labs: Not recommended for stage 0, IA, IB, and II. Can
consider nodal basin ultrasound prior to SLNB in patients with stage
I/II disease with equivocal LN physical exam. For stage III-IV or
recurrent disease, obtain C/A/P CT imaging w/ contrast or whole-body
FDG PET/CT. Obtain MRI brain w/ contrast if clinically indicated.
M S (AJCC 8 )
T
R T T
SIM: Primary: Radiopaque wire to outline scar or entire primary site.
If using electrons, patient positioning important to allow for en face
beam arrangement. Consider lateral penumbra when shaping field
around CTV.
Dose: 30 Gy in 6 Gy/fx, given twice weekly over 2.5 weeks.
Alternative TROG regimen: 48 Gy in 2.4 Gy/fx for 20 fractions
Target: Primary: Primary site/Scar + 1.5 cm margin = CTV
a Whether perineural invasion of small- and medium-sized nerves is a

risk factor for local recurrence remains and matter of debate. Invasion
of large caliber or named nerves should be considered a high-risk
factor for local recurrence, and adjuvant RT is thus indicated.
Nodal: Involved nodal region if high risk features. Do not electively

treat LNs.
Head and neck: ipsilateral neck levels I-V, including supraclav fossa.
(High facial/scalp primary: include pre/post auricular [superficial]
parotid.)Axilla: Ipsilateral levels I-III. Unless there is bulky or high
disease, we usually do not include supraclavicular field.Groin: Need 2
or more high-risk factors and BMI < 25 kg/m2 to consider treating
groin. Do no electively cover pelvic nodes.
Technique: 3DCRT when possible.
Primary: Consider electrons to achieve adequate dose to the surface.
Bolus often needed for primary tumor. Electrons dosed to D max. May
normalize to 100%-105% to prevent hot spots >30 Gy. Consider skin
collimation when appropriate.Nodal: 3D electrons or photons
depending on site.
For head and neck primaries with need for skin collimation and
electrons: draw/wire field and cut out field on mask. If near areas of
air gap (ie, ear) consider TX-151 bolus.
Nodal:
1. Head and Neck: Open neck (to allow for appositional electrons)
can use tissue equivalent bolus to pull dose more superficial and
out of critical structures like larynx and temporal lobe.
2. Axillary: Head away and arm akimbo or, if patient able, can flex
at elbow and extend arm superiorly to open axilla. Avoid skin
folds in axilla and low neck if possible. Typically AP/PA photon
beams
3. Groin: Slight frog leg position/decrease skin fold. In thin patient
can consider appositional electrons
IGRT: Daily kV for hypofractionated schedule. MD verifies kV prior to

first fraction. If electrons, see set up on table prior to first fraction to
verify setup.
Planning directive: For 30 Gy in 5 fractions: evaluate the 24 Gy line
on all axial slices. 24 Gy line should be off of any critical structure
(brain, eye, brachial plexus, spinal cord, bowel). Evaluate 27 Gy
isodose line for target coverage, as opposed to the 30 Gy line (Fig.
59.1). For 48 Gy in 20 fractions regimen: Max dose to brain and spinal
cord <40 Gy.
Figure 59.1 Sample RT treatment plan for a patient with a
melanoma of the scalp. This patient was treated postoperatively
with electrons to the tumor bed to a total dose of 30 Gy in 5
fractions. Note the 27 Gy isodose line in yellow, which is used to
evaluate target coverage. 30 Gy hotspots are seen in red. See
color insert.
S
Primary: Wide local excision with goal of negative margin. Adequate
margin is determined by depth of primary.
cN0+/− Sentinel lymph node biopsy. SLNB must be done prior to WLE
as to not alter the drainage to the sentinel basin. If SLNB+, consider
completion LN dissection.
cN+: Complete involved/regional nodal basin dissection. For certain
head and neck primaries, this will involve superficial parotidectomy.
C
Interferon-alpha historically used and still considered appropriate.
Patients may have fatigue, low blood counts, and a flulike syndrome
as side effects.
Dabrafenib/trametinib for patients with tumors harboring BRAF V600
activating mutations can be used in select patients as adjuvant
therapy or for treatment of metastases (Long et al. Lancet 2015).
Immunotherapy (combination nivolumab and ipilimumab) used first
line if no actionable BRAF mutation. Side effects include rash,
dermatitis, and increased risk of developing autoimmune conditions.
S E M
Side effects may not be present during RT if using 30 Gy in 5 fractions
hypofractionated regimen. Advise patients that acute side effects may
appear 1-2 weeks after completion of radiotherapy.
Skin Care: First-line emollients. Can add domeboro soaks. If having
further grade 2+ skin toxicity, consider mepilex. Grade 3 dermatitis,
consider silvadene cream (on weekends or after RT has been
completed entirely).
F -
Depending on initial stage, complete skin and regional nodal
examination every 3-6 months for 2 years. (More frequent follow-ups
for higher-stage patients.) Can space to every 3-12 months after
For patients with initial stage IIB-III melanoma, consider labs and CT
c/a/p or PET/CT to detect asymptomatic recurrence the first 3 years.
N P
Primary site adjuvant radiation
Review, RT for malignant melanoma (Ballo and Ang Surg Clin North
Am 2003). Adjuvant radiotherapy improves the local-regional control
rate in certain patients with primary melanoma in difficult surgical
locations or with high-risk pathologic features. Impact of RT on
OS/DM is yet to be determined.
Guadagnolo et al. Cancer 2014: Retrospective review of 130 patients
with desmoplastic melanoma treated with surgery alone (45%) or with
adjuvant post-op RT (55%). Median follow-up 6.6 years. Surgery-
alone patients; 24% developed local recurrence vs 7% for patients
treated with PORT (on MVA, use of PORT significantly associated
with improved LC, P < .05).
Adjuvant nodal RT decreases lymph node relapse in high-risk

patients
TROG 02.01 (Burmeister et al. Lancet Oncol 2012; Henderson et al.

Lancet Oncol 2015): RCT for 250 patients, cN+ s/p LAD with one of
following inclusion criteria: ≥1 parotid node, ≥2 cervical/axillary nodes,
≥3 inguinal nodes, ECE, ≥3 cm cervical node, or ≥4 cm inguinal or
axillary node randomized to adjuvant 48 Gy in 20 fractions vs
observation of dissected lymph node field and scar. Adjuvant RT
decreased lymph node field relapses by ~50%, No impact on RFS or
OS. Grade 3-4 toxicities after adjuvant RT in head and neck, axilla,
and groin were 8%, 21%, and 29%, respectively. Rate of grade 2-4
toxicities numerically but not statistically higher in RT arm: 68% vs
58% (NS). Measured limb volume ratio over 5 years in both arms; for
lower extremities increase in mean volume ratio was higher in pts
receiving RT 15% vs 7% in observation group (P = .014).
Immediate completion lymph node dissection decreases regional

failures, but does not increase melanoma-specific survival
MSLT-II (Faries et al. NEJM 2017): RCT of 1934 patients with positive
sentinel lymph node biopsy randomized to completion dissection vs
“nodal observation” with ultrasound. Primary end point was
melanoma-specific survival. Immediate completion lymph node
dissection increased the rate of regional disease control (3 year: 92%
vs 77%, P < .001), but does not increase melanoma-specific survival
(3 year: 86% vs 86%, P = .42). Lymphedema was higher in LN
dissection group (24% vs 6%, P < .001).
Adjuvant RT for high-risk nodal metastases
Guadagnolo et al. Lancet Oncol 2009: Review paper. Regional

recurrence rates improved with nodal irradiation. Risk of
complications differ with anatomic location of nodal basin involved.
Additional details about fields and planning.
RT field extent for axillary metastases
Beadle et al. IJROBP 2009: Retrospective review of 200 patients

treated with PORT, 48% treated axilla only, and 52% treated extended
field including supraclavicular fossa. Median follow-up 59 months.
Axillary control rates 89% for axilla only vs 86% for extended field
(NS). Treatment with extended field resulted in more treatment-related
complications on MVA.
NON-MELANOMA SKIN CANCER
ANNA LIKHACHEVA
B
Incidence/prevalence: Non-melanoma skin cancers (NMSCs)
include basal cell carcinoma and squamous cell carcinoma, which
together constitute the most common malignancy worldwide. The
highest worldwide incidence is in Australia. Approximately 3.5 million
new cases are diagnosed each year in the United States. Incidence is
rising. Lifetime risk is 1 in 5.
Risk factors: Cumulative exposure to UV light, increasing age,
Fitzpatrick skin types 1-4, immunosuppression (HIV and organ
transplant), human papillomavirus (HPV), and certain syndromes or
genetic disorders (basal cell nevus syndrome [Gorlin syndrome],
xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous
albinism).
T B S C
Prevention: Reduction in sun exposure and oral nicotinamide
(vitamin B3) (Chen et al. N Engl J Med 2015)
Pathology: BCC (~80%) and SCC (~20%) make up the majority of
NMSC. Minority are neuroendocrine, sweat gland, mesenchymal
tumors, or lymphomas.
Pathologic risk factors are listed in the table below.
A
Predominately occurs on sun-exposed areas. Skin layers are
epidermis → papillary dermis → reticular dermis → subcutaneous
tissues.
W
History and physical: Focused and complete examination of the skin
as many may have additional cancers and are at increased risk of
developing melanoma.
Procedures/biopsy: Shave/punch/excisional biopsies may be used
for diagnosis. Skin biopsy should include the deep reticular dermis if
suspicion is high for invasion.
Imaging: The majority of NMSCs can be successfully managed
without formal imaging. Consider CT if bony invasion and MRI if
orbital involvement or perineural spread depending on presenting
symptoms and exam. If there is concern for lymph node spread, it is
reasonable to obtain a PET/CT scan.
Table 60.1 Risk Factors for Recurrence for Basal Cell Carcinoma
(BCC) and Recurrence/Metastasis for Squamous Cell
Carcinomas (SCC)
a H (mask area), M (cheek, forehead, scalp, neck, pretibial), L (trunk and extremities).
b PNI is defined as involvement of large-caliber nerves with a diameter of >0.1 mm.
Table 60.2 Skin Cancer Staging (AJCC 8th edition)

T A
Definitive RT is recommended for nonsurgical candidates and clinical
instances where skin cancer is located in cosmetically sensitive areas or
where surgery might result in a functional deficit.
R T T
SIM: CT simulation–based treatment planning is recommended for
IMRT, history of adjacent RT, or in anticipation of future retreatment.
Clinical setup is reasonable for orthovoltage, fixed geometry
electronic brachytherapy, and palliation. Wire CTV. Skin collimation for
field size <4 cm or for protection of adjacent uninvolved sensitive
structures. Bolus to bring dose to the surface.
Dose:
Definitive RT:
For most lesions and optimal cosmesis: 66 Gy/33 fx (2 Gy/fx) or
55 Gy/20 fx (2.5 Gy/fx) delivered daily; 44 Gy/10 fx (4.4 Gy/fx)
delivered 4 times a week
For <2-cm lesions or palliation of large lesions: 50 Gy/15 fx (3.3
Gy/fx); 40 Gy/10 fx (4 Gy/fx), 35 Gy/5 fx (7 Gy/fx) delivered daily
Skin surface brachytherapy: 40 Gy/8 fx (5 Gy/fx); 44 Gy/10 fx (4.4
Gy/fx) delivered twice or 3 times per week, at least 48 hours
apart
Adjuvant RT to primary site:

60 Gy/30 fx (2 Gy/fx) or 50 Gy/20 fx (2.5 Gy/fx) delivered daily
Consider 66 Gy/33 fx if positive margins
Adjuvant RT to regional nodes:

66 Gy (2 Gy/fx) for ECE or gross residual adenopathy
60 Gy (2 Gy/fx) for no ECE/no residual adenopathy to the
involved neck
50 Gy (2 Gy/fx) to the undissected neck
Target:
Definitive RT:
CTV = Primary tumor with 0.5- to 2-cm margin. CTV margin
varies based on tumor histology, risk factors, location, and mode
of therapy.
Adjuvant RT to primary site:

CTV = Primary tumor bed with 1- to 2-cm margin +/− ipsilateral
parotid and neck nodes, +/− trigeminal or facial nerve pathways
CTV boost = Primary tumor bed with 0.5- to 1-cm margin
Technique: Electron beam therapy, orthovoltage, brachytherapy, and
IMRT in special circumstances, that is, total scalp and neurotropic
spread along CN
Planning directive (for conventional fractionation): Electron beam
doses are prescribed to 90% of D max. Orthovoltage x-ray doses are
specified at D max (skin surface). For normal tissue tolerance, refer to
Head and Neck section for planning directive tolerances.
S
Wide local excision (WLE): Requires the removal of healthy skin; it
results in a larger wound.
Mohs micrographic surgery: Specialized technique for removal of skin
cancer. Allows precise microscopic control of the margins by utilizing
tangentially cut frozen section histology.
Curettage and electrodessication (C&E): Commonly performed
procedure to remove low-risk BCC and SCC by scraping off the lesion
with a curette followed by cauterization. Not recommended for high-
risk NMSC.
S T
Vismodegib (Erivedge) and sonidegib (Odomzo) are inhibitors of the
sonic hedgehog pathway and FDA approved for adult patients with
advanced BCC. Common side effects are GI upset, muscle spasms,
fatigue, alopecia, and dysgeusia.
Topical 5FU (Efudex) is approved for treatment of actinic keratosis
(AK) and superficial BCC.
Concurrent: Chemoradiation with platinum agents can be considered
for patient with high-risk features.
S E M
Radiation dermatitis: Bland emollient application and sterile
nonadherent dressings to keep site clean and moist.
F -
BCC: H&P, complete skin exam q6-12mo for life
SCC localized: H&P q3-12mo for 2 years, then q6-12mo for 3 years,
and then q1y for life
SCC regional: H&P q1-3mo for year 1, then q2-4mo for year 2, then
q4-6mo for years 3-5, and then q6-12mo for life
N
Adjuvant RT in node + head and neck SCC
Veness et al. Laryngoscope 2005: 167 patients were treated with

curative intent at Westmead Hospital, Sydney. Patients underwent
surgery (21/167; 13%) or surgery and adjuvant radiotherapy (146/167;
87%). The majority (98/167; 59%) of metastatic nodes were located in
the parotid and/or cervical nodes. The remaining 69 (41%) had
metastatic cervical nodes (levels I-V). Patients undergoing a
combined treatment had a lower rate of locoregional recurrence (20%
vs 43%) and a significantly better 5-year disease-free survival rate
(73% vs 54%; P = .004) compared to surgery alone.
Elective neck management for SCC metastatic to parotid
Herman et al. Eur Arch Otorhinolaryngol 2015: Retrospective review

of 107 patients with SCC metastatic to parotid lymph nodes planned
for post-op RT. All patients with cN0 cervical nodes. 42 patients with
elective neck dissection + RT vs 65 patients with RT alone. Regional
control excellent, no difference between surgery + RT vs RT alone.
Concluding 50-60 Gy to cN0 neck is a suitable alternative to neck
dissection.
Recommendations for CTV margins in RT planning for NMSC
Khan et al. Radiother Oncol 2012: Prospective study measuring the

distance of microscopic tumor extension from the gross lesion after
excision. The microscopic tumor extent correlated with the size of
gross lesion and histology. CTV recommendations are made to
provide at least a 95% chance of covering microscopic disease: 10
mm for BCC <2 cm, 13 mm for BCC >2 cm, 11 mm for SCC <2 cm,
and 14 mm for SCC >2 cm.
Efficacy of hypofractionation with electrons for epithelial skin

cancers
van Hezewijk et al. Radiother Oncol 2010: Retrospective review of
434 NMSCs (332 BCC, 102 SCC) evaluated after the use of 54 Gy in
18 fractions or 44 Gy in 10 fractions. No significant difference
between fraction schedules for LRC. 3-year LC for BCC ~97% and
93%-97% for SCC. Electron beam hypofractionation is safe and
effective for NMSC.
MERKEL CELL CARCINOMA
KAITLIN CHRISTOPHERSON • B. ASHLEIGH GUADAGNOLO •
ANDREW J. BISHOP
B
Incidence/prevalence: Rare aggressive skin cancer with
neuroendocrine differentiation. Cell of origin is Merkel cell
mechanoreceptor bound to the ends of sensory nerve fibers in the
skin. 1500 cases are diagnosed annually in the United States.
Incidence has been increasing over the last three decades. Higher
incidence rates are reported in Australia and New Zealand.
Outcomes: 5-Year survival across all stages is variable. Stage I
patients have estimated 5-year OS, 60%-80%; stage II, 50%-60%;
and stage III, 25%-45%. High rate of recurrence (local recurrence
25%-30%, regional recurrence 50%-60%, distant recurrence
30%-36%). Worst prognosis of all skin cancers.
Demographics: Median age at diagnosis is 75; majority of patients
are older than 50. More common in males (2:1 male to female
incidence). 90% of cases occur in Caucasians.
Risk factors: Immunosuppression (increases risk 10× that of general
population). UV exposure. Merkel cell polyomavirus (MCPyV) is
detected in over 75% of cases.
T
Histologic subtypes: Small cell, intermediate cell, and trabecular
(best prognosis).
Pathology: MCC typically presents as a dermal mass with rare
involvement of the epidermis. It is a small, round blue cell tumor.
Staining with immunopanel including CK20 (typically positive in
paranuclear “dotlike” pattern), CK7, and TTF-1 (both typically
negative) is important to rule out metastatic SCLC. Additional IHC
staining for neuroendocrine markers can be done for equivocal
lesions (ie, chromogranin, synaptophysin, CD56). MCPyV can be
detected via IHC.
Genetics: Associated with mutations in RB1 and TP53, especially in
MCPyV-negative tumors.
A
Can occur anywhere on skin, predominantly on sun-exposed areas.
Most common location is the skin of the head and neck > upper
extremities > lower extremities > trunk.
W
History and physical: Focused and complete skin examination of the
skin and regional lymph nodes.
Procedures/biopsy: Core biopsy is preferred.
Imaging: PET/CT has emerged as important study for staging. Consider
CT C/A/P with brain MRI, particularly if PET/CT is unavailable.
M C C TNM (AJCC 8
)
T
a Consider observation following WLE if small tumor (<1 cm), without LVSI, and no history of
immunosuppression.
R T T
SIM: Depending on anatomic location. Bolus is necessary to ensure
that superficial dose is adequate for the skin primary.
For head and neck location: Aquaplast mask, wire scar or primary
site, draw field, and cut out field on mask if using electrons. Consider
skin collimation. If near the ear, consider the use of TX-151 bolus.
Dose: Primary:
Tumor >2 cm, R0 resection → 50-56 Gy at 2 Gy/fx
R1 resection → 56-60 Gy at 2 Gy/fx
R2 resection or unresected disease → 60-66 Gy at 2 Gy/fx
Nodal Basin
cN0, no nodal evaluation → 46-50 Gy
cN0, SLNB negative → no RT (unless potential for false-negative
SLNB due to anatomic, operator, or histologic failure)
cN0, SLNB positive, no formal dissection → 50 Gy
cN+, no dissection → chemotherapy, then consider 50-60 Gy
cN+, formal dissection with multiple LNs and/or ECE → 50-56 Gy
Target: Primary: Primary site/scar + 4-cm margin for CTV; when
planning electrons, consider penumbra and need to expand edges of
field another 7-10 mm to cover the target.
Lymph nodes: Involved/sentinel nodal basins
Technique: Consider electrons to get adequate dose to the surface
for RT to the primary.
Consider skin collimation and bolus. Photons may be needed for deep
primary tumors and for regional RT.
IGRT: Related to modality used and site of the body. Typically weekly
kV for 3D plans.
Planning directive: Standard dose constraints for 2 Gy/fx for ROIs in
nearby treatment field (see Appendix).
S
Primary: Wide local excision with a goal of negative margin when
feasible (1- to 2-cm margins). Mohs surgery is an acceptable
alternative for smaller lesions. Balance with morbidity of surgery.
Avoid complex procedures that would lead to a delay in RT.
cN0 → sentinel lymph node biopsy. SLNB must be done prior to WLE
as to not alter the drainage to the sentinel basin. If SLNB is +,
consider completion dissection or RT for cN0.
cN+ → Nodal basin dissection
C
Retrospective series fail to show survival benefit. If used, typically
given adjuvantly on case-by-case basis; regimen is typically platinum
+/− etoposide.
Metastatic disease: First line is immune checkpoint inhibitor.
S E M
Skin care: First-line emollients. Can add Domeboro soaks thereafter.
If having further grade 2+ skin toxicity, consider Mepilex. If grade 3
dermatitis, consider Silvadene cream (on weekends or after RT has
been completed entirely).
F -
Complete skin and regional nodal examination every 3-6 months for 2
years. (Most recurrences occur within 2 years.) Can space to every 6-
12 months thereafter.
Can consider imaging in high-risk patients (ie, PET/CT)
N
Postoperative RT after WLE
Strom et al. Ann Surg Oncol 2016: Retrospective review of 171

patients treated between 1994 and 2012 at Moffitt Cancer Center. On
multivariate analysis, patients receiving XRT had improved 3-year LC
(91.2% vs 76.9%, respectively; P = .01), LRC (79.5% vs 59.1%; P =
.004), DFS (57.0% vs 30.2%; P < .001), and OS (73% vs 66%; P =
.02) at 3 years. RT was associated with improved 3-year DSS among
node-positive patients (76.2% vs 48.1%; P = .035) but not node-
negative patients (90.1% vs 80.8%; P = .79).
Radiation for stage I-III disease
Bishop et al. Head Neck 2015: Retrospectively analyzed 106 patients

treated at MDACC. Majority of patients were post-op. 92% of patients
with cN0 disease treated with regional lymph node RT to a median
dose of 46 Gy. 5-Year LRC, CSS, and OS were 96%, 76%, and 58%,
respectively. Acceptable, 5% long-term grade 3 toxicity noted in this
series.
HODGKIN LYMPHOMA
TOMMY SHEU • JILLIAN GUNTHER • BOUTHAINA DABAJA
B
Incidence/prevalence: 10% of all lymphomas in the United
States, 8500 new cases per year
Demographics: Predominantly young adults with slight male
predominance, bimodal age distribution (20 and 65)
Risk factors: Delayed/reduced antigen exposure (single family
housing, small family size), immunosuppression, EBV virus
exposure, autoimmune disease, radiation exposure especially at
young age
Outcomes: Stage I/II: 90%-95% OS at 8 years
Stage III/IV (based on IPS): 0-1, 90%; 2-3, 80%; 4-5, 60% OS at
5 years
IPS, 1 point each: Age ≥ 45, albumin < 4, stage IV, Hgb < 10.5,
absolute lymphocyte count < 8%, WBC > 15K, male
T
Genetics: Association with BCL translocations
Pathology: Classical (CD15+/CD30+/CD20−, 95% of cases):
nodular sclerosing, mixed cellularity, lymphocyte rich, lymphocyte
depleted; NLPHL (CD15−/CD30−/CD20+/CD45+, 5% of cases)
Imaging: Heterogeneously enhancing mass on CT imaging.
PET-avid disease graded utilizing Deauville criteria
D S T
R (C .
B . JCO 2014)
W
Laboratory studies: Core needle or excisional biopsy (FNA is
not acceptable), CBC w/ diff, LFTs, LDH, ESR, albumin, bone
marrow biopsy (if B symptoms, stage III/IV or BM PET negative),
and pregnancy test
Imaging: PET/CT, CT with contrast of the neck, chest, abdomen,
and pelvis
Other studies: PFT (for bleomycin) and echocardiogram (for
doxorubicin)
Referrals: Oncofertility, cardiology, and endocrinology
S R S
a Acceptable thresholds for bulky include ≥10 cm on x-ray, 7.5 cm on CT imaging, and >1/2
diaphragm diameter on x-ray.
Nodal regions (“L/R” are considered to be separate)

Supradiaphragmatic regions: Waldeyer ring, L/R
cervical/supraclavicular/occipital/preauricular, infraclavicular nodes,
L/R axillary/pectoral, mediastinal, L/R hilar, L/R epitrochoidal/brachial
Infradiaphragmatic regions: Spleen, mesenteric, para-aortic, L/R
iliac, L/R inguinal/femoral, L/R popliteal
Adapted from https://en.ghsg.org/disease-stages. Reprinted by
permission of Dr. Andreas Engert.
a MDACC uses GHSG criteria for risk stratification, ≥1 risk factor = unfavorable risk.
a Separate lymph node regions are considered for the purpose of Ann Arbor staging and risk
stratification.
T
Standard of care treatment regimens exist that involve omission of
radiation therapy.
ISRT, involved site radiation therapy. More generous involved site is permitted.
ABVD refers to potentially holding the last two cycles of bleomycin.
Interim PET/CT imaging should be obtained at the end of planned

cycles of chemotherapy for early unfavorable and advanced stage
cases. In the event that this is positive (Deauville 4-5), consider
additional cycles of ABVD or R-CHOP until a maximum of 6 cycles; if
at 6 cycles and PET/CT is positive, consider salvage treatment
options including high-dose chemotherapy and stem cell transplant.
R T T
The goal is to reduce low-dose exposure to adjacent OARs.

Depending on patient-specific anatomy and tumor location, other
techniques and setups may be more optimal.
Planning directive
a Goal is to keep 5 Gy isodose line off as many critical structures as possible.

Figure 62.1 Simulation set up for mediastinal HL. (1) Hip
stopper, (2) Vac-Lok, (3) Dabaja or incline board at 10-15
degrees, and (4) thermoplastic mask. The patient is wearing
goggles that provide real-time visual feedback on the breath
cycle.
Figure 62.2 Axial view of DIBH (left three images) and normal
breathing (right three images). DIBH can significantly reduce
radiation to the coronary arteries, heart, and lungs. Confirm
positioning with daily CT on rails or cone beam CT.
Figure 62.3 Deep inspiratory breath hold with a butterfly

technique beam arrangement for anterior mediastinal HL.
Anterior beam angles were restricted between 310 and 50
degrees. 30 Gy isodose line is thick white; 5 Gy isodose line is
thin white.
C
ABVD—doxorubicin (Adriamycin), bleomycin, vinblastine,
dacarbazine
Bleomycin held in the following scenarios: last cycle in early
unfavorable, last two cycles in stage IIB bulky if six cycles, and
last two cycles of advanced
BEACOPP—bleomycin, etoposide, doxorubicin (Adriamycin),
cyclophosphamide, vincristine (Oncovin), procarbazine,
prednisone
Not routinely used in the United States due to toxicities.
S E M
Esophagitis: Xyloxylin (1:1:1 ratio of diphenhydramine, Maalox,
viscous lidocaine), 10-15 mL swish/swallow up to 4 times a day
Pneumonitis (dyspnea or cough): Prednisone 60 mg/day for 4
weeks, taper slowly over 2-3 months
F -
Full-body CT with contrast at 6, 12, and 24 months after therapy;
PET/CT if previous Deauville 4-5
Interim H&P 3 months after completion of therapy then Q6
months for first 3 years, then annually
Late cardiovascular toxicities: Echocardiogram/stress and carotid
ultrasound if RT to neck Q10 years
TSH at least annually if RT to neck to evaluate for potential
hypothyroidism, supplement with levothyroxine if detected
Secondary malignancies: Start annual breast screening the
earlier of 8-10 years after therapy or age 40 if chest radiation
N T
DIFFUSE LARGE B-CELL LYMPHOMA
SHANE R. STECKLEIN • CHELSEA C. PINNIX
B
Incidence/prevalence: Most common form of high-grade non-
Hodgkin lymphoma (NHL); accounts for 30%-40% of all NHLs.
Approximately 22 000 cases diagnosed in the United States each
year.
(SEER data).
Demographics: Typically in middle-aged and elderly adults,
median age at diagnosis is 64.
Risk factors: Age, HIV infection, immunosuppression,
preexisting B-cell lymphoproliferative disorder (eg, follicular
lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma [CLL/SLL]).
T
Pathology: Immunophenotype, CD20+, CD45+, and CD3−.
Designated as germinal center B cell (GCB) or nongerminal
center B cell/activated B cell (non-GCB/ABC) based on gene
expression profiling (GEP) studies (Alizadeh et al. Nature 2000).
GCB DLBCL: Arises from centroblasts in the light zone of
the lymph node germinal center and may have chromosomal
abnormalities affecting MYC [t(8;14), MYC;IgH/t(2;8),
Igκ;MYC/t(8;22), MYC;Igλ (observed in 10%)] and BCL2
[t(14;18), IgH:BCL2 (observed in 40%)] detected by FISH.
Non-GCB/ABC DLBCL: Arises from postgerminal center
lymphocytes that have committed to plasmablastic
differentiation and is characterized by NF-κB activation and
blockade of terminal differentiation into plasma cells. In
general, GCB DLBCL has a better prognosis than non-
GCB/ABC DLBCL.
The Hans algorithm (Hans et al. Blood 2004) is a widely
used immunohistochemical surrogate for gene expression
profiling to discriminate GCB and non-GCB/ABC DLBCL.
Double-hit lymphoma (DHL) and double-protein expression

lymphoma: Aggressive subsets of DLBCL that arise from
coexisting genomic rearrangement of MYC and BCL2 or BCL6 or
overexpression of MYC and BCL2 in the absence of
simultaneous gene rearrangements (double-protein expression)
(Johnson et al. JCO 2012). DHL lymphomas are typically GCB
DLBCL and have the worst prognosis of all subtypes, while
double-protein expression lymphomas are typically non-
GCB/ABC DLBCL.
Imaging: 18FDG PET-CT is the most sensitive imaging modality.
CT may be used for follow-up. MRI may be useful for imaging the
central nervous system (CNS), bulky, or extranodal sites of
disease.
D T
R (C .
B . JCO 2014)
W
Laboratory studies: Core needle or excisional biopsy (FNA is
not acceptable), CBC w/diff, ESR, CMP, uric acid, LDH, albumin,
bone marrow biopsy (if cytopenic and PET negative)
Imaging: PET/CT, CT with contrast of the neck, chest, abdomen,
pelvis
Other studies: Hepatitis B and HIV testing (for rituximab),
echocardiogram or MUGA (for doxorubicin). Lumbar puncture is
considered for HIV-associated lymphoma, testicular lymphoma,
or hit/expression lymphoma.
Referrals: Consider cardiology and infectious diseases.
A A S S (L
M ,C . JCO 2014)
See “Hodgkin Lymphoma” chapter.
I P I (Z
. JCO 2009)
T C
R C
Standard-of-care treatment regimens exist that involve omission of
radiation therapy.
a For patients with DHL, double-protein expression, or other concerning pathologic features,
more aggressive chemotherapy with DA-R-EPOCH can be considered (Landsburg et al.
JCO 2017).
T A
R P
The role of radiotherapy for patients with relapsed or refractory
DLBCL is individualized and depends on patient- and treatment-
related factors, including prior systemic therapy, the extent of
disease at diagnosis and relapse, patient performance status,
and potential future therapies. Please refer to the International
Lymphoma Radiation Oncology Group (ILROG) guidelines for
further details and guidance (Ng et al. IJROBP 2018).
R T T (N
I P CNS )
Sim: Highly variable; dependent on area(s) being treated
Head and neck: Supine, thermoplastic mask ± bite block,
stent as appropriate
Axilla: Supine, upper Vac-Lok, arms akimbo
Mediastinum: Supine, incline board, upper Vac-Lok, deep
inspiration breath hold (DIBH)
Abdomen: Supine, upper and/or lower Vac-Lok; consider
NPO for 3 hours prior to sim/treatment, may require
respiratory motion management
Pelvis: Supine, lower Vac-Lok
Dose:
a For patients with low-volume residual Deauville 4-5 disease, radiation therapy alone can
be attempted (in lieu of salvage chemotherapy and autologous stem cell rescue).
Targets:
Involved site radiation therapy (ISRT)
Prechemotherapy site(s) of disease
CTV takes into account changes in size/extent of the
tumor, position of nearby normal tissues and organs,
and disease pattern and areas of potential subclinical
involvement.
Technique: Generally IMRT/VMAT, though 3DCRT may be
appropriate for certain geometries. “Butterfly” technique
commonly used for mediastinal lymphoma to minimize dose to
the heart, lungs, breasts, and spinal cord (Voong et al. Radiat
Oncol 2014).
IGRT: Dependent on technique and targets; daily kV, CBCT, or
CT on rails
Dose constraints:
a Goal is to keep 5 Gy isodose line off as many critical structures as possible.

C
R-CHOP-21: Rituximab (375 mg/m2 IV on d1),
2
cyclophosphamide (750 mg/m IV on d1), hydroxydaunorubicin
(doxorubicin; 50 mg/m2 IV on d1), Oncovin (vincristine; 1.4
mg/m2 [max dose 2 mg] on d1), and prednisone (40 mg/m2 po on
d1-5) every 21 days.
DA-R-EPOCH: Rituximab (375 mg/m2 IV on d1), etoposide (50
mg/m2/d IV on d1-4), prednisone (60 mg/m2 po bid on d1-5),
Oncovin (vincristine; 0.4 mg/m2/d IV on d1-4), cyclophosphamide
(750 mg/m2 IV on d5), and hydroxydaunorubicin (doxorubicin; 10
mg/m2/d on d1-4) every 21 days. Subcutaneous Neupogen
(filgrastim) is given once daily starting on d6 and continued until
WBC count normalizes (can substitute for Neulasta
(pegfilgrastim)). Dose-adjusted (DA) protocol increases
(etoposide, doxorubicin, cyclophosphamide) or decreases
(cyclophosphamide) doses for subsequent cycles based on
neutrophil and/or platelet nadirs.
S DLBCL
Primary central nervous system lymphoma (PCNSL)
Classically seen in individuals with primary or acquired
immunodeficiency
Workup: Slit lamp examination, lumbar puncture, spine MRI
(if symptomatic or CSF is positive), HIV test, testicular
examination, and testicular ultrasound (especially for men
>60 years old)
If possible, delay initiation of steroids until biopsy is
performed
Treatment:
R-MPV (rituximab, high-dose methotrexate,
procarbazine, vincristine, ± intrathecal chemotherapy).
Complete response: High-dose chemotherapy with
autologous stem cell transplant or low-dose whole brain
radiotherapy (23.4 Gy in 13 fractions at 1.8 Gy/fx; Morris
et al. JCO 2013).
Residual disease: Whole brain radiotherapy (30.6-36
Gy, boost gross disease to 45 Gy) or high-dose
chemotherapy with autologous stem cell transplant.
Consider omission of radiation in patients with poor
functional status or age >60.
Primary testicular lymphoma
Generally seen in men >60 years of age.
Workup: Lumbar puncture and bilateral testicular ultrasound.
R-CHOP or DA-R-EPOCH given per standard DLBCL
protocol; intrathecal or high-dose methotrexate for CNS
prophylaxis.
High risk of contralateral testicular failure after chemotherapy
(Ho et al. Leuk and Lymphoma 2017). All patients should
receive testicle/scrotal/spermatic cord irradiation to 30.6 Gy
in 17 fractions (1.8 Gy/fx) after completing chemotherapy
(Vitolo et al. JCO 2011).
Primary mediastinal B-cell lymphoma
Commonly presents in adolescents and young adults (esp.
women).
Putatively arises from thymic B cells and has significant
molecular overlap with nodular sclerosing Hodgkin
lymphoma (NSHL). PMBCL cells are typically weakly
positive for CD30 and negative for CD15, which helps
discriminate PMBCL from NSHL.
DA-R-EPOCH x6 without consolidation radiotherapy for
patients with Deauville ≤3 metabolic response on 18FDG
PET-CT offers excellent cure rates (Dunleavy et al. NEJM
2013).
Residual FDG avidity after DA-R-EPOCH should be
interpreted cautiously, as not all postchemotherapy
metabolic activity denotes active or residual lymphoma
and necessitates radiotherapy.
For patients with low burden residual PET-CT–avid
lymphoma after DA-R-EPOCH, salvage radiotherapy to a
dose of 45-50 Gy may be considered. Alternate approaches
include salvage chemotherapy followed by autologous stem
cell transplant with posttransplant consolidative radiotherapy.
For patients with significant disease progression after DA-R-
EPOCH, radiation therapy alone is not desirable (Filippi et al.
Red J 2016).
Consolidation radiotherapy to 30.0-36.0 Gy is indicated for
patients who receive R-CHOP chemotherapy in lieu of DA-R-
EPOCH.
F -
No PET-CT for a minimum of 8 weeks after radiotherapy due to
chance of false positives.
H&P and laboratory studies every 3-6 months for 5 years. For
stages I and II, repeat imaging only as clinically indicated, and for
stages III and IV, CT scan no more often than every 6 months for
2 years and then yearly afterward. TSH at least annually if RT to
the neck.
Secondary malignancies: Start annual breast screening the
earlier of 8-10 years after therapy or age 40 if chest radiation.
N
Role of consolidation radiotherapy for early and advanced stage
DSHNHL-2004-3/UNFOLDER 21/14 (Ongoing; Interim results

Held ICML RT Workshop 2013). Phase III trial with 2 × 2
randomization of patients with early-stage DLBC IPI = 0-1 with
bulky (≥7.5 cm) disease to R-CHOP-21 ×6 vs R-CHOP-21 ×6 →
involved field radiotherapy (IFRT) vs R-CHOP-14 ×6 vs R-CHOP-
14 ×6 → involved field radiotherapy. Interim analysis terminated
no RT arms due to inferior 3-year EFS (81% vs 65%, P = .004).
SWOG 8736 (Miller et al. NEJM 1998; Stephens et al. JCO
2016). Randomized trial of patients with stage I-IE and nonbulky
II-IIE DLBCL to CHOP ×8 vs CHOP ×3 + IFRT to 40 Gy (with
boost to 50 Gy for residual disease). CHOP ×3 + IFRT increased
PFS (5 years: 77% vs 64%, p = .03) and OS (5 years: 82% vs
72%, p = .02) compared to CHOP ×8 on initial analysis, but on
long-term analysis (median f/u of 17.7 years), the curves
overlapped with no significant difference in PFS (median: 12 vs
11.1 years, p = .73) or OS (13 vs 13.7 years, p = .38) between
groups. No significant difference in cumulative incidence of
secondary malignancy between groups. Seven patients died from
heart failure in CHOP ×8 arm compared to one patient in CHOP
×3 + IFRT arm.
Phan et al. JCO 2010. Retrospective analysis of MDACC patients
with stage I-IV DLBCL who received R-CHOP. Approximately
30% received consolidation IFRT to 30-39.6 Gy. Radiotherapy
improved PFS and OS for all patients.
Consolidation radiotherapy for bulky and extralymphatic disease
RICOVER-noRTh (Held et al. JCO 2014). Patients >60 years of

age with aggressive B-cell lymphoma who received R-CHOP-
14+2R + 36 Gy IFRT to bulky (≥7.5 cm) and/or extralymphatic
sites of disease (RICOVER-60) were compared to patients
treated with same chemotherapy but no radiotherapy on
amendment of RICOVER-60 (RICOVER-noRTh). Omission of
radiotherapy in patients with bulky or extralymphatic lymphoma
was associated with lower EFS (HR = 2.1, p = .005) with trends
toward lower PFS (HR = 1.8, p = .058) and OS (HR = 1.6, p =
.13).
German High-Grade NHL Study Group retrospective analysis of
patients with skeletal involvement from nine consecutive studies
(Held et al. JCO 2013). Rituximab failed to improve EFS or OS in
patients with skeletal involvement, but consolidation radiotherapy
significantly improved EFS.
Consolidation radiotherapy for primary bone DLBCL
MDACC experience with primary bone DLBCL (Tao et al.

IJROBP 2015). 72% of patients received rituximab. Receipt of
consolidation radiotherapy was associated with improved PFS (5
years: 88% vs 63%, p = .007) and OS (5 years: 91% vs 68%, p =
.006).
MISCELLANEOUS HEMATOLOGIC
MALIGNANCIES
ZEINA AYOUB • SARAH MILGROM
F L
Background and presentation
Incidence/prevalence: Most common indolent non-Hodgkin

lymphoma subtype (70% of indolent lymphomas). Common
asymptomatic lymphadenopathy, waxing, and waning for years;
rarely with B symptoms. Bone marrow involvement in >70% of
patients.
Outcomes: Indolent clinical course with possibility of late
relapse; median OS > 10 years.
Demographics: Median age at diagnosis is 60 years.
Risk factors: Age; common association with a history of
autoimmune disease, hepatitis, or chronic immunosuppression,
exposure to pesticides or chemical plants. Potential for
transformation to more aggressive lymphoma can be high (up to
70% in long-time survivors).
Arises from the germinal center B cells.

85% have the t(14;18), which results in Bcl2 overexpression
Morphology shows closely packed follicular nodules
Immunophenotype: CD10+, Bcl2, Bcl6
Ki-67 significantly lower than DLBCL
Grade is defined by the number of centroblasts (large cells) per
HPF.
Grade 1: 0-5 centroblasts/HPF
Grade 2: 6-15 centroblasts/HPF
Grade 3: >15 centroblasts/HPF
3A: >15 centroblasts, but centrocytes are still present.
3B: Centroblasts form solid sheets with no residual
centrocytes.
Workup
History and physical: Physical examination of all node-bearing
areas including Waldeyer ring and of size of the spleen and liver.
Assessment of performance status and B symptoms (night
sweats, weight loss, and fevers).
Labs: CBC, CMP, LDH, ESR, uric acid, β2-microglobulin, hep
B/C, HIV, and pregnancy test
Procedures/biopsy: Excisional biopsy is preferred. Bone
marrow biopsy (bilateral is encouraged but not mandatory). When
chemotherapy is planned, consider MUGA/echo and
fertility/sperm banking.
Imaging: CT C/A/P/neck with contrast and/or PET/CT.
Staging (Lugano modification of Ann Arbor Staging System)

See “Hodgkin Lymphoma” chapter.
Prognosis
FLIPI score (Solal-Celigny et al. Blood 2004)

Age > 60
Stages III-IV
Hemoglobin level < 12 g/dL
Number of nodal areas > 4
LDH level > ULN
FLIPI 2 score (Federeico et al. JCO 2009)

Age > 60
Hemoglobin level < 12 g/dL
Bone marrow involvement
β2-microglobulin > upper limit normal
Largest diameter of largest involved lymph node > 6 cm
Treatment algorithm
Notable trials
M Z L
Background
Incidence/prevalence: 5%-10% non-Hodgkin lymphoma.

Outcomes: Indolent disease. Death due to disease is extremely
rare. Gastric site has longer time to progression vs nongastric
MALT (8.9 vs 4.9 years). 50% gastric, other sites include orbit,
lung, skin, thyroid, salivary gland, etc.
Demographics: Variable age groups depending on the subtype.
Risk factors: Associated with chronic inflammation: autoimmune
disease (Sjögren disease), infections (H. pylori, C. psittaci, B.
burgdorferi, C. jejuni).
Neoplasm of mature B cells.

Arise from postgerminal center marginal zone B cells.
B-cell markers: CD19, CD20, CD22+ (CD5/10/23 −).
Characterized by proliferation of cells within a lymphoid area
where clonal expansion of B cells occurs. Subtypes include:
Splenic marginal zone B cells
Nodal marginal zone B cells
Marginal zone B cells of Peyer patches/extranodal
Primary cutaneous
Mucosa-associated lymphoid tissue (MALT) lymphoma
G M
Presentation
Majority present with localized stage I/II extranodal disease.

Most commonly present with abdominal pain and peptic ulcer
disease.
B symptoms are uncommon.
Outcomes: 5-year OS of 90%-95% and DFS of 75%-80%
Workup
History and physical: Physical examination of all node-bearing

areas including Waldeyer ring and of size of the spleen and liver.
Assessment of performance status and B symptoms (uncommon
for gastric malt).
Labs: CBC, CMP, LDH, ESR, uric acid, β2-microglobulin, hep
B/C, HIV, and pregnancy test. Bone marrow biopsy is not
routinely done.
Procedures/biopsy: Endoscopic biopsy with H. pylori testing by
histopathology:
If negative → noninvasive testing: Stool antigen test, urea
breath test, and blood antibody test
PCR or FISH for t(11;18). Translocation associated with lack
of response to combination antibiotic therapy
Imaging: CT C/A/P with contrast and/or PET/CT.
Staging (Lugano Staging for Gastrointestinal Lymphomas;

Rohatiner et al. Ann Oncol 1994)
Treatment algorithm
Combination antibiotic therapy includes antacid medication and
antibiotics (eg, clarithromycin, amoxicillin, and omeprazole).
Consider chemoimmunotherapy for advanced or relapsed
disease.
O M
Presentation
Most common nongastric MALT.

Can affect the conjunctiva, eyelid, lacrimal gland, and retrobulbar
area.
Associated with Chlamydia psittaci.
Treatment approach
Doxycycline (complete response 65%).

Consider ISRT if antibiotic therapy failure.
4 Gy in 2 fractions can achieve CR in 90%; for those who do not

achieve CR, complete the dose with additional 20 Gy in 10
fractions.
P C B-C L
Background
Associated with B. burgdorferi infection, preexisting

acrodermatitis chronica atrophicans, and vaccination sites
20% of all primary cutaneous lymphomas and divided into five
subtypes
Primary cutaneous marginal zone B-cell lymphoma (PCMZL)
Primary cutaneous follicle center lymphoma (PCFCL).
Primary cutaneous diffuse large B-cell lymphoma, leg-type
(PCLBCL, LT)
Primary cutaneous diffuse large B-cell lymphoma, other
(PCLBCL, O)
Intravascular large B-cell lymphoma (IVLBCL)
P C M Z B-
L (PCMZL)
Pathology shows nodular to diffuse infiltrates of small to medium

lymphocytes, with sparing of the epidermis. A reactive germinal
center is frequently seen.
Marginal zone B cells express CD20, CD79, and bcl-2 and are
typically negative for CD5, CD10, and bcl 6; translocation t(18;21)
is rare.
Presentation
Multiple painless, nonulcerative, red to violaceous papules,

plaques, or nodules occurring mainly on the trunk or the
extremities.
Indolent clinical presentation and spontaneous resolution have
been reported.
Treatment approach
Lesions respond to different treatments (resection, systemic

therapy, and radiation). General approach is to treat with least
toxic option: ISRT 4 Gy in 2 fractions.
A noticeable clinical response might not be seen before 4-8
weeks, as effect of radiation may be mostly on the
microenvironment rather than on the actual malignant cells.
Outcomes
The lymphoma-specific survival is close to 100%, while the

relapse-free survival for solitary lesions is 77% vs 39% for
multifocal lesions.
P C F C
L (PCFCL)
Pathology demonstrates a monotonous population of large follicle

center cells, with nodular or diffuse infiltrates sparing the
epidermis.
Cells that are CD20+, CD79a+, and bcl6+, in a network of CD21+
or CCD35+ follicular dendritic cells.
Rarely express t(14;18) or bcl2.
Presentation
Difficult to differentiate from PCMZL, as lesions present as

nonulcerative plaques or nodules, most commonly on the scalp,
forehead, or trunk.
Treatment approach
ISRT 4 Gy in 2 fractions.
Outcomes
Complete remission rates up 100% and a relapse-free survival of

73%-89%; the majority of patients can be salvaged with local
radiation.
P C T- L
Mycosis Fungoides (MF)
Background
Represents 2/3 of cutaneous T-cell lymphoma cases

Indolent disease, may take several years and repeat biopsies
Incurable disease unless autologous or allogeneic transplant is
being considered
Pathology shows a clonal T-cell population clustered at the

basement membrane of the epidermis.
Characterized by loss of CD7, CD5, and CD2; dim CD3+; and
mature clonal CD4+ and CD45RO+.
Rarely express t(14;18) or bcl2.
Presentation
Presents with patches, but eventually plaques and tumors with or

without erythroderma may develop. Concomitant skin infections
are frequent.
Workup
Inspection and determination of the total body surface area.

Flow cytometry to determine CD4+/CD8+; if above 4.5, indicates
a high level of circulating T-cell lymphoma cells in the blood.
Imaging and bone marrow biopsy in appropriate cases.
When limited to the skin, T1 and T2 are patches or plaques
involving more than 10% of the skin; T3 is tumor, and T4 is
erythroderma.
Treatment approach
Initial topical therapies: steroids, chemotherapy, bexarotene gel,

phototherapy
Systemic therapies: Retinoids, histone deacetylase inhibitors,
denileukin diftitox, monoclonal antibodies, interferon alpha,
cytotoxic chemotherapy
Total skin or local radiation therapy with the goal of avoiding
excess skin toxicity
TSEBT reserved for substantial surface involvement and
may take up to 8-12 weeks for maximal response
Given in 2 Gy fractions twice per week with
boosts/supplemental fields for axilla, shoulders,
inframammary fold, groins, perineum, perianal area,
soles, and skinfolds
10-12 Gy overall response rate of 88% with mild toxicity
30-36 Gy for high disease burden or for pretransplant
conditioning
Local radiation
4-12 Gy to lesion with 1- to 2-cm margin to minimize RT to
nonsymptomatic areas. Can retreat with radiation if needed.
Electron beam RT in most cases starting at 9 MeV for
patch/plaque with higher energy for tumors with bolus to
ensure full skin dose.
Use simulation CT scan if adjacent to sensitive normal tissue
(consider skin collimation also) or unknown tumor depth.
Figure 64.1 A–D. Pre- and posttreatment examples of local
radiation (4-12 Gy) for the treatment of mycosis fungoides.
P A L C
L (PALCL)
Background
Second most common type of cutaneous T-cell lymphoma

Can present along with M
May take weeks/months for response to radiation and wound
healing
Presentation
Deeper skin involvement and often ulcerative lesions
Treatment approach
Local radiation
Responds to as low as 6 Gy
P C D /S
P
Solitary Plasmacytoma
Background
Incidence/prevalence: 10% of plasma cell neoplasms

Outcomes: Localized disease with no evidence of additional
lesions, bone marrow involvement, or clinical/laboratory findings
consistent with MM (serum calcium > 12, renal dysfunction, Hgb
< 10, multiple bone lesions, or >10% plasma cells in bone
marrow). Excellent locoregional control with radiation (up to 95%)
80% solitary plasmacytoma of bone (SPB): 55%-80%
progress to multiple myeloma
20% extramedullary plasmacytoma (SEP): 35%-50%
progress to multiple myeloma
Demographics: Male predominance (2/3 cases); younger
median age (55-65) than multiple myeloma
Risk factors: Family prevalence, older age, and male gender
Treatment approach
Use CT, PET, and MRI (check marrow signal) for target
delineation. PTV expansion depending on tumor location. Neither
elective vertebral body (superior/inferior) nor elective nodal
coverage is necessary if using PET and MRI.
Typically ISRT to 40-50 Gy
If <5 cm, can consider <45 Gy.
Lower dose of 30-36 Gy may be sufficient.
M C L (MCL)
Background
Usually presents with advanced stage, following an aggressive

course
Male predominance (78%), median age at diagnosis 63 years
Majority (75%) present in the head and neck
Age (>60), bulky disease (>5 cm), and stage II → increased
treatment failure risk
Characterized by overexpression of cyclin D and t(11;14)
chromosomal translocation
Prognosis
MCL International Prognostic Index (MIPI) (Lim et al. Oncol Lett
2010)
Overall prognosis
5-Year freedom from progression, 65% and OS, 76%

10-Year freedom from progression, 42% and OS, 64%
Treatment approach
Stage I-II MCL
Excellent and similar outcomes for chemotherapy,
chemoradiation, or radiation alone
Goal to deintensify therapy to limit treatment-related toxicity.
Consider 4 Gy in 2 fractions
Advanced-stage MCL
RT to palliate bulky nodal or extranodal masses, often after being

heavily pretreated.
4 Gy in 2 fractions is associated with high response rates,
although may take up to 4 weeks to respond.
Consider additional 24-30 Gy if no response after 4 weeks.
BRAIN METASTASES
BHAVANA S. VANGARA CHAPMAN • JING LI • AMOL
JITENDRA GHIA
B
Incidence/prevalence: Most common intracranial tumor, 20%-40% of
all cancer patients will develop intracranial metastases. ~175-200 K
diagnosed annually. Incidence increasing due to widespread adoption
of MRI, where small lesion detection has improved.
Single metastasis, one intracranial lesion (may have other sites of
extracranial disease), vs solitary metastasis, one intracranial lesion,
which is also the only site of metastatic disease.
Outcomes: Historically, median survival for observation 1 month,
steroids 2 months, WBRT 4-6 months, surgical resection for single
lesion 6 months, and with adjuvant WBRT 10 months. Outcomes for
SRS ± WBRT 6-10 months. Advances in targeted and immunotherapy
have resulted in improved outcomes but questionable use due to
limitations of the blood-brain barrier.
T B C
Pathology:
Common histologies: Lung, breast, melanoma
Less common histologies: GU, GI, H&N, sarcoma, leukemia,
lymphoma
Hemorrhagic metastases: Melanoma, RCC, choriocarcinoma
Imaging: MRI of the brain ± contrast to visualize abnormal
enhancement or ring-enhancing lesions on T1 postcontrast and
vasogenic edema on T2 FLAIR; restaging CT CAP and PET-CT to
evaluate systemic disease burden
A
Most located at gray-white matter junction (watershed areas)
80% cerebral hemispheres, 15% cerebellum, 5% brainstem
W
History and physical: Common presenting symptoms include
headache, nausea, vomiting, seizures, focal neurologic deficits, and
vision changes. Assess extent and control of intracranial/extracranial
disease, performance status, and neuro exam.
Labs: CBC, CMP (tumor markers to r/o cns primaries vs brain mets)
Imaging/procedures/biopsy: MRI of the brain ± contrast, biopsy or
resection if solitary brain lesion or long latency from last known
malignancy
Initial management: For symptomatic lesions, steroids 4-16 mg/d in
divided doses depending on symptom severity with PPI for
gastroprotection, AEDs for seizures (prophylaxis not recommended),
radiation oncology, and neurosurgery consults.
Prognostic factors: Age, KPS, cancer type/histology, control of
primary disease, extent of metastatic disease, number/size/location of
brain metastases, severity of symptoms
Common prognostic scores: Diagnosis-Specific Graded
Prognostic Assessment (DS-GPA) (Sperduto et al. JCO 2012),
Recursive Partitioning Analysis (RPA) (Gaspar et al. IJROBP
1997), Basic Score-Brain Metastasis (BS-BM) (Lorenzoni et al.
IJORBP 2004), and Score Index for Radiosurgery (SIR)
(Weltman et al. IJROBP 2000)
T A
Prognosis ≥3 months
*For 4-9 lesions, standard care remains WBRT due to lack of level 1
evidence to support the use of SRS in this patient population. We offer
SRS only on trials or due to patient refusal.
Prognosis <3 months or KPS < 50
Recommend WBRT or supportive care.
R T T
SIM
WBRT, SRT, and LINAC-based SRS: Supine, head in neutral
position, AquaPlast RT mask, bite block for SRS/SRT
Gamma Knife SRS: see SRS chapter.
Dose
WBRT
Most common: 30 Gy/10 fx
For patient with better prognosis and to minimize late
toxicity: 37.5 Gy/15 fx or 35 Gy/14 fx
SRT
21-27 Gy/3 fx or 25-30 Gy/5 fx
SRS (Based off N107C/CEC•3; Brown Lancet Oncol 2017)
Target
WBRT: Inferior to bottom of C1 or C2, multiple techniques can be
utilized to avoid optic lenses (we typically rotate gantry 5 degrees
and treat with RAO/LAO technique).
SRT or LINAC-based SRS: GTV +2-mm PTV margin (*PTV
margin based on institutional setup uncertainty and IGRT
availability).
Gamma Knife SRS: see “SRS” chapter.
Technique
WBRT: Opposed laterals or IMRT-based hippocampal sparing on
trial (Gondi et al. IJROBP 2010). Hippocampal sparing is
investigational.
SRT or LINAC-based SRS: IMRT or dynamic conformal arcs
IGRT:
WBRT: Weekly mV imaging
SRT and LINAC-based SRS: Daily kV imaging, CBCT, ExacTrac
Planning directive
SRT
Brainstem* V20 < 1 cc (3 fx), D max < 21 Gy/3 fx, 25 Gy/5 fx
Optic nerve D max < 18 Gy/3 fx, 25 Gy/5 fx
SRS
Prescribed to ~80% isodose line for LINAC-based SRS and
~50%-80% isodose line for Gamma Knife SRS depending on
size of lesion
Brain V12 Gy <5-10 cc; brainstem ≤12 Gy to 1cc*; optic
chiasm D max ≤ 10 Gy
For additional information, see SRS chapter.
*For targets in the brainstem, normal brainstem defined as brainstem—

GTV
S E M
WBRT
Acute: Fatigue, alopecia, and ototoxicity.
Nausea/vomiting/headaches/vision changes from increased ICP:
po dexamethasone + PPI, ondansetron (4 mg q6h prn), or
prochlorperazine (10 mg q6h prn)
Long term: Neurocognitive deficits, leukoencephalopathy, and
radiation necrosis (higher for >3 Gy/fx). We recommend
prophylactic memantine (based on RTOG 0614) for all WBRT
patients, at 10 mg daily for week 1, followed by 10 mg bid for 6
months; consider indefinitely.
SRT/SRS
Adverse effects are rare. In one modern SRS series, the 1-year
probabilities of symptomatic adverse events are 3% after SRS
alone, 4% for SRS preceded by WBRT, and 8% for sequential
SRS/WBRT (Sneed et al. J Neurosurg 2015).
Acute (rare): Headache, nausea, vomiting, vestibular
dysfunction, seizures; for Gamma Knife SRS, pain at headframe
pin sites (OTC analgesic/anti-inflammatory meds; may consider
prophylactic dexamethasone, eg, 8-10 mg ×1, when treating
large lesions with significant edema seen on recent MRI)
Long term: Radiation necrosis (PO dexamethasone + PPI, may
require surgery or bevacizumab for refractory cases)
F -
H&P and MRI of the brain in 4-6 weeks → every 3 months for 2 years
→ then as clinically indicated
N T
Surgery
Patchell II (Patchell et al. JAMA 1998): Two-arm prospective, RCT of

patients with a single-brain metastasis, other distant metastases
allowed, KPS ≥ 70 with complete resection verified by MRI of the
brain randomized to WBRT (50.4 Gy/28 fx) vs observation. WBRT
reduced local recurrence (10% vs 46%, P < .001), other intracranial
recurrence (18% vs 70%, P < .01), and neurologic death (14% vs
44%, P = .003). There was no difference in OS or time patient
remained functionally independent.
MD Anderson (Mahajan et al. Lancet Oncol 2017): Two-arm
prospective phase III RCT of patients with 1-3 completely resected
brain metastases, ≤4-cm cavity, and KPS ≥ 70 randomized to SRS
(12-16 Gy) vs observation. Primary end point was time to local
recurrence, which was reduced in the SRS arm (42% vs 72%, P
=.015). OS was not different between groups.
N107C/CEC•3 (Brown et al. Lancet Oncol 2017): Two-arm
prospective phase III RCT of patients with a single resected brain
metastasis with a cavity ≤5 cm, ≤3 unresected intracranial
metastases, and ECOG 0-2 randomized to postoperative SRS (12/20
Gy) vs WBRT (30 Gy/10 fx or 37.5 Gy/15 fx). On intention-to-treat
analyses, OS was not different between groups, but cognitive-
deterioration-free survival was improved in the SRS arm (median
3.7 vs 3.0 months, P < .001).
WBRT vs WBRT + SRS
RTOG 9508 (Andrews et al. Lancet 2004): Two-arm prospective

phase III RCT of patients with 1-3 brain metastases, largest lesion ≤4
cm, additional lesions ≤3 cm, and KPS ≥ 70 randomized to WBRT (30
Gy/10 fx) vs WBRT + SRS (18-24 Gy). Primary end point was OS,
which was similar between groups. In patients with a single-brain
metastasis, OS improved with the addition of SRS (6.5 vs 4.9 months,
P = .04). Multivariate analysis also showed patients with RPA I or lung
cancer primary had improved OS with an SRS boost. The WBRT +
SRS group had improved 1-year local control (82% vs 71%, P =.013)
and stable or improved KPS at 6 months (43% vs 27%, P =.033).
JROSG 99-1 (Aoyama et al. JAMA 2006): Two-arm prospective,
multi-institutional, RCT of patients with 1-4 brain metastases, ≤3 cm,
and KPS ≥ 70 randomized to SRS alone (18-25 Gy) vs WBRT (30
Gy/10 fx) + SRS (30% dose reduction). Primary end point was OS,
which was not different between groups (SRS alone 8 months; WBRT
+ SRS 7.5 months, P = .42). Intracranial relapse at 1 year and
salvage treatment occurred less frequently in the WBRT + SRS arm
vs SRS-alone arm (47% vs 76%, P < .001).
SRS for multiple brain metastases (2-10)
JLGK0901 (Yamamoto et al. Lancet Oncol 2014): Prospective

observational study of patients with 2-4 vs 5-10 brain metastases, <3
cm, KPS ≥ 70 treated with SRS alone (20-22 Gy). Primary end point
was OS with a noninferiority margin of 95% CI with a HR 1.3 on an
intention-to-treat analysis. OS was similar between 2-4 vs 5-10 brain
metastases groups (median 10.8 months for both). The rate of
adverse events was also similar between the arms.
Surgery or SRS → WBRT vs observation
EORTC 22952-26001 (Kocher et al. JCO 2011): Two-arm prospective

phase III RCT of patients with 1-3 brain metastases and WHO PS 0-2
treated with complete surgical resection or SRS (minimum 25 Gy to
center and 20 Gy to surface) randomized to WBRT (30 Gy/10 fx) vs
observation. Primary end point was time to WHO PS > 2, which was
10 months in the observation arm and 9.5 months in the WBRT arm
(not significant). OS was similar between arms. WBRT reduced 2-
year local relapse rate (surgery, 59%-27%, P < .001; SRS, 31%-19%,
P = .04) and 2-year relapse at other intracranial sites (surgery,
42%-23%, P = .008; SRS, 48%-33%, P = .023). Salvage therapies
and intracranial progression-related death occurred more frequently in
the observation arm.
Neurocognitive function
MD Anderson (Chang et al. Lancet Oncol 2009): Two-arm
prospective phase III RCT of patients with 1-3 brain metastases, size
eligibility for SRS, KPS ≥ 70, RPA class 1 or 2 randomized to SRS
alone (15-24 Gy) vs SRS + WBRT (30 Gy/12 fx) within 3 weeks.
Primary end point was neurocognitive function based on HVLT-R
recall test at 4 months. SRS + WBRT led to a decline in learning and
memory function (52% vs 24%; Bayesian probability P = 96% that
proportion of SRS + WBRT patients has significant worse
neurocognitive function). SRS + WBRT improved local (100% vs 67%,
P = .012) and distant control (73% vs 27%, P = .003). OS was better
with SRS (15.2 vs 5.7 months, P = .003).
RTOG 0614 (Brown et al. Neuro-Onc 2013): Two-arm prospective,
randomized, double-blind, placebo-controlled trial of patient with brain
metastases undergoing WBRT (37.5 Gy/15 fx) randomized to
memantine during and after WBRT vs placebo. Primary end point was
preserved delayed recall as per the HVLT-R DR at 24 weeks from the
start of drug treatment, which trended toward improvement in the
memantine arm but was not statistically significant (P = .059); a lack
of significance was thought to be due to limited statistical power.
However, time to cognitive failure improved with memantine (54% vs
65%, P = .01).
Alliance N0574 (Brown et al. JAMA 2016): Two-arm prospective
phase III RCT of patients with 1-3 brain metastases <3 cm and ECOG
PS randomized to SRS alone (20-24 Gy) vs SRS (18-22 Gy) + WBRT
(30 Gy/12 fx) within 2 weeks. Primary end point was cognitive decline
>1 SD from baseline on at least 1/7 cognitive tests at 3 months.
Cognitive decline was more frequent in the WBRT arm (92% vs 64%,
P < .001). Although WBRT improved 6 and 12 months local and
distant control and decreased salvage rates, there was no difference
in OS with the addition of WBRT.
SPINE METASTASES
VINCENT BERNARD • ADNAN ELHAMMALI • AMOL JITENDRA
GHIA
B
Incidence/prevalence: Osseous disease third most common site of
metastases. The spine most common site of bone metastases. 70%
involve thoracic spine, 20% lumbar, and 10% cervical. Breast, lung,
and prostate account for 50%-60% of cases.
Radiosensitive histologies: Breast, prostate, ovarian, and
neuroendocrine carcinoma. Patients achieve symptomatic relief and
effective local control rates with conventional external beam
radiotherapy (cEBRT).
Radioresistant histologies: Sarcoma, melanoma, chordoma,
hepatobiliary, and renal cell carcinoma. Do not have good local
control rates with conventional radiation. Radiosurgery should be
considered.
Intermediate resistance histologies: Lung, colon, and thyroid.
Treatment typically dependent on institutional classification and
experience.
W
History and physical: Characterize pain: Mechanical pain worse with
movement and neurologic pain worse when supine. Pain is the most
common initial presenting symptom and usually precedes neurologic
deficits. Mechanical pain indicates possible need for stabilization.
Inquire about neurologic deficits that indicate possible acute cord
compression. Does patient have known cancer diagnoses? Ask about
prior surgery, prior radiation therapy, concurrent chemotherapy.
Assess PFS and ability to tolerate simulation/treatment. Perform
complete neurologic examination.
Imaging: MRI T1 with/without contrast of entire spine to delineate
disease and identify other sites of involvement. Axial T2 to localize
spinal cord. CT myelogram is useful in postoperative SRS above the
conus where instrumentation causes increased T2 artifact signal
making cord visualization difficult.
Surgery consult: Patient should be evaluated by neurosurgery or
spine surgery to determine the need for emergent decompression or
spine stabilization prior to radiation therapy.
G T O
Disease touching the cord (MESCC grade IC or greater)? If patient
is a surgical candidate, we prefer surgery followed by radiation
therapy. If not a surgical candidate but otherwise meets clinical
indications for SSRS as outlined below, proceed with SSRS
respecting spinal cord dose tolerance. Otherwise, cEBRT (see RT
Emergencies chapter).
Assess the need for surgical stabilization: Refer patient to
neurosurgery or spine surgery for assessment of spine stability and
need for stabilization prior to RT based on SINS score (spine
instability neoplastic score; Fisher Radiat Oncol 2014). Score 0-6,
stable; 7-12, indeterminate; and 13-18, unstable.
Spine radiosurgery:
Indications: Reirradiation, radiation-resistant histology,
oligometastatic, oligoprogressiveContraindications: >3 spinal level
involvement, poor PFS, unable to tolerate SRS simulation or
treatment (eg, lay flat for an extended period of time)
R T T
Conventional radiotherapy (cEBRT)
SIM: Varies by site and technique. Consider patient pain tolerance.

Dose: Typically 30 Gy in 10 fractions or 20 Gy in 5 fractions; 20 Gy in
8 fractions for lymphoma/multiple myeloma
Target: One vertebral body above and below the site of disease + soft
tissue extension + 1-2 cm laterally from the vertebral body
Technique: Depends on level. In general:
Cervical (C1-C7): Opposed lateral
Thoracic (T1-T12): AP:PA or PA
Lumbar (L1-L5): AP:PA or PA
Sacrum: Laterals, AP:PA, or 3 field (PA: laterals)
Spine stereotactic surgery
SIM: Supine, full body stereo cradle, head/neck/shoulder Aquaplastic

mask for c-spine, body fix device for thoracic/lumbar/sacral spine (Fig.
66.1).
Dose: *Dosing and target dependent on IGRT availability and
physics support.MDACC SSRS simultaneous integrated boost (SIB)
technique:
Image fusion: Axial T1 and/or T1+C for GTV. Identify true cord on
axial T2 MRI for intact. CT myelogram preferred for post-op cases as
hardware causes T2 artifact.
Target (based on SSRS consensus guidelines; Cox et al. IJROBP
2012):
Intact tumor
GTV: Visible tumor on CT or MRI
CTV: Contiguous at risk bone as per guidelines (1 echelon beyond;
see below) + 5 mm expansion around paraspinal/soft tissue extension
of disease
PTV: Depends on institutional setup uncertainty. No expansion at
MDACC
Post-op:
GTV: Pre-op disease + residual disease in postoperative imaging
CTV: Same as intact, if bone resected, contour virtual CTV referring
to post-op consensus guidelines (Redmond et al. IJROBP 2017)
PTV: Same as intactreferring to post-op consensus guidelines
(Redmond et al. IJROBP 2017)
PTV: Same as intact
Planning directive constraints: *PRV expansion based on

institutional setup uncertainty. No PRV expansion used at MDACC
Spinal cord:
Single fraction: V8-10 Gy ≤ 1 cc, D max < 10-12 Gy
Three fraction (prior cEBRT): 9 Gy ≤ 1 cc, D max ≤ 10 Gy
Cauda equina:
Single fraction: V12-14 Gy ≤ 1 cc, D max < 16 Gy
Esophagus:
Single fraction: V12 Gy ≤ 1 cc, D max < 17 Gy
Treatment planning: Step and shoot IMRT with nine coplanar
posterior/posterolateral beams. Goal GTV D min > 14 Gy/1 fx or > 21
Gy/3 fx (Bishop IJROBP 2015). GTV coverage typically 80%-90%.
IGRT: Daily ExacTrac, CBCT, and orthogonal ports prior to treatment
and ExacTrac “snapshot” between each beam. Repeat CBCT if
patient moves between beams.
Figure 66.1 Typical set-up for cEBRT (left picture) and SSRS
(right picture). Note the use of a full body fix device that covers the
entire length of the spine for SSRS treatments, to ensure minimal
patient movement and reduce positional error.
Figure 66.2 Anatomic classification system for consensus target

volumes for spine SRS adapted from the international SRS
consortium consensus guidelines. 1, Vertebral body; 2, left
pedicle; 3, left transverse process and lamina; 4, spinous process;
5, right transverse process and lamina; and 6, right pedicle.
(Adapted from Cox BW, Spratt DE, Lovelock M, et al. International
Spine Radiosurgery Consortium consensus guidelines for target
volume definition in spinal stereotactic radiosurgery. Int J Radiat
Oncol Biol Phys. 2012;83(5):e597-605. Copyright © 2012 Elsevier.
With permission.)
Figure 66.3 Representative treatment plan of a patient

undergoing SSRS in axial, sagittal, and coronal (L → R) cross-
sectional views. The CTV is highlighted in yellow color wash and
GTV in red. The blue isodose line represents 16 Gy and white
isodose line 24 Gy. This patient was treated with a single fraction.
See color insert.
S E M
Acute
Pain flare: Incidence 20%-63%. Typically self-limiting and

salvageable by treating with dexamethasone 4 mg bid over 5-7 days
Esophagitis: Dietary modifications (pureed/bland/soft food, frequent
small meals), topical anesthetics (magic mouthwash, etc.), analgesics
(acetaminophen, narcotics)
Late
Vertebral body fracture: Rates range from 10% to 40%, although a

significant portion is asymptomatic. Risk correlated to dose/fraction,
SINS, and preexisting fracture.
Myelopathy: <1%
Radiculopathy: ~10%, risk greatest if disease involves the foramen
Esophageal stricture or perforation: <1%
F -
Every 3 months with MRI of the entire spine w/contrast for 1-2 years
and then every 6 months.
Local control expected to be >90% at 1 year in radiation-naïve
patients regardless of histology and >75% in those receiving
reirradiation.
N T
MDACC prospective phase I/II trial (Garg Cancer 2012): Safety and
efficacy using SSRS in 61 patients with 63 tumors receiving 18-24 Gy
in a single fraction. 1- and 2-year local control rates were 91% and
88%, respectively, with no significant differences in outcomes with
respect to tumor histology. 87% of patients reported complete or
partial pain relief. Two patients experienced grade 3 and grade 4
neurologic toxicities.
MDACC prospective phase I/II (Wang Lancet Oncol 2012): Safety
and efficacy of SSRS in metastatic spine tumors among 149 patients.
Patients who had received prior radiation therapy, treated with 27-30
Gy in 3 fractions, experience 1- and 2-year LC rates of 80.5% and
72.4%, respectively, with 92.9% of patients reporting some degree of
pain relief with a significant reduction in opioid use from baseline to 3
(P = .021) and 6 months (P = .011) post SSRS. Rare instances of
non-neurologic grade 3 toxicities were reported with no grade 4
toxicities noted.
Phase II RTOG 0631 trial (Ryu PRO 2014): Assessing the feasibility
and safety of delivery of an image-guided single 16 Gy SSRS dose for
localized spine metastases among 65 institutions. The adopted spinal
cord constraints in the study have been reported to be safe with a D
max of 10 Gy, ≤0.35 cc or ≤10% of partial spinal cord. There is an
ongoing phase III trial comparing single-dose 16 Gy SSRS to single-
dose 8 Gy cEBRT for pain control.
NON-SPINE BONE METASTASES
ADNAN ELHAMMALI • QUYNH-NHU NGUYEN
B
Incidence/prevalence: Approximately 350 000 patients die each year
with bone metastases. Pain is the most common presenting symptom.
Demographics: Third most common site of metastatic disease (1st
lung, 2nd liver). Axial skeleton more commonly involved (spine >
pelvis > ribs > femur > skull)
Outcomes: Highly variable, dependent on histology and extent of
disease
B P
Pathology: Most to least common: Prostate > breast > kidney >
thyroid > lung. Bone metastases can occur either by direct extension
or via hematogenous spread. Alters normal bone remodeling process
mediated by osteoblasts and osteoclasts and can present as either
lytic (classically RCC, myeloma, melanoma) or blastic (classically
prostate and SCLC) lesions
W E
History and physical: Identify the source of pain, severity, weight-
bearing ability, neurologic deficits, pain medication use, performance
status, and systemic disease burden.
Imaging: Bone scan (technetium-99) for asymptomatic blastic bone
mets. Uptake in bone scan more indicative of osteoblastic activity and
may not be as reliable for lytic lesions. For focal assessment of
symptomatic lesions, plain films to assess fracture risk, CT, MRI, or
PET/CT. For myeloma, get skeletal survey.
Biopsy: Consider if no prior hx of cancer or if site of 1st relapse.
Fracture risk: Determine if surgical stabilization is needed prior to
RT. Use Mirels criteria, weight-based scoring system to assess
fracture risk (Mirels et al. Clin Orthop Res 1989), scoring table shown
below
Predictors of pathologic fracture of the femur: >30-mm axial cortical
involvement or circumferential cortical involvement >50%, based on
analysis of Dutch Bone Metastases Study (Van der Linden et al. J
Bone Joint Surg Br 2004).
T P
If significant fracture risk (Mirels score ≥ 8, >30 mm femoral cortical
involved, >50% femoral circumferential cortical involvement) →
surgical fixation followed by radiation therapy.
Single fraction (SF, 8 Gy) or multifraction (MF, 30 Gy in 10 fractions,
20 Gy in 5 fractions)
Equal efficacy of pain relief but higher rates of retreatment in 8
Gy single fraction
SF more convenient and cost-effective
The United States lags behind SF utilization compared to other
countries.
Consider PFS, prognosis, risk of cord compression, and
tolerance for retreatment.
Consider radiosurgery for oligometastatic disease (<3 bony sites) or
reirradiation. At MDACC, only done on protocol for non-spinal bone
metastases.
Consider radium-223 for diffuse osteoblastic metastatic disease
without visceral involvement.
Reirradiation safe and feasible. Generally 8 Gy in 1 or 20 Gy in 5.
Achieves ~50% overall response rate (Chow et al. Lancet Oncol
2013)
R T T
SIM: Varies by site and technique. Consider patient pain tolerance.
Dose: 8 Gy single fraction, 20 Gy in 5 fractions, or 30 Gy in 10
fractions. Post-op: 30 Gy in 10 fractions.
Target (intact): Contour GTV. PTV = GTV + 1-2 cm (depending on
setup reliability and patient’s ability to stay still). Add 1.5-2 cm to block
edge for dose buildup. Post-op: Cover the entire rod (unless multiple
myeloma); split joint space. Leave untreated strip of the skin.
Target (post-op): CT is entire prosthesis and resection area (may
require extended SSD technique or may not be able to cover entire
prosthesis). PTV = GTV + 1-2 cm (depending on setup reliability and
patient’s ability to stay still). Add 1.5-2 cm to block edge for dose
buildup.
Technique: Depends on location. Generally 2D or 3DCRT, beam
arrangement varies by site. Consider IMRT or radiosurgery if
retreatment.
Figure 67.1 Repre sentative postoperative field treating to 20 Gy
in 5 fractions.
S
Done to prevent and/or treat pathologic fractures. For pelvic lesions,
orthopedic surgeons typically opt for total hip arthroplasty if the lesion
involves the neck and if the patient is able to tolerate. Other options
include proximal hip endoprosthesis or stabilization with
intramedullary rods (if lesion in the midbone).
C
RANK-L inhibitors (denosumab): Monoclonal antibody that inhibits the
RANK/RANK-L pathway (involved in osteoclast maturation and
activity). Has been shown to decrease skeletal-related events in
patients with bony mets from advanced cancers when compared to
zoledronic acid (Lipon Eur J Cancer 2012). Approved for use in
metastatic solid tumors. Typically given subcutaneously 120 mg q4wk
and continued indefinitely.
Bisphosphonates (zoledronic acid, pamidronate): Inhibit osteoclast
activity, preventing bone resorption. Used in castrate-resistant
prostate cancer and breast cancer. Typically given IV q3-4wk (dose
adjusted for creatinine clearance). Can also be given q3mo.
N T
RTOG 97-14 ( Hartsell et al. JNCI 2005): 898 breast and prostate
points, 1-3 painful bone metastases, randomized to 8 Gy in 1 fraction
vs 30 Gy in 10 fractions. Primary outcome was pain relief at 3 months.
G2-4 tox greater in 30/10 arm (17% vs 10%, P = .002), late tox 4% in
both arms. At 3 months, overall response rate to pain was 66%.
Complete and partial response rates were 15% and 50%,
respectively, in the 8 Gy arm vs 18% and 48% in the 30 Gy arm (P =
.6). Retreatment was higher in 8 Gy arm vs 30 Gy arm (18% vs 9%, P
< .001).
Norwegian/Swedish Trial (Kaasa et al. Radiother Oncol 2006):
Phase III RCT, 376 points (planned 1000) with painful bone mets
randomized to 8 Gy in 1 vs 30 Gy in 10. Primary end point was pain
relief. Trial ended early as initial data showed similar rates of pain
control, fatigue, QOL, and survival (8-9 months) between both arms.
Chow et al. Meta-analysis ( Chow et al. JCO 2007): 16 published
randomized trials from 1986 onward, SF vs MF (8 Gy in 1 and 30 Gy
in 10 most common) regimens compared. Primary outcomes were
overall and complete response rate (OR and CR). SF and MF were
found to be equivalent in palliation of pain with CR rates of 23% vs
24% for SF and MF, respectively, and OR rates of 58% and 59%.
Retreatment rate 2.5× higher with SF (95% CI, 1.76-3.56, P <
.00001). No difference in pathologic fracture risk.
RADIATION EMERGENCIES
ADNAN ELHAMMALI • MARY FRANCES MCALEER
C C
Definition: Acute, potentially life-threatening or morbid event caused
by cancer for which radiation therapy may be therapeutic and/or offer
palliation.
Cauda equina syndrome: Lower extremity weakness, saddle
anesthesia, bowel/bladder incontinence
Incidence/prevalence: Breast, lung, and prostate account for
50%-60% of cases.
70% involve thoracic spine, 20% lumbar, 10% cervical.
Outcomes: Median OS ~3 months. Pretreatment ambulatory status
biggest predictor of functional outcome. If ambulatory medina, OS ~7
months; if nonambulatory, OS ~1.5 months.
Workup
History: Patient must be seen and assessed immediately. Inquire

about pain, motor/sensory/bowel/bladder deficits, and duration of
symptoms. Also weakness, sensory deficits, bowel/bladder
dysfunction. Establish whether patient has known cancer diagnosis
with pathology or elevated cancer biomarker (PSA, AFP, CEA, etc.)?
Assess performance status. Enquire about prior radiation treatment
and last chemotherapy.
Examination: Complete neurologic examination with clinical
localization. Check for saddle anesthesia and rectal tone. Back pain
most common initial presenting symptom and precedes neurologic
deficits, typically worse when lying down.
Imaging: Must image the entire spine as many patients will have
epidural disease outside primary symptomatic site. MRI with at least
T1 and T2 sequences, preferable with and without contrast.
Enhancing mass usually best visualized on T1+C and cord
impingement on T2 as CSF is bright (Fig. 68.1). Consider CT
myelogram if contraindication to MRI.
Figure 68.1 MRI T2-FLAIR (left) and T1+C (right) sequences
showing cord compression at C3-C4 and T4-T5 presenting in a 7-
year-old male with a new diagnosis of a primitive neuroectodermal
tumor (PNET). T2 sequence clearly shows the cord impingement
with loss of bright CSF signal in areas where tumor has invaded
the spinal canal (arrows).
Treatment principles
Must establish a cancer diagnosis before radiation therapy, either with

tissue or elevated biomarker(s)
Begin steroids: Dexamethasone 10 mg IV loading dose → 4 mg IV
every 6 hours. Start proton pump inhibitor for GI prophylaxis.
Neurosurgery evaluation to determine if operative candidate. For
nonhematologic malignancies, surgery → radiation achieves superior
functional outcomes than radiation alone.
SIM: Varies by site and technique. Consider patient pain tolerance. In

emergent cases where CT-based simulation not available (evening,
weekends), clinical setup should be used (refer to Clinical Setup
chapter for further details).
Dose: Most commonly used regimens: 30 Gy in 10 fractions or 20 Gy
in 5 fractions; 20 Gy in 8 fractions for lymphoma/multiple myeloma.
Consider radiosurgery postoperatively after decompression for
oligometastatic or radioresistant histology (see Spine Metastases
chapter for more detail).
Target: One vertebral body above and below site of disease + soft
tissue extension + 1-2 cm laterally from the vertebral body.
Technique: Depends on level. In general:
Cervical (C1-C7): Opposed lateral beams
Thoracic (T1-T12): AP:PA or PA
Lumbar (L1-L5): AP:PA or PA
Sacrum: Opposed laterals, AP:PA, or 3 field (PA:laterals)
Side effect management
Pain management: NSAIDS, acetaminophen, narcotics. Initiate bowel

regimen if narcotics are prescribed.
Esophagitis: Dietary modification (pureed/bland/soft food, frequent
small meals), topical anesthetics (magic mouthwash, glutamine),
analgesics (acetaminophen, narcotics).
Nausea: Antiemetics prior to treatment and PRN. First-line Zofran,
add second line if needed.
Diarrhea: First-line Imodium titrating to a max of 8 pills/day → second
line alternating Lomotil and Imodium.
Cystitis: Rule out UTI, analgesics, cranberry juice, phenazopyridine.
Reirradiation
If cord compression is identified in a previously irradiated field and

patient is not a candidate for surgery or spine stereotactic
radiosurgery (SSRS), reirradiation may be offered to select patients.
Consider life expectancy and extent of neurologic deficit since
likelihood of restoring neurologic function is low, but reirradiation may
limit progression.
Based on analysis by Nieder et al. IJROBP 2006, risk of myelopathy
is <3% if the following conditions are met:
Interval between radiation courses ≥6 months
Cumulative spinal cord BED ≤ 135 Gy assuming α/β value of 2
for cervical/thoracic cord and 4 for lumbar cord
≤98 Gy BED delivered in any single course
Notable trials
Patchell Lancet 2005: 101 patients with MRI evidence of cord

compression with at least 1 symptom (including pain) randomized to
surgery + RT vs RT alone (30 Gy in 10 fractions). Excluded: cauda
equina–only lesions, paraplegic for >48 hours, radiosensitive
histologies, and CNS primary tumors. Primary end point was
ambulation at 3 months and was found to be 84% vs 57% (P = .001)
favoring surgery. Among patients not ambulatory at time of treatment,
62% of surgery patients regained ability to walk vs only 19% of
radiation patients (P = .01).
L D
Background
Definition: Tumor involvement of the CSF or leptomeninges (pia

mater and arachnoid). Note: Involvement of the dura mater does not
constitute LMD as CSF is between pia and arachnoid meningeal
layers.
Incidence/prevalence: Diagnosed in ~5% of all cancer patients,
most commonly in the breast and lung and melanoma.
Outcomes: Prognosis is poor with median survival of 4 months or
less.
Workup
Patients often present with multifocal neurologic symptoms as

disease can involve the entire neuroaxis: For example, combination of
cranial neuropathy and extremity weakness. Also can present with
headache, cerebellar dysfunction, altered mental status, seizure, and
cauda equina syndrome.
Patients suspected of having LMD should have MRI of the complete
neuroaxis (brain and cervical, thoracic, lumbar spine) as well as
lumbar puncture for CSF cytology analysis. Note: (1) LP should be
performed after spine imaging is completed to prevent false-positive
sampling and/or unnecessary procedure if gross evidence of LMD
seeding along the spinal cord/cauda nerve roots and (2) sensitivity of
CSF cytology 80%-95%, thus repeat LP is warranted in patients with
high clinical suspicion or radiographic findings concerning for LMD.
Symptomatic patients should receive dexamethasone as outlined in

the section on Cord Compression above.
Primary treatment is intrathecal chemotherapy while radiation therapy
reserved for symptomatic sites.
Note that symptomatic sites may not have radiographic correlate.
Localized treatment to suspected site of disease in these patients is
reasonable (eg, RT to lumbosacral spine in patient with cauda equina
syndrome).
Use appropriate palliative dosing: 30 Gy in 10 fractions, 20 Gy in 5
fractions, or 8 Gy in 1 fraction for the spine.
SVC S
Definition: Obstruction of blood flow through the SVC
Incidence/prevalence: 60%-80% caused by malignancy of which
50% NSCLC, 25% SCLC, 10% NHL. Note 20%-40% caused by
benign processes (thrombosis from intravascular devices such as
catheters or pacemakers, infection). 60% of patients present without
prior cancer diagnosis
Outcomes: If SVC syndrome is appropriately managed, survival is
comparable to tumor type/stage patients without it.
Workup and treatment
History and physical: Assess respiratory status, signs of airway

compromise (stridor, oropharyngeal swelling), and ability of patients to
lie down supine. Presenting symptoms include dyspnea, swelling of
the face/arm/chest, laryngeal edema causing hoarseness/stridor,
cough. Symptoms may be worsened with bending forward or lying
down
Imaging: Chest x-ray, CT of the chest with contrast. Consider US if
with concern for thrombus.
As majority of patients present with undiagnosed cancer, must

establish tissue diagnosis prior to initiating treatment unless severe
SVC causing airway compromise or, rarely, coma secondary to
cerebral edema.
Consider minimally invasive techniques for rapid diagnoses
(sputum/pleural fluid cytology, biopsy of superficial nodes, BM biopsy
for lymphoma, cancer biomarkers such as AFP or β-HCG).
Alternatively, obtain tissue with CT or bronchoscopic-guided needle
techniques.
For patients with severe symptoms, rapid relief can be achieved with
intraluminal stenting to allow time for establishment of a pathologic
diagnosis and prior to treatment with chemotherapy/radiation therapy.
For chemosensitive histologies (SCLC, lymphoma, germ cell tumors),
can treat with chemotherapy alone.
SIM: Generally upper Vac-Lok, arms above head, incline board if

unable to lie flat.
Dose: If clinically stable, treat to appropriate dose for the primary
histology (eg, 66 Gy in 33 fractions for NSCLC). For palliative intent,
30 Gy in 10 fractions or 20 Gy in 5 fractions. Can consider 3-4 Gy for
the first few fractions and then convert to definitive dosing.
Target: Contour GTV. CTV = GTV + 0.5- to 2-cm margin (depending
on histology). PTV = CTV + 0.3-1 cm depending on setup and
patient’s ability to lay still.
Technique: For definitive, consider IMRT, 3DCRT. For palliative or
rapid initiation of treatment, 3DCRT or 2D (AP/PA, obliques).
Side effect management
Esophagitis: Dietary modifications (pureed/bland/soft food, frequent

small meals), topical anesthetics (magic mouthwash, glutamine),
analgesics (acetaminophen, narcotics).
Cough: Tessalon Perles, Tussin (dextromethorphan)
A C
Incidence/prevalence: Approximately 80 000 cases of malignant
airway obstruction occur annually.
Can lead to cough, dyspnea, and pneumonia and cause significant
morbidity and/or mortality.
Nonradiation treatment options include therapeutic bronchoscopy with

resection or stenting and surgery. These treatment options may
provide rapid relief and tissue for diagnostic workup if needed.
For candidates of definitive radiation therapy, bronchoscopy is
preferred to allow for treatment planning and appropriate fractionation.
Palliative radiation therapy can be offered, typically external beam for

emergent cases. Intraluminal or interstitial brachytherapy can be
considered in nonemergent situations.
Typical external beam doses include 45 Gy in 15 fractions, 30 Gy in
10 fractions (ASTRO guidelines preference), or 20 Gy in 5 fractions. If
plan is to convert to definitive therapeutic intent, give 3-4 Gy for the
first few fractions and then switch to definitive dosing regimen.
U B
Incidence/prevalence: Occurs in 6%-10% of cancer patients most
typically in the form of hemoptysis, upper/lower GI bleed, epistaxis,
hematuria, or vaginal bleeding.
Workup
Assess patient to confirm he/she is hemodynamically stable, and rule

out platelet abnormality, coagulopathy, or iatrogenic (anticoagulants)
cause of bleeding.
Nonradiation treatment options

Packing, if accessible, is a least invasive approach and may
achieve rapid hemostasis.
Endoscopy (EGD, colonoscopy, bronchoscopy, and cystoscopy)
can achieve rapid hemostasis and provide tissue for diagnostic
workup.
IR embolization can achieve rapid hemostasis but requires
identification of feeder artery that will not result in significant
normal tissue ischemia if embolized.
Surgery appropriate for some patients with localized disease.
Radiation therapy: Typically takes days to weeks to achieve
hemostasis. If patient is a candidate for definitive treatment,
preferable to achieve rapid hemostasis with nonradiation treatment to
allow for definitive planning and fractionation.
Dosing varies by site, prognosis, severity of bleeding, and desire to

convert to definitive treatment.
Consider 45 Gy in 15 fractions, 30 Gy in 10 fractions, 20 Gy in 5
fractions, 8-10 Gy in 1 fraction, “Quad-shot” for HN cancer (Corry et
al. Radiother Oncol 2005): 14.8 Gy in 4 fractions bid with >6-hour
interfractional interval. If possibly converting to definitive intent, give 3-
4 Gy for the first few fractions and then convert to definitive dosing.
BENIGN DISEASE: NON-NEURAL
RACHIT KUMAR • CHRISTOPHER WILKE
H O
Heterotopic ossification (HO) typically appears in the periarticular soft
tissues following trauma or surgery. While the estimated frequency
varies widely between 10% and 80% of cases, ~10% result in
extensive HO, resulting in pain and impairment.
Highest risk of HO is in patients with previous history of HO, either on
the ipsilateral or contralateral side (following second surgery, the risk
may be as high as 100%).
Pain and immobility are the clinical hallmarks of this diagnosis.
Typically, clinically relevant osteophytes may be initially seen on plain
radiographs of the joint. Brooker, in 1973, described a classification
system for HO.
Management of HO generally involves surgery and radiotherapy but

may also include medical management.
Surgery: Remove clinically meaningful ossifications resulting in
discomfort.
Medical management: NSAIDs (indomethacin) and COX-2
inhibitors have shown promising results in reducing the risk of HO
development in the perioperative setting.
Radiation: Typically completed 24 hours prior to or within 72
hours after surgery.
Low-dose radiation has been an effective technique in reducing the
risk of HO formation. Both preoperative (24 hours prior to surgery)
and postoperative (within 72 hours after surgery) regimens
demonstrate efficacy in reducing the risk of HO. Single-fraction doses
of 7-8 Gy in the preoperative setting and 7 Gy in the postoperative
setting demonstrate excellent efficacy with low toxicity, including no
worsening of wound healing. An example field for a patient with
heterotopic ossification treated in the postoperative setting is
demonstrated in Figure 69.1.
Figure 69.1 Standard AP field for heterotopic ossification.

K
Keloids are defined as areas of irregular fibrous tissue formed at the
site of a scar or injury. Unlike hypertrophic scars, keloids do not
regress over time. They may result in local pain and inflammation as a
consequence of their infiltrating character. They occur more frequently
in areas of high skin tension and are often seen in the upper body,
around the joints, and in the earlobes. While the exact cause of
keloids remains unknown, a genetic/racial predisposition, particularly
in individuals of African descent, has been identified.
Surgical resection of keloids is the initial treatment, acknowledging
that >50% of patients will recur following surgery alone. Nonradiation
options following surgery include pressure silicone dressings and
steroid injections.
Radiation helps to reduce the rate of keloid formation after surgery to
20%-25%. Detailed coordination following surgery is required to
optimally reduce the rate of keloid formation, with radiation typically
completed within 24 hours of operation.
Typical radiation dose-fractionation schemes vary from single-fraction
7.5-10 Gy to 12-25 Gy in 3 or 4 Gy fractions. Electrons are utilized to
optimize dose to the scar with a 1-cm margin, with bolus applied to
ensure generous coverage to the postoperative field. Depth of
coverage is generally not specified as long as the postoperative field
is well treated.
G
The use of androgen deprivation therapy in men with prostate cancer,
particularly in those receiving antiandrogen monotherapy (eg,
bicalutamide 150 mg), frequently results in gynecomastia, a benign
proliferation of breast tissue, in up to 80% of patients. Prevalence is
~15% in men treated with total androgen blockade (GnRH agonists +
antiandrogen).
This breast enlargement is frequently painful (mastodynia) and is a
significant toxicity for many men receiving androgen deprivation
therapy.
Data on the role of radiation therapy in this setting demonstrate that
radiation may reduce the incidence of gynecomastia (decreasing from
~80%-50%) but does not decrease mastodynia.
Classically, radiation has been delivered to a dose of 12-15 Gy in 3
Gy fractions, but single-dose treatment of 9-10 Gy has also been
investigated. When used in the prophylactic setting, 10 Gy vs sham
radiotherapy successfully reduced the incidence of gynecomastia but
did not decrease mastodynia (Tyrrell IJROBP 2004).
A recent PLoS One systematic review article compared the results of
radiotherapy to tamoxifen, and while both appeared to be effective,
tamoxifen was found to be more efficacious (Fagerlund PLoS One
2015).
Based on these results, the utilization of tamoxifen rather than
radiotherapy as first-line treatment for gynecomastia should be
considered, acknowledging the lack of conclusive trials on the topic
and side effect profile of tamoxifen. Prophylactic tamoxifen or
radiotherapy should be considered for men treated with long-term
antiandrogen therapy.
Figure 69.2 Standard electron field for gynecomastia.
D C
Dupuytren contracture, also known as Morbus Dupuytren, is a
connective tissue disorder involving the palmar or plantar
aponeurosis. This progressive disorder begins with subcutaneous
lumps with skin fixation, eventually resulting in periosteal reaction,
and connective tissue hardening.
Eventually, the disorder results in severe flexion contractures of the
metacarpophalangeal or proximal interphalangeal joints, limiting the
use of the hands or impaired ambulation. The most commonly
affected joints are the 4th/5th fingers of the hand and 1st/2nd toes of
the foot.
In more than half of patients, disease progression will occur 5 years
after diagnosis. Steroids may be used for small, painful nodules,
though the disease will likely progress. Collagenase is effective in
patients with limited contractures but with short-term efficacy. If a
patient is functionally limited as a consequence of the disorder,
surgical intervention is recommended.
Radiation is typically implemented in the early stages of the disease
to limit progression, particularly in patients with asymptomatic lesions
or minimal flexion deformities. Doses of 30 Gy in 10 fractions (split
course with a 6-week break) or 21 Gy in 3 Gy fractions are used.
Targeted disease includes palpable cords and nodules with 1- to 2-cm
proximal/distal and 0.5- to 1-cm lateral margins. Orthovoltage (120
kV) or electrons with bolus are used to ensure adequate
surface/superficial dose coverage.
Radiation was able to reduce the risk of progression in a significant
number (>70%) of patients with early-stage lesions but rarely resulted
in the regression of hallmark lumps and strands. Long-term data
demonstrate the most utility for radiation when utilized within the 1st
year of diagnosis.
Figure 69.3 Standard field for Dupuytren contracture.
CLINICAL SETUP
CHAD TANG • PETER BALTER
S C
For each beam, there will be a reference point/geometry for which 1
MU will deliver 1 cGy of dose.
The most commonly used reference geometries for linear
accelerators are source surface distance (SSD) and source axial
distance (SAD) (Fig. 70.1):
SSD: 100 cm to the surface, D max depth for a 10 × 10 cm field 1
MU = 1 cGy (water). Uses constant distance between source and
surface/skin. The patient is moved for each field.
SAD: 100 cm to the calculation point, D max depth for a 10 × 10
cm field 1 MU = 1 cGy (water). Uses constant distance between
source and the isocenter (100 cm for the modern linear
accelerator). The gantry is moved for each field.
If calculations are being done (SSD) and the machine calibration
geometry is SSD, PDD tables can be used with no further inverse
square corrections.
If calculations are being done (SAD) and the machine calibration is
SAD, the TMR tables can be used with no further inverse square
corrections.
To calculate an SAD setup on a machine with an SSD calibration,
multiply the calibration dose rate by the inverse square correction of
((reference SSD + D max Depth)/(reference SSD))2. This will generally
be ((100 + 1.5 cm)/(100 cm))2 = 1.03 for 6× photons.
To calculate SSD setup on a machine with an SAD calibration,
multiply the calibration dose rate by ((reference SSD)/(reference SSD
+ D max depth))2. This will generally be (100 cm)/(10 + 1.5))2 = 0.971
for 6× photons.
For SSD, depth factor is percent depth dose (%DD)*

For SAD, depth factors are TMR*
Field size factors are collimator scatter (Sc) for the jaw setting and
phantom scatter (Sp)* for the field size at the reference distance.
Off-axis factors are presented, but it is not recommended to treat
based on hand calculations when using a geometry that requires a
significant (>3%) off-axis correction. For nonwedged beams, this is
generally true even for significantly off-axis points.
Beam attenuation factors include wedge factors, tray factors, and
other attenuations.
*These factors are usually found in machine-specific tables.
Figure 70.1 Illustration highlighting the difference between SAD

and SSD techniques for referencing geometries. Note how the
SSD technique maintains constant distance between the source
and skin of the patient, whereas the SAD references the isocenter
(maroon spot).
G L
T1: Most prominent posterior process
T3: Suprasternal notch, root of spine of scapula
T4: Sternal angle and 2nd rib
T5: Carina
T7: Bottom of scapula
T9: Xiphoid process
L4: Top of iliac crest
S2: Posterior superior iliac spine
G R
SAD setup is generally used for photon-based plans to treat deep
lesions.
SSD setup is generally used for electron or orthovoltage-based plans
to treat superficial lesions or for single-field treatment.
Dose falloff: 6 MV ~3.5% per cm; 18 MV ~2.0% per cm
MU calculations is ~110% of field prescription (eg, prescribe 150 cGy
anticipate ~170 MU).
Agreement between independent calculations must be ±3% (or within
1 MU, whichever is larger).
If separation <20 cm, consider 6 MV photons.
G F S
First: Decide on setup (SAD vs SSD)
Second: Beam arrangement
Third: Beam energy
Fourth: Treatment depth
Fifth: Field size (X, Y)
Whole brain: 20 × 20 cm opposed lateral fields covering the entire

head, rotate collimator to block face, typical separation 15 ± 2 cm.
Expected MUs/field = 166 ± 5 for 300 cGy, 6 MV based on machine
calibrated at 100 SSD + D max depth
Spine: Center field at site of epidural disease or compression, cover 1
vertebral body above and below target vertebral body, expand to
cover soft tissue extension, laterally cover 1-2 cm from edge of
vertebral body. Review patient records for possible overlap of
previous treatment.
G T P
3DCRT 3-D conformal radiation therapy
4DCRT 4-D conformal radiation therapy
4DCT 4D computed tomography
5-FU fluorouracil
6-MP mercaptopurine
ABH lorazepam, diphenhydramine, haloperidol
ABMT autologous bone marrow transplant
ABVD adriamycin, bleomycin, vinblastine, dacarbazine
AC adriamycin cyclophosphamide
ACh acetylcholine
AChE acetylcholine esterase
ACTH adrenocorticotropic hormone
ADC apparent diffusion coefficient
AF applicator factor
AFP alpha fetoprotein
AJCC American Joint Committee on Cancer
ALK anaplastic lymphoma kinase
ALL acute lymphoblastic leukemia
ALN axillary lymph node
ALND axillary lymph node dissection
AML acute myelogenous leukemia
AP anterior-posterior
APBI accelerated partial breast irradiation
APCs antigen-presenting cells
APR abdominoperineal resection
ARR absolute risk reduction
ASTRO American Society for Radiation Oncology
ATM ataxia-telangiectasia mutated
AUA American Urological Association
AUC area under curve
AVM arteriovenous malformation
β-hCG beta-human chorionic gonadotropin
BCC basal cell carcinoma
BCL B-cell lymphoma
BCNU Carmustine
BCS breast conserving surgery
BEACOPP bleomycine, etoposide, doxorubicin (adriamycin),
cyclophosphamide, vincristine (oncovin),
procarbazine, prednisone
BED biologically effective dose
BID two times a day
BI-RADS breast imaging-reporting and data system
BM bone marrow
BMBx bone marrow biopsy
BMI body mass index
BMT bone marrow transplant
BOT base of tongue
BP blood pressure
BPH benign prostatic hyperplasia
BSO bilateral salpingo-oophorectomy
BUN blood urea nitrogen
Cr creatinine
C&E curettage and electrodessication
CAPOX capecitabine/oxaliplatin
CAR-T chimeric antigen receptor-T cells
CBC complete blood count
CBCT cone beam CT
CCNU lomustine
CR clinical response
CCSK clear cell sarcoma of the kidney
CEA carcinoembryonic antigen
cEBRT conventional external beam radiation therapy
CFS colostomy-free survival
CF-WBI conventionally fractionated-whole breast irradiation
ChemoRT chemoradiotherapy
CHF congestive heart failure
CHT chemotherapy
CI conformity index
CIMP CpG island methylator phenotype
CIN chromosomal instability
CLL chronic lymphocytic leukemia
CML chronic myelogenous leukemia
CMP comprehensive metabolic panel
CNS central nervous system
CRM continual reassessment method
CRPC castrate resistant prostate cancer
CSF cerebrospinal fluid
CSI craniospinal irradiation
CSS cancer specific survival
CT computed tomography
CTCL cutaneous T-cell lymphoma
CTV clinical target volume
CV cardiovascular
CW chest wall
CXR chest X-ray
DA dose-adjusted
DAMPs damage-associated molecular patterns
DCIS ductal carcinoma in-situ
DD death dose
ddAC dose-dense AC
DE-EBRT dose-escalated external beam radiation therapy
DES diethylstilbestrol
DEXA dual-energy X-ray absorptiometry
DFS disease-free survival
DHL double-hit lymphoma
DIBH deep inspiration breath hold
DIPG diffuse intrinsic pontine gliomas
DLBCL diffuse large B-cell lymphoma
DM distant metastasis
DMFS distant metastasis free survival
DMSO dimethyl sulfoxide
DNA deoxyribonucleic acid
DNA-PKcs DNA-dependent protein kinases
DOI depth of invasion
DPFS distant progression free survival
DRE digital rectal exam
DRR digitally reconstructed radiography
DSB double strand break
DS-GPA diagnosis-specific graded prognostic assessment
DSS disease specific survival
DTPA diethylenetriaminepentacetate
DVH dose-volume histogram
DWI diffusion-weighted imaging
DX diagnosis
EBCTCG Early Breast Cancer Trialists’ Collaborative Group
EBRT external beam radiation therapy
EBUS endobronchial ultrasound
EBV Epstein–Barr virus
ECC epirubicin, cisplatin, capecitabine
ECE extracapsular extension
ECF epirubicin, cisplatin, 5-fluorouracil
ECG electrocardiogram
ECOG Eastern Cooperative Oncology Group
EFRT extended field radiation therapy
EFS event-free survival
EFT Ewing family of tumors
EGD esophagogastroduodenoscopy
EGFR epidermal growth factor receptor
EGFR-MAPK EGFR-mitogen activated protein kinase
EI-CESS European Intergroup Cooperative Ewing Sarcoma
Studies
ENE extranodal extension
EOC epirubicin, oxalipatin, capecitabine
EORTC European Organisation for Research and Treatment
of Cancer
EPID electronic portal imaging device
EPP extrapleural pneumonectomy
EQD2 equivalent dose at 2 Gy
ER estrogen receptor
ERCP endoscopic retrograde cholangiopancreatography
ESBC early stage breast cancer
ESMO European Society of Medical Oncology
ESR erythrocyte sedimentation rate
ES-SCLC extensive stage small cell lung cancer
ETV evaluation target volume
EUA examination under anesthesia
EUS endoscopic ultrasound
EWS Ewing Sarcoma
FA focal anaplasia
FAC fluorouracil, adriamycin, and cyclophosphamide
FAP familial adenomatous polyposis
FAS-L Fas ligand
FB free breathing
FDA Food and Drug Administration
FDG fludeoxyglucose
FEV1 forced expiratory volume (1 second)
FGFR fibroblast growth factor receptors
FH favorable histology
FIGO International Federation of Gynecology and
Obstetrics
FISH fluorescence in-situ hybridization
FLAIR fluid-attenuation inversion recovery
FLIPI Follicular Lymphoma International Prognostic Index
FNA fine needle aspiration
FOLFIRINOX folinic acid, fluorouracil, irinotecan, oxaliplatin
FOLFOX folinic acid, fluorouracil, oxaliplatin
FOV field-of-view
FSH follicle-stimulating hormone
GBM glioblastoma multiforme
GCB germinal center B-cell
G-CSF granulocyte-colony-stimulating factor
GCT germ cell tumor
GEJ gastroesophageal junction
GEP gene expression profiling
GERD gastroesophageal reflux disease
GFAP glial fibrillary acidic protein
GH growth hormone
GHSG German Hodgkin Study Group
GI gastrointestinal
GIST gastrointestinal stromal tumor
GM-CSF granulocyte-macrophage colony-stimulating factor
GnRH gonadotropin releasing hormone
GOG Gynecologic Oncology Group
GS genomically stable
GTR gross total resection
GTV gross tumor value
GU genitourinary
GVHD graft versus host disease
H&N head and Neck
H&P history and physical examination
HA hinge angle
HAV hepatitis A virus
HBsAg hepatitis B surface antigen
HBV hepatitis B virus
HCC hepatocellular carcinoma
HDAC histone deacetylase
HDR high dose rate
HF-WBI hypofractionated whole breast irradiation
HGG high-grade glioma
HIV human immunodeficiency virus
HL Hodgkin lymphoma
HLA human leukocyte antigen
HNC head and neck cancer
HNPCC hereditary nonpolyposis colorectal cancer
HNSCC head and neck squamous cell carcinoma
HO heterotopic ossification
HPV human papilloma virus
HPV16 human papilloma virus16
HR hazard ratio
HR-CTV high risk clinical target volume
HSCT hematopoietic stem cell transplantation
HSV-1 herpes simplex virus type 1
HTN hypertension
HVA homovanillic acid
HVL half-value layer
HVLT-R Hopkins Verbal Learning Test-Revised
IAC internal auditory canal
IBC inflammatory breast cancer
IBD inflammatory bowel disease
IBTR ipsilateral breast tumor recurrence
ICBT intracavitary brachytherapy
ICP intracranial pressure
ICRP International Commission on Radiological
Protection
ICRT intracavitary radiation therapy
ICRU International Commission on Radiation Units and
Measurements
iCTV internal clinical target volume
ICV infraclavicular
IDH isocitrate dehydrogenase
IDL isodose line
IFNγ interferon-gamma
IFRT involved-field radiotherapy
IGBT image-guided brachytherapy
IGF-1 insulin growth factor 1
IGRT image-guided radiation therapy
iGTV internal gross tumor volume
IHC immunohistochemistry
IJROBP International Journal of Radiation Oncology,
Biology, Physics
IJV internal jugular vein
IL interleukin
IL-2 interleukin 2
ILROG International Lymphoma Radiation Oncology Group
IM internal mammary / internal margin
IMA internal mammary artery
IMC internal mammary chain
iMLD ipsilateral mean lung dose
IMN internal mammary nodes
IMPT intensity modulated proton therapy
IMRT intensity-modulated radiation therapy
INR international normalized ratio
INRT involved nodal radiation therapy
INSS International Neuroblastoma Staging System
IPI International Prognostic Index
IPS International Prognostic Score
IPSS International Prostate Symptom Score
IR interventional radiology
IRB Institutional Review Board
ISRT involved site radiation therapy
ISUP International Society of Urologic Pathologist
ITC isolated tumor cell
ITV internal target volume
iTVI internal tumor vessel interface
IUGR intrauterine growth restriction
IV intravenous / irradiated volume
IVF in vitro fertilization
IVLBCL intravascular large B-cell lymphoma
JPA juvenile pilocytic astrocytoma
KPS Karnofksy Performance Status
KUB kidney, ureter, and bladder
KV kilovoltage
LABC locally advanced breast cancer
LAO left anterior oblique
LAR low anterior resection
LC local control
LDH lactate dehydrogenase
LDR low dose rate
LDR-PB low dose rate prostate brachytherapy
LET linear energy transfer
LF local failure
LFTs liver function tests
LGG low grade glioma
LH luteinizing hormone
LHRH luteinizing hormone-releasing hormone
LINAC linear accelerator
LMD leptomeningeal disease
LN lymph node
LND lymph node dissection
LOET late onset efftox model
LOH loss of heterozygosity
LP lumbar puncture
LR local recurrence
LRC locoregional control
LRF locoregional failure
LRFS locoregional failure survival
LRR local recurrence rate
LSS limb-sparing surgery
LS-SCLC limited-stage small cell lung cancer
LUL left upper lobe
LV left ventricle
LVI lymphovascular invasion
LVSI lymphovascular stromal invasion
MALT mucosa associated lymphoid tissue
MCC Merkel cell carcinoma
MCL mantle cell lymphoma
MCPyV Merkel cell polyoma virus
mCRC metastatic colorectal cancer
mCRPC metastatic castrate resistant prostate cancer
MDACC MD Anderson Cancer Center
MDP methylene diphosphonate
MDR medium dose rate
MDS myelodysplastic syndrome
MDSC myeloid-derived suppressor cells
MEC mucoepidermoid carcinoma
MEN-1 multiple endocrine neoplasia type 1
MEN2 multiple endocrine neoplasia type 2
MESCC metastatic epidural spinal cord compression
MF mycosis fungoides
MFO multi-field optimization
MGMT O6-alkylguanine DNA alkyltransferase
MHC major histocompatibility complex
MIBG meta-iodobenzylguanidine
MIP maximum intensity projection
MIPI MCL International Prognostic Index
MLB multi-lumen balloon
MLD metachromatic leukodystrophy
MMC mitomycin C
MMG mammogram
MMMT malignant mixed Müllerian tumor
MMR mediastinal mass ratio
MMT mixed malignant tumors
MOPP mechlorethamine, vincristine, procarbazine,
prednisone
MRCP magnetic resonance cholangiopancreatography
MRI magnetic resonance imaging
MRM modified radical mastectomy
mRNA messenger RNA
MS multiple sclerosis
MSI microsatellite instability
MSKCC Memorial Sloan Kettering Cancer Center
MTD maximal tolerated dose
MTV mucosal target volume
MTX methotrexate
MUGA multigated acquisition scan
MVA multivariable analysis
MVAC methotrexate, vinblastine, adriamycin and cisplatin
MyoD1 myogenic differentiation 1
NAC neoadjuvant chemotherapy
NASH nonalcoholic steatohepatitis
NB neuroblastoma
NCCN National Comprehensive Cancer Network
NCCTG North Central Cancer Treatment Group
NCDB National Cancer Database
NCIC National Cancer Information Center
NEJM New England Journal of Medicine
NF neurofibromatosis
NF1 neurofibromatosis type 1
NGGCT non-germinomatous GCT
NHEJ non-homologous end-joining
NHL non-Hodgkin lymphoma
NK natural killer
NLPHL nodular lymphocyte predominant Hodgkin
lymphoma
NMSC non-melanoma skin cancer
NNT number needed to treat
NPC nasopharyngeal carcinoma
NPO nothing by mouth
NPV negative predictive value
NSABP National Surgical Adjuvant Breast and Bowel
Project
NSAID non-steroidal anti-inflammatory drug
NSCLC non-small cell lung cancer
NSHL nodular sclerosing Hodgkin lymphoma
NTCP normal tissue complication probability
NTR near-total resection
NWTS National Wilms’ Tumor Society
OAR organs at risk
OER oxygen enhancement ratio
OF output factor
OPC oropharyngeal cancer
OR odds ratio
OS overall survival
OTC over the counter
PA posterior-anterior
PAI pubic arch interference
PALCL primary anaplastic large cell lymphoma
PAMPs pathogen associated molecular patterns
PARP poly(ADP)ribose polymerase
PBI partial breast irradiation
PC posterior commissure
PCA prostate cancer
PCFCL primary cutaneous follicle center lymphoma
PCI prophylactic cranial irradiation
PCLBCL primary cutaneous diffuse large B-cell lymphoma
PCMZL primary cutaneous marginal zone B-cell lymphoma
PCNSL primary central nervous system lymphoma
PCOS polycystic ovarian syndrome
PCP primary care physician
PCR polymerase chain reaction
PCV procarbazine, lomustine, vincristine
PD progressive disease
PD-1 programmed cell death protein 1
PDAC pancreatic ductal adenocarcinoma
PDD percent depth dose
PDGF platelet-derived growth factor
PDGFR platelet-derived growth factor receptor
PD-L1 programmed death-ligand 1
PDR pulsed dose rate
PE photoelectric effect
PEG percutaneous endoscopic gastrostomy
PeIN penile intraepithelial neoplasia
PET positron emission tomography
PFS progression-free survival
PFT pulmonary function test
PGI prompt gamma imaging
PLAP placental alkaline phosphatase
PLT platelet
PMBCL primary mediastinal B-cell lymphoma
PMN polymorphonuclear cell
PMRT postmastectomy radiation therapy
PNA pneumonia
PNET primitive neuroectodermal tumor
PNI perineural invasion
PNS peripheral nervous system
PO by mouth
PORT post-operative radiation therapy
PP pair production
PPI proton pump inhibitor
PPV positive predictive value
PR partial response
PR/SD partial response/stable disease
PRL prolactin
PRN as needed
PRV planning risk volume
PS performance status
PSA prostate specific antigen
PSPT passive scattering proton therapy
pSV pathologic seminal vesicle specimen
PTC percutaneous trans-hepatic cholangiography
pts patients
PTV planning target volume
QA quality assurance
QD every day
QOD every other day
QOL quality of life
QUANTEC quantitative analyses of normal tissue effects in the
clinic
RAI radioactive iodine
RAO right anterior oblique
RB retinoblastoma
RBC red blood cell
RBE relative biological effectiveness
RCC renal cell carcinoma
R-CHOP rituximab-cyclophosphamide, doxorubicin,
vincristine, prednisone
RCT randomized controlled trial
RDL recommended dose level
RF radiofrequency
RFA radiofrequency ablation
RFS recurrence/relapse-free survival
RHDVRT reduced high-dose volume radiation therapy
RILD radiation induced liver disease
R-MPV rituximab, methotrexate, procarbazine, and
vincristine
RMS rhabdomyosarcoma
RNI regional nodal irradiation
ROI region of interest
RP retroperitoneal
RPA recursive partitioning analysis
RPLND retroperitoneal lymph node dissection
RPO right posterior oblique
RR risk ratio or relative risk
RT radiation therapy
RTK rhabdoid tumor of the kidney
RTOG Radiation Therapy Oncology Group
RT-PCR real-time PCR
SABR stereotactic ablative radiotherapy
SAD source axial distance
SBC secondary breast cancer
SBO small bowel obstruction
SBRT stereotactic body radiation therapy
SC short course
SCC squamous cell carcinoma
SCD source to calibration distance
SCLC small-cell lung cancer
SCM sternocleidomastoid
SCT stem-cell transplantation
SCV supraclavicular
SD stable disease
SEER surveillance, epidemiology, and end results
SEP solitary extramedullary plasmacytoma
SERD selective estrogen receptor degrader
SERM selective estrogen receptor modulator
SF single fraction
SFO single field optimization
SHH sonic hedgehog
SHIM sexual health inventory for men
SI sacroiliac
SIADH syndrome of inappropriate antidiuretic hormone
secretion
SIB simultaneous integrated boost
SIM simulation
SINS spine instability neoplastic score
SIOP International Society of Paediatric Oncology
SIR score index for radiosurgery
SLL small lymphocytic lymphoma
SLN sentinel lymph node
SLNB sentinel lymph node biopsy
SLND sentinel lymph node dissection
SM setup margin / surgical margin
SMA superior mesenteric artery
SMN second malignancy
SMV superior mesenteric vein
SNEC small cell neuroendocrine carcinoma
SNL sentinel lymph node
SNUC sinonasal undifferentiated carcinoma
SOB shortness of breath
SOBP spread-out Bragg peak
SOD superoxide dismutase
SPB solitary plasmacytoma of bone
SPD source to point distance
SRS stereotactic radiosurgery
SRT stereotactic radiotherapy
SSBs single strand breaks
SSD source surface distance
SSRS spine stereotactic radiosurgery
STD sexually transmitted disease
STIR short T1 inversion recovery
STR subtotal resection
STS soft tissue sarcoma
STV scanning target volume
SUV standardized uptake value
SV seminal vesicle
SVC superior vena cava
SVI seminal vesicle involvement
TACE transcatheter arterial chemoembolization
TAH total abdominal hysterectomy
TAM tamoxifen
TBI tolerance by inhibiting
TCGA The Cancer Genome Atlas
TCHP paclitaxel, carboplatin, herceptin, pertuzumab
TCR T-cell receptor
TG Tamifen, Genox
THP paclitaxel, herceptin, pertuzumab
TID three times a day
TIL tumor infiltrating lymphocyte
TKI tyrosine kinase inhibitor
TLD thermoluminescent dosimetry
TLH total laparoscopic hysterectomy
TLM transoral laser microsurgery
TME total mesorectal excision
TMR tissue maximum ratio
TMZ temozolamide
TNBC triple-negative breast cancer
TNF tumor necrosis factor
TNM tumor, nodes, metastasis classification system
ToGA trastuzumab for gastric cancer
TORS transoral robotic surgery
TPF docetaxel, cisplatin, fluorouracil
TRUS transrectal ultrasound
TS tumor size
TSEBT total skin electron beam therapy
TSH thyroid stimulating hormone
TTF tumor-treating fields
TTP time to progression
TURBT transurethral resection of bladder tumor
TURP transurethral resection of the prostate
TV treated volume
TVI tumor vessel interface
TVL tenth-value layer
UA urinalysis
UH unfavorable histology
UPS undifferentiated pleomorphic sarcoma
URI upper respiratory infection
US ultrasound
USPSTF United States Preventive Services Task Force
UTI urinary tract infection
UV ultraviolet
VAA vincristine/actinomycin D/adriamycin
VAC vincristine/dactinomycin/cyclophosphamide
VATS video-assisted thoracic surgery
VBT vaginal brachytherapy
VCE vincristine/carboplatin/etoposide
VDC vincristine/doxorubicin/cyclophosphamide
VDC/IE vincristine/doxorubicin/cyclophosphamide (VDC)
alternating w/ ifosfamide/etoposide (IE)
VEGF vascular endothelial growth factor
vGTV virtual gross tumor volume
VIP VP-16/ifosfamide/cisplatin
VMA vanillylmandelic acid
VMAT volumetric-modulated arc therapy
VOD veno-occlusive disease
VTE venous thromboembolism
WA wedge angle
WAGR WT, aniridia, GU malformations, retardation
WAI whole abdomen irradiation
WART whole pelvic radiation therapy
WBC white blood cell count
WBI whole breast irradiation
WBRT whole brain radiation therapy
WF weighting factor
WHO World Health Organization
WLE wide local excision
WPRT whole-pelvis RT
WT Wilms tumor
WV-PTV whole ventricular planning target volume
WVRT whole ventricle RT
XRT radiation therapy
INDEX
A
Abiraterone
Absolute risk reduction (ARR)
Accelerated partial breast irradiation (APBI)
early-stage breast cancer
IGRT
planning directive
radiation treatment technique
dose
SIM
target
technique
suitability criteria
Accelerated titration (AT)
Acetaminophen
Actinomycin D
antibiotics
Wilms tumor
Activated B cell (ABC)
Adaptive immunity
Adenocarcinoma
definitive prostate cancer
vaginal cancer
Adjuvant lymph node radiation
Adjuvant prostate cancer
anatomy
androgen deprivation therapy
chemotherapy
follow-up
history
hormone therapy
image-guided biopsy
imaging
labs
prostate fossa
prostatic lymph node drainage
radiation
advantage
after prostatectomy
treatment technique
sagittal and axial views
side effect management
staging
studies
SV fossa
treatment algorithm
workup for PSA recurrence
Adoptive T-cell therapy
Ado-trastuzumab emtansine
Adrenal gland cancer
Adriamycin
ADT with EBRT
Adult soft tissue sarcoma
anatomy
cell cancer staging
chemotherapy
consensus papers
demographics
extraosseous Ewing sarcoma
histologic subtypes
imaging
incidence
limb-sparing surgery
local recurrences
outcomes
papers on
pathology
prognostic factors
rhabdomyosarcoma sarcoma
risk factors
sagittal and coronal images of IMRT treatment
surgery
treatment algorithm
workup
Afatinib
Airway obstruction
Aldesleukin
Alectinib
Alendronate
ALK
Alkylating agents
bendamustine
busulfan
carboplatin
carmustine
chlorambucil
cisplatin
cyclophosphamide
dacarbazine
ifosfamide
lomustine
mechlorethamine
melphalan
oxaliplatin
temozolomide
α-decay
Alpha/beta ratios
American Cancer Society
Amifostine
Amoxicillin
Anal cancer
chemotherapy
follow-up
history and physical
HPV association
imaging
incidence/prevalence
labs
outcomes
pathology
procedures/biopsy
elective nodal volume
high pelvis
IGRT
MDACC dose
mid pelvis
planning directive
primary and nodes
resources
RTOG0529 dose
SIM
target
target delineation
technique
risk factors
staging
treatment algorithm
trials on
tumor biology and characteristics
workup
Anastrozole
Androgen
Androgen deprivation therapy
adjuvant prostate cancer
Ann Arbor staging system
Anorexia
Antibiotics, at brachytherapy
Aortic anatomy
Apalutamide
Apoptosis
Apparent diffusion coefficient (ADC)
Area dose limits
Arteriovenous malformation
clinical presentation
embolization
imaging
medical therapy
microsurgery
pathology
radiosurgery
Artifact, computed tomography
ring
shading
streak
Atezolizumab
Avelumab
Average annual human exposure
Axillary lymph node dissection (ALND)
Axitinib
B
Basal cell carcinoma (BCC) recurrence
Base excision repair
B cells
BCR-ABL
β-decay
Bendamustine
Benign CNS
arteriovenous malformation
paraganglioma (jugulotympanic)
trigeminal neuralgia
vestibular schwannoma
Benign disease, nonneural. Nonneural benign disease
Bevacizumab
mesothelioma
nonchemotherapy systemic agents
Bicalutamide
Biostatistics
Bisphosphonates
Bladder cancer
anatomy
characteristics
chemotherapy
cystectomy
cystitis
diarrhea
follow-up
genetics
imaging
IMRT bladder conservation
incidence
lymphadenectomy
nausea
obstruction
papers on
pathology
proctitis
risk factors
staging
transurethral resection of bladder tumor
treatment algorithm
tumor biology
workup
Bleeding, brachytherapy
Bleomycin
antibiotics
Hodgkin lymphoma
Bone cancer, oligomets
Bone metastasis
general treatment plans
non-spine (Non-spine bone metastases)
Bosutinib
Bowel prep, brachytherapy
Brachytherapy
antibiotic at procedure
bowel prep
breast
contraindications
critical considerations
definition
definitive penile cancer
dose rate
gynecologic
cervical
endometrial
HDR
BED calculation
common indications
contraindications
dose
evaluation metrics
follow-up
loading technique
management
side effects
SIM
target
interstitial penile cancer
invasive procedures considerations
isotopes
lab
LDR
BED calculation
D0 evaluation metrics
follow-up
prostate planning metrics
side effects and management
SIM
target
MDR
NPO
papers on
prostate treatment algorithms
pulsed dose rate
rationale
screening colonoscopy
skin
Bragg peak
Brain metastases
anatomy
follow-up
hemorrhagic metastases
imaging
incidence
neurocognitive function
outcomes
pathology
prognosis
recursive partitioning analysis
single metastasis
solitary metastasis
SRS for multiple
surgery
treatment algorithm
trials
workup
Brainstem glioma
Breast cancer
American Cancer Society
anatomy
axillary level
BI-RADS categories for MMGs
brachytherapy
dose
evaluation metrics/dose constraints
indications
papers on
SIM
target/technique
breast anatomic breast borders
breast MR imaging
characteristics
chemotherapy
early-stage (Early-stage breast cancer (ESBC))
genetics
herceptin-based chemotherapy
Her2+ regimen
high-risk patients
hormone therapy
inflammatory
internal mammary
locally advanced (Locally advanced breast cancer (LABC))
proton therapy
recurrent
regional nodal borders
risk factors
screening guidelines
staging
supraclavicular
systemic therapy
tumor biology
U.S. Preventive Task Force
Breast-conserving surgery (BCS)
ductal carcinoma in situ
Brigatinib
Busulfan
C
Cabozantinib
11C acetate PET
Capecitabine
antimetabolites
esophageal cancer
Carboplatin
esophageal cancer
intracranial germ cell tumor
oral cavity
small cell lung cancer
stage III NSLC
Carcinogenesis and heritable effects
area dose limits
average annual human exposure
effective dose-Sievert (Sv)
fertility effects
hereditary effects
ICRP risk estimate
individual dose limits
radiation carcinogenesis
risk estimate for malignancy
Carcinoma of unknown primary (CUP)
chemotherapy
definition
follow-up
outcomes
risk factors
site anatomy
treatment algorithm
trials on
unknown primary staging
workup
Carmustine
Cauda equina syndrome
CD4
CD8
Cell death mechanisms
Cellular signaling pathways
Cerebellar vermis anatomy
Cerebrovascular syndrome
Ceritinib
Cervarix
Cervical cancer
anatomy
brachytherapy
cervix
chemotherapy
concurrent chemoradiation
cystitis
definitive radiotherapy
demographics
diarrhea
4-field 3D CRT technique
follow-up
imaging
IMRT for posthysterectomy radiotherapy
incidence
lymph node drainage
MRI T2 sequence in sagittal axis
nausea
outcomes
papers on
pathology
postoperative chemoradiotherapy
postoperative radiotherapy
risk factors
staging
surgery vs. radiotherapy
target lymph nodes
treatment algorithm
uterocervix
workup
Cervical spine, treatment plans
Cetuximab
11C /18F choline PET
Chemotherapy
adult soft tissue sarcoma
agents and toxicities
alkylating agents
antibiotics
antimetabolites
bladder cancer
bone-modifying agents
breast cancer
cervical cancer
concurrent chemoradiation
cutaneous melanoma
diffuse large B-cell lymphoma (DLBCL)
endometrial cancer
vs. chemoradiation
vs. WPRT
WPRT vs. VBT
gastric cancer
high-grade gliomas
Hodgkin lymphoma
hormonal therapy
larynx cancer
medulloblastoma
Merkel cell carcinoma
nonspine bone metastases
ovarian cancer
WART vs. pelvic radiotherapy and
pancreatic cancer
plant alkaloids
sinonasal cancer
targeted therapies
testicular cancer
vaginal cancer
vulvar cancer
Wilms tumor
Chest wall pain, early-stage NSCLC
Chimeric antigen receptor (CAR-T cells)
Chlorambucil
Cholangiocarcinoma
evaluation/workup
risk factors
stereotactic body radiation therapy
treatment algorithm for
trials on
Chordoma/chondrosarcoma, skull base
Cisplatin
esophageal cancer
mesothelioma
oral cavity
stage III NSLC
Clarithromycin, gastric MALT lymphoma
Classification bias
Clinical statistics
absolute risk reduction (ARR)
accelerated titration (AT)
basic biostatistics
classification bias
clinical trial design
confounding bias
CONSORT guidelines
continual reassessment model (CRM)
crossover design
3 + 3 design
EffTox
hazard ratio (HR)
inclusion and exclusion criteria
institutional review board (IRB)
intention-to-treat analysis
levels of evidence (per NCCN)
levels of evidence (per USPSTF)
median overall survival (OS)
model-based designs
multivariate analyses
negative predictive value (NPV)
noninferiority trial
number needed to treat (NNT)
odds ratio (OR)
per protocol analysis
phase I study designs
phase II study designs
phase III study designs
positive predictive value (PPV)
P-value
randomization
randomized controlled trial (RCT)
randomized phase II/III study designs
recurrence/relapse-free survival (RFS)
risk ratio or relative risk (RR)
selection bias
sensitivity
single-arm designs
specificity
statistical test
statistical testing
superiority trials
TITE-CRM
traditional rule-based designs
two-by-two/“factorial” design
type I (or α) error
univariate analyses
Clinical trial design
11C metomidate
Cobimetinib
Coincidence detection, PET
Colon anatomy
Colon cancer
Colorectal cancer
anatomy
chemotherapy
demographics
follow-up
genetics
imaging
labs
lymph node drainage
outcomes
pathology
procedures/biopsy
elective nodal volume
high pelvis
IGRT
MDACC dose
mid pelvis
planning directive
primary and nodes
resources
risk factors
RTOG0529 dose
SIM
staging
surgery
target
target delineation
technique
treatment algorithm
trials on
workup
Compazine
esophageal cancer
mesothelioma
oral cavity
Comprehensive breast/chest wall irradiation
planning directive considerations
radiation treatment technique for
inflammatory breast cancer
locally advanced breast cancer
Compton scatter
Computed tomography (CT)
artifact
ring
shading
streak
contrast
field of view (FOV)
Hounsfield units (HU)
image noise
probability
protocols
Cone beam CT (CBCT)
Confounding bias
CONSORT guidelines
Continual reassessment model (CRM)
Contrast, computed tomography
Conventional external beam radiotherapy (cEBRT)
Cord compression
cystitis
definition
diarrhea
esophagitis
incidence
nausea
outcomes
pain management
reirradiation
treatment principles
trials
workup
Craniopharyngioma
anatomy
demographics
follow-up
imaging
medical management
outcomes
pathology
proton therapy
risk factors
studies on
surgery
treatment algorithms
workup
Craniospinal cancer
Crizotinib
Crossover design
Cryoablation
CTV margin
Cutaneous melanoma
adjuvant radiation
anatomy
axillary metastases
chemotherapy
dabrafenib/trametinib
demographics
follow-up
histologic subtypes
imaging
immunotherapy
incidence
interferon-alpha
outcomes
papers on
pathology
risk factors
RT for nodal metastases
side effects
skin care
staging
surgery
treatment algorithm
workup
Cyclophosphamide
alkylating agents
Hodgkin lymphoma
rhabdomyosarcoma
Cyclotron
Cystectomy
Cystitis
bladder cancer
cervical cancer
cord compression
rectal cancer
vaginal cancer
Cytarabine
Cytokines
D
Dabrafenib
melanoma
Dacarbazine
alkylating agents
Hodgkin lymphoma
Dactinomycin
Dasatinib
Daunorubicin
Definitive prostate cancer
abiraterone
acinar adenocarcinoma
anatomy
chemotherapy
cystitis
demographics
diarrhea
docetaxel
follow-up
genetics
hormone therapy
imaging
incidence
obstruction
outcomes
overactivity
pathology
proctitis
risk factors
simulation
staging
surgery
treatment algorithm
trials
high risk
intermediate risk
low risk
workup
Degarelix
Dendritic cells
Denosumab
Dexamethasone
mesothelioma
Diarrhea
bladder cancer
cervical cancer
cord compression
rectal cancer
vaginal cancer
Diffuse large B-cell lymphoma (DLBCL)
chemotherapy
consolidation radiotherapy
for bulky and extralymphatic disease
for early and advanced stage
for primary bone
Deauville scale for treatment response
demographics
double-hit lymphoma
double-protein expression lymphoma
follow-up
GCB
Hans algorithm
imaging
incidence
International Prognostic Index
non-GCB/ABC
outcomes
pathology
primary central nervous system lymphoma
primary mediastinal B-cell lymphoma
primary testicular lymphoma
risk factors
Rituximab
special subtypes of
treatment algorithm
chemotherapy response
relapsed or refractory
trials and papers on
workup
DNA damage
DNA repair
DNX-2401
Docetaxel
plant alkaloids
Donor lymphocyte infusion
Dose specification
Double exposure
Double-hit lymphoma (DHL)
Doxorubicin
antibiotics
Hodgkin lymphoma
Doxycycline
Ductal carcinoma in situ (DCIS)
bilateral diagnostic mammogram
breast-conserving surgery
characteristics
core needle biopsy
CT-based XRT planning images
follow-up
hypofractionated whole breast radiation
imaging
incidence
lumpectomy
tamoxifen after
WBI after
omission of RT after BCS for
outcomes
pathology
pathology information
pathology report
prevalence
radiation treatment technique for WBI
sentinel lymph node biopsy
surgical definitions
systemic therapy
total/skin-sparing mastectomy
trials
tumor biology
workup
Dupuytren contracture
Durvalumab
Dysuria
E
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG RT
meta-analysis)
Early-stage breast cancer (ESBC)
accelerated partial breast irradiation
IGRT
planning directive
suitability criteria
adjuvant systemic therapy approach
axillary lymph node dissection
breast-conserving surgery
characteristics
core needle biopsy
definition
follow-up
imaging
incidence
lumpectomy
lymphedema
molecular subtypes
multigene panels
neoadjuvant systemic therapy approach
outcomes
pathology
postmastectomy radiation therapy
sentinel lymph node biopsy
signature scores
systemic therapy
total/skin-sparing mastectomy
trials
tumor biology
whole breast irradiation
workup
Early-stage non-small cell lung cancer (NSCLC)
follow-up
imaging
labs
literature on
outcomes
procedures/biopsy
prognostic factors
risk factors
screening
staging
treatment algorithm
workup
Effective dose-Sievert (Sv)
EffTox
Efudex
Electromagnetic 4-D tracking
Electron capture
Electron dosimetry
Embryo and fetus, radiation biology effects
dose
fetal stage
organogenesis
preimplantation
sensitive period
teratogenesis
Emergencies, radiation
airway obstruction
cord compression
cystitis
definition
diarrhea
esophagitis
incidence
nausea
outcomes
pain management
reirradiation
trials
workup
leptomeningeal disease
SVC syndrome
uncontrolled bleeding
Endometrial cancer
adnexal involvement
anatomy
chemotherapy
chemotherapy vs. chemoradiation
concurrent chemoradiation + chemotherapy
demographics
endometrioid
extended-field IMRT plan
extensive cervical involvement
FIGO Grade
follow-up
grade and staging
imaging
incidence
inoperable
lymph node drainage
nonendometrioid
observation vs. WPRT
outcomes
pathology
radiation vs. concurrent chemoradiation
risk factors
serous carcinoma
treatment algorithm
uterine sarcoma
uterine sarcoma and carcinosarcoma—observation vs. RT
vaginal involvement
workup
WPRT
vs. chemotherapy
vs. VBT
vs. VBT + chemotherapy
Endometrium anatomy
Engerix-B
Engineered TCR
Enzalutamide
Ependymoma
cranial spinal axis anatomy
demographics
follow-up
genetics
grade
imaging
labs
outcomes
pathology
procedure/biopsy
radiation treatment
infratentorial tumor
spinal tumor
supratentorial tumor
risk factors
treatment algorithm
trials on
Epirubicin
Epithelial ovarian cancers (EOC)
Equivalent dose, radiation biology
Erectile dysfunction
Erlotinib
Esophageal cancer
anatomy
Barrett esophagus
chemotherapy
conduits
demographics
follow-up (per NCCN)
genetics
imaging
labs
literature on
outcomes
pathology
procedures/biopsy
proton therapy
risk factors
RT side effect management
screening
summative stage
surgery
TNM cancer staging
treatment algorithm
workup
Esophagectomy
Esophagitis
cord compression
early-stage NSCLC
esophageal cancer
Hodgkin lymphoma
superior vena cava (SVC) syndrome
Esophagus anatomy
Estrogen
Ethmoid sinus and nasal cavity
Etidronate
Etoposide
Hodgkin lymphoma
intracranial germ cell tumor
plant alkaloids
rhabdomyosarcoma
stage III NSLC
Everolimus
Ewing sarcoma
anatomy
chemotherapy
demographics
follow-up
outcomes
prognostic factors
risk factors
side effects
staging
treatment algorithm
trials on
workup
Exemestane
External beam radiotherapy (EBRT)
ADT with
brachytherapy boost + ADT
definitive penile cancer
to lymph nodes
Extraosseous Ewing sarcoma
Extrapleural pneumonectomy (EPP)
F
18FDG-PET images glucose uptake
Fertility effects
18F fluciclovine
Field of view (FOV)

Filgrastim
Fludarabine
Flutamide
Follicular lymphoma
characteristics
demographics
grade
incidence
outcomes
prognosis
FLIPI score
FLIPI 2 score
risk factors
treatment algorithm
trials
tumor biology
workup
5-FU
antimetabolites
esophageal cancer
topical
Fulvestrant
Fundus anatomy
G
Gamma emission
Gamma knife
Gardasil
Gardasil-9
Gastric cancer
chemotherapy
demographics
follow-up
genetics
imaging
labs
Lauren histologic classification
outcomes
pathology
procedures/biopsy
adjuvant/post-op
preoperative
risk factors
staging
surgery
treatment algorithm
trials on
Gastric MALT lymphoma
presentation
staging
treatment algorithm
workup
Gefitinib
Gemcitabine
Germ cell tumors (GCTs)
nonseminomatous tumors
seminoma
Germinal center B cell (GCB)
GI syndrome
Glioblastoma
high-grade gliomas trials
alternative EORTC approach
alternative hypofractionated regimes
alternative RTOG approach, sequential radiation
considerations
IGRT
MDACC approach
planning directive
Glossectomy
Glutamine
early-stage NSCLC
mesothelioma
Gonadotropin-releasing hormone (GnRH)
Goserelin
Grade I glioma
Grade II glioma
Grade III gliomas
CATNON
EORTC 26951
high-grade gliomas trials
types and subtypes
Grade IV gliomas
Gynecologic brachytherapy
cervical
endometrial
Gynecomastia
H
Haldol
mesothelioma
Half-value layer (HVL)
Hand and foot syndrome
gastric cancer
rectal cancer
Hazard ratio (HR)
HDR, brachytherapy
BED calculation
common indications
contraindications
dose
evaluation metrics
follow-up
loading technique
management
side effects
SIM
target
Head and neck cancer
per MDACC Protocol
trials and ongoing protocols
Hematologic malignancies
follicular lymphoma
gastric MALT lymphoma
mantle cell lymphoma
marginal zone lymphoma
orbital MALT lymphoma
primary anaplastic large cell lymphoma
primary cutaneous B-cell lymphomas
primary cutaneous follicle center lymphoma (PCFCL)
primary cutaneous marginal zone B-cell lymphoma (PCMZL)
primary cutaneous T-cell lymphomas
solitary plasmacytoma
Hematopoietic syndrome
Hematuria
Hepatobiliary cancer
cholangiocarcinoma
hepatocellular carcinoma
Hepatocellular carcinoma (HCC)
evaluation/workup
local therapy
risk factors
trials on
Herceptin-based chemotherapy
Hereditary effects
Heterotopic ossification (HO)
High-grade gliomas
anatomy
chemotherapy
demographics
follow-up
genetics
grade III gliomas
grade IV gliomas
imaging
pathology
alternative EORTC approach
alternative RTOG approach, sequential radiation
dose and target
MDACC approach
SIM
risk factors
staging/grading
treatment algorithm
trials on
workup
Hodgkin lymphoma
ABVD
Ann Arbor staging
axial view of DIBH
BEACOPP
butterfly technique beam arrangement
chemotherapy
Deauville scale for treatment response
demographics
esophagitis
follow-up
genetics
imaging
incidence
interim PET/CT imaging
lymph node areas for risk stratification
outcomes
pathology
planning directive
pneumonitis
risk factors
staging and risk stratification
treatment algorithm
trials
unfavorable risk factors
workup
Homologous recombination
Hormonal therapy
androgen
breast cancer
estrogen
gonadotropin-releasing hormone (GnRH)
with salvage radiation
Hounsfield units (HU)
Hydrocodone
Hydroxyurea
Hypopharynx cancer. See also Larynx cancer
anatomy
staging
treatment algorithm
Hypophysitis
I
Ibandronate
ICRP risk estimate
Ifosfamide
alkylating agents
rhabdomyosarcoma
123I iodine scan
131I iodine scan
Image-guided radiation therapy (IGRT)
approaches
cone beam CT (CBCT)
CT on rails
CTV margin
double exposure
electromagnetic 4-D tracking
incorporating IGRT into margination
kV imaging
localization film
magnetic resonance imaging
MV electronic portal imaging devices (EPIDs)
OAR margin
optical (surface) imaging
random error
single exposure
stereotaxy
surface markers
systematic error
tomotherapy imaging
ultrasound
verification film
corrections
geometric uncertainties sources
Image noise, computed tomography
Imaging radiation
basics
computed tomography
image-guided radiation therapy
magnetic resonance imaging
nuclear medicine imaging
positron emission tomography
X-ray radiography
Imatinib
Immune checkpoint inhibitor–associated adverse events
Immunology
Immunotherapy
adoptive T-cell therapy
agents
cytokines
immune checkpoint inhibitor–associated adverse events
immunology
melanoma
oncolytic viruses
and radiation
vaccines
Inclusion and exclusion criteria
Individual dose limits
Infection
Inferior border, breast cancer
Inferior mediastinal anatomy
Inflammatory breast cancer (IBC)
aggressive local therapy in metastatic
definition
dose escalation/patient selection
incidence
molecular/biologic features
non–8-skin-sparing modified radical mastectomy
outcomes
pathology
pathology report
risk factors
studies
systemic therapy
treatment algorithm
workup
Innate immunity
Institutional review board (IRB)
Intensity-modulated radiation therapy (IMRT)
for posthysterectomy radiotherapy, cervical cancer
proton beam therapy and
Intention-to-treat analysis
Interferon-alpha, melanoma
International Lymphoma Radiation Oncology Group (ILROG)
International Neuroblastoma Staging System (INSS)
International Prognostic Index
Interstitial brachytherapy
Intracranial germ cell tumor
chemotherapy
demographics
differential diagnosis
germinoma
historical note
imaging
labs
NGGCT
outcomes
pineal tumors
procedures/biopsy
dose
IGRT
SIM
target
risk factors
staging
suprasellar tumors
treatment algorithm
trials on
Intraperitoneal chemotherapy
Ipilimumab
Irinotecan
plant alkaloids
rhabdomyosarcoma
Isotopes, brachytherapy
J
JX-594
K
Keloids
kV imaging
L
Lapatinib
Larynx cancer
advanced stages
chemotherapy
follow-up
glottis anatomy
lymph node drainage
neck dissection after definitive XRT/CRT
outcomes
post-Op
proton therapy
risk factors
staging
subglottis anatomy
supraglottis anatomy
surgery
treatment algorithm
trials on
workup
Late effects
factors affecting
by organ site
CNS
musculoskeletal
second malignancy
overview on
strategies to reduce
Lauren histologic classification, gastric cancer
LD50
LDR, brachytherapy
BED calculation
D0 evaluation metrics
follow-up
prostate planning metrics
side effects and management
SIM
target
Leptomeningeal disease
Letrozole
Leukopenias
Leuprolide
Linear energy transfer (LET)
Liver cancer. See also Hepatocellular carcinoma
anatomy
oligomets, MDA dose/fractionation schemes
proton therapy
Locally advanced breast cancer (LABC)
definition
dose constraints
genetics
IGRT
incidence
molecular subtypes
neoadjuvant chemotherapy
outcomes
outcomes with PMRT
pathology
planning directive considerations
comprehensive breast/chest wall irradiation
trials
Lomustine
Low-grade gliomas (LGGs)
anatomy
cerebellum
chemotherapy
demographics
follow-up
frontal lobe
genetics
grade I glioma
grade II glioma
imaging
labs
occipital lobe
outcomes
parietal lobe
pathology
procedures/biopsy
risk factors
RT timing
staging/grading
temporal lobe
treatment algorithm
trials on
workup
Lumpectomy
after whole breast radiation
tamoxifen after
whole breast irradiation after
Lung cancer
proton therapy
Lymphadenectomy
Lymphatic drainage
Lymphedema
Lymph node
drainage
anal region
bladder cancer
cervical cancer
colorectal region
endometrial cancer
Markel cell carcinoma
oral cavity
ovarian cancer
penile cancer
radiation, adjuvant penile cancer
stomach
vaginal cancer
vulvar cancer
Lymphoma
diffuse large B-cell lymphoma (Diffuse large B-cell lymphoma
(DLBCL))
follicular
gastric MALT
Hodgkin (Hodgkin lymphoma)
mantle cell
marginal zone
mucosa-associated lymphoid tissue (MALT)
orbital MALT
primary anaplastic large cell lymphoma
primary cutaneous
primary cutaneous B-cell
primary cutaneous follicle center
primary cutaneous marginal zone B-cell
primary cutaneous T-cell
M
Macrophages (MΦ)
Magnetic resonance imaging (MRI)
apparent diffusion coefficient (ADC)
diffusion-weighted imaging
FLAIR
STIR
T1
T2
Mantle cell lymphoma (MCL)
Marginal zone lymphoma
B-cell markers
demographics
incidence
neoplasm
nodal marginal zone B cells
outcomes
risk factors
splenic marginal zone B cells
MDR, brachytherapy
Mechanoreceptor
Mechlorethamine
MEDI6469
Median overall survival (OS)
Medulloblastoma
cerebellar vermis anatomy
chemotherapy
demographics
dose
dose constraints
follow-up
IGRT
imaging
labs
outcomes
pathology
procedures/biopsy
risk factors
SIM
staging and risk stratification
subtypes of
target
technique
treatment
treatment algorithm
trials on
Melanoma, cutaneousCutaneous melanoma
Melphalan
Memantine
Meningioma
anatomy
chemotherapy
demographics
follow-up
genetics
history
imaging
labs
outcomes
pathology
physical examination
procedures/biopsy
dose and target
IGRT
planning directive
SIM
technique
risk factors
Simpson grading system
staging and grading
studies on
treatment algorithm
workup
Merkel cell carcinoma (MCC)
anatomy
chemotherapy
demographics
follow-up
genetics
histologic subtypes
incidence
mechanoreceptor
outcomes
pathology
postoperative RT after WLE
radiation for stage I-III disease
risk factors
skin care
surgery
TNM
treatment algorithm
workup
Merkel cell polyomavirus (MCPyV)
Mesothelioma
anatomy
chemotherapy
demographics
follow-up
genetics
imaging
labs
literature on
outcomes
pathology
procedures/biopsy
risk factors
staging
surgery
treatment algorithm
workup
Mesothelium anatomy
Metastasectomy
Metastasis
brain (Brain metastases)
clinical setup
nonspine
RT emergencies
airway obstruction
cord compression
leptomeningeal disease
SVC syndrome
uncontrolled bleeding
spine (Spine metastases)
statements of calibration
Metastatic osseous disease
Methotrexate
Mismatch repair
Mitomycin-C
Mitotic catastrophe
Model-based designs
Molecular signaling and pathways
Morbus DupuytrenDupuytren contracture
6-MP
Mucosa-associated lymphoid tissue (MALT) lymphoma
Multivariate analyses
MV electronic portal imaging devices (EPIDs)
Mycosis fungoides (MF)
Myeloid-derived suppressor cells (MDSCs)
Myelopathy
N
Nab-paclitaxe
Na18F
Narcotics
Nasopharynx cancer
anatomy
chemotherapy
demographics
follow-up
outcomes
proton therapy
risk factors
staging
treatment algorithm
trials on
workup
Negative predictive value (NPV)
Neoadjuvant chemotherapy (NAC)
breast cancer
ovarian cancer
rectal cancer
short-course (SC) radiation
trials on
Neuroblastoma
anatomy
chemotherapy
demographics
follow-up
imaging
labs
outcomes
procedures/biopsy
risk factors
staging/grading
treatment algorithm
trials on
Neutron shielding
Nilotinib
Nilutamide
Niraparib
Nivolumab
NK cells
Nongerminal center B cell (non-GCB)
Nongerminomatous GCT (NGGCT)Intracranial germ cell tumor
Nonhomologous end joining (NHEJ)
Noninferiority trial
Nonmelanoma skin cancers (NMSCs)
anatomy
curettage and electrodessication
follow-up
incidence
Mohs micrographic surgery
papers on
pathology
prevention
radiation dermatitis
risk factors
staging
systemic therapy
treatment algorithm
wide local excision
workup
Nonneural benign disease
Dupuytren contracture
gynecomastia
heterotopic ossification
keloids
Nonseminomatous tumors
testicular cancer
treatment algorithm
Non–small cell lung cancer (NSCLC)
early stage (Early-stage non-small cell lung cancer (NSCLC))
oligometastatic disease, trials on
Non-spine bone metastases
chemotherapy
demographics
evaluation
incidence
outcomes
pathology
surgery
trials
workup
NPO, brachytherapy
Nuclear medicine imaging
bone scan
123I iodine scan
131I iodine scan
MIBG
myocardial perfusion
renal scan
sentinel node identification
V/Q scan
Nucleotide excision repair
Number needed to treat (NNT)
O
OAR margin
Odds ratio (OR)
Olaparib
Oligometastases per NRG-LU002
Oligometastatic disease
biologic basis for
classification
definition
fractionation schemes, oligomets
local therapy for
MDA dose
patient selection
sites of treatment
stereotactic ablative body radiotherapy (SBRT )
stereotactic radiosurgery (SRS)
subtypes
timing with systemic therapy
trials of
Omeprazole
Oncogene
Oncolytic viruses
Optical (surface) imaging
Oral cavity
anatomy
chemotherapy
demographics
follow-up
genetics
head and neck lymph node levels
outcomes
pathology
risk factors
staging
surgery
treatment algorithm
trials on
workup
Orbital MALT lymphoma
Oropharynx
additional consultations
anatomy
demographics
imaging
labs
outcomes
pathology
procedures/biopsy
proton therapy
boosting stoma with post-op XRT
definitive radiation therapy
IGRT
Ipsilateral treatment
neck dissection after definitive XRT/CRT
PORT indications
post-op
transoral robotic surgery (TORS)
risk factors
staging
symptoms
treatment algorithm
trials on
workup
Osimertinib
Osteosarcoma
prevalence
RT role
treatment paradigm
Ovarian cancer
adjuvant platinum/taxane chemotherapy
anatomy
chemotherapy
demographics
genetics
incidence
intraperitoneal chemotherapy
intraperitoneal dissemination
neoadjuvant chemotherapy
outcomes
papers on
pathology
risk factors
staging
treatment algorithm
workup
Oxaliplatin
alkylating agents
esophageal cancer
Oxygen effects
oxygen enhancement ratio
oxygen fixation
therapeutic approaches to hypoxia
tumor hypoxia
P
Paclitaxel
esophageal cancer
plant alkaloids
stage III NSLC
Pair production
Pamidronate
Pancreatic cancer
anatomy
chemotherapy
definitions of resectability
demographics
follow-up
genetics
imaging
outcomes
pathology
per ALLIANCE A021501
conventional
SBRT
risk factors
staging
surgery
treatment schema
trials on
workup
Panitumumab
Paraganglioma (jugulotympanic)
dose constraints
follow-up
imaging
observation
pathology
radiotherapy
surgery
Parallel organ tissue toxicity
Parameningeal rhabdomyosarcoma
Parotid gland anatomy
Pazopanib
Pediarix
Pembrolizumab
Pemetrexed
Penile cancer
adjuvant lymph node radiation
anatomy
definitive brachytherapy
definitive external beam radiation
definitive external beam RT
demographics
external beam RT for LN management
follow-up
genetics
head of penis (glans penis)
incidence
interstitial brachytherapy
lymph node drainage
neoadjuvant treatment
organ preservation surgery
outcomes
pathology
penectomy
penile organ-sparing approaches
penile shaft
primary treatment
radiation therapy
regional lymph node management
risk factors
staging
workup
Per protocol analysis
Pertuzumab
Photoelectric effect
Photon dosimetry
Photon interactions
PI3K-Akt-mTOR pathway
Pituitary adenoma
anatomy
demographics
follow-up
imaging
medical management
outcomes
pathology
risk factors
studies on
surgery
workup
Pituitary fossa
Pituitary gland
Plasma cell dyscrasias
Pleurectomy and decortication (P/D)
Pleurodesis
Pneumonitis
early-stage NSCLC
esophageal cancer
Hodgkin lymphoma
Polyuria
Positive predictive value (PPV)
Positron emission tomography (PET)
Postmastectomy radiation therapy (PMRT)
Postmenopausal Danish Trial
Prednisone, Hodgkin lymphoma
Premenopausal Danish Trial
Primary anaplastic large cell lymphoma (PALCL)
Primary central nervous system lymphoma (PCNSL)
Primary cutaneous B-cell lymphomas
Primary cutaneous follicle center lymphoma (PCFCL)
Primary cutaneous lymphomas
Primary cutaneous marginal zone B-cell lymphoma (PCMZL)
Primary cutaneous T-cell lymphomas
Primary mediastinal B-cell lymphoma
Primary testicular lymphoma
Probability, computed tomography
Procarbazine
Proctitis
brachytherapy
rectal cancer
Prodromal syndrome
Prolia
Prophylactic cranial irradiation (PCI)
Prostate cancer
adjuvant
anatomy
chemotherapy
follow-up
history
hormone therapy
image-guided biopsy
imaging
labs
prostate fossa
prostatic lymph node drainage
sagittal and axial views
staging
studies
SV fossa
treatment algorithm
workup for PSA recurrence
brachytherapy
papers on
definitive
abiraterone
acinar adenocarcinoma
anatomy
chemotherapy
cystitis
demographics
diarrhea
docetaxel
follow-up
genetics
high risk trials
hormone therapy
imaging
incidence
intermediate risk trials
low risk trials
obstruction
outcomes
overactivity
pathology
proctitis
risk factors
simulation
staging
surgery
treatment algorithm
workup
per MDACC protocol
postop, proton therapy
proton therapy
Prostate lymph node drainage
Prostvac-VF
Proton therapy
clinical indications
atypical teratoid/rhabdoid tumor
breast
chordoma/chondrosarcoma, skull base
craniopharyngioma
craniospinal
esophageal
larynx
liver
lung
nasopharynx
oropharynx
postop prostrate
prostate
rhabdomyosarcoma
seminoma
history
principles of
biological effectiveness
Bragg peak
cyclotron
interactions with matter
linear energy transfer (LET)
proton accelerators
spread-out Bragg peak (SOBP)
synchrotron
techniques of
adaptive planning
beam selection
dose and fractionation
image guidance
intensity-modulated proton therapy (IMPT)
passive scattering proton therapy (PSPT)
simulation
target delineation
Pterional craniotomy
Pulsed dose rate (PDR)
P-value
PVSRIPO
R
Radiation biology
alpha/beta ratios
cancer
carcinogenesis and heritable effects
cell death mechanisms
DNA damage
DNA repair
embryo and fetus, effects on
equivalent dose
linear energy transfer
molecular signaling and pathways
normal tissue toxicity
oxygen effects
radioprotectors
4 Rs of
telomerase
telomeres
total body irradiation, acute effects
Radiation carcinogenesis
Radiation-induced senescence
Radiation physics
basics of
brachytherapy
dose specification
electron dosimetry
photon dosimetry
radioisotopes
shielding
treatment techniques
wedges
Radical prostatectomy
Radiculopathy
Radioactive decay
Radioisotopes
Radioprotectors
Raloxifene
Ramucirumab
Random error
Randomized controlled trial (RCT)
Rayleigh scatter
REAC/TS triage
Recombivax HB
Rectal cancer. See also Colorectal cancer
abdominoperineal resection (APR)
low anterior resection (LAR)
staging
transanal excision (TAE)
Rectum anatomy
Recurrence/relapse-free survival (RFS)
Recurrent breast cancer
considerations
definition
outcomes
surgical options
systemic therapy
treatment algorithm
workup
Regional nodal irradiation (RNI)
high-risk patients
in low-risk patients
in high-risk patients
in low-risk patients
Reglan
esophageal cancer
mesothelioma
Regorafenib
Reolysin
Retinoblastoma (RB)
Retinoids
Rhabdomyosarcoma (RMS)
anatomy
chemotherapy
demographics
diagnostic evaluation
outcomes
risk factors
risk stratification/staging
side effects
treatment algorithm
trials on
Risedronate
Risk ratio/relative risk (RR)
Rituximab
diffuse large B-cell lymphoma
primary central nervous system lymphoma
4 Rs, radiation biology
S
Sacral spine
Salivary gland neoplasms
chemotherapy
conventional borders
follow-up
modern radiation treatment technique
outcomes
parotid gland anatomy
postoperative radiotherapy indications
risk factors
staging
major
minor
surgery
trials on
workup
Salvage radiation
after prostatectomy
with hormone therapy
Sargramostim
Selection bias
Seminoma
proton therapy
testicular cancer
para-aortic and ipsilateral iliac lymph node
stage I
treatment algorithm
Sensitivity
Sentinel lymph node biopsy (SLNB)
axillary LN dissection
Serial organ tissue toxicity
Serous carcinoma
Shielding
Short-course (SC) radiation
Siewert classification, stomach
Single-arm designs
Single exposure
Sinonasal cancer
anatomy
chemotherapy
demographics
follow-up
outcomes
risk factors
staging
treatment algorithm
ethmoid sinus and nasal cavity
sinonasal-maxillary sinus
workup
Sinonasal-maxillary sinus
Sinonasal undifferentiated carcinoma (SNUC)
Sipuleucel-T
Skin brachytherapy
dose
follow-up
indications
SIM
target
technique
Skin cancers
epithelial tumor
nonmelanoma (Nonmelanoma skin cancers (NMSCs))
Skin tolerance, tissue toxicity
Small cell lung cancer
chemotherapy treatment guidelines
demographics
extensive stage
follow-up
genetics
imaging
labs
limited stage
outcomes
pathology
procedures/biopsy
prophylactic cranial irradiation (PCI)
risk factors
staging
surgery
treatment algorithm
trials on
workup
Small cell neuroendocrine carcinoma (SNEC)
Soft tissue sarcoma
adult
anatomy
cell cancer staging
chemotherapy
consensus papers
demographics
extraosseous ewing sarcoma
histologic subtypes
imaging
incidence
limb-sparing surgery
local recurrences
outcomes
papers on
pathology
prognostic factors
rhabdomyosarcoma sarcoma
risk factors
sagittal and coronal images of IMRT treatment
surgery
treatment algorithm
workup
pediatric
Solitary plasmacytoma
Sonidegib
Sorafenib
Specificity, statistics
Spine metastases
anatomic classification system
conventional radiotherapy
follow-up
incidence
intermediate resistance histology
MDACC prospective phase I/II
osseous disease
Phase II RTOG 0631 trial
radioresistant histology
radiosensitive histology
spine radiosurgery
spine stereotactic surgery
surgical stabilization
workup
Spread-out Bragg peak (SOBP)
Squamous cell carcinomas (SCC)
elective neck management
head and neck cancer
penile cancer
recurrence for
Stage III NSLC
demographics and risk factors
follow-up
literature and trials on
outcomes
surgery
systemic therapy
treatment algorithm
Standardized uptake value (SUV)
Statistical test
Stereotactic body radiation therapy
Stereotactic body radiation therapy (SBRT)
characteristics
cholangiocarcinoma
critical considerations
definition
head and neck per MDACC Protocol
hepatocellular carcinoma
lung cancer
oligometastases per NRG-LU002
oligometastatic disease
pancreatic cancer per ALLIANCE A021501
prostate cancer per MDACC protocol
Stereotactic radiosurgery (SRS)
alliance N0574
clinical considerations
control rates
day-of-procedure (gamma knife)
dosing strategy
follow-up
imaging
indications
JLGK0901
NCCTG N107C/CEC·3
oligometastatic disease
plan evaluation
postoperative benefits
radiosurgery efficacy and toxicity
RTOG
workup
Stereotaxy
Sulfhydryl compounds
Sunitinib
Superiority trials
Superior mediastinal anatomy
Superior vena cava syndrome
Superior vena cava (SVC) syndrome
cough
definition
esophagitis
incidence
outcomes
workup
Supraclavicular anatomy
Surface markers
Synchrotron
Systematic error
T
Tamoxifen
T cells
Telomerase
Telomeres
Temozolomide
Temsirolimus
Tenth-value layer (TVL)
Teratogenesis
Teratoid/rhabdoid tumor, atypical
Testicular cancer
chemotherapy
demographics
follow-up
incidence
nonseminomatous tumors
treatment algorithm
outcomes
pathology
risk factors
seminoma
para-aortic and ipsilateral iliac lymph node
stage I
treatment algorithm
trials
staging
surgery
workup
Testicular lymphoma
Th17
Thoracic spine
3 + 3 design
Thymoma and thymic carcinoma
anatomy
chemotherapy
demographics
follow-up
literature on
outcomes
risk factors
staging
treatment algorithm
workup and staging
Thyroid cancer
anatomy
chemotherapy
demographics
external radiation treatment technique
follow-up
outcomes
risk factors
staging
surgery
treatment algorithm
workup
Tissue toxicity
TITE-CRM
Tobacco use
Tomotherapy imaging
Topotecan
Tositumomab
Total body irradiation, acute effects
cerebrovascular syndrome
GI syndrome
hematopoietic syndrome
LD50
prodromal syndrome
REAC/TS triage
treatment
Tracheoesophageal fistula
Traditional rule-based designs
Trametinib
melanoma
Transsphenoidal resection
Transurethral resection of bladder tumor (TURBT)
Trastuzumab
Treg
Tremelimumab
Trigeminal neuralgia
imaging
medical management
pathology
radiosurgery
surgery
Tumor hypoxia
Tumor-infiltrating lymphocytes (TIL)
Tumor suppressor gene
T-Vec
Twinrix
Two-by-two/“factorial” design
Type I (or α) error
U
Uncontrolled bleeding
Univariate analyses
Unknown head and neck primary cancerCarcinoma of unknown
primary (CUP)
Urinary retention
Urothelial carcinomas
U.S. Preventive Task Force
Uterine sarcoma
Utomilumab
V
Vaccines
Vaginal cancer
anatomy
chemotherapy
cystitis
dermatitis
diarrhea
follow-up
incidence
lymph node drainage
MDACC experience with vaginal
adenocarcinoma
SCC
nausea
NCDB analysis
outcomes
pathology
risk factors
staging
treatment algorithm
workup
VEGFR
Verification film
Vertebral body fracture
Vestibular schwannoma
anatomy
demographics
follow-up
Koos grading scale
outcomes
risk factors
studies on
surgery
treatment algorithm
workup
Vinblastine
Hodgkin lymphoma
plant alkaloids
stage III NSLC
Vincristine
Hodgkin lymphoma
plant alkaloids
rhabdomyosarcoma
Wilms tumor
Vincristine + doxorubicin + cyclophosphamide (VDC)
Vinorelbine
Vismodegib
nonmelanoma skin cancer
Vorinostat
Vulvar cancer
adjuvant radiotherapy, inguinal lymph nodes
anatomy
chemotherapy
contouring atlas
follow-up
groin dissection vs. radiotherapy, N0-N1 patients
incidence
lymph node drainage
outcomes
papers on
pathology
risk factors
sentinel lymph node metastasis, non-SLNs
staging
treatment algorithm
workup
W
Wedges, radiation physics
Weight loss
esophageal cancer
proton therapy
Whole abdominal radiation therapy (WART)
endometrial cancer
vs. chemotherapy
vs. VBT
vs. VBT + chemotherapy
general treatment plans
ovarian cancer
vs. pelvic radiotherapy and chemotherapy
Whole breast irradiation (WBI)
after lumpectomy
considerations
dose
IGRT
planning directive
SIM
target
technique
Whole breast radiation therapy, lumpectomy boost after
Wilms tumor
chemotherapy
demographics
follow-up
imaging
labs
outcomes
procedures/biopsy
dose
planning directive
SIM
target
risk factors
staging
treatment algorithm
trials on
workup
X
Xgeva
X-ray radiography
Z
Zofran
mesothelioma
oral cavity
Zoledronate/zoledronic acid

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Copyright © 2020 Wolters Kluwer

Library of Congress Cataloging-in-Publication Data

This work is no substitute for individual patient assessment based upon

Given continuous, rapid advances in medical science and health information,

Alexander Augustyn, MD, PhD

Alexander F. Bagley, MD, PhD

Peter Balter, PhD

Vincent Bernard, PhD

Eric D. Brooks, MD, MHS

Bhavana S. Vangara Chapman, MD

Caroline Chung, MD, MSc

Lauren Elizabeth Colbert, MD, MSCR

Prajnan Das, MD, MPH

Brian J. Deegan, MD, PhD

Adnan Elhammali, MD, PhD

Ahsan Farooqi, MD, PhD

Clifton David Fuller, MD, PhD

Adam Seth Garden, MD

Amol Jitendra Ghia, MD

Aaron Joseph Grossberg, MD, PhD

David Grosshans, MD, PhD

B. Ashleigh Guadagnolo, MD, MPH

Jillian Gunther, MD, PhD

Karen Elizabeth Hoffman, MD, MPH

Albert C. Koong, MD, PhD

Jing Li, MD, PhD

Anna Likhacheva, MD, MPH

Ethan Bernard Ludmir, MD

Mary Frances McAleer, MD, PhD

Shane Mesko, MD, MBA

Hubert Young Pan, MD

Jack Phan, MD, PhD

Chelsea C. Pinnix, MD, PhD

Jay Paul Reddy, MD, PhD

Mohammed Salehpour, PhD

Tommy Sheu, MD, MPH

Shervin ‘Sean’ Shirvani, MD, MPH

Lisa Singer, MD, PhD

Shane R. Stecklein, MD, PhD

Erik P. Sulman, MD, PhD

Cullen Taniguchi, MD, PhD

Gary Walker, MD, MPH

Christopher Wilke, MD, PhD

Wendy Woodward, MD, PhD

Debra Nana Yeboa, MD

RADIATION ONCOLOGY PRINCIPLES

SPECIAL RADIATION TECHNIQUES

CENTRAL NERVOUS SYSTEM

HEAD & NECK

RADIATION EMERGENCIES, BENIGN DISEASE, AND

Oxygen enhancement ratio

Reoxygenation: Vasoconstriction or free radical scavenging

Amifostine is the only FDA-approved radioprotector

Administer 30 minutes prior to RT; reduces mucositis and

Photon/e− WF = 1; proton WF = 2; neutron WF up to 20; heavy

Average annual human exposure to ionizing radiation

Deterministic: Effect occurs after exceeding threshold dose and

Risk estimate for malignancy

Hereditary effects: Radiation effects that can be transferred from