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For The Clinician: Estimation of Kidney Function in Oncology
For The Clinician: Estimation of Kidney Function in Oncology
Abstract
Estimation of kidney function in patients with cancer directly affects drug dosing, agent selection, and eligibility for
clinical trials of novel agents. Overestimation of kidney function may lead to overdosing or inappropriate agent Departments of
1
Pharmacy and
selection and corresponding toxicity. Conversely, underestimation of kidney function may lead to underdosing or
Therapeutics and
inappropriate agent exclusion and subsequent therapeutic failure. It would seem obvious that the most accurate 3
Pharmaceutical
estimates of kidney function should be used to reduce variability in decision making and ultimately, the therapeutic Sciences, School of
outcomes of toxicity and clinical benefit. However, clinical decision making is often more complex. The Cockcroft– Pharmacy, 2Renal-
Gault formula remains the most universally implemented estimator of kidney function in patients with cancer, Electrolyte Division
and 4Hematology/
despite its relative inaccuracy compared with the Chronic Kidney Disease Epidemiology Collaboration equation. Oncology Division,
The Chronic Kidney Disease Epidemiology Collaboration equation is a more precise estimator of kidney function; Department of
however, many currently used kidney function cutoff values were determined before the development of the Medicine, School of
Chronic Kidney Disease Epidemiology Collaboration equation and creatinine assay standardization using Medicine, University
of Pittsburgh,
Cockcroft–Gault estimates. There is a need for additional studies investigating the validity of currently used
Pittsburgh,
estimates of kidney function in patients with cancer and the applicability of traditional anticancer dosing and Pennsylvania; and
eligibility guidelines to modern and more accurate estimates of kidney function. In this review, we consider 5
Cancer Therapeutics
contemporary calculation methods used to estimate kidney function in patients with cancer. We discuss the clinical Program, University of
implications of using these various methods, including the potential influence on drug dosing, drug selection, and Pittsburgh Medical
Center, Hillman
clinical trial eligibility, using carboplatin and cisplatin as case studies. Cancer Center,
Clin J Am Soc Nephrol 14: 587–595, 2019. doi: https://doi.org/10.2215/CJN.11721018 Pittsburgh,
Pennsylvania
Correspondence:
Introduction exposure, leading to therapeutic failure. Therefore, Dr. Jan H. Beumer,
Patients with cancer often receive multiple narrow accurate and clinically practical estimates of kidney University of
Pittsburgh Medical
therapeutic index drugs, many of which are eliminated function are required to optimize clinical outcomes Center Hillman
by the kidneys and therefore, exhibit decreased clear- in all patients but especially those receiving anti- Cancer Center, Room
ance in patients with impaired kidney function. Anti- cancer agents for which the adverse effect profile can G27E, Hillman
cancer drugs are no exception; these drugs are highly be severe and maximal dosing may be important to Research Pavilion,
toxic with narrow therapeutic indices. Their adverse 5117 Centre Avenue,
optimize anticancer response.
Pittsburgh, PA 15213-
effects are often severe, but they are typically manage- In this review, we present contemporary bedside 1863. Email:
able when patient exposure to the drug is prospectively calculation methods used to estimate kidney function [email protected]
estimated and doses are adjusted accordingly. Thus, in the population of patients with cancer. The clini-
accurate patient-specific dosing and agent selection on cal implications of using various estimates of kidney
the basis of drug clearance and exposure are vital to function in these patients, including the potential
ensure safety while maintaining anticancer activity. influence on drug dosing decisions, agent suitability,
Quantitative estimates of kidney function have and eligibility for clinical trial enrollment, are dis-
been used for decades to guide patient suitability, cussed. Finally, the effect of the most recent Food and
drug selection, and dose adjustments for anticancer Drug Administration (FDA) draft guidance regarding
agents cleared by the kidney. Kidney function estimates pharmacokinetic studies in patients with impaired
are also used to determine eligibility for clinical trials kidney function is explored.
of novel agents. This process is not without risk.
Overestimation of kidney function may lead to over-
dosing or inappropriate agent selection, lower than Kidney Function Estimates in the General
expected clearance of the drug, and an unanticipated Population
increase in systemic exposure, leading to a correspond- GFR is routinely used to quantify kidney function and
ing increase in toxicity. Conversely, underestimation of diagnose CKD. GFR may be measured (measured GFR
kidney function may lead to underdosing or inappro- [mGFR]) directly by determining clearance of exogenous
priate agent exclusion, higher than expected clearance markers, such as inulin, radioactive agents (51Cr-EDTA),
of the drug, and an unanticipated decrease in systemic or radiocontrast agents (iothalamate and iohexol),
www.cjasn.org Vol 14 April, 2019 Copyright © 2019 by the American Society of Nephrology 587
588 Clinical Journal of the American Society of Nephrology
although this is not clinically practical due to time, cost, and Quality Initiative (NKF-KDOQI) guideline groups, but this
convenience. More commonly, GFR is estimated (eGFR) on recommendation has not yet been fully adopted by many
the basis of endogenous serum creatinine (SCr) values (1–3). non-nephrology specialties, including oncology (10–12)
Implementation of isotope dilution mass spectrometry- (Table 1).
traceable standardization of SCr assays in 2010 has led to
reduced interlaboratory variability and improved consis-
tency in SCr measurements in the United States (1). One Kidney Function Estimates in Patients with Cancer
method of determining kidney function has been to use Patients with cancer commonly present with underlying
creatinine clearance (CrCl), reported in milliliters per impaired kidney function. Over one half and up to one fifth
minute, as a surrogate for GFR. CrCl can be measured of patients with solid tumors have eCrCl (milliliters
(measured creatinine clearance [mCrCl]) by 12- or 24-hour per minute) or eGFR (milliliters per minute per 1.73 m2)
urine collections, but this method is time consuming and measures of ,90 and ,60, respectively (2,13). These
inconvenient. The Cockcroft–Gault (CG) formula was pub- numbers likely underestimate the true prevalence of de-
lished in the 1970s as a bedside equation for estimated creased GFR in patients with cancer, because the studies
creatinine clearance (eCrCl). However, this equation is an from which they were derived excluded patients with
imprecise estimate of true GFR in large part due to its failure hematologic malignancies, diseases that are associated
to adequately compensate for several non-GFR determi- with a high prevalence of kidney impairment. Importantly,
nants of SCr, including body composition, diet, age, sex, use of SCr in isolation (i.e., assessment of eligibility for
race, tubular secretion, and extrarenal elimination of creat- treatment defined as SCr,1 or 1.5 times the upper limit of
inine, as well as the original study’s reliance on mCrCl by normal) typically overestimates kidney function, with about
24-hour urine collection as a surrogate for true GFR (1,4,5). 60% of patients with “normal” SCr values presenting with
Additionally, after the isotope dilution mass spectrometry decreased kidney function. In fact, 5%–15% of patients with
standardization of SCr assays, eGFR values decreased by eCrCl (milliliters per minute) or eGFR (milliliters per minute
10%–20% compared with nonstandardized values, further per 1.73 m2) ,60 present with “normal” SCr values (2,13).
placing the accuracy of the CG formula into question in Moreover, the high toxicity of anticancer drugs and fatal
conjunction with the widespread modern use of standard- consequences of the disease if treated ineffectively under-
ized SCr values (1). Despite these limitations and its small and score the need for routine and accurate estimation of GFR to
nondiverse study population (a subselection of mostly men optimize drug safety and efficacy. The older age of patients
and all white patients) (6), the CG formula has been widely with cancer portends additional risk, because it is associ-
adopted into clinical practice due to its convenience and ated with a normal age-related decline in kidney function as
perceived accuracy. Since its incorporation into the 1998 FDA well as increased risks of developing a malignancy, suffer-
guidance on pharmacokinetics for patients with impaired ing cancer-related death, and experiencing chemother-
kidney function, the CG formula has become the most apy-related toxicity (4,14,15). Therefore, it is essential that
common measure by which recommendations for kidney estimates of kidney function can maintain accuracy in this
function-based drug dosing and agent selection are made (1,7). older patient subpopulation.
Improved methods for determining eGFR have been Kidney function plays a large role in determining
developed in the last 20 years, notably the several itera- anticancer therapy, including anticancer agent selection,
tions of the Modification of Diet in Renal Disease (MDRD) dosing, and eligibility for investigational drugs and clinical
Study equation (MDRD-4 and MDRD-6) and the Chronic trials, and thereby, it affects clinical outcomes of patients
Kidney Disease Epidemiology Collaboration (CKD-EPI) with cancer. Although definition of the appropriate way to
and the CKD-EPI cystatin C equations (1,3,5,8,9). These estimate kidney function is important to the dosing of many
equations report eGFR indexed for body surface area (BSA) drugs within the general medical population, it is partic-
in milliliters per minute per 1.73 m2. Importantly, when ularly crucial in patients with cancer due to the highly toxic
comparing kidney function estimates within individuals, adverse event profiles and often steep dose-therapeutic
the estimates must be expressed in equivalent units. response relationships that characterize anticancer agents
Therefore, estimation of a patient’s absolute eGFR in units as a class. Typically, anticancer drug dosing is on the basis of
of milliliters per minute (nonindexed for BSA) must be the maximum tolerated dose, which is the highest dose that
performed by multiplying the indexed eGFR value by may be administered without unacceptable toxicity, to
(patient’s BSA/1.73 m2). This allows for a direct compar- maximize anticancer efficacy. Dose reductions or alterna-
ison of absolute eGFR as calculated by the CKD-EPI tive agent selection due to decreased eGFR may lead to
equation or the MDRD equation, with CrCl by achieving reduced effectiveness, failure of therapy, use of less
congruent units (milliliters per minute) between the two effective or more toxic second- or third-line agents, and
measures. These equations were developed with standard- ultimately, decreased survival. Investigational oncology
ized SCr values and iothalamate clearance as the reference, drug clinical trials offer patients with advanced-stage,
and they incorporate easily measured surrogates (age, sex, relapsed, and refractory cancer potentially effective novel
and race) to account for the effects of some non-GFR therapeutics, but many require minimum kidney func-
determinants of SCr. Use of these equations results in a tion thresholds for enrollment. Patients with cancer may
value that is closer to the true GFR compared with the CG benefit from aggressive anticancer regimens. Therefore,
formula, especially for older patients (1,3). The CKD-EPI underestimation of true kidney function may unnecessar-
equation is recommended for use in routine clinical practice ily preclude patients from more effective agents, higher
by the Kidney Disease Improving Global Outcomes and the doses, or clinical trial enrollment and thereby, potentially
National Kidney Foundation-Kidney Disease Outcomes worsen outcomes. Conversely, overestimation of kidney
Clin J Am Soc Nephrol 14: 587–595, April, 2019
Table 1. Comparison of bedside equations used to estimate kidney function
CG (1976)
Age, SCr, sex, weight eCrCl, ml/min n5236 (subpopulation Average CrCl Convenient to use Estimates creatinine clearance
of 534 patients on the approximately 78 as a surrogate for GFR
basis of duplicate 24- ml/min
h mCrCl being within
20%)
Mean age 53 yr, 24% Model used for determining Correlation between mCrCl
.70 yr, 96% men recommendations for drug and eCrCl R250.69
Veterans Hospital dose adjustment for kidney Uses 24-h urine collection as
patients function standard
Does not use standardized SCr
laboratory values, and
eGFRs before
standardization were
10%–20% higher
Underestimates at severely
reduced kidney function
Less accurate in patients with
extremes of age or body size
Adjustment for sex is empirical
MDRD (2006)
Age, SCr, sex, race eGFR, ml/min per n51628 Average GFR 39.8 P30 values range 73%–93% Underestimates at normal and
1.73 m2 ml/min per 1.73 m2 mildly reduced kidney
function (.60 ml/min)
Mean age 50.6 yr Few patients with Uses iothalamate clearance as Not used for determining most
GFR.90 ml/min per standard kidney drug-dosing
60% men 1.73 m2 MDRD-4 uses standardized recommendations
SCr laboratory values
88% white Improves on CG estimation at
6% diabetic GFR,60 ml/min per 1.73 m2
Patients with CKD
CKD-EPI (2009)
CG, Cockcroft–Gault; eCrCl, estimated creatinine clearance; mCrCl, measured creatinine clearance; CrCl, creatinine clearance; SCr, serum creatinine; MDRD, Modification of Diet in Renal
Disease; P30, percentage of estimates that were within 30% of the reference value; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
589
590 Clinical Journal of the American Society of Nephrology
function may put patients with cancer at unnecessary risk muscle mass, scenarios that are common to many patients
for major organ toxicity from narrow therapeutic index with cancer (1). However, many oncology clinicians continue
anticancer drugs cleared by the kidneys (4,14,15). Most to use CG-based eCrCl to guide anticancer drug dosing for
patients with cancer and impaired kidney function have kidney function and selection, and some groups and inves-
stage 2 or 3 (eGFR560–89 and 30–59 ml/min per 1.73 m2, tigators even use multiples of SCr upper limit of normal to
respectively) kidney disease (approximately 40%–50% and determine enrollment into clinical trials. Despite its relative
15%–20% of all patients with cancer, respectively) according inaccuracy compared with the CKD-EPI equation, the CG
to NKF-KDOQI classification (2,11,13). These two stages formula continues to be the most universally implemented
straddle many important drug dose, drug selection, and estimator of kidney function in patients with cancer
clinical trial enrollment thresholds (16–18). (12,14,19).
The process of deciding which kidney function estimate
to implement in modern oncology practice remains com- Implications for Anticancer Drug Dosing
plicated. Many anticancer drug cutoffs were determined Many anticancer drugs have a narrow therapeutic index
before the development of the CKD-EPI equation using CG with potentially severe toxicity, and a large number of
estimates of kidney function and before creatinine assay drugs are excreted predominantly as unchanged drug or
standardization in 2010. Although it has been firmly active metabolite in the urine and therefore, may require
established that the CKD-EPI equation is superior to the dose adjustment for kidney function (16,17,21). For patients
CG formula in estimating GFR, the real clinical question with decreased kidney function, this translates to dimin-
that needs to be answered is the method of assessing ished drug clearance and increased exposure, possibly
kidney function that is best suited to dose adjust anticancer leading to unacceptable toxicity. Underestimation of kid-
agents for kidney function. Important considerations in- ney function, however, can result in unintentional pre-
clude the accuracy of the model as it relates to estimation of scription of a subtherapeutic dose and diminished
kidney function in the individual patient and the kidney anticancer activity. Patient-specific dose adjustments of
function model used to determine unacceptable toxicity anticancer drugs cleared by the kidneys are, therefore, vital
when the chemotherapeutic agent was developed. Addi- to ensure safety while maintaining anticancer drug efficacy
tionally, one must evaluate the risk-benefit scenario (i.e., (Table 2). Up to 50% of anticancer drugs either need dose
the potential severity and complications of adverse effects adjustment for kidney function or do not have data on
when overdosing versus potential therapeutic failure when whether dose adjustments are required (2,13,21). Intensive
underdosing). There may be clinical scenarios in which pharmacotherapy and polypharmacy are common features
the use of the CG formula may be preferable, despite its of clinical oncology practice; as such, approximately 50%
decreased precision and accuracy in the estimation of GFR. of kidney function–impaired patients with solid tumors
Admittedly, one of the weaknesses of using GFR to dose receive at least one anticancer drug that requires dose
drugs is that it does not account for the contribution of adjustment for kidney function (2,13,21). However, many
tubular secretion to drug clearance, which can be signif- patients do not receive appropriate chemotherapy dosage
icant for some drugs. Unless a drug has a secretion profile adjustments on the basis of their kidney function. In
similar to that of creatinine, neither eCrCl- nor creatinine- one retrospective study, approximately one half of kidney
based estimates of GFR are good representations of that function–impaired patients with solid tumors who were
drug’s net kidney clearance. However, the fact remains that receiving a drug that necessitated dose adjustments for
the CKD-EPI equation provides an eGFR that is closer to kidney function received almost 50% of their prescriptions
true GFR than eCrCl. Accurate estimations of kidney at standard doses (i.e., without appropriate dose adjustment),
function are imperative for optimizing anticancer efficacy potentially causing unacceptable toxicity to the patient.
while avoiding unacceptable toxicity in patients with cancer, The most commonly implicated drugs included cisplatin,
especially the elderly, in whom both decreased kidney carboplatin, capecitabine, etoposide, and zoledronate. In fact,
function and malignancies are more common. approximately 3% of patients received a drug for which a dose
Several clinical oncology groups, including the Interna- adjustment would be necessary in the setting of im-
tional Society of Geriatric Oncology (SIOG) and the paired kidney function without receiving any kidney function
National Comprehensive Cancer Network (NCCN), recom- evaluation (13). This illustrates the lack of a universal approach
mend an assessment of kidney function to adjust dose and to evaluating kidney function in patients with cancer
reduce toxicity in patients before chemotherapy, even when and applying the clinical information to tailor pharmacother-
SCr is within the normal range. However, there are apy for individual patients.
currently no universal guidelines stating which method of Many anticancer drugs are routinely dosed according
estimating kidney function is preferred in patients with to BSA in an effort to account for the effect of body size
cancer. The NCCN vaguely recommends use of CrCl in on pharmacokinetics, although this often does nothing to
their guidelines pertaining to elderly adults and “GFR reduce variability in exposure (22). Despite many oncology
calculations” in their guidelines related to adolescent and drugs being dosed according to BSA, the most commonly
young adults, whereas the SIOG does not state a preferred used method of estimating kidney function in oncology
estimation method (4,14,19,20). Most currently published remains the CG formula, which yields an absolute kidney
models of estimating kidney function and all of those function metric (milliliters per minute) that is not indexed
regularly used in clinical practice are derived from pop- to BSA. This is problematic, because the use of an absolute
ulations of patients without cancer (3,6,9). The CG formula kidney function estimate to prescribe anticancer drugs that
is known to be markedly less accurate in the elderly and are dosed according to BSA will likely alter the dose
patients with extremes of body composition and decreased assignment compared with dosing decisions on the basis of
Clin J Am Soc Nephrol 14: 587–595, April, 2019 Kidney Function in Oncology, Casal et al. 591
Table 2. Selected drugs with kidney function cutoffs for eligibility and dose modifications
Bendamustine 30 — 42
Bleomycin — 5%–10% to 40% 41
10%–20% to 45%
20%–30% to 55%
30%–40% to 60%
40%–50% to 70%
Capecitabine 30 30%–50% to 75% 43
Cisplatin 60 — 37
Etoposide 15 15%–50% to 75% 44
Fludarabine 30 30%–49% to 60% 45
50%–79% to 80%
Methotrexate 60 — 46
Mitomycin 30a — 47
Oxaliplatin — ,30%–75% 48
Pemetrexed 45 — 49
Pentostatin — 50%–60% to 50% 50
Topotecan 10 20%–39% to 50% 51
—, not applicable.
a
Related to hydroxypropyl-b-cyclodextrin excipient.
BSA-indexed kidney function estimates. Small patients will (26,27). Even small changes in carboplatin dosing and
be penalized for having a low absolute kidney function, exposure can have meaningful clinical consequences. For
although their drug dose will already accommodate this example, a carboplatin dose reduction as small as 10% may
size difference (Figure 1). In a post hoc analysis of a study result in a doubling of the 5-year relapse rate (28). Currently,
using the CG formula (milliliters per minute) to dose carboplatin is dosed on the basis of the Calvert equation
stratify patients with impaired kidney function being (29), with carboplatin dose being directly related to the
administered oxaliplatin to develop dosing guidelines, it patient’s GFR as follows:
was revealed that BSA indexing of eCrCl (milliliters per
minute per 1.73 m2) did alter dose classification of several DoseðmgÞ 5 target AUC 3 ½GFR 1 25:
patients versus absolute eCrCl classification. Although this
reclassification did not alter the results of the dose guide- Carboplatin dosing varies significantly depending on the
lines for kidney function determined by the study, it does estimate of GFR incorporated into the Calvert formula, and
show that dose stratification of patients can be affected by there is poor concordance of carboplatin dose measured
whether measures of kidney function are indexed for BSA, with eGFR or eCrCl versus mGFR. Up to three quarters of
and this can have potential clinical implications (23,24). The patients dosed by the CG formula and one quarter of
effect of these internal inconsistencies would be most patients dosed by the CKD-EPI equation receive a carbo-
pronounced in the dosing of patient groups with BSAs platin dose over 10% and 20% different, respectively, than
that differ significantly from 1.73 m2. Therefore, it would the dose that they should receive on the basis of mGFR
seem pertinent to use BSA-indexed estimates of kidney (12,30). Similarly, only between one fifth and one third of
function for drugs dosed by BSA and absolute estimates of patients prescribed carboplatin have a calculated eGFR or
kidney function for drugs dosed absolutely so that the units eCrCl within 10% of their mGFR (30). Differences in
are congruent (23,25). Notably, the output of the CKD-EPI carboplatin dosing are dependent not only on the method
equation can be easily converted to absolute values used to calculate GFR (e.g., the CKD-EPI equation versus
through multiplication by (patient’s BSA/1.73 m2). the CG formula) but also, on whether the BSA-indexed
or absolute eGFR is incorporated into the Calvert for-
Case Study: Carboplatin mula. eGFR indexed for BSA as calculated by the CKD-EPI
Carboplatin is a platinum-based alkylating agent that equation is less likely to overdose but more likely to
is widely used in the treatment of lung, ovarian, underdose patients versus absolute eGFR calculated by the
testicular, bladder, breast, and head and neck cancers. same method, further illustrating that the choice of using
Carboplatin exhibits an exposure-response relationship BSA-indexed versus absolute estimates of kidney function
with increasing area under the curve (AUC), resulting in will significantly affect drug dosing and potential clinical
increased antitumor activity; the exposure-response efficacy and safety outcomes (Figure 2) (31). Importantly,
relationship plateaus, and additional increases in expo- no studies to date have documented exposure by measur-
sure result in increased toxicity. An ultrafilterable car- ing ultrafilterable carboplatin AUC or examined the dif-
boplatin target AUC of 4–6 mg/ml per minute is ferences in clinical safety and toxicity profiles of
suggested, because it seems to optimize anticancer effi- carboplatin dosing and exposure on the basis of GFR
cacy within acceptable toxicities as shown in ovarian cancer estimation method incorporated into the Calvert formula,
592 Clinical Journal of the American Society of Nephrology
C Dose
BSA-indexed kidney function 70% of dose Final dose =
10 U/m2 eGFR = 50 mL/min/1.73 m2 9.5 U
adjustment
Figure 1. | Many anticancer drugs are dosed according to body surface area (BSA), but they are dose adjusted according to measures of
absolute kidney function (i.e., estimated creatinine clearance as milliliters per minute) as opposed to BSA-indexed measures of kidney function
(i.e., eGFR as milliliters per minute per 1.73 m2). (A) This practice will likely alter dose assignments of patients at the extremes of body size
(patients who are obese and patients who are cachectic) compared to patients with BSA of 1.73 m2. (B) Larger patients (BSA.1.73 m2) are already
receiving a larger dose of BSA-dosed drugs due to their increased BSA. Use of an absolute kidney function value may preclude necessary dose
reduction, because the absolute kidney function value of patients with BSA.1.73 m2 will be greater than the BSA-indexed value and may be
above a dose-adjustment breakpoint. (C) Smaller patients (BSA,1.73 m2) are already receiving a smaller dose of BSA-dosed drugs due to their
decreased BSA. Use of an absolute kidney function value may lead to additional unnecessary dose reduction, because the absolute kidney
function value of patients with BSA,1.73 m2 will be less than the BSA-indexed value and may be below a dose-adjustment breakpoint.
Bleomycin dosing of 10 U/m2 was on the basis of manufacturer recommendations (41). Absolute eGFR values (milliliters per minute) were
calculated by multiplying the BSA-indexed eGFR (milliliters per minute per 1.73 m2) by (patient’s BSA/1.73 m2).
an effort that is currently being pursued within the minute per 1.73 m2. In fact, many studies investigating
Cancer Therapy Evaluation Program of the National suitability of cisplatin therapy on the basis of the MDRD
Cancer Institute. equation– or the CKD-EPI equation–derived eGFRs either
make no mention of normalizing for patient-specific BSAs
Implications for Anticancer Drug Selection but report eGFR in milliliters per minute or use identical
For many anticancer drugs, patients are placed into GFR numerical cutoffs for both eCrCl (milliliters per minute) and
stratifications, below which administration of the drug eGFR (milliliters per minute per 1.73 m2) (32–36). In both the
is not recommended due to reduced elimination or high oncopharmacology and clinical oncology communities,
potential for toxicity (Table 2). These drugs are generally more emphasis should be placed on the clinical implications
dosed in a dichotomous fashion as opposed to continuous of using BSA-indexed versus absolute estimates of GFR to
dosage adjustments, and therefore, accurate determination minimize the likelihood of incorrectly assuming that esti-
of patient GFR is critical, because small variations in GFR mates of kidney function are numerically equivalent across
estimates may completely preclude patients from receiving incongruent units.
potentially effective anticancer therapy. This is especially
pertinent in stage 2/3 kidney disease, because these stages Case Study: Cisplatin
include the majority of patients with cancer and impaired Cisplatin is a platinum-based alkylating agent that is
kidney function and contain important dose adjustment highly effective at treating many types of cancer. The drug
thresholds for many drugs (e.g., 60, 45, and 30 ml/min) is excreted predominantly unchanged in the urine, and
(2,13,14,16). Suitability of a drug is most often assessed unfortunately, it is extremely nephrotoxic. Although no
depending on kidney function as estimated by the CG universal guidelines exist, some recommendations and
formula and reported in milliliters per minute; hence, there is typical clinical practice discourage use of cisplatin in
considerable ambiguity in assessing drug suitability on the patients with GFR,60 ml/min (37). In fact, impaired
basis of eGFR estimates of kidney function in milliliters per kidney function is the reason for precluding anywhere
Clin J Am Soc Nephrol 14: 587–595, April, 2019 Kidney Function in Oncology, Casal et al. 593
Conc
clearance (mL/min)
RATEin 100
SCr
Cl 75
Incidence
Calvert formula Time
Muscle production + diet Patient carboplatin 50
SCr Sex Age Weight Race BSA Dose = AUCtarget*(GFR+25)
GFR + active secretion clearance
25
0 2 4 6 8 10 12
Conc
AUC
eGFRCKD eGFRCKD Carboplatin
CKD-EPI 2
doseCKD
(mL/min/1.73m ) (mL/min)
Time
Figure 2. | Area under the curve (AUC)–targeted dosing of carboplatin using either the Cockcroft–Gault formula or the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equation to inform kidney function may result in different doses and exposures. The CKD-EPI
equation estimates a body surface area (BSA)–normalized GFR value from assumed steady-state serum creatinine (SCr) and anthropomorphic
variables. This estimate is converted to an absolute value using the patient’s BSA. Similarly, the Cockcroft–Gault formula estimates an absolute
value for creatinine clearance, which is then used as a surrogate of GFR. The GFR value is imputed into the Calvert equation with a target AUC
(often 6 mg/ml per min), which results in a carboplatin dose to be administered to the patient. On the basis of the true carboplatin clearance of the
patient, an exposure is observed. On the basis of a probability of response (green curve) or toxicity (red curve), the exposure and corresponding
probability of response and toxicity can be quite different depending on the kidney function estimate used and the corresponding carboplatin
dose administered.
from 20% to 83% of patients from receiving cisplatin patients with only mild kidney impairment according
therapy (32,33,35,36,38). to FDA classification who are disqualified from poten-
Cisplatin eligibility varies significantly depending on the tially effective clinical trials due to their kidney function.
kidney function estimate used. For example, CG formula– However, a retrospective analysis of over 10,000 patients
derived kidney function estimates exclude cisplatin ther- from 373 single-agent phase 1 clinical trials found that
apy at an approximately 20% higher rate than the CKD-EPI there was no clinically meaningful increase in grade 3 or 4
equation–derived estimates (32,33,35,36,38). This bias is nonhematologic, grade 4 hematologic, or any clinically
especially pronounced in women, the elderly, and whites relevant toxicities in the approximately 36% of enrolled
(32). Patient eligibility on the basis of the CG formula patients with mild kidney impairment compared with
versus eGFR has high discordance, with about 15% of those with normal kidney function (18). Therefore, ex-
patients changing eligibility status on the basis of the panding inclusion of patients to the full FDA classification
estimation used (32,33,36). Significantly more patients are range of mild impairment (i.e., CrCl.50 ml/min) may
deemed ineligible for cisplatin with any method of eCrCl or increase eligibility of patients without any clinically
eGFR compared with mCrCl (38). Potentially inappropri- meaningful difference in determination of the dose-limit-
ate denial of cisplatin eligibility is again seen more ing toxicity.
prominently in the elderly, with 24%–53% of patients Current FDA guidelines recommend use of the CG
over 65 years old being denied by eCrCl or eGFR but not formula to determine kidney function (7); however, the
by mCrCl (34). Notably, the ability of a patient to complete draft revision of the guidelines for assessing pharmacoki-
three full cycles of chemotherapy has been correlated with netics in kidney impairment suggests that the newer eGFR
mCrCl.60 ml/min (P50.02) but not eCrCl.60 ml/min or formula also should be used to estimate kidney function
eGFR.60 ml/min per 1.73 m2 (34). It is notable that (40). Importantly, these draft guidelines do not state a
there exists a correlation between a clinical outcome preference as to which formula is used to estimate kidney
that may directly affect survival and mCrCl, a measured function, although it is established that the CKD-EPI
(although admittedly flawed) marker of kidney function, equation is a more accurate estimate of mGFR across a
but not eGFR, an estimated and supposedly more accurate wider range of kidney function than the CG formula. This is
measure of kidney function. This calls into question the of particular importance in patients with cancer, because at
utility of current drug selection thresholds and their cor- the border of mild to moderate kidney impairment for both
relation to the various estimates and measures of kidney FDA classification (50 ml/min) and the majority of phase 1
function in patients with cancer. cancer trials (60 ml/min), the CG formula is known to
underestimate kidney function at a higher degree than newer
Implications for Oncology Clinical Trials formulas. As such, this may unnecessarily preclude patients
Historically, patients with impaired kidney function with mild kidney impairment from trial participation.
have tended to be excluded from phase 1 studies of Additionally, there are significant inconsistencies re-
anticancer drugs because of a perceived increased risk for garding the use of BSA-indexed versus non–BSA-indexed
major dose-limiting toxicity. Recently, however, there has estimates of kidney function to determine dosing and
been a call to be more inclusive of patients with mild to eligibility for anticancer drugs. Recognition of this
moderate kidney impairment in oncology clinical trials problem, development of guidelines with the purpose
(17) as well as warnings to be cautious about sweeping of maintaining consistency in this regard (milliliters per
changes (39). Current FDA classification of mild kidney minute for drugs dosed absolutely or on the basis of any
impairment is defined as CrCl550–79 ml/min, but typical non-BSA parameter versus milliliters per minute per
phase 1 eligibility disqualifies patients from enrollment 1.73 m2 for drugs dosed on the basis of BSA), completion
at CrCl,60 ml/min. Therefore, there is a proportion of of pharmacokinetic trials including patients with impaired
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that the most accurate estimates of kidney function should Tamura M, Feldman HI: KDOQI US commentary on the 2012
be used to reduce unexplained variability in decision KDIGO clinical practice guideline for the evaluation and man-
making and ultimately, the therapeutic outcomes of tox- agement of CKD. Am J Kidney Dis 63: 713–735, 2014
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between eGFR and true GFR and how these values Tavaré S, Earl H: New model for estimating glomerular filtration
correlate to absolute and BSA-indexed drug dosing, drug rate in patients with cancer. J Clin Oncol 35: 2798–2805, 2017
eligibility, and clinical trial enrollment. This illustrates 13. Janus N, Launay-Vacher V, Byloos E, Machiels JP, Duck L, Kerger J,
the need for additional studies investigating the validity Wynendaele W, Canon JL, Lybaert W, Nortier J, Deray G, Wildiers
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dosing and eligibility guidelines to modern and more Aapro M: International Society of Geriatric Oncology (SIOG)
accurate estimates of kidney function, and clinical har- recommendations for the adjustment of dosing in elderly
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2007
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Gross CP, Lichtman SM, Gajra A, Glezerman I, Katheria V, Zavala
L, Smith DD, Sun CL, Tew WP: Association between renal
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J.H.B. received grants P30-CA47904 and UM1-CA186690 from cancer. J Geriatr Oncol 8: 96–101, 2017
the National Cancer Institute, National Institutes of Health during 16. Kintzel PE, Dorr RT: Anticancer drug renal toxicity and elimi-
the conduct of the study. nation: Dosing guidelines for altered renal function. Cancer Treat
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Disclosures Thompson MA, Roach N, Schenkel C, Bruinooge SS, Cortazar P,
T.D.N. reports personal fees from MediBeacon outside the sub- Walker D, Fehrenbacher L: Modernizing clinical trial eligibility
mitted work. M.A.C. and J.H.B. have nothing to disclose. criteria: Recommendations of the American Society of Clinical
Oncology-Friends of Cancer Research Organ Dysfunction, Prior
or Concurrent Malignancy, and Comorbidities Working Group. J
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