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Cachexia,

Malnutrition, the
R e f e e d i n g S y n d ro m e ,
a n d L e s s o n s f ro m
Goldilocks
a,b b,c,
J. Alexander Palesty, MD , Stanley J. Dudrick, MD *

KEYWORDS
 Cachexia  Malnutrition  Nutritional support
 Refeeding syndrome

Although the explosion of interest in clinical nutrition became manifest more than two
decades ago, the keen attention to nutrition and its practical applications to clinical
situations continues at an unprecedented rate in the arenas of basic research, clinical
investigation, and technologic development. Recognition of the importance of nutri-
tional care has allowed patients with even the most advanced and/or complicated
diseases to survive major physiologic insults with minimal morbidity and mortality.
The advent of total parenteral nutrition (TPN), followed by the extraordinary progress
in parenteral and enteral feedings and their currently widespread availability, in addi-
tion to the improved understanding of cellular biomechanics and biochemistry, has
allowed clinicians to combat starvation and malnutrition with much more zeal and
effectiveness because of their ability to deliver diets formulated and designed not
only for general nutritional support but also specifically for the treatment of special
patient problems and deficiencies.
Cachexia, in particular the cachexia of cancer, is one of the areas in which recent
advances in clinical nutrition have had a profound impact on patient care. It is appre-
ciated widely by clinicians that significant malnutrition accompanies malignant

The authors have nothing to disclose.


a
Department of Surgery, University of Connecticut School of Medicine, 263 Farmington
Avenue, Farmington, CT 06030, USA
b
Department of Surgery, Saint Mary’s Hospital, 56 Franklin Street, Waterbury, CT 06706, USA
c
Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven,
CT 06510, USA
* Corresponding author. Department of Surgery, Saint Mary’s Hospital, 56 Franklin Street,
Waterbury, CT 06706.
E-mail address: [email protected]

Surg Clin N Am 91 (2011) 653–673


doi:10.1016/j.suc.2011.02.007 surgical.theclinics.com
0039-6109/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
654 Palesty & Dudrick

processes in approximately 50% of patients and eventually leads to severe wasting,


which accounts for approximately 30% of cancer-related deaths overall.1,2 The
body wasting known as cancer cachexia is a complex syndrome characterized by
progressive tissue depletion and decreased nutrient intake that is manifested clinically
as inexplicable, recalcitrant anorexia and inexorable host weight loss. Decreased
nutritional intake, increased metabolic expenditure, and dysfunctional metabolic
processes, including hormonal and cytokine-related abnormalities, all seem to play
roles in the development of cancer cachexia.1,3 Although this condition of advanced
protein-calorie malnutrition, sometimes described as the cancer anorexia-cachexia
syndrome, is not entirely understood, it seems to be multifactorial, is a major cause
of morbidity and mortality in cancer patients, and ultimately leads to death.
Therapeutic nutritional interventions to correct or reverse cachexia have met with
little success, and, despite tremendous efforts throughout the decades, the exact
nature of the mediators responsible for cancer cachexia remain elusive. The patho-
genesis of cancer cachexia seems related to proinflammatory cytokines, alterations
in the neuroendocrine axis, and tumor-derived catabolic factors. Despite trials of
conventional and/or aggressive nutritional support by myriad feeding techniques,
patients with cancer cachexia have failed to gain consistent significant benefits in
terms of weight gain, functional ability, quality of life, or survival. Additionally, attempts
to ameliorate the abnormal clinical and metabolic features of cancer cachexia with
a variety of pharmacologic agents have met with only rare and limited success.
A thorough understanding of the basic metabolic derangements and the effects of
the available nutritional supportive measures can assist in reducing the morbidity and
mortality of malnourished and/or starving patients. It is the responsibility of health care
providers to sick patients to maintain optimal organ and system integrity to allow cells
to perform their individual specialized functions to their maximal capacity, thereby
restoring and maintaining patients’ homeostasis and nutritional health. Herein,
a detailed overview of the cachexia of cancer and review of two of the sentinel articles
on malnutrition, starvation, and refeeding and the lessons gleaned therefrom provide
clinicians, both novice and expert, with efficacious and thought-provoking knowledge
of the still rapidly evolving and vital discipline of nutritional care of malnourished
patients.4,5 An additional goal is to caution and familiarize practitioners of nutritional
support regarding some of the consequences associated with attempting to re-
establish the delicate physiologic balance of metabolic and nutritional homeostasis
too rapidly and/or excessively.

CACHEXIA AND CANCER

Cachexia results from the inexorable and recalcitrant progression of nutritional dete-
rioration, which occurs in approximately 50% of patients with malignant disorders and
in approximately 80% of patients with cancers involving the upper gastrointestinal
tract. It is among the most debilitating and life-threatening aspects of cancer and
results in body mass wasting that accounts for up to 30% of cancer-related deaths.2
Clinically, the cancer-cachexia syndrome is characterized primarily by anorexia, early
satiety, wasting, weight loss, weakness, fatigue, poor mental and physical perfor-
mance, decreased capacity for wound healing, impaired immunologic function, and
a compromised quality of life, none of which is resolved by forced nutrient intake.1,2
Diminished nutritional intake, increased metabolic expenditure, and disordered or
malfunctioning metabolic processes, including hormonal and cytokine-related abnor-
malities, all seem to play roles in the development of cancer cachexia.2,3 Although this
condition of advanced protein-calorie malnutrition, frequently referred to as the cancer
Cachexia, Malnutrition, and the Refeeding Syndrome 655

anorexia-cachexia syndrome, is not entirely understood, it seems to be multifactorial,


is a major cause of morbidity and mortality in cancer patients, and ultimately leads to
death.3,6
The origin of the word, cachexia, is both descriptive and incriminating. It is derived
from the Greek words, kakos (meaning bad) and hexis (meaning condition, habit, or
state of being).1,3 Cancer cachexia was first reported as a commonly occurring
syndrome more than 70 years ago, when an autopsy series of 500 cancer patients
documented that the immediate cause of death in cancer patients was secondary
to inanition in 114 (22%) of the patients, and that up to two-thirds of this cadre of
patients exhibited some degree of cachexia.7 Since then, the scope of malnutrition
in cancer patients has been studied in a wide variety of patient groups. In a series
of 3047 patients enrolled in the Eastern Cooperative Oncology Group chemotherapy
protocols, who were all assessed for weight loss before initiating chemotherapy,
survival was significantly lower in the patients who demonstrated weight loss when
compared with those who had not lost any weight before starting chemotherapy.8,9
In this study group, patients with breast cancer or sarcomas had the lowest frequency
of weight loss (31% to 40%), patients with colon cancer had an intermediate
frequency of weight loss (48% to 61%), and patients with pancreatic or gastric cancer
had the highest frequency of weight loss (83% to 87%), with approximately one-third
of these patients having presented initially with greater than 10% weight loss.8,9 In
a prospective study of 280 cancer patients, malnutrition was related predominantly
to tumor type and site, with stomach and esophageal cancer patients demonstrating
significantly higher degrees of malnutrition compared with the other groups. More-
over, as expected, malnutrition was shown to increase in severity as the disease
advanced.10 In another study of 365 patients with gastrointestinal cancer, almost
50% percent were shown to be malnourished. The incidence of malnutrition was
related to the site of the disease, and the stage of the disease was identified as
a predictor of weight loss, with more than 50% of stage III patients manifesting
malnutrition.11
Although nutritional status is usually evaluated by a combination of clinical assess-
ment and anthropometric tests, including body weight, skin-fold thickness, and mid-
arm circumference, most clinicians rely on body weight as the major measure of
nutritional status, using usual adult body weight as a point of reference.1 Cachexia
should be expected if an involuntary or unexpected weight loss of greater than 5%
has occurred within a previous 6-month period, especially when combined with
muscle wasting. A weight loss of 10% or more ordinarily indicates severe depletion
but can also be used as a starting criterion for the anorexia-cachexia syndrome in
obese patients. Body compartment analysis has shown that patients with cachexia
lose approximately equal amounts of fat and fat-free mass. Losses of fat-free mass
occur primarily from skeletal muscle and reflect decreases both in cellular mass and
intracellular potassium concentration.12 In comparison to patients with stable weight,
cancer patients with documented 5% weight loss have a shorter median survival rate,
respond more poorly to chemotherapy, and experience increased toxicity to
chemotherapy.1,8,13
Understanding the multiple nutritional, metabolic, and physiologic changes that can
occur provides the basis for evaluating the requirements for nutritional support in
various clinical situations and for planning and providing support as indicated.
Although a localized tumor may exert various initial systemic and generalized effects
in a patient, as the tumor grows and metastasizes, these effects often become even
more obvious as a result of the increased tumor burden and its local and distant inva-
sion. Additionally, some malignant tumors can produce effects at a distance from the
656 Palesty & Dudrick

original tumor or its metastases, further compounding malnutrition.14 The nutritional


problems associated with neoplastic disease that can cause or contribute to the
development of cancer cachexia are outlined in Box 1.

METABOLIC PATHOPHYSIOLOGY OF CANCER CACHEXIA

Inability to gain and/or maintain weight despite seemingly adequate nutrient intake
could be due to these obvious possibilities: (1) increased metabolic needs generated
by the accentuated nutritional demands of the semiautonomous tumor; (2) generalized
increased energy expenditure in the cancer patient; and (3) maladaptive metabolism
(ie, failure of the cancer patient’s host tissues to use the nutrients available efficiently
and effectively to satisfy the energy requirements of the body).3 Although malignant
cells do have their own specific nutrient requirements and do expend energy, it has
been shown that these does not fully explain the cancer cachexia-anorexia syndrome
in human cancer patients.15 Therefore, it is important to differentiate data reported
from animal tumors, which tend to represent a much larger proportion of the total
body weight of the organism, from data reported from human tumors, which generally
represent a much smaller proportion of the weight of the host.
Many studies of resting energy expenditure (REE) and basal energy expenditure
have been performed to establish whether cancer patients are hypermetabolic.15
These studies have demonstrated that approximately 60% of cancer patients have
abnormal REE, of whom approximately 35% are hypometabolic and 25% are hyper-
metabolic. A confounding aspect of these studies is that lean body mass, rather
than total body mass, correlated with alterations found in measured REE. Thus, cancer
patients, who ordinarily have early diminished lean body mass, may be expected to
have energy expenditure levels which are low for their total weight and what seems
to be hypometabolism may really represent a eumetabolic state. Despite this nonstan-
dard interpretation of REE data in cachectic cancer patients, it seems that although
hypermetabolism of the host and/or tumor plays a role in cancer cachexia, hyperme-
tabolism does not suffice as a complete explanation of the cancer-cachexia syndrome.
A summary of the current status of the understanding of the metabolic maladapta-
tion of cancer patients to decreased nutrient intake and increased metabolic caloric
needs of both the tumor and the host includes increased hepatic glucose production;
failure of uptake of the gluconeogenic glucose by muscle, resulting in proteolysis and
production of glycogenic amino acids; uptake and use of glucose by tumor cells with
resulting lactate production and occasional lactic acidosis; and increased lipolysis
with production of fatty acid and glycerol, ultimately used for energy and further gluco-
neogenesis (Box 2). Thus, the nutritional requirements of the tumor are selectively
favored over those of the host by these aberrant metabolic mandates in cancer
patients.3

PATHOGENIC MECHANISMS OF ANOREXIA

The intake of energy substrates is significantly reduced in cancer patients who lose
weight, and although anorexia is unlikely to be responsible solely for the wasting
seen in cancer patients, it may be a substantial contributing factor.3,16,17 Cancer
patients, especially those with gastrointestinal cancer, may frequently suffer from
physical obstruction of the alimentary tract, pain, constipation, maldigestion, malab-
sorption, debility, or the side effects of therapy, including opiates, radiotherapy, or
chemotherapy, any of which may lead to decreased food intake.18,19 Additionally,
hypercalcemia associated with cancer is a fairly common condition that can cause
nausea, vomiting, and weight loss as well as other untoward side effects. Moreover,
Cachexia, Malnutrition, and the Refeeding Syndrome 657

Box 1
Nutritional problems associated with the development of cancer cachexia

1. Anorexia and early satiety with progressive weight loss and undernutrition
2. Altered taste or dysgeusia causing hypophagia, food aversion, or altered food intake
3. Alterations in protein, carbohydrate, and fat metabolism
4. Increased energy expenditure despite decreased body mass
5. Impaired food intake secondary to
a. Mechanical obstruction of the gastrointestinal tract at any level
b. Intestinal dysmotility induced by various tumors
6. Malabsorption secondary to
a. Deficiency or inactivation of pancreatic digestive enzymes
b. Deficiency or inactivation of bile salts
c. Failure of ingested food to mix and interact effectively with digestive enzymes
d. Intestinal fistulas—internal and/or external
e. Infiltration of the small bowel wall or lymphatics and mesentery by malignant cells
f. Blind loop syndrome with associated bacterial overgrowth
g. Malnutrition-induced villous hypoplasia in the small intestine
7. Protein-losing enteropathy
8. Metabolic abnormalities induced by tumor-derived eutopic hormones or peptides
a. Hypoglycemia induced by insulin-secreting tumors
b. Hyperglycemia induced by islet glucagonoma or somatostatinoma
c. Hypercalcemia and hypophosphatemia with osteomalacia induced by parathyroid
hormone–like polypeptides secreted by some tumors
d. Anemia secondary to chronic blood loss and/or bone marrow suppression
9. Electrolyte and fluid derangements secondary to
a. Persistent vomiting and intestinal obstruction or intracranial tumors
b. Intestinal fluid losses through fistulas or diarrhea
c. Intestinal secretory abnormalities with hormone-secreting tumors, such as
i. Carcinoid syndrome
ii. Zollinger-Ellison syndrome (gastrinoma)
iii. Verner-Morrison syndrome (VIPoma)
iv. Villous adenoma
v. Increased calcitonin
d. Inappropriate antidiuretic hormone secretion associated with specific tumors, such as
lung carcinomas
e. Hyperadrenalism secondary to tumors producing corticotropins or corticosteroids
10. Miscellaneous organ dysfunction with nutritional complications, such as intractable gastric
ulcers with gastrinomas, Fanconi syndrome with light chain disease, or coma with brain
tumors
11. Tumor products stimulating monocyte production of various interleukins

Data from Shils ME. Nutrition and diet in cancer management. In: Shils ME, Olson JA, Shike M,
editors. Modern nutrition in health and disease. 8th edition. Philadelphia: Lea & Febiger; 1994.
p. 1317–48.
658 Palesty & Dudrick

Box 2
Abnormalities of carbohydrate, protein, and fat metabolism associated with cancer cachexia

Carbohydrate Metabolism
Glucose intolerance
Insulin resistance
Abnormal insulin secretion
Impaired glucose clearance
Increased glucose production
Increased glucose turnover
Increased Cori cycle activity
Protein Metabolism
Increased whole-body protein turnover
Increased protein fractional synthesis rates in the liver
Decreased fractional synthesis rates in muscle
Increased hepatic protein synthesis
Recalcitrant muscle protein breakdown
Decreased plasma levels of branched-chain amino acids
Fat Metabolism
Excess body fat depletion relative to body protein loss
Increased lipolysis
Increased free fatty acids
Increased glycerol turnover
Decreased lipogenesis
Hyperlipidemia
Failure of glucose to suppress oxidation of free fatty acids.
Decreased serum lipoprotein lipase activity despite normal insulin availability

Data from Shils ME. Nutrition and diet in cancer management. In: Shils ME, Olson JA, Shike M,
editors. Modern nutrition in health and disease. 8th edition. Philadelphia: Lea & Febiger; 1994.
p. 1317–48.

anorexia is an extremely distressing syndrome because appetite and the ability to eat
have been reported to be the most important factors in the physical and psychological
aspects (especially depression) of a patient’s quality of life.20,21 No clinical cause of
reduced food intake is obvious, however, in a large number of patients with cancer
and cancer cachexia. The early satiety that accompanies reduced appetite in anorectic
cancer patients has been postulated to be caused by the production of tumor cell
factors that exert their effects by acting on hypothalamic sensory cells.22 Possible
factors include the satietins, in particular satietin D, which have been purified from
human plasma and have been shown to produce a long-lasting anorectic effect
when injected into rats, although the role of the satietins in the development of anorexia
has not been established. Another possible cause of anorexia is the increased seroto-
nergic activity within the central nervous system of patients with cancer cachexia,
attributed to the enhanced availability of tryptophan to the brain. A close relationship
Cachexia, Malnutrition, and the Refeeding Syndrome 659

between elevated plasma-free tryptophan and anorexia has been observed in patients
having cancer and reduced food intake.23 The fact that uptake of tryptophan into the
brain is competitive with uptake of branched-chain amino acids has suggested the
use of branched-chain amino acids to decrease the incidence of anorexia.23 Because
weight loss is such a potent stimulus to food intake in healthy human beings, the persis-
tence of anorexia in cancer patients implies a failure of this adaptive feeding response,
which is so impressive and effective in normal human beings.24–27
A hormone secreted by adipose tissue, leptin, is now known to be an integral
component of the mechanism for body weight recognition.19,28–35 Because weight
loss causes leptin levels to fall in proportion to the loss of body fat, it seems that leptin
plays an important role in triggering the adaptive response to starvation.1 The activity
of the hypothalamic or orexigenic signals that stimulate feeding and suppress energy
expenditure are increased by low leptin levels in the brain, which also increase the
activity of anorexigenic signals that suppress appetite and increase energy
expenditure.1,24–27 In experimental animals that are fasted, most of the orexigenic
signals are known to be up-regulated, suggesting that these signals play an important
role in facilitating the recovery of lost weight. It seems that neuropeptide Y produced in
the hypothalamus binds to a receptor (Y-5) in adjacent hypothalamic cells, which in
turn increases the response of additional neuropeptide Y and stimulates the neuronal
basis of appetite.3 It has further been shown that leptin also binds to Y-5, inhibiting
neuropeptide Y activity and producing satiety.36 Recently, glucagon-like peptide 1
and urocortin have also been shown to be appetite suppressants.3,37,38
The cancer-anorexia syndrome may result from circulating factors produced by the
tumor or by the host in response to the tumor, and several cytokines have been
proposed as possible mediators of the cachetic process.19 Elevated serum levels of
tumor necrosis factor a, interleukin 1, and interleukin 6 have been found in some
but not all cancer patients, and the serum levels of these cytokines seem to correlate
with the progression of the tumor.22,39,40 Interferon alpha, interferon gamma, and
leukemia inhibitory factor are additional cytokines that have been postulated as play-
ing a role in the etiology of cancer cachexia but have not been proved to be respon-
sible solely for the induction of cachexia.22 Chronic administration of these cytokines,
however, either alone or in combination, is capable of inducing reduced food intake
and reproducing the cancer anorexia-cachexia syndrome.19,22,39–43 These cytokines
may produce long-term inhibition of appetite and feeding by stimulating the produc-
tion and release of leptin and/or by mimicking the hypothalamic effect of excessive
negative feedback signaling from leptin, leading to the normal compensatory mecha-
nisms for decreases in food intake and body weight.1,19,24–27,29,30,32,35,44–47 Thus, the
weight loss that occurs in cancer patients differs considerably from that which occurs
in simple starvation in otherwise healthy human beings.
Melanocortins, a family of regulatory peptides, which include corticotropin and the
melanocyte-stimulating hormones, have recently been reported as potential contribu-
tory factors in anorexia and cachexia.1,48–50 This group of peptides and their receptors
are important in memory, behavior, and immunity but also help to regulate appetite
and body temperature.19,31,33,34 In animal studies, the melanocortin system remained
active during cancer-induced cachexia, whereas the normal response to marked loss
of body weight would have resulted in down-regulation of the anorexigenic melano-
cortin signaling system to conserve energy stores. Moreover, blockade of the melano-
cortin receptor reversed the anorexia and cachexia in the animals, suggesting
a pathogenetic role for this system.19,48–50
The specific role of the various factors in the cancer anorexia-cachexia syndrome
and their relative importance remain to be clarified. It is presumed that anorexia is
660 Palesty & Dudrick

caused by the same mediator or mediators that also produce the metabolic derange-
ments of cancer cachexia itself. Use of antianorectic agents alone may improve quality
of life in cancer patients but may not solve the problem of anorexia and its associated
morbidity and mortality in cancer patients.16
The role of hormones in the cancer anorexia-cachexia syndrome must be consid-
ered because of the obvious roles that hormones play in the intermediary metabolism
of carbohydrates.51 Insulin, epinephrine, corticotropin, human growth hormone, and
insulin-like growth factor have all been suggested to have a role in the anorexia-
cachexia syndrome. During early starvation, decreased insulin levels and increased
glucagon and epinephrine result in activation of cyclic adenosine monophosphate
and of a protein kinase that activates hormone-sensitive lipase. Failure of this normal
mechanism may account for the weight loss in cancer patients, who have increased
rates of glycerol and free fatty acid turnover compared with starved healthy patients.16
Recent studies have indicated the presence of an acidic peptide in animal tumors,
which seems to have lipolytic properties that could lead to some of the characteristics
of the cancer-cachexia syndrome.16,52 This factor seems to be a proteoglycan
which has been found in the urine of murine species with tumors as well as in human
patients with cancer anorexia-cachexia syndrome involving weight loss of greater than
1.4 kg.16,52 This proteoglycan has been shown to mobilize free fatty acids from
adipose tissue and amino acids from muscle in animals, which prompted the investi-
gators to suggest that the role of these tumor products is to mobilize nutrients for
which the tumor has the greatest affinity and which results in further increased tumor
growth. Investigations are currently under way to determine whether this proteoglycan
is widely present in cachectic human cancer patients and whether its pathophysio-
logic actions mimic those of the cancer anorexia-cachexia syndrome.3 A potentially
clinically useful feature of this research is the discovery of an antagonist (eicosapen-
taenoic acid) of this proteoglycan which could have a role in the treatment of the
human anorexia-cachexia syndrome.16,53
It is highly likely that multiple mediators rather than a single mediator probably
account for the metabolic and pathophysiologic abnormalities associated with the
anorexia-cachexia syndrome. It is possible, indeed likely, that tumor cells produce
multiple active peptides or glycopeptides, that they also stimulate the induction of
additional cytokines or lymphokines from host immune cells and that they stimulate
abnormal hormonal responses to the metabolic stress induced by the malignancy.
Alternatively, it is unlikely that a single factor could account for the hypermetabolism,
abnormal glucose metabolism, protein gluconeogenesis, and insulin resistance in
addition to the anorexia, anemia and fever that accompany the cancer anorexia-
cachexia syndrome.

NUTRITIONAL SUPPORT WITH CANCER CACHEXIA

Early studies promoted optimism that judicious enteral or parenteral nutritional


support might overcome cancer anorexia, and modulate or obviate malnutrition and
cancer cachexia.19,54–56 The failure of aggressive nutritional support to increase
lean body mass, however, especially skeletal muscle mass, in patients with cancer
cachexia has been disappointing. In a meta-analysis of 28 randomized studies
of cancer patients receiving TPN, the use of TPN preoperatively in patients with
gastrointestinal cancer helped reduce major surgical complications and operative
mortality significantly, but no significant benefit was shown on survival, tolerance of
treatment, toxicity, or tumor response in patients receiving chemotherapy and
TPN.57 A survey analyzing results individually for patients receiving radiation therapy
Cachexia, Malnutrition, and the Refeeding Syndrome 661

and chemotherapy and for patients undergoing major surgery concluded that the
routine use of preoperative intravenous feeding should be limited to patients unable
to sustain lean body mass by oral or enteral feeding.58 The investigators stated further
that intravenous feeding had not been documented to affect responses either to
therapy or survival favorably in patients receiving radiation therapy or chemotherapy.
Rhey further stated, however, that selecting patients for support with TPN remains
a matter of clinical judgment and that when therapy response rates and malnutritional
morbidity are high, intravenous feeding should be instituted until the host can recover
from the effects of antitumor therapy.58 The investigators concluded additionally that
there is clear evidence that in individual patients with cancer, intravenous feeding can
prevent death from starvation and decrease the morbidity of treatment, but only those
patients undergoing surgery for gastrointestinal tract neoplasia have benefited signif-
icantly from the addition of adjuvant intravenous feeding.58 Another subsequent
review concluded that chronically malnourished patients given nutritional support
often have restoration of a sense of well-being and become more physically functional;
however, whether this support results in long-term clinical benefits is difficult to
evaluate.59 The investigators stated also that it seems that routine application of nutri-
tional support to all patients undergoing treatment for malignancy is not justified and
that the primary indication for nutritional support is for malnourished patients under-
going a major operation for upper gastrointestinal malignancy and for chemotherapy
patients with severe gastrointestinal dysfunction.59 In another analysis of 18 trials in
children with cancer, the investigator acknowledged the clear benefits of nutritional
support in patients undergoing bone marrow transplantation; however, he stated
that there seems to be little support for routine aggressive nutritional support in
nonsurgical oncology patients.60 Nonetheless, the investigator concluded further
that circumstances exist in which aggressive nutritional support by any and all routes
should be provided, especially during prolonged inability to eat, when nutrition is
secondary to poor intake, when a nutrition support team is available to decrease
related complications, and when the tumor present is deemed likely to respond to anti-
neoplastic treatment.60 Additionally, parenteral nutrition (PN) may facilitate administra-
tion of complete chemoradiation therapy dosages in esophageal cancer patients and
may have beneficial effects for certain patients with decreased food intake because of
mechanical obstruction of the gastrointestinal tract.61–63 Home PN can also be effica-
cious and rewarding for such patients.1 If the gastrointestinal tract can be used for
nutritional support, enteral nutrition has the advantage of maintaining the integrity of
the enterocytes, the mucosal barrier, and immunologic function as well as the advan-
tage of having lower cost and fewer adverse side effects.1,61,64 Experience, clinical
judgment, and wisdom all are important, although often subjective rather than objec-
tive, in making the usually difficult and challenging decisions in the management of
these unfortunate patients with their multiple ill-defined, poorly understood, and
vexing problems, which have few or no obvious solutions.
The effects of aggressive nutritional support on tumor growth and development
have been difficult to delineate in cancer patients and are still being debated.1,65 A
clear benefit of nutritional support, however, may be derived in cancer patients with
severe malnutrition who may require surgery or may have an obstructing tumor but
one that is potentially responsive to therapy.1,62,66,67 Experience has also indicated
that cancer patients with a severely dysfunctional alimentary tract resulting from radi-
ation, chemotherapy, surgery, or combinations thereof, but who are free of residual
malignant disease, are entitled to proper management by oral, enteral, and/or paren-
teral feeding support, which can lead to a prolonged life of good quality.14 The best
treatment for cancer cachexia, especially that related to cancer of the gastrointestinal
662 Palesty & Dudrick

tract, is to cure the cancer. Unfortunately, this lofty goal remains an infrequent
achievement currently among patients with solid tumors. Because a cure for cancer
is still under investigation and forthcoming, the best palliative or therapeutic options
available are to stimulate increased nutritional intake and ameliorate or prevent the
catabolism of muscle and fat. This can be accomplished to varying degrees with
a multitude of pharmacologic agents. A goal as monumental as this, however, would
be much easier to achieve if it were possible to identify the exact causes and mech-
anisms of the cancer cachexia-anorexia syndrome. Currently, only those elements of
decreased food intake directly related to the antineoplastic treatment, such as nausea,
vomiting, mucositis, and dysfunctional gastrointestinal motility, can be somewhat
controlled or modulated clinically. The most realistic and practical options at this
time are directed toward minimizing adverse gastrointestinal side effects or complica-
tions and increasing appetite and nutritional intake in an effort to improve quality of life.
The ability to target the myriad consequences caused by cachexia and its treatment as
related to cancer are derived in part from observations made by Cahill4 in a landmark
New England Journal of Medicine article that clearly and concisely outlined the phys-
iologic and metabolic derangements and adaptations that occur in fat, carbohydrate,
and protein metabolism in the starving human organism.

THE GENESIS OF MODERN THEORIES ON STARVATION AND MALNUTRITION

Intense interest in studying the effects and management of malnutrition followed


World War II, primarily because the scale of the global challenge was so broad and
because few scientific data existed on the basic physiologic responses to starvation.68
Cahill, in his article titled, “Starvation in Man,” submitted the proposition that fat and
protein are practically the only two fuel repositories in the human body with the caveat
that because proteins are metabolically active molecules integral to the daily operation
of the human engine, the more expendable fat is the primary and predominant energy
cache that is consumed during catabolism, thus conserving the more vital protein for
function. His fundamental conclusion was that 3 compensatory mechanisms interact
during starvation to spare protein from being used as the fuel for metabolism in the
human organism: (1) the exclusion of glucose as a fuel source from the majority of
tissues in favor of fatty acids; (2) the adaptation of the Cori cycle to shuttle glucose
to the peripheral tissue by breaking down lipid, then returning lactate to the liver, which
resynthesizes the lactate into glucose; and (3) the ability of the brain to use keto acids
for energy to spare glucose, thus ultimately also preserving protein. He observed
further that insulin is the dominant hormone that controls and maintains homeostasis
during starvation and that glucagon also has an important role, which at that time was
undefined. In addition, he noted that fat and fat-derived fuels are used preferentially
and almost exclusively in starvation for energy and demonstrated that during the fast-
ing state, muscle, adipose tissue, the liver, and kidneys all work in conjunction to
supply, convert, and conserve fuel for the body.
According to Cahill, the human body in its normal metabolic state incorporates
approximately 0.3 kg of glycogen, 10 to 15 kg of triacylglycerol, and 6 kg of mobiliz-
able muscle as potential energy sources. Only skeletal muscle and the liver have
enough glycogen stores to provide for the daily needs of the entire body under ordi-
nary circumstances. Liver glycogen is exhausted within 18 to 24 hours of starvation,
however, and muscle glycogen is not easily available for use, but it can be converted
to glucose through exportation to the liver as pyruvate, lactate (the Cori cycle), and/or
alanine. Conversely, liver glycogen is readily available for mobilization and, in the fast-
ing state, is quickly depleted.69 Hence, as the available glycogen is depleted,
Cachexia, Malnutrition, and the Refeeding Syndrome 663

gluconeogenesis is required for the production of glucose. Another source of glucose


is fat but, unfortunately, most of the energy stored as fat by most organs and tissues is
not available completely for general use because it is required to provide this source of
glucose primarily to the organ or tissue of origin. In the starved state, other glucose
dependent organs, such as the brain, have adapted to the relative glucose deficiency
that accompanies starvation by using ketone bodies converted from free fatty acids as
their energy source.
The primary goal in caring for nutritionally depleted patients is the preservation of
functional protein. Although it was initially thought that supplemental dietary protein
would have no effect on lean muscle mass in starvation, studies have now confirmed
that high protein intake in energy deficient states does spare and/or restore lean
muscle mass.70–76 This is a most important factor to take into consideration when
formulating nutrition support regimens for malnourished critically ill patients regard-
less of the avenue of nutrient administration.
Despite the scientific progress since Cahill’s article, the events leading to, or driving,
the metabolic changes in starvation are still incompletely understood. Subtle
decreases in plasma glucose concentrations and the subsequent fall in the plasma
insulin/glucagon ratio, as well as an increase in plasma epinephrine, has been docu-
mented to occur.77,78 Intuitively, one would think that because these hormones are
catabolic, there would be an increase in muscle protein breakdown; however, it is
spared. It is postulated that protein preservation is stimulated by the decrease in
production of triiodothyronine toward its inactive form, reverse triiodothyronine, which
effectively reduces the body’s metabolic rate. This may subsequently reduce the rate
of overall protein consumption.79
Notwithstanding the improved understanding of the biomechanics and physiology
of starvation, the rate of malnutrition has not changed significantly in the past 40 years,
and malnourishment continues to be documented in up to 50% of hospitalized
patients who present with various degrees of protein-calorie malnutrition.80,81 The
degree to which patients are malnourished directly correlates with outcome, in partic-
ular, morbidity and mortality. The misunderstanding that patients with a normal serum
albumin level cannot be malnourished can lead to inappropriate management. In order
to treat these individuals appropriately, it is helpful to categorize them into one of 3
groups: marasmus, kwashiorkor, or mixed malnutrition. The improved understanding
of the basic biochemical and physiologic derangements that occur in each of these
very different malnourished states has allowed clinicians to focus their attention and
management on the fundamental cellular disorder.
Marasmus, or simple starvation, develops insidiously, and it results from the body’s
attempt to adapt to an insufficient caloric intake. Causative factors include alcoholism,
central nervous system insult, old age, and chronic debilitating disease. Cachexia,
wasting, and clinical signs of nutritional deficiencies are the clinical hallmarks of
marasmic patients. Attempts at aggressive nutritional resuscitation may precipitate
development of peripheral edema, which is not otherwise a component of this form
of malnutrition.
Experience with kwashiorkor, also known as immunorepressive malnutrition or
hypoalbuminemic malnutrition, is drawn predominantly from the third world countries.
This form of malnutrition is manifest in patients who have adequate caloric intake but
inadequate protein intake.68 They often have a fatty liver, edema, hypoalbuminemia,
hyponatremia, and dermatosis.82 Although these patients may overtly appear well
nourished, they have severe deficits in protein stores and immune function, which
have prompted the use of more descriptive, alternative names for kwashiorkor, immu-
nosuppressive malnutrition or hypoalbuminemic malnutrition.83
664 Palesty & Dudrick

Those patients with mixed malnutrition exhibit a combination of marasmus and


immunosuppressive or hypoalbuminemic malnutrition and have a higher morbidity
and mortality because of the increased magnitude of the physiologic insult.82 Patients
may initially present with one form of malnutrition secondary to the original physiologic
insult that eventually transitions to the other because of advancing metabolic severity.
The principal goal of nutritional therapy in these clinical scenarios is to preserve lean
muscle mass and function. Clinicians’ intuitive response in coping with any of these
forms of malnutrition is to re-establish nutritional integrity as quickly and as completely
as possible. A pivotal article in 1981 by Weinsier and Krumdieck,84 who revisited the
refeeding syndrome induced by the overenthusiastic application of TPN in starving
patients, seemingly paradoxically, cautions against rapid nutritional restoration, espe-
cially in chronically cachetic patients who have become well adapted to caloric
deprivation.
Their report describes two chronically malnourished patients who were aggressively
administered nutritional support with PN and who, in contradistinction to expected
results, deteriorated secondary to cardiopulmonary failure and died within 48 hours.
Both patients had received approximately twice the recommended load of carbohy-
drate and protein in their initial PN regimen. Each of these individuals abruptly devel-
oped hypophosphatemia, which was postulated to be induced by increased
intracellular transport of phosphate for glycolysis in these depleted patients. Because
fat catabolism, which is the primary source of energy in the starved state, does not
require phosphate, the sudden shift to glucose as a fuel source increased the demand
for phospate. Both patients also had clinical and laboratory findings consistent with
myocardial ischemia, and their acute cardiac decompensation was thought to be
directly related to the rapid onset of hypophosphatemia. They also suffered from other
collateral metabolic abnormalities, such as hypomagnesemia, hypocalcemia, hypoka-
lemia, hyperglycemia, and acidosis. The resultant complications from refeeding were
all associated with the abrupt shift from the consumption of endogenous fat to the use
of exogenously infused glucose as the primary fuel source. After recognition of this
problem, it was recommended that total calorie/protein requirements not be provided
vigorously in nutritional repletion regimens initially but rather be started cautiously at
lower levels and reached gradually over several days, with approximately 20% to
30% of total calories derived from fat.

THE REFEEDING SYNDROME

Interest in the refeeding syndrome initially arose during World War II when little was
known scientifically about human starvation or how to deal with refeeding people
who had severe degrees of nutritional deprivation.85 The question to be answered
at that time, and one that remains to be answered completely, is, What is the most
effective way of providing nutritional rehabilitation? In 1944, Keys and colleagues5
designed a human experiment to attempt to answer this question. The results of their
studies have prompted researchers to explore the metabolic adaptation of the human
body to gain insight into the optimal clinical management of starvation. The main
objective of Keys’ work was to observe and characterize the physical and mental
effects that starvation had on 36 otherwise healthy subjects. The young male volun-
teers were observed under normal conditions for 3 months while ingesting a 3200-
kcal diet. This was followed by a period of 6 months of starvation during which they
received an 1800-kcal low-protein diet to simulate the diets of the starved survivors
of the ravages of warfare. Subjects then under went a nutritional rehabilitative period
for 3 months. Each of 4 groups received different amounts of calories, and within those
Cachexia, Malnutrition, and the Refeeding Syndrome 665

groups, various subjects received different amounts of protein. Throughout each


phase of the study, a detailed record of each patient’s physiologic state was main-
tained, including ECGs, radiographs, laboratory studies, body weight, muscle mass,
and the results of endurance tests. During the period of nutritional replenishment,
several subjects developed cardiac failure, and Keys’ conclusions as to the cause,
although rudimentary, were fundamentally the same as those of more recent
investigators.84
There has been much investigation of the refeeding syndrome since the publication
of Weinsier and Krumdieck,84 and although hypophosphatemia and its associated
complications remain the hallmark signs, it is now well documented that patients
with refeeding syndrome also develop global electrolyte disorders, dyspnea, hyper-
capnia, tachycardia, elevated central venous pressure, congestive heart failure, and
cardiac arrest, among other clinical manifestations. Refeeding syndrome after the
overzealous feeding of malnourished patients via oral, enteral, and/or parenteral
routes is well recognized in starved individuals, chronic alcoholics, patients with
anorexia nervosa, depleted patients admitted from skilled nursing facilities, morbidly
obese patients with recent massive weight loss, and some critically ill postoperative
patients.86–90
Repleting malnourished patients nutritionally is a complex process and to coun-
teract prolonged starvation effectively, the intricate physiologic and metabolic effects
that occur when these depleted individuals are fed again at prestarvation levels must
be understood. The effects of depletion, repletion, and compartmental shifts of elec-
trolytes, fluids, and other substrates in response to excessive nutritional resuscitation
after prolonged starvation are defined as the refeeding syndrome. This so-called
syndrome was originally thought secondary only to hypophosphatemia but is under-
stand to also include hypokalemia, hypomagnesemia, and other derangements in
glucose control. The essential features of overly enthusiastic carbohydrate administra-
tion in severely undernourished patients include rapid falls in the plasma levels of phos-
phorus, potassium, and magnesium, coupled with sodium and water retention, leading
to fluid overload and altered glucose homeostasis. It must be re-emphasized that
aggressive attempts to correct the malnourished state by the well-intended reinstitu-
tion of feeding that causes these iatrogenic derangements is not without dire physio-
logic consequences that can be rather sudden, multiple, diverse, and potentially fatal.
More recent biochemical investigations support earlier work that the overzealous
reintroduction of carbohydrate into the system either orally, enterally, or parenterally
inhibits fat metabolism and promotes glucose metabolism, causing an increase in
the use of phosphate to produce phosphorylated intermediates of glycolysis, adeno-
sine triphosphate (ATP) and 2,3 diphosphoglycerate (2,3 DPG).91,92 This results in the
hypophosphatemia of refeeding. Additionally, the high glucose load induces hyperin-
sulinemia, which is postulated to be the cause of the increased intracellular water that
accompanies refeeding. Although the exact mechanism of this phenomenon is yet to
be delineated, it is thought that increased insulin levels may have an antinatriuretic
effect.93 Increased demand for the water-soluble vitamin thiamine also is noted in
malnourished patients, and it is difficult to determine if this results from a pre-
existing deficiency or if it is a result of refeeding. It is known that in malnourished
patients, high carbohydrate loads increase the demand for thiamine because it is
essential for the metabolism of carbohydrates during glycolysis.94 Its induced or
unmasked deficiency in the refeeding syndrome may be secondary to its increased
use when it is already in a scarce state in a malnourished individual.
Clinical manifestations of the refeeding syndrome are related directly to electrolyte
and vitamin deficiencies. Hypophosphatemia can lead to critical neurologic,
666 Palesty & Dudrick

respiratory, and cardiac abnormalities, as can hypokalemia and hypomagnesemia.


Vitamin deficiencies can cause severe encephalopathy and lactic acidosis. Sodium
retention can contribute to fluid overload, pulmonary edema, and cardiac
decompensation86,95 (Table 1). Hence, volume status and electrolyte intake and
balance must be closely monitored along with caloric intakes and sources, providing
patients with an appropriate mixture of fat and carbohydrate calories.5,96
In order to prevent and counteract the deleterious consequences of refeeding, clini-
cians must understand the homeostatic changes that take place in the starving human
organism under a variety of circumstances. The primary step in preventing refeeding
syndrome is to identify those individuals at risk before initiating nutritional support.
Regardless of the patient, avoiding overfeeding is essential, and, therefore, the
feeding regimen should be initiated with a small number of calories and the amount
incrementally increased slowly. The first day of nutritional support should comprise
approximately 25% of the estimated caloric goal and the quantity increased toward
the goal in a graduated manner over 3 to 5 days. Electrolyte abnormalities should
be addressed before initiating feedings, and electrolyte supplementation should be
provided as needed.95 Phosphate in particular should be closely monitored since
patients with severe malnutrition are likely to have depleted total body concentrations,
and, therefore, relatively higher requirements.97,98 In addition to fluid and sodium
intake, body weight should also be closely monitored during the first few days of nutri-
tional repletion to prevent cardiac decompensation in patients with an already
compromised cardiovascular system. It is recommended initially that approximately
20 mEq of sodium be given per day, that fluid be restricted to less than 1000 mL
per day, and that weight gain be limited to 1 kg per week because any greater accu-
mulation of weight is probably attributable to excessive water retention.95,99 In criti-
cally ill patients, it can also be helpful to monitor central venous pressure and
peripheral edema. Multiple vitamins should also be provided in therapeutic doses
according to the recommendations of the American Medical Association on a daily
basis, and additional supplementation should be given according to a patient’s
requirements.100 Clinicians should actively examine patients frequently for the signs
and symptoms associated with refeeding syndrome.
If the signs and symptoms of the refeeding syndrome become apparent, the treat-
ment consists of immediate cessation of the nutritional support being administered,
the correction of any electrolyte abnormalities, and any other indicated supportive
care. Neurologic, cardiac, and pulmonary dysfunction should all be addressed
accordingly (ie,intravenous thiamine for mental status changes, supplemental oxygen
for respiratory distress, and pressors for hypotension). Once all of these abnormalities
have been appropriately managed, nutritional support should be restarted cautiously,
preferably at 50% of the rate before symptom development. The volume and rate of
nutrient infusion should then be slowly advanced toward goal over several days
with close monitoring.92
Nutritional care in starved patients is a dynamic process that requires continual
monitoring and modification according to the metabolic needs of the patients to main-
tain stability and to promote nutritional restoration. It is of paramount importance that
clinicians understand that cachexia and starvation or malnourishment are separate
entities and require an appreciation for the unique complex metabolic abnormalities
of each to counteract them most effectively. The development of nutritional support
teams has allowed cachectic, starving, and/or malnourished patients to receive coor-
dinated and optimal nutritional care in an effort to correct and reverse the pathophys-
iologic state in a safe, efficient, and effective manner. These multidisciplinary, expert
teams also allow for prevention of the metabolic complications associated with
Table 1
Signs and symptoms of refeeding syndrome

Hypophosphatemia Hypokalemia Hypomagnesemia Vitamin Deficiencies Sodium Retention


Neurologic Neurologic Neurologic Encephalopathy Fluid overload
Paresthesias Paralysis Weakness Lactic acidosis Pulmonary edema
Weakness Weakness Tremor Cardiac decompensation
Delirium Cardiac Muscle twitching
Disorientation Arrhythmias Changed mental status
Encephalopathy Contraction changes Tetany

Cachexia, Malnutrition, and the Refeeding Syndrome


Areflexic paralysis Respiratory Convulsions
Seizures Failure Seizures
Coma Gastrointestinal Coma
Tetany Nausea Cardiac
Cardiac Vomiting Arrhythmias
Hypotension Constipation Gastrointestinal
Shock Other Anorexia
Deceased stroke volume Rhabdomyolysis Nausea
Deceased mean arterial pressure Muscle necrosis Vomiting
Deceased left ventricular stroke volume Diarrhea
Increased wedge pressure
Pulmonary
Diaphragmatic weakness
Respiratory failure
Dyspnea
Hematologic
Hemolysis
Thrombocytopenia
Leukocyte dysfunction

667
668 Palesty & Dudrick

refeeding by identifying those patients at risk, providing proper assessment, coordi-


nating interdisciplinary communication, and delivering timely and effective nutritional
intervention. Because of improved understanding of these deranged metabolic states,
conscientious, rational, informed, and thoughtful approaches to these patients have
decreased the morbidity and mortality associated with attempts to treat them. Now
and in the future, all clinicians should be sufficiently knowledgeable, trained, and
competent in nutritional support techniques and principles to avoid virtually
completely the adverse consequences of uninformed or ill-advised, overly aggressive,
nutritional rehabilitation. The paradigm to follow is that the state of starvation of
a patient did not occur acutely overnight and, therefore, should not, indeed must
not, be corrected acutely in the first few hours or days of treatment. Controversy
remains regarding the influence of aggressive nutritional support on the quality of
life of patients with advanced cancer, and it is important to consider the risks, benefits,
and ethical aspects involved before embarking on such a regimen. Physician atti-
tudes, patient age and prognosis, and family or patient perceptions often play impor-
tant roles in the decision to administer nutritional support, and these variables will
continue as issues during the patient’s course.101
Finally, the principles, practices, and procedures for safe oral, parenteral, and enteral
nutritional repletion of starved patients have been established for oral feeding by Keys
and associates more than 50 years ago; for PN by Dudrick and colleagues more than 35
years ago; and for enteral nutrition by the American Society for Parenteral and Enteral
Nutrition Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pedi-
atric Patients more than 10 years ago.5,102,103 In accordance with the principles derived
from “Goldilocks and the Three Bears” (ie, too large, too small, just right; too hot, too
cold, just right; and too high, too low, just right), the ultimate goal is to provide optimal
nutritional support to all patients under all conditions at all times in a judicious, rational,
and orderly manner. It is incumbent upon all members of the healthcare professions to
continue their dedication to teaching excellence, vigilance, prudence, and conscien-
tiousness in efforts to providing nutritional support that is “just right.”104

REFERENCES

1. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and


management. CA Cancer J Clin 2002;52(2):72–91.
2. Toomey D, Redmond HP, Bouchier-Hayes D. Mechanisms mediating cancer
cachexia. Cancer 1995;76(12):2418–26.
3. Puccio M, Nathanson L. The cancer cachexia syndrome. Semin Oncol 1997;
24(3):277–87.
4. Cahill GF Jr. Starvation in man. N Engl J Med 1970;282(12):668–75.
5. Keys A, Austin JB, Henshel A, et al. The biology of human starvation, volumes
I–II. Minneapolis (MN): University of Minnisota Press; 1950.
6. DeWys WD. Pathophysiology of cancer cachexia: current understanding and
areas for future research. Cancer Res 1982;42(Suppl 2):721s–6s.
7. Warren S. The immediate causes of death and cancer. Am J Med Sci 1932;184:
610–5.
8. DeWys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to
chemotherapy in cancer patients. Eastern cooperative oncology group. Am J
Med 1980;69(4):491–7.
9. Harrison L, Fong Y. Enteral nutrition in the cancer patient. In: Rombeau JL,
Rolandelli RH, editors. Clinical nutrition enteral and tube feeding. 3rd edition.
Philadelphia: WB Saunders; 1997. p. 300–23.
Cachexia, Malnutrition, and the Refeeding Syndrome 669

10. Bozzetti F, Migliavacca S, Scotti A, et al. Impact of cancer, type, site, stage and
treatment on the nutritional status of patients. Ann Surg 1982;196(2):170–9.
11. Meguid MM, Meguid V. Preoperative identification of the surgical cancer patient
in need of postoperative supportive total parenteral nutrition. Cancer 1985;
55(Suppl 1):258–62.
12. Kotler DP. Cachexia. Ann Intern Med 2000;133(8):622–34.
13. Rosenbaum K, Wang J, Pierson RN Jr, et al. Time-dependent variation in weight
and body composition in healthy adults. JPEN J Parenter Enteral Nutr 2000;
24(2):52–5.
14. Shils ME. Nutrition and diet in cancer management. In: Shils ME, Olson JA,
Shike M, editors. Modern nutrition in health and disease. 8th edition. Philadel-
phia: Lea & Febiger; 1994. p. 1317–48.
15. Heber D, Tchekmedyian NS. Mechanisms of cancer cachexia. Contemp Oncol
1995;(Special Issue):6–10.
16. Langstein HN, Norton JA. Mechanisms of cancer cachexia. Hematol Oncol Clin
North Am 1991;5(1):103–23.
17. Staal-van den Brekel AJ, Schols AM, ten Velde GP, et al. Analysis of the energy
balance in lung cancer patients. Cancer Res 1994;54(24):6430–3.
18. Barber MD, Ross JA, Fearon KC. Cancer cachexia. Surg Oncol 1999;8(3):
133–41.
19. Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition. BMJ 1997;
315(7117):1219–22.
20. Brennan MF. Uncomplicated starvation versus cancer cachexia. Cancer Res
1977;37(7 Pt 2):2359–64.
21. Padilla GV. Psychological aspects of nutrition and cancer. Surg Clin North Am
1986;66(6):1121–35.
22. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997;89(23):1763–73.
23. Cangiano C, Laviano A, Meguid MM, et al. Effects of administration of oral
branched-chain amino acids on anorexia and caloric intake in cancer patients.
J Natl Cancer Inst 1996;88(8):550–2.
24. Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic
role. J Clin Endocrinol Metab 1998;83(5):1407–13.
25. Inui A. Feeding and body-weight regulation by hypothalamic neuropeptides—
mediation of the actions of leptin. Trends Neurosci 1999;22(2):62–7.
26. Schwartz MW, Dallman MF, Woods SC. Hypothalamic response to starvation:
implications for the study of wasting disorders. Am J Physiol 1995;269(5 Pt 2):
R949–57.
27. Schwartz MW, Seeley RJ. Seminars in medicine of the Beth Israel Deaconess
Medical Center. Neuroendocrine responses to starvation and weight loss.
N Engl J Med 1997;336(25):1802–11.
28. Bray GA, York DA. The MONA LISA hypothesis in the time of leptin. Recent Prog
Horm Res 1998;53:95–117 [discussion: 117–8].
29. Elmquist JK, Maratos-Flier E, Saper CB, et al. Unraveling the central nervous
system pathways underlying responses to leptin. Nat Neurosci 1998;1(6):
445–50.
30. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals.
Nature 1998;395(6704):763–70.
31. Inui A. Transgenic approach to the study of body weight regulation. Pharmacol
Rev Mar 2000;52(1):35–61.
32. Inui A. Transgenic study of energy homeostasis equation: implications and con-
founding influences. FASEB J 2000;14(14):2158–70.
670 Palesty & Dudrick

33. Kalra SP, Dube MG, Pu S, et al. Interacting appetite-regulating pathways in the
hypothalamic regulation of body weight. Endocr Rev 1999;20(1):68–100.
34. Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of
food intake. Nature 2000;404(6778):661–71.
35. Woods SC, Seeley RJ, Porte D Jr, et al. Signals that regulate food intake and
energy homeostasis. Science 1998;280(5368):1378–83.
36. Gerald C, Walker MW, Criscione L, et al. A receptor subtype involved in
neuropeptide-Y-induced food intake. Nature 1996;382(6587):168–71.
37. Donaldson CJ, Sutton SW, Perrin MH, et al. Cloning and characterization of
human urocortin. Endocrinology 1996;137(5):2167–70.
38. Spina M, Merlo-Pich E, Chan RK, et al. Appetite-suppressing effects of urocor-
tin, a CRF-related neuropeptide. Science 1996;273(5281):1561–4.
39. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key?
Cancer Res 1999;59(18):4493–501.
40. Moldawer LL, Rogy MA, Lowry SF. The role of cytokines in cancer cachexia.
JPEN J Parenter Enteral Nutr 1992;16(Suppl 6):43S–9S.
41. Gelin J, Moldawer LL, Lonnroth C, et al. Role of endogenous tumor necrosis
factor alpha and interleukin 1 for experimental tumor growth and the develop-
ment of cancer cachexia. Cancer Res 1991;51(1):415–21.
42. Matthys P, Billiau A. Cytokines and cachexia. Nutrition 1997;13(9):763–70.
43. Noguchi Y, Yoshikawa T, Matsumoto A, et al. Are cytokines possible mediators of
cancer cachexia? Surg Today 1996;26(7):467–75.
44. Haslett PA. Anticytokine approaches to the treatment of anorexia and cachexia.
Semin Oncol 1998;25(2 Suppl 6):53–7.
45. Mantovani G, Maccio A, Lai P, et al. Cytokine activity in cancer-related anorexia/
cachexia: role of megestrol acetate and medroxyprogesterone acetate. Semin
Oncol 1998;25(2 Suppl 6):45–52.
46. Moldawer LL, Copeland EM 3rd. Proinflammatory cytokines, nutritional support,
and the cachexia syndrome: interactions and therapeutic options. Cancer 1997;
79(9):1828–39.
47. Wigmore SJ, Plester CE, Ross JA, et al. Contribution of anorexia and hyperme-
tabolism to weight loss in anicteric patients with pancreatic cancer. Br J Surg
1997;84(2):196–7.
48. Lechan RM, Tatro JB. Hypothalamic melanocortin signaling in cachexia. Endo-
crinology 2001;142(8):3288–91.
49. Marks DL, Ling N, Cone RD. Role of the central melanocortin system in
cachexia. Cancer Res 2001;61(4):1432–8.
50. Wisse BE, Frayo RS, Schwartz MW, et al. Reversal of cancer anorexia by
blockade of central melanocortin receptors in rats. Endocrinology 2001;
142(8):3292–301.
51. Bartlett DL, Charland SL, Torosian MH. Reversal of tumor-associated hyperglu-
cagonemia as treatment for cancer cachexia. Surgery 1995;118(1):87–97.
52. Todorov P, Cariuk P, McDevitt T, et al. Characterization of a cancer cachectic
factor. Nature 1996;379(6567):739–42.
53. Beck SA, Smith KL, Tisdale MJ. Anticachectic and antitumor effect of eicosa-
pentaenoic acid and its effect on protein turnover. Cancer Res 1991;51(22):
6089–93.
54. Copeland EM 3rd, MacFadyen BV Jr, Lanzotti VJ, et al. Intravenous hyperalimen-
tation as an adjunct to cancer chemotherapy. Am J Surg 1975;129(2):167–73.
55. Copeland EM, Souchon EA, MacFadyen BV Jr, et al. Intravenous hyperalimen-
tation as an adjunct to radiation therapy. Cancer 1977;39(2):609–16.
Cachexia, Malnutrition, and the Refeeding Syndrome 671

56. Dudrick SJ, MacFadyen BV Jr, Souchon EA, et al. Parenteral nutrition tech-
niques in cancer patients. Cancer Res 1977;37(7 Pt 2):2440–50.
57. Klein S, Simes J, Blackburn GL. Total parenteral nutrition and cancer clinical
trials. Cancer 1986;58(6):1378–86.
58. Lowry SF, Brennan MF. Intravenous feeding of the cancer patient. In:
Rombeau JL, Caldwell MD, editors. Parenteral nutrition. Philadelphia: WB Saun-
ders; 1986. p. 445–70.
59. Shike M, Brennan MF. Supportive care of the cancer patient. In: DeVita VT,
Hellman S, Rosenburg SA, editors. Principles and practice of oncology. 3rd
edition. Philadelphia: JB Lippincott; 1989. p. 2029–44.
60. Lipman TO. Clinical trials of nutritional support in cancer. Parenteral and enteral
therapy. Hematol Oncol Clin North Am 1991;5(1):91–102.
61. Body JJ. The syndrome of anorexia-cachexia. Curr Opin Oncol 1999;11(4):
255–60.
62. Body JJ. Metabolic sequelae of cancers (excluding bone marrow transplanta-
tion). Curr Opin Clin Nutr Metab Care 1999;2(4):339–44.
63. Sikora SS, Ribeiro U, Kane JM 3rd, et al. Role of nutrition support during induc-
tion chemoradiation therapy in esophageal cancer. JPEN J Parenter Enteral Nutr
1998;22(1):18–21.
64. Nelson KA, Walsh D, Sheehan FA. The cancer anorexia-cachexia syndrome.
J Clin Oncol 1994;12(1):213–25.
65. Miller M. Can reducing caloric intake also help reduce cancer? J Natl Cancer
Inst 1998;90(23):1766–7.
66. Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol 2000;27(1):
64–8.
67. Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and
dilemmas. Crit Rev Oncol Hematol 2000;34(3):137–68.
68. Golden MH. The development of concepts of malnutrition. J Nutr 2002;132(7):
2117S–22S.
69. Rothman DL, Magnusson I, Katz LD, et al. Quantitation of hepatic glycogenol-
ysis and gluconeogenesis in fasting humans with 13C NMR. Science 1991;
254(5031):573–6.
70. Gelfand RA, Hendler R. Effect of nutrient composition on the metabolic
response to very low calorie diets: learning more and more about less and
less. Diabetes Metab Rev 1989;5(1):17–30.
71. Calloway DH, Spector H. Nitrogen balance as related to caloric and protein
intake in active young men. Am J Clin Nutr 1954;2(6):405–12.
72. Blackburn GL, Flatt JP, Clowes GH Jr, et al. Protein sparing therapy during
periods of starvation with sepsis of trauma. Ann Surg 1973;177(5):588–94.
73. Greenberg GR, Jeejeebhoy KN. Intravenous protein-sparing therapy in patients
with gastrointestinal disease. JPEN J Parenter Enteral Nutr 1979;3(6):427–32.
74. Hoffer LJ, Bistrian BR, Young VR, et al. Metabolic effects of very low calorie
weight reduction diets. J Clin Invest 1984;73(3):750–8.
75. Dickerson RN, Rosato EF, Mullen JL. Net protein anabolism with hypocaloric
parenteral nutrition in obese stressed patients. Am J Clin Nutr 1986;44(6):747–55.
76. Choban PS, Burge JC, Scales D, et al. Hypoenergetic nutrition support in hospi-
talized obese patients: a simplified method for clinical application. Am J Clin
Nutr 1997;66(3):546–50.
77. Klein S, Holland OB, Wolfe RR. Importance of blood glucose concentration in
regulating lipolysis during fasting in humans. Am J Physiol 1990;258(1 Pt 1):
E32–9.
672 Palesty & Dudrick

78. Jensen MD, Miles JM, Gerich JE, et al. Preservation of insulin effects on glucose
production and proteolysis during fasting. Am J Physiol 1988;254(6 Pt 1):
E700–7.
79. Gardner DF, Kaplan MM, Stanley CA, et al. Effect of tri-iodothyronine replace-
ment on the metabolic and pituitary responses to starvation. N Engl J Med
1979;300(11):579–84.
80. Bistrian BR, Blackburn GL, Hallowell E, et al. Protein status of general surgical
patients. JAMA 1974;230(6):858–60.
81. Schofield C, Ashworth A. Why have mortality rates for severe malnutrition
remained so high? Bull World Health Organ 1996;74(2):223–9.
82. Foxx-Orenstein A, Kirby DF. Understanding malnutrition and reefeeding
syndrome. In: Kirby DF, Dudrick SJ, editors. Practical handbook of nutrition in
clinical practice. Boca Raton (FL): CRC Press; 1994. p. 19–30.
83. Blackburn GL, Bistrian BR, Maini BS, et al. Nutritional and metabolic assess-
ment of the hospitalized patient. JPEN J Parenter Enteral Nutr 1977;1(1):11–22.
84. Weinsier RL, Krumdieck CL. Death resulting from overzealous total parenteral
nutrition: the refeeding syndrome revisited. Am J Clin Nutr 1981;34(3):393–9.
85. Kalm LM, Semba RD. They starved so that others be better fed: remembering
Ancel Keys and the Minnesota experiment. J Nutr 2005;135(6):1347–52.
86. Solomon SM, Kirby DF. The refeeding syndrome: a review. JPEN J Parenter
Enteral Nutr 1990;14(1):90–7.
87. Hayek ME, Eisenberg PG. Severe hypophosphatemia following the institution of
enteral feedings. Arch Surg 1989;124(11):1325–8.
88. Marinella MA. Refeeding syndrome and hypophosphatemia. J Intensive Care
Med 2005;20(3):155–9.
89. Mehler PS. Eating disorders: 1. Anorexia nervosa. Hosp Pract (Off Ed) 1996;
31(1):109–13, 117.
90. Cumming AD, Farquhar JR, Bouchier IA. Refeeding hypophosphataemia in
anorexia nervosa and alcoholism. Br Med J (Clin Res Ed) 1987;295(6596):
490–1.
91. Travis SF, Sugerman HJ, Ruberg RL, et al. Alterations of red-cell glycolytic inter-
mediates and oxygen transport as a consequence of hypophosphatemia in
patients receiving intravenous hyperalimentation. N Engl J Med 1971;285(14):
763–8.
92. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin
Pract 2005;20(6):625–33.
93. DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal handling
of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1975;55(4):
845–55.
94. Van Way CW, Longoria M, Sacks GS. Do surgeons need to worry about vitamin
deficiencies? Nutr Clin Pract 2001;16(Suppl):S5–7.
95. Brooks MJ, Melnik G. The refeeding syndrome: an approach to understanding
its complications and preventing its occurrence. Pharmacotherapy 1995;
15(6):713–26.
96. Heymsfield SB, Bethel RA, Ansley JD, et al. Cardiac abnormalities in cachectic
patients before and during nutritional repletion. Am Heart J 1978;95(5):584–94.
97. Ruberg RL, Allen TR, Goodman MJ, et al. Hypophosphatemia with hypophos-
phaturia in hyperalimentation. Surg Forum 1971;22:87–8.
98. Hill GL, Guinn EJ, Dudrick SJ. Phosphorus distribution in hyperalimentation
induced hypophosphatemia. J Surg Res 1976;20(6):527–31.
Cachexia, Malnutrition, and the Refeeding Syndrome 673

99. Apovian CM, McMahon MM, Bistrian BR. Guidelines for refeeding the marasmic
patient. Crit Care Med 1990;18(9):1030–3.
100. Multivitamin preparations for parenteral use. A statement by the nutrition advi-
sory group. American medical association department of foods and nutrition,
1975. JPEN J Parenter Enteral Nutr 1979;3(4):258–62.
101. Mercadante S. Parenteral versus enteral nutrition in cancer patients: indications
and practice. Support Care Cancer 1998;6(2):85–93.
102. Dudrick SJ, Wilmore DW, Vars HM, et al. Long-term total parenteral nutrition with
growth, development, and positive nitrogen balance. Surgery 1968;64(1):
134–42.
103. Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all
nutrients exclusively by vein. JAMA 1968;203(10):860–4.
104. Palesty JA, Dudrick SJ. The goldilocks paradigm of starvation and refeeding.
Nutr Clin Pract 2006;21(2):147–54.

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