Professional Documents
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Cachexia and Refeeding Syndrome
Cachexia and Refeeding Syndrome
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
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
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
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.
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.
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
667
668 Palesty & Dudrick
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