(CANCER RESEARCH 37, 2327-2335, July 1977]

Cachexia, the Metabolic Component of Neoplastic Diseases' Giovanni Costa2 Department of Medicine, State University of New York at Buffalo, Buffalo, New York 14214

Summary The growth of cancer leads to profound alterations of host organs and functions. The overall result is cachexia, a syndrome characterized primarily by weakness, anorexia, and the depletion and redistribution of host components. Cachexia is the consequence of anatomical alterations, de creased food intake or absorption, and altered metabolism. Anatomical alterations are always present in a cancer patient. It has been repeatedly observed, however, that the degree of cachexia bears no simple correlation to tumor burden, tumor cell type, or anatomical site of involvement. The consequences of impaired food intake or food ab sorption are a major contributor to the overall morbidity of the cancer patient. Depletion of protein and/or fat stores, hypovitaminoses, and decrease in the concentration of trace elements, variously combined, lead to states nearly identical to kwashiorkor or marasmus. Clear guidelines for recognition of these states have been set recently for cancer patients. Awareness of these syndromes is of enormous clinical importance since they are potentially reversible by the modern techniques of hyperalimentation. It is also important to recognize metabolic effects pro duced by tumors and independent of either anatomical alterations or insufficient delivery of nutrients. Such effects, exemplified by the endocrine syndromes produced by nonendocrine tumors, are of substantial conceptual impor tance inasmuch as they imply secretion by the tumor of toxic substances that act at sites distant from the sites of anatomic involvement. The study of such defects might well pave the way to understanding of the mechanisms of cancer aggression.

The growth of cancer leads to profound alterations of organs and functions, a consequence of multiple interac tions between destruction, attempted repair, homeostasis, and production by the tumor of biochemical toxins. The overall result is the widely recognized although poorly Un derstood syndrome known as cachexia (24, 25, 29, 33, 37, 47, 50, 93, 94, 101). Cachexia occurs in man and animals. Its more apparent manifestations are weakness, anorexia, de pletion and redistribution of host components, hormonal aberrations and, finally, a progressive alteration of vital functions. The patients affected appear chronically ill and ‘Presentedat the Conference on Nutrition and Cancer Therapy, Novem ber 29 to December 1, 1976, Key Biscayne, Fla. Supported in part by Contract NO1-CP-65779-56 from the National Cancer Institute, NIH. Department of Health, Education, and Welfare. 2 To

whom

requests

for

East Aurora, N. V. 14052.

reprints

should

be

addressed,

at

100

Riley

Street,

often emaciated. Their skin is pale and atrophic. Edema, ulcerations, tumor masses, fractures, and abnormal drain ages (when present) completely subvert familiar shapes, habits, and frames of reference. The progressive fading of physical wholeness is eventually associated with a flatness of the affects and a longing for annihilation. Cachexia is at least in part due to anatomical alterations that are always present in a cancer patient, the extent and distribution of which can span pathological anatomy. It has been repeatedly observed, however, that the degree of cachexia bears no simple correlation to caloric intake, tu mor burden, tumor cell type, or anatomical site of involve ment. Individual patients might have obvious widespread tumors and no recognizable cachexia. In accounting for this fact, the attention of investigators has been focused on distant metabolic effects produced by cancers. Such effects are well documented in both cancer patients and experi mental models and are known collectively as “systemic effects of tumors―or “paraneoplastic syndromes―(Chart 1; Refs. 24, 25, 29, 33, 37, 47, 50, 93, 94, and 101). Because such effects occur at sites remote from the site of anatomi cal involvement, the postulation of chemical mediators ap pears inescapable. It has been well established that tumors can indeed elaborate pharmacologically active substances; this is shown convincingly by the various hormonal syn dromes associated with lung cancer (71) and by the endo crine effects of cancers originating from nonendocrine or gans (59). Besides hormones, other substances can be pos tulated, and the literature overflows with claims (often poorly documented) of their isolation (25, 69, 80, 81, 91, 96). Study of the systemic effects of tumors is of fundamental importance. They affect significantly the ability of the host to tolerate cancer intervention (21 , 39, 70) or to re spond immunologically (12). Their impact on the overall morbidity is such that they are credited with the death of a significant number of patients (94). They are potentially reversible (at least in part) by nutritional means. They are useful models for the study of the mechanisms of cancer aggression. It is reasonable to infer that the devastations produced by cancers, rather than being due to the juxtapo sition of a neoplastic cell to a normal cell, are due to the destruction of the latter by the former via the production of chemically definable toxic mediators active in the immedi ate vicinity of the tumor cell or on more distant targets. The subject has been reviewed extensively in the past 5 years (22, 25, 47, 83, 93). In this paper the author will attempt to discuss only events characterized by all of the following properties. (a) They are clinically well docu mented. Nonclinical material will be discussed only if it contributes to clarification of clinical events. (b) They are examples of depletion of important host compartments and

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2327

G. Costa

CANCER 1

Destruction

Abn. Routes

___________ IFistuta.. etc.

I

_

@Absorption of Nutrients

I Anorexia I

fltered

Metabolism [lObstruction. MalabsorPtion.etcJI [ IHypoph.gi.j@ IHOrmOneS;TOXiC Factor?)

HOST DEPLETION I

@

DEATH]

___________

MORBIDITY

[CACHEXIA]__

Shorter Survival Inadequate Honseostasis @ToI.ranceto Intervention

@ @

+

—————

Respons, to Intervention Immunocompetence

Chart 1. Pathways of cancer aggression.

are mediated through either inadequate nutrition or hu moral factors. (c) They either contribute significantly to the overall morbidity of the patient or exemplify important mechanisms. With this paper it is hoped that the substantial morbidity accrued to patients by inadequate nutrition (a condition potentially reversible at present) will be brought to the at tention of the clinician. At the same time those manifesta tions of cachexia in which neither direct invasion by the tumor nor nutritional inadequacy play a detectable role will be pointed out.

WeightLossand Anorexia Weight loss or, more precisely, the loss of biomass oc curs commonly in both man and animals that succumb to cancer. In principle it can occur as a consequence of anor exia (i.e. , a decrease in the spontaneous consumption of food) or of decreased absorption of food from the alimen tary canal. It can also occur in the absence of the above factors as a consequence of altered metabolism. Weight loss is listed in the older literature as one of the initial and common manifestations of cancer (53), a warning signal. The documentation is largely anecdotal. Equally anecdotal clinical impressions by contemporary observers imply that weight loss occurs only or predominantly later in the natural history of cancer. This discrepancy is at least in part due to the recent refinement in diagnostic techniques that allows earlier detection. Yet even today unexplained weight loss in a patient requires a search for a possible occult neoplasm. In considering weight loss on the part of the host, one must keep in mind that severe depletion can be masked by the abnormal expansion of one body compartment (most often water) at the expense of another. One must also re member that a given compartment might be depleted selectively. Among the very few well-documented data describing the incidence of weight loss in patients with cancer are those by Lanzotti (V. Lanzotti, personal communication) who has

2328

noted a loss of at least 6% of body weight in @40% of 129 patients with limited bronchogenic carcinoma. In 187 pa tients with extensive disease, weight loss was of the same magnitude. The biological consequences of weight loss were clearly recognized. Median survival times of the de pleted patients were less than one-half those observed in their better nourished counterparts. More extensive data on a variety of tumor types are critically needed. It is not difficult to understand how weight loss might occur in patients with extensive disease and destructions when loss of appetite and/or decreased absorption of food are such general and possibly nonspecific phenomena. On the other hand the weight loss that occurs in patients with limited disease is of particular significance inasmuch as it is more likely to be cancer specific and mediated humorally through either the induction of anorexia or some other mechanism. Anorexia is unquestionably one of the possible causes of weight loss. A clinical impression, which is probably well founded, suggests that anorexia is a common phenomenon in most cancer patients at some time during their illness. it might reach such a degree of severity that spontaneous nutrition is almost completely suppressed. It is not uncom mon to observe patients in whom a meager breakfast repre sents the only form of intake p.o. One must remember that many of these patients may be bedridden, febrile, nau seated, plagued by intractable pain, and devastated by the thought of impending death. One does not have to look far to understand their loss of appetite although the precise mechanism may not be obvious. In these circumstances anorexia is certainly a nonspecific symptom experienced by the majority of acutely or severely ill patients. It would be of great interest to determine whether ano rexia, like weight loss, might occur in patients with limited disease and therefore might be truly a paraneoplastic syn drome. Unfortunately, reliable data on the incidence and timing of anorexia are practically nonexistent. This is not surprising. In determining changes in food consumption, one must either prospectively follow patients or compare appropriate groups. The difficulties of obtaining reliable

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RESEARCH

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Cachexia nutritional data on free-living populations are known (1). Existing surveys have centered primarily on low-income groups and are therefore of limited value even as historical controls (16, 20, 55, 61). Simultaneous studies by a single set of investigators of groups of patients with various cancer types and of appropriate control groups have not yet been performed and are urgently needed. Within these limitations the available data suggest that anorexia is a widespread phenomenon. Thus, DeWys (36) has studied (by the 5-day food diary technique) 50 patients with a variety of tumors; he noted that the severity of ano rexia was related to the extension of the tumor. Theologides (95) has compared

the food consumption

of 39 patients who

bear a variety of tumor types and tumor burdens with their recalled “normal― food intake. Marked anorexia was sug gested. In our laboratory (31) we have studied by the nutri tion interview technique the food consumption of 17 female and 13 male patients with a variety of neoplastic diseases. In each patient, food consumption was then compared with the recalled normal intake. The female patients had de creased their average food intake from 1718 kcal/day (pro tein, 256 kcal/day; fat, 883 kcal/day; carbohydrates, 579 kcal/day) to an average 1444 kcal/day (protein, 200 kcal/ day; fat, 630 kcal/day; carbohydrates, 614 kcal/day). The weight of the females prior to diagnosis exceeded ideal weight by an average of 31 lb. The average weight loss of the females was 23 lb. Male patients had changed their intake from an average 2827 kcal/day (protein, 424 kcal/ day; fat: 1371 kcal/day; carbohydrates, 1032 kcal/day) to an average 1772 kcal/day (protein, 257 kcal/day; fat, 810 kcal/ day; carbohydrates, 705 kcal/day). The weight of the males prior to diagnosis exceeded ideal weight by an average 21 lb. The average weight loss in the male was 38 lb. In further studies (M. Aragon and G. Costa, unpublished observa tions) we have noted that the average daily caloric intake of 50 adult

ambulatory

women

who

were

receiving

active

chemotherapy was 1463 kcal/day compared to 1706 kcal/ day consumed by 50 healthy women matched for age and socioeconomic characteristics. The pathogenesiS of anorexia is unclear (Table 1). A change in taste perception has been described by DeWys (36) and is discussed

more extensively

elsewhere

(37). The

postulation that lactate, known to be produced abundantly by tumors, could serve as an anorexogenic agent is attrac tive (2) but requires further documentation in man. The data obtained by Morrison (67) that show that, with the general reduction in energy available to the host, energy for seeking and processing food has almost vanished might provide an explanation for the anorexia of termina! patients only. It is probable that pain, fever, and anxiety (49) might well con tribute to the lessening of food consumption. The effects of Table 1 anorexia1 Possible

causes of

.Nonspecific diseases2.Alterations manifestationof perception3.Production of taste and/or smell

lactate4.Production of ketones5.Hypothetical of toxins6.Direct tumor center7.Psychological eftect on appetite factors

cancer intervention on appetite are well known and are discussed elsewhere (39, 57, 70, 84). A more specific patho genesis can be postulated in the rare subjects with small tumors of the 4th ventricle (97). One could think here in terms of a direct effect on the appetite center. In addition to anorexia, interference with the patency and function of the alimentary canal or losses through abnormal drainages are unquestionably the leading causes of weight loss (84) and possibly of anorexia itself. Poor intake and poor absorption of food are not the only determinants of weight loss. This point is of fundamental importance. It is exemplified quite convincingly by children with the diencephalic syndrome (see below), in whom loss of fat (but not loss of lean body mass) occurs in the pres ence of normal or even supranormal intake. The fact that anemia can occur in cancer patients without overt hemoly sis, bleeding, marrow replacement, or recognizable nutri tional deficiencies (5, 56) reinforces the concept that addi tional explanations of host depletion are required, besides decreased delivery of nutrients into the blood stream, and that newer forms of intervention, in addition to increased nutrition, should be devised. Loss of Specific Body Compartments Tumor and host are metabolically separated but not to tally independent districts. In certain circumstances the tumor can parasitize the host and thus add to the depletion produced by insufficient intake. This is well illustrated by tumor growth in totally starved animals. It is therefore easy to understand how specific needs of the tumor might result in specific depletions of the host. To what extent these processes occur if food supply is adequate is not known. One must remember that, in the great majority of patients who have been studied at autopsy and who have therefore played out the ultimate act of the metabolic drama, the tumor mass seldom exceeds 500 g (J. W. Pickren, personal communication) and thus remains a small fraction of the host biomass. Parasitization per se therefore is not likely to be an important mechanism except possibly in the case of trace nutrients. By whatever mechanism, specific deple tions do occur in cancer patients and are discussed below. Fat Depletion Profound alterations of host lipid metabolism occur dur ing the growth of a variety of tumors in both experimental animals and man (4, 22, 23, 25). Often the changes ob served are clearly related to anorexia and involve other body compartments. There are nevertheless models in which nei ther anorexia nor parasitization of the host by the tumor play a significant role. These models are of very special interest because they are prima fade examples of distant, humorally mediated metabolic effects of neoplasms. In man the best known example is represented by the diencephalic syndrome, (3, 81, 82, 87), described first by Russell. The diencephalic syndrome, which is not generally known, affects children under 10 years of age and is charac terized by an almost complete arrest or even reversal of the normal weight growth. Height, however, is not affected. The

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2329

G. Costa children appear extremely emaciated with a loss of most of their adipose tissue, as gauged by clinical criteria (Fig. 1). Preservation of lean body mass in the face of fat loss has been implied. Associated with the fat loss, there is fre quently motor hyperactivity and a change of mood toward joviality. Nystagmus is common , but the neurological exam ination of these patients is otherwise within normal limits. Body temperature is usually normal. Laboratory examina tions including serum protein levels are by and large nor mal. Nonesterified serum fatty acids have been measured in only 1 case and found to be markedly elevated. Other serum lipids are usually normal. Hormonal studies have shown no abnormalities. The syndrome has been associated with tumors of the 3rd ventricle and of the anterior hypothalamus, which are de monstrable by standard neuroradiological techniques. As trocytomas have been the most common tumors although glioblastomas, oligodendrogliomas, and ependymomas have been described. Interestingly, the syndrome develops in the great majority of cases in the absence of anorexia. In a few cases increased appetite and increased food intake have been described. The syndrome finds a parallel in the experimental tumors described by Liebelt et al. (60) and in those studied in our

Table 2 Average fat contentof muscleGroupSurgerynFat

human

(g/kg)'INoncancer35106 20bIICancer3051 a I versus S Mean

II, p

± ±11

< 0.001

± S.E.

laboratory (28), in which severe fat loss was documented in animals with noninvasive tumors, without changes of care fully measured food intake and body temperature. The met abolic effects could be reproduced with a frozen and thawed tumor extract. More recently, Cox and Gocken (34) have described changes in a variety of serum lipid fractions, changes that occurred as early as 4 days after the injection of SV4O cells into golden hamsters. in further experiments in our laboratory (31), we have demonstrated that the rate of excretion of ‘4CO2 by mice that were bearing 24-hr-old s.c. tumors and were given i.p. injections of [‘4C]tripalmitinwas reduced to 15 to 20% of that of controls. The rapidity of the effect (already present 24 hr after implantation of the tumor) militates against tumor parasitization as the explanation. Studies on the composition of human muscle conducted in our laboratory tend to support the hypothesis that early fat loss is a common event in patients with cancer (32).

.@ @ Muscle ,:samples were obtained at primar surge from

.@

@‘ :@

@‘

patients

with

various

tumors

(primarily

breast

and

colon)

and from patients with a variety of acute and chronic surgi cal conditions. In cancer patients, on the average, muscle @

-

.

;

fat

content

was

approximately

one-half

that

of

controls

(Ta

ble 2). The mechanism underlying the fat loss in these patients @1

and

in the

experimental

animals

is unknown.

It is well

known, at least in certain animals bearing transplanted tumors (67) and sporadically in cancer patients (25, 102, 103, 106), that the energy expenditures of the host are increased. It is unlikely that this is due solely to the thermo dynamic cost of synthesizing tumor protoplasm. The hy pothesis that the tumor can produce an uncoupler of oxida tive phosphorylation, however attractive, has not been sub stantiated (35). Energy loss associated with a high rate of glyconeogene @

..@

.

sis

from

lactate

has

been

suggested

as

an

explanation

for

increased energy expenditures in some cancer patients, which thus contributes to mechanisms that promote fat loss (45, 52). Such losses appear inadequate quantitatively as an explanation of the fat loss described above. Other potential biochemical pathways through which energy might be lost are known and are discussed more extensively elsewhere (107).

@

.,.

Since the determinants of the amount of total body fat and of its major compartments are poorly understood at present, explanations for the fat loss described in this sec tion remain speculative (14, 54). Critical well-designed ex periments are needed to elucidate this area. The contribution of host fat depletion to the total morbid

... .@ -.@

Fig. 1. Infant with diencephalic syndrome (courtesy of Professor H. W. Bain, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada).

2330

ity

of

the

patient

is

difficult

to

assess.

One

could

speculate

that, in the more severe cases, loss of structural lipids occurs with irreversible consequences for cell function. Lipid metabolites could produce systemic effects and be

CANCERRESEARCHVOL. 37

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Cachexia responsible for anorexia, apathy, and some of the less palpable manifestations of the neoplastic cachexia. Experi mental documentation of such considerations is not yet available. Protein Depletion and Hypoalbuminemia It is a common observation that many cancer patients lose a significant fraction of their stable proteins. The mecha nism subtending the loss is unknown. In the recent past it was common to think of tumors as 1way nitrogen traps and to infer that the nutritional conse quences of tumor growth on the host were dominated by this irreverisble step. Thus, selective depletion of the pro tein compartment or parasitization of strategic enzymes was considered the key issue (25). Recently, generalization of this concept to other animal models was proven to be unjustified (28, 51). Its applicability to cancer patients is at best questionable. This was foreseen, and Mider et al. (66) had warned against extension of the concept of the nitro gen trap beyoild its original experimental conditions. Nitrogen balance studies have been a common starting point for the investigation of the effects of cancer on protein metabolism. Balance experiments in rats bearing Walker 256 carcinoma

have shown that growing

hosts fed ad libi

tum can continue to store the same amount of nitrogen as do pair-fed controls, until the tumor has reached about 30% of the weight of the animal (65, 66). At this point protein storage in the tumor compartment is greater than the over all positive nitrogen .balance of the animal, and the host loses protein to the tumor (65). Such loss had been con firmed by carcass analysis (66). Attempts made to increase caloric and protein intake by force feeding were successful only in delaying the depletion of host protein (4, 90), which eventually occurred even at very high intakes. The rele vance of these studies to man is questionable. It is very exceptional that the tumor compartment exceeds 10% of the weight of the cancer patient. Nitrogen balance studies in patients have been generally unrewarding. Nitrogen equilibrium, nitrogen loss, and ni trogen retention have all been reported (mostly in short term studies) without a clear correlation with intake and overall behavior of the weight of the patient (43, 64, 73, 92, 102, 103, 105@, 106). Positive nitrogen balances in patients who were actively losing weight have been explained with the quantitatively inaccurate concept of synthesis of tumor protoplasm. The validity of the nitrogen balance technique is at this time controversial (Footnote 3; Refs. 23, 26, 44, and 48). The criticisms have been based on 2 sets of considerations. The 1st set has to do with the length of the observations and is very pertinent to the studies discussed above. The 2nd set involves conceptual difficulties that deal with the inherent inaccuracies of the method and with the possibilities of unmeasured losses (Footnote 3; Refs. 26, 44, and 48). Such considerations become particularly cogent at the high in takes at which one is likely to study cancer patients (Chart 2), At these intakes substantial retention of nitrogen can be 3 G.

Costa

and

V.

A.

Young.

Metabolic

Production

of

N2.

Status

of

the

Controversy. WHO Conference, Geneva, 1975, manuscript in preparation.

observed over long periods of time without any correspond ing changes of body weight. A case in point is a patient studied in our laboratory (30). The subject is a 44-year-old male who during the past 8 years has lost 18 kg and has developed a severe, disabling neuropathy in spite of adequate food intake. Normalcy of en docrine functions and of intestinal absorption was supported by extensive testing. Although he received daily a docu mented 3000 cal and 20 g protein nitrogen (as a liquid semisynthetic diet), the patient lost weight rapidly. Yet, his apparent nitrogen balance data indicated a “retention' ‘ of over 6 g nitrogen per day. Suspecting that the patient might be producing N2at an exceptionally high rate (23, 26, 30), we measured pN2 in mixed venous (right atrium) and in arterial blood. Venous pN2was about 10% higher than arterial. This gradient, which is larger than in healthy controls, supports the thesis that N2was being excreted through the lungs at a higher than normal rate. As compensation for this loss, protein intake was increased to 25 g nitrogen per day. The patient began gaining weight. Seven months later he had gained 18 kg, had lost most of his symptoms, and had shown near normalization of nerve conduction and of nerve and muscle biopsies. Even several months after stabiliza tion of his body weight, his nitrogen balance remained strongly positive (Chart 3). These data show the necessity of careful noninvasive studies of body composition before the fundamental de fects of protein metabolism in cancer patients can be eluci dated by the balance technique. Because of the methodological simplicity, studies of the protein metabolism of the host have often centered on serum albumin. Hypoalbuminemia occurs frequently in can cer-bearing patients and animals. The degree of hypoalbu minemia has been correlated with the extension of cancer (25). Theoretically, hypoalbuminemia can be the consequence of appropriate changes in the rate of production or in the rate of destruction and can be the consequence of expanded dilution spaces o- of abnormal losses. Attempts to measure the various determinants of hypoalbuminemia in can

C Normals,

liquid

a Re@ession 0 NOfiflOiS, S LLC,

Ii@id

diet

@e solid

diet

a

diet

U .@

c@J

I i.________

5

t@

10 15 N Intake (g/24 hr.)

I

I

20

25

Chart 2. Relationship between nitrogen intake and nitrogen balance in healthy adult volunteers who maintained constant body weight. Each point Is the average of 30 consecutive daily observations.

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2331

G. Costa cer patients have generated an abundant literature. The rate of synthesis of albumin can be measured with precursors labeled with 14C, ‘5N, 355, or “Se. The available data sug gest that in cancer patients the rate of albumin synthesis is decreased (27, 51, 63, 75, 89, 99). Such data have been obtained at certain times by indirect considerations and at other times without complete assessment of all the involved pools; thus they should not yet be looked upon as conclu sive. The explanation for the hypoalbuminemia remains therefore speculative. It would seem inescapable that hypoalbuminemia is at least to some extent due to the malnutrition of the host (7679, 86). Serum albumin levels of cancer patients have been restored to normal by parenteral hyperalimentation, which suggests that any decrease in synthesis may not be irrevers ible even in the absence of change in the tumor (41). Consumption of albumin by the tumor is an attractive hypothesis and has found some support in preclinical work (13). Confirmation of such data by other laboratories and by incorporation of the albumin label into chemically purified tumor fractions (an absolute prerequisite in view of the notorious stickiness of albumin) would be especially valua ble. Distribution of albumin into abnormal spaces (a reason able thought in view of the subclinical edema so common in cancer pateints) has been suggested by results obtained in my laboratory (27) and by others (99). Definitive proof is not at hand. Nephrotic syndromes and protein-losing enteropa thies have been well described in patients with cancer (62, 98, 100), but such abnormal losses are so infrequent com pared to hypoalbuminemia that they cannot be taken as a general explanation. The central point, which still needs to be established , is to what extent is hypoalbuminemia secondary to poor nutri tion and to what extent is it due to the specific effects of the tumorperse. That poor intake might not be the only expla nation for hypoalbuminemia is supported by the observa tion on occasion of patients in whom the loss of nearly 50% of body weight and a substantial reduction in midarm cir cumference coexist with normal hemoglobin and serum albumin levels. In this context it is useful to mention the observations by Goodlad and Clark (17, 18, 46) who have shown that, with adult rats bearing Walker 256, there is a marked inhibition of amino acid incorporation by muscle polyribosomes. The results are interpreted as suggesting some translation de fect possibly mediated through the serum factor described by Toporek (96). A defect in the postinitiation stage of translation was also described in a more recent paper by Clark and Goodlad (19). These studies therefore illustrate alterations in the synthesis of host protein, which are inde pendent from nutritional intake. Whether or not these are relevant to albumin metabolism remains to be established. Recently, protein malnutrition in man has been studied effectively by Bistrian et al. and by Blackburn et al. (7-10) with a combination of anthropometric and biochemical pa rameters.

The

simplicity

of the

methods

gives

hope

that

effective guidelines can be developed for quantifying over all protein depletion and for monitoring the effects of hyper alimentation. The contribution of hypoalbuminemia to the overall mor

2332

bidity, as long as albumin levels do not decrease below 2 g/ 100 ml, is hard to assess at the present time. There is no question that protein depletion can contribute significantly to the overall morbidity of the cancer patient. The pathology of protein malnutrition as it occurs within the context of starvation is well known. Shorter survival time; inability to tolerate chemotherapy, radiotherapy, or surgery; loss of immunological competence (24); and altered respiratory homeostasis (38) have all been described in protein-de pleted patients. The cumulative effects of protein depletion on the viability of the patient can therefore be overwhelm ing. Glucose Depletion The syndrome of hypoglycemia associated with tumors of nonpancreatic origin is a well-documented entity. Since 1929, when the 1st report appeared in the literature, about 150 cases have been described . Nearly 50% of the tumors have been fibrosarcomas and another 30% have been hepa tomas. Nearly 90% of the tumors were growing in the retro peritoneal space or in the liver (15, 72, 85). The hypoglyce mia induced by the above tumors is at variance with the tendency of most other neoplasms to impair glucose utiliza tion in the host (104). One of the outstanding characteristics of these tumors is their size. The great majority of those that were weighed exceeded 1 kg. A 9-kg tumor is probably the largest of the series. The age or sex distribution of the syndrome is not substantially different from that of tumors in general. The pathogenesis of the hypoglycemia is the subject of considerable controversy. The large size of the majority of these tumors has suggested overutilization of glucose by the neoplasm (15). The other potential pathogenetic mecha

Caler@ lntoksMar 70 WeigM 66 kg

Body

62

58 54 50 Nitrogen 0 lfltoke g,Idoy

4 8 12 16

20 24 2

4

6

8

November,972

10

8 10 2 14 16 8 20 April, 1973

Chart 3. Relationship between nitrogen intake, nitrogen balance, and body weight in Patient LLC. •,body weight (kg).

CANCERRESEARCHVOL. 37

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Cachexia

CANCER]

Abn. Routes I IFistula,,

@Absorption of Nutrients I Obstruction, Malabeorptlon. etc.)

Anorexia

I Altered Metabolism

Hypophaglat

[tHormon.s;Tozlc

Factor?)

I HYPERALIMENTATION [HOST DEPLETION 4, MORBIDITY

@

IDEATH][CACHEXIA]—. Shorter Survival

Inadequate Homeostasts @

Tolerance to InterventIon

@ @

Response to Intervention Immunocompetence

+

_____J

Chart 4. Pathways of cancer aggression and the role of hyperalimentation.

nism proposes secretion by the tumor of a substance or substances capable of producing hypoglycemia. In a num ber of cases, insulin-like activity has been demonstrated in the tumor, whereas in an approximately equal number of cases this claim could not be substantiated (25, 85). The hypoglycemic syndrome can add significantly to the morbidity of patients. On occasion a blood glucose level compatible with life can be maintained only with great diffi culty. The predominance of 2 types of tumors and substan tially 1 general localization makes the syndrome anatomi cally and clinically a well-defined entity. Its pathogenesis remains to be further elucidated. Conclusions We have discussed manifestations of cachexia character ized by depletion of protein, fat, and carbohydrates, and we have attempted in each case to evaluate the relative patho genetic roles of decreased delivery of nutrients and of al tered host metabolism. Until recently the student of cachexia was limited to the description and the interpretation of phenomena. The added dimension of metabolic intervention was not availa ble. In the 1960's the recognition that undernutrition was highly prevalent in patients hospitalized for nonneoplastic diseases (11, 58) stimulated the development by Dudrick et al. (41) of methods of parenteral nutrition, which were shown to be effective in repleting such individuals. These same techniques are now being applied to cancer patients and appear already to be nutritionally effective and syner gistic with other modalities of cancer intervention (21, 40). Their application to cancer patients will do more than re plete the patient. They will finally allow (having wholly re versed the consequences of poor intake) adequate identifi cation of the nonnutritional effects of cancer, if indeed these effects exist (Chart 4). The question of parasitization of the host by the tumor will come under proper perspective by observing the growth of cancer in the well-fed host. A number of studies in animal

JULY

models have implied that cancer grows best in a well-fed host (6, 42, 68, 74, 88). This fear of stimulating tumor growth has in the past been a deterrent (in the minds of some) to the institution of hyperalimentation to cancer pa tients. It seems unlikely that such fear is justified. In the animal models studied, the tumor biomass exceeds 30% of the host, a condition which makes parasitization an impor tant factor but which is not applicable to man in whom tumor mass rarely exceeds 5% of the host. Moreover, the improved therapeutic effects that can be obtained in well fed patients (21) will probably prove conclusive in showing the beneficial effects of hyperalimentation. It is probable (in the mind of this reviewer) that distant effects of tumors will still be observable in well-fed patients. It is hoped that recognition of these effects will finally give impetus to the search and isolation of those chemical me diators of tumor aggression, the existence of which was broadly hinted at in our discussion. The technology for this task can be borrowed initially from the investigations of the chemical mediators of inflammation and of lymphocyte fac tors. The unambiguous demonstration of the existence of tumor toxins and the definition of their role might well be the significant breakthrough in oncology. References 1. Anonymous. The Validity of 24-Hour Dietary Recalls. Nutr. Rev., 34: 310-311, 1976. 2. Baile, C. A., Zinn, W. M., and Mayer, J. Effects of Lactate and Other Metabolites on Food Intake of Monkeys. Am. J. Physiol., 219: 16061613, 1970. 3. Bain, H. W., Darte, J. M., Keith, W. S.. and Kruytf, E. The Diencephalic Symdrome of Early Infancy due to Silent Brain Tumor: With Special Reference to Treatment. Pediatrics, 38: 473-482, 1966. 4. Begg, R. W. , and Dickenson, T. E. Systemic Effects of Tumors in Force Fed Rats. Cancer Rca., 11: 409-412, 1951. 5. Berlin, N. I. Anemia of Cancer. Ann. N. V. Acad. Sci., 230: 209-211, 1974. 6. Bertino, J. A., and Nixon, P. F. Nutritional Factors in the Design of More Selective Antitumor Agents. Cancer Res., 28: 2417-2421 , 1969. 7. Bistrian, B. R., Blackburn, G. L., Hallowell, E., and Heddle, A. Protein Status of General Surgical Patients. J. Am. Med. Assoc., 230: 858-860, 1974.

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