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

Summary

The growth of cancer leads to profound alterations ofhost organs and functions. The overall result is cachexia, asyndrome characterized primarily by weakness, anorexia,and the depletion and redistribution of host components.Cachexia is the consequence of anatomical alterations, decreased food intake or absorption, and altered metabolism.

Anatomical alterations are always present in a cancerpatient. It has been repeatedly observed, however, that thedegree of cachexia bears no simple correlation to tumorburden, tumor cell type, or anatomical site of involvement.

The consequences of impaired food intake or food absorption are a major contributor to the overall morbidity ofthe cancer patient. Depletion of protein and/or fat stores,hypovitaminoses, and decrease in the concentration oftrace elements, variously combined, lead to states nearlyidentical to kwashiorkor or marasmus. Clear guidelines forrecognition of these states have been set recently for cancerpatients. Awareness of these syndromes is of enormousclinical importance since they are potentially reversible bythe modern techniques of hyperalimentation.

It is also important to recognize metabolic effects produced by tumors and independent of either anatomicalalterations or insufficient delivery of nutrients. Such effects,exemplified by the endocrine syndromes produced bynonendocrine tumors, are of substantial conceptual importance inasmuch as they imply secretion by the tumor oftoxic substances that act at sites distant from the sites ofanatomic involvement. The study of such defects might wellpave the way to understanding of the mechanisms of canceraggression.

The growth of cancer leads to profound alterations oforgans and functions, a consequence of multiple interactions between destruction, attempted repair, homeostasis,and production by the tumor of biochemical toxins. Theoverall result is the widely recognized although poorly Understood syndrome known as cachexia (24, 25, 29, 33, 37,47, 50, 93, 94, 101). Cachexia occurs in man and animals. Itsmore apparent manifestations are weakness, anorexia, depletion and redistribution of host components, hormonalaberrations and, finally, a progressive alteration of vitalfunctions. The patients affected appear chronically ill and

‘Presentedat the Conference on Nutrition and Cancer Therapy, November 29 to December 1, 1976, Key Biscayne, Fla. Supported in part by ContractNO1-CP-65779-56 from the National Cancer Institute, NIH. Department ofHealth, Education, and Welfare.

2 To whom requests for reprints should be addressed, at 100 Riley Street,

East Aurora, N. V. 14052.

often emaciated. Their skin is pale and atrophic. Edema,ulcerations, tumor masses, fractures, and abnormal drainages (when present) completely subvert familiar shapes,habits, and frames of reference. The progressive fading ofphysical wholeness is eventually associated with a flatnessof the affects and a longing for annihilation.

Cachexia is at least in part due to anatomical alterationsthat are always present in a cancer patient, the extent anddistribution of which can span pathological anatomy. It hasbeen repeatedly observed, however, that the degree ofcachexia bears no simple correlation to caloric intake, tumor burden, tumor cell type, or anatomical site of involvement. Individual patients might have obvious widespreadtumors and no recognizable cachexia. In accounting forthis fact, the attention of investigators has been focused ondistant metabolic effects produced by cancers. Such effectsare well documented in both cancer patients and experimental models and are known collectively as “systemiceffects of tumors―or “paraneoplasticsyndromes―(Chart 1;Refs. 24, 25, 29, 33, 37, 47, 50, 93, 94, and 101). Becausesuch effects occur at sites remote from the site of anatomical involvement, the postulation of chemical mediators appears inescapable. It has been well established that tumorscan indeed elaborate pharmacologically active substances;this is shown convincingly by the various hormonal syndromes associated with lung cancer (71) and by the endocrine effects of cancers originating from nonendocrine organs (59). Besides hormones, other substances can be postulated, and the literature overflows with claims (oftenpoorly documented) of their isolation (25, 69, 80, 81, 91, 96).

Study of the systemic effects of tumors is of fundamentalimportance. They affect significantly the ability of thehost to tolerate cancer intervention (21, 39, 70) or to respond immunologically (12). Their impact on the overallmorbidity is such that they are credited with the death of asignificant number of patients (94). They are potentiallyreversible (at least in part) by nutritional means. They areuseful models for the study of the mechanisms of canceraggression. It is reasonable to infer that the devastationsproduced by cancers, rather than being due to the juxtaposition of a neoplastic cell to a normal cell, are due to thedestruction of the latter by the former via the production ofchemically definable toxic mediators active in the immediate vicinity of the tumor cell or on more distant targets.

The subject has been reviewed extensively in the past 5years (22, 25, 47, 83, 93). In this paper the author willattempt to discuss only events characterized by all of thefollowing properties. (a) They are clinically well documented. Nonclinical material will be discussed only if itcontributes to clarification of clinical events. (b) They areexamples of depletion of important host compartments and

JULY 1977 2327

Cachexia, the Metabolic Component of Neoplastic Diseases'

Giovanni Costa2

Department of Medicine, State University of New York at Buffalo, Buffalo, New York 14214

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G. Costa

CANCER

1 _

Destruction Abn. Routes I @Absorptionof Nutrients I Anorexia I fltered Metabolism___________IFistuta..etc. [lObstruction.MalabsorPtion.etcJI[ IHypoph.gi.j@IHOrmOneS;TOXiCFactor?)

HOST IDEPLETION

___________ MORBIDITY@ DEATH] [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 humoral factors. (c) They either contribute significantly to theoverall morbidity of the patient or exemplify importantmechanisms.

With this paper it is hoped that the substantial morbidityaccrued to patients by inadequate nutrition (a conditionpotentially reversible at present) will be brought to the attention of the clinician. At the same time those manifestations of cachexia in which neither direct invasion by thetumor nor nutritional inadequacy play a detectable role willbe pointed out.

WeightLossand Anorexia

Weight loss or, more precisely, the loss of biomass occurs commonly in both man and animals that succumb tocancer. In principle it can occur as a consequence of anorexia (i.e. , a decrease in the spontaneous consumption offood) or of decreased absorption of food from the alimentary canal. It can also occur in the absence of the abovefactors as a consequence of altered metabolism.

Weight loss is listed in the older literature as one of theinitial and common manifestations of cancer (53), a warningsignal. The documentation is largely anecdotal. Equallyanecdotal clinical impressions by contemporary observersimply that weight loss occurs only or predominantly later inthe natural history of cancer. This discrepancy is at least inpart due to the recent refinement in diagnostic techniquesthat allows earlier detection. Yet even today unexplainedweight loss in a patient requires a search for a possibleoccult neoplasm.

In considering weight loss on the part of the host, onemust keep in mind that severe depletion can be masked bythe abnormal expansion of one body compartment (mostoften water) at the expense of another. One must also remember that a given compartment might be depletedselectively.

Among the very few well-documented data describing theincidence of weight loss in patients with cancer are those byLanzotti (V. Lanzotti, personal communication) who has

noted a loss of at least 6% of body weight in @40%of 129patients with limited bronchogenic carcinoma. In 187 patients with extensive disease, weight loss was of the samemagnitude. The biological consequences of weight losswere clearly recognized. Median survival times of the depleted patients were less than one-half those observed intheir better nourished counterparts. More extensive dataon a variety of tumor types are critically needed.

It is not difficult to understand how weight loss mightoccur in patients with extensive disease and destructionswhen loss of appetite and/or decreased absorption of foodare such general and possibly nonspecific phenomena. Onthe other hand the weight loss that occurs in patients withlimited disease is of particular significance inasmuch as it ismore likely to be cancer specific and mediated humorallythrough either the induction of anorexia or some othermechanism.

Anorexia is unquestionably one of the possible causes ofweight loss. A clinical impression, which is probably wellfounded, suggests that anorexia is a common phenomenonin most cancer patients at some time during their illness. itmight reach such a degree of severity that spontaneousnutrition is almost completely suppressed. It is not uncommon to observe patients in whom a meager breakfast represents the only form of intake p.o. One must remember thatmany of these patients may be bedridden, febrile, nauseated, plagued by intractable pain, and devastated by thethought of impending death. One does not have to look farto understand their loss of appetite although the precisemechanism may not be obvious. In these circumstancesanorexia is certainly a nonspecific symptom experienced bythe majority of acutely or severely ill patients.

It would be of great interest to determine whether anorexia, like weight loss, might occur in patients with limiteddisease and therefore might be truly a paraneoplastic syndrome. Unfortunately, reliable data on the incidence andtiming of anorexia are practically nonexistent. This is notsurprising. In determining changes in food consumption,one must either prospectively follow patients or compareappropriate groups. The difficulties of obtaining reliable

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Possible causes ofanorexia1

.Nonspecific manifestationofdiseases2.Alterationsof taste and/or smellperception3.Productionoflactate4.Productionofketones5.Hypothetical

tumortoxins6.Directeftect on appetitecenter7.Psychological

factors

Cachexia

cancer intervention on appetite are well known and arediscussed elsewhere (39, 57, 70, 84). A more specific pathogenesis can be postulated in the rare subjects with smalltumors of the 4th ventricle (97). One could think here interms of a direct effect on the appetite center.

In addition to anorexia, interference with the patency andfunction of the alimentary canal or losses through abnormaldrainages are unquestionably the leading causes of weightloss (84) and possibly of anorexia itself.

Poor intake and poor absorption of food are not the onlydeterminants of weight loss. This point is of fundamentalimportance. It is exemplified quite convincingly by childrenwith the diencephalic syndrome (see below), in whom lossof fat (but not loss of lean body mass) occurs in the presence of normal or even supranormal intake. The fact thatanemia can occur in cancer patients without overt hemolysis, bleeding, marrow replacement, or recognizable nutritional deficiencies (5, 56) reinforces the concept that additional explanations of host depletion are required, besidesdecreased delivery of nutrients into the blood stream, andthat newer forms of intervention, in addition to increasednutrition, should be devised.

Loss of Specific Body Compartments

Tumor and host are metabolically separated but not totally independent districts. In certain circumstances thetumor can parasitize the host and thus add to the depletionproduced by insufficient intake. This is well illustrated bytumor growth in totally starved animals. It is therefore easyto understand how specific needs of the tumor might resultin specific depletions of the host. To what extent theseprocesses occur if food supply is adequate is not known.One must remember that, in the great majority of patientswho have been studied at autopsy and who have thereforeplayed out the ultimate act of the metabolic drama, thetumor mass seldom exceeds 500 g (J. W. Pickren, personalcommunication) and thus remains a small fraction of thehost biomass. Parasitization per se therefore is not likely tobe an important mechanism except possibly in the case oftrace nutrients. By whatever mechanism, specific depletions do occur in cancer patients and are discussed below.

Fat Depletion

Profound alterations of host lipid metabolism occur during the growth of a variety of tumors in both experimentalanimals and man (4, 22, 23, 25). Often the changes observed are clearly related to anorexia and involve other bodycompartments. There are nevertheless models in which neither anorexia nor parasitization of the host by the tumorplay a significant role. These models are of very specialinterest because they are prima fade examples of distant,humorally mediated metabolic effects of neoplasms.

In man the best known example is represented by thediencephalic syndrome, (3, 81, 82, 87), described first byRussell. The diencephalic syndrome, which is not generallyknown, affects children under 10 years of age and is characterized by an almost complete arrest or even reversal of thenormal weight growth. Height, however, is not affected. The

nutritional data on free-living populations are known (1).Existing surveys have centered primarily on low-incomegroups and are therefore of limited value even as historicalcontrols (16, 20, 55, 61). Simultaneous studies by a singleset of investigators of groups of patients with variouscancer types and of appropriate control groups have not yetbeen performed and are urgently needed.

Within these limitations the available data suggest thatanorexia is a widespread phenomenon. Thus, DeWys (36)has studied (by the 5-day food diary technique) 50 patientswith a variety of tumors; he noted that the severity of anorexia was related to the extension of the tumor. Theologides(95) has compared the food consumption of 39 patients whobear a variety of tumor types and tumor burdens with theirrecalled “normal―food intake. Marked anorexia was suggested. In our laboratory (31) we have studied by the nutrition interview technique the food consumption of 17 femaleand 13 male patients with a variety of neoplastic diseases. Ineach patient, food consumption was then compared withthe recalled normal intake. The female patients had decreased their average food intake from 1718 kcal/day (protein, 256 kcal/day; fat, 883 kcal/day; carbohydrates, 579kcal/day) to an average 1444 kcal/day (protein, 200 kcal/day; fat, 630 kcal/day; carbohydrates, 614 kcal/day). Theweight of the females prior to diagnosis exceeded idealweight by an average of 31 lb. The average weight loss ofthe females was 23 lb. Male patients had changed theirintake from an average 2827 kcal/day (protein, 424 kcal/day; fat: 1371 kcal/day; carbohydrates, 1032 kcal/day) to anaverage 1772 kcal/day (protein, 257 kcal/day; fat, 810 kcal/day; carbohydrates, 705 kcal/day). The weight of the malesprior to diagnosis exceeded ideal weight by an average 21lb. The average weight loss in the male was 38 lb. In furtherstudies (M. Aragon and G. Costa, unpublished observations) we have noted that the average daily caloric intake of50 adult ambulatory women who were receiving activechemotherapy was 1463 kcal/day compared to 1706 kcal/day consumed by 50 healthy women matched for age andsocioeconomic characteristics.

The pathogenesiS of anorexia is unclear (Table 1). Achange in taste perception has been described by DeWys(36) and is discussed more extensively elsewhere (37). Thepostulation that lactate, known to be produced abundantlyby tumors, could serve as an anorexogenic agent is attractive (2) but requires further documentation in man. The dataobtained by Morrison (67) that show that, with the generalreduction in energy available to the host, energy for seekingand processing food has almost vanished might provide anexplanation for the anorexia of termina! patients only. It isprobable that pain, fever, and anxiety (49) might well contribute to the lessening of food consumption. The effects of

Table 1

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Average fat contentof humanmuscleGroupSurgerynFat

(g/kg)'INoncancer35106±20bIICancer3051±11

laboratory (28), in which severe fat loss was documented inanimals with noninvasive tumors, without changes of carefully measured food intake and body temperature. The metabolic effects could be reproduced with a frozen andthawed 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 injectionof SV4Ocells into golden hamsters. in further experimentsin our laboratory (31), we have demonstrated that the rate ofexcretion of ‘4CO2by mice that were bearing 24-hr-old s.c.tumors and were given i.p. injections of [‘4C]tripalmitinwasreduced to 15 to 20% of that of controls. The rapidity of theeffect (already present 24 hr after implantation of the tumor)militates against tumor parasitization as the explanation.

Studies on the composition of human muscle conductedin our laboratory tend to support the hypothesis that earlyfat loss is a common event in patients with cancer (32)..@@,:Musclesampleswereobtainedatprimarysurgeryfrom

.@ @‘:@ @‘ patients with various tumors (primarily breast and colon)

and from patients with a variety of acute and chronic surgical 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 transplantedtumors (67) and sporadically in cancer patients (25, 102,103, 106), that the energy expenditures of the host areincreased. It is unlikely that this is due solely to the thermodynamic cost of synthesizing tumor protoplasm. The hypothesis that the tumor can produce an uncoupler of oxidative phosphorylation, however attractive, has not been substantiated (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 anexplanation of the fat loss described above. Other potentialbiochemical pathways through which energy might be lostare known and are discussed more extensively elsewhere(107).

Since the determinants of the amount of total body fatand of its major compartments are poorly understood atpresent, explanations for the fat loss described in this section remain speculative (14, 54). Critical well-designed experiments are needed to elucidate this area.

The contribution of host fat depletion to the total morbid.@ -.@ ity of the patient is difficult to assess. One could speculate

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

G. Costa

children appear extremely emaciated with a loss of most oftheir adipose tissue, as gauged by clinical criteria (Fig. 1).Preservation of lean body mass in the face of fat loss hasbeen implied. Associated with the fat loss, there is frequently motor hyperactivity and a change of mood towardjoviality. Nystagmus is common , but the neurological examination of these patients is otherwise within normal limits.Body temperature is usually normal. Laboratory examinations including serum protein levels are by and large normal. Nonesterified serum fatty acids have been measured inonly 1 case and found to be markedly elevated. Other serumlipids are usually normal. Hormonal studies have shown noabnormalities.

The syndrome has been associated with tumors of the 3rdventricle and of the anterior hypothalamus, which are demonstrable by standard neuroradiological techniques. Astrocytomas have been the most common tumors althoughglioblastomas, oligodendrogliomas, and ependymomashave been described. Interestingly, the syndrome developsin the great majority of cases in the absence of anorexia. Ina few cases increased appetite and increased food intakehave been described.

The syndrome finds a parallel in the experimental tumorsdescribed by Liebelt et al. (60) and in those studied in our

Table2

a I versus II, p < 0.001

S Mean ± S.E.

.,. ...@@

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

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Cachexia

responsible for anorexia, apathy, and some of the lesspalpable manifestations of the neoplastic cachexia. Experimental documentation of such considerations is not yetavailable.

Protein Depletion and Hypoalbuminemia

It is a common observation that many cancer patients losea significant fraction of their stable proteins. The mechanism subtending the loss is unknown.

In the recent past it was common to think of tumors as 1-way nitrogen traps and to infer that the nutritional consequences of tumor growth on the host were dominated bythis irreverisble step. Thus, selective depletion of the protein compartment or parasitization of strategic enzymeswas considered the key issue (25). Recently, generalizationof this concept to other animal models was proven to beunjustified (28, 51). Its applicability to cancer patients is atbest questionable. This was foreseen, and Mider et al. (66)had warned against extension of the concept of the nitrogen trap beyoild its original experimental conditions.

Nitrogen balance studies have been a common startingpoint for the investigation of the effects of cancer on proteinmetabolism. Balance experiments in rats bearing Walker256 carcinoma have shown that growing hosts fed ad libitum can continue to store the same amount of nitrogen asdo pair-fed controls, until the tumor has reached about 30%of the weight of the animal (65, 66). At this point proteinstorage in the tumor compartment is greater than the overall positive nitrogen .balance of the animal, and the hostloses protein to the tumor (65). Such loss had been confirmed by carcass analysis (66). Attempts made to increasecaloric and protein intake by force feeding were successfulonly in delaying the depletion of host protein (4, 90), whicheventually occurred even at very high intakes. The relevance of these studies to man is questionable. It is veryexceptional that the tumor compartment exceeds 10% ofthe weight of the cancer patient.

Nitrogen balance studies in patients have been generallyunrewarding. Nitrogen equilibrium, nitrogen loss, and nitrogen retention have all been reported (mostly in shortterm studies) without a clear correlation with intake andoverall behavior of the weight of the patient (43, 64, 73, 92,102, 103, 105@,106). Positive nitrogen balances in patientswho were actively losing weight have been explained withthe quantitatively inaccurate concept of synthesis of tumorprotoplasm.

The validity of the nitrogen balance technique is at thistime 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 andis very pertinent to the studies discussed above. The 2nd setinvolves conceptual difficulties that deal with the inherentinaccuracies of the method and with the possibilities ofunmeasured losses (Footnote 3; Refs. 26, 44, and 48). Suchconsiderations become particularly cogent at the high intakes 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 corresponding 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 8years has lost 18 kg and has developed a severe, disablingneuropathy in spite of adequate food intake. Normalcy of endocrine functions and of intestinal absorption was supportedby extensive testing. Although he received daily a documented 3000 cal and 20 g protein nitrogen (as a liquidsemisynthetic diet), the patient lost weight rapidly. Yet, hisapparent nitrogen balance data indicated a “retention'‘ofover 6 g nitrogen per day. Suspecting that the patient mightbe producing N2at an exceptionally high rate (23, 26, 30), wemeasured pN2 in mixed venous (right atrium) and in arterialblood. Venous pN2was about 10% higher than arterial. Thisgradient, which is larger than in healthy controls, supportsthe thesis that N2was being excreted through the lungs at ahigher than normal rate. As compensation for this loss,protein intake was increased to 25 g nitrogen per day. Thepatient began gaining weight. Seven months later he hadgained 18 kg, had lost most of his symptoms, and hadshown near normalization of nerve conduction and of nerveand muscle biopsies. Even several months after stabilization of his body weight, his nitrogen balance remainedstrongly positive (Chart 3).

These data show the necessity of careful noninvasivestudies of body composition before the fundamental defects of protein metabolism in cancer patients can be elucidated by the balance technique.

Because of the methodological simplicity, studies of theprotein metabolism of the host have often centered onserum albumin. Hypoalbuminemia occurs frequently in cancer-bearing patients and animals. The degree of hypoalbuminemia has been correlated with the extension of cancer(25).

Theoretically, hypoalbuminemia can be the consequenceof appropriate changes in the rate of production or in therate of destruction and can be the consequence of expandeddilution spaces o- of abnormal losses. Attempts to measurethe various determinants of hypoalbuminemia in can

.@

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

C Normals, liquid diet

a Re@ession @e

0 NOfiflOiS, solid diet

S LLC, Ii@id diet

a

U

c@J

Ii.________ t@

5 10 15N Intake (g/24 hr.)

I I

20 25

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G. Costa

cer patients have generated an abundant literature. The rateof synthesis of albumin can be measured with precursorslabeled with 14C,‘5N,355, or “Se.The available data suggest that in cancer patients the rate of albumin synthesis isdecreased (27, 51, 63, 75, 89, 99). Such data have beenobtained at certain times by indirect considerations and atother times without complete assessment of all the involvedpools; thus they should not yet be looked upon as conclusive. The explanation for the hypoalbuminemia remainstherefore speculative.

It would seem inescapable that hypoalbuminemia is atleast to some extent due to the malnutrition of the host (76-79, 86). Serum albumin levels of cancer patients have beenrestored to normal by parenteral hyperalimentation, whichsuggests that any decrease in synthesis may not be irreversible even in the absence of change in the tumor (41).

Consumption of albumin by the tumor is an attractivehypothesis and has found some support in preclinical work(13). Confirmation of such data by other laboratories and byincorporation of the albumin label into chemically purifiedtumor fractions (an absolute prerequisite in view of thenotorious stickiness of albumin) would be especially valuable. Distribution of albumin into abnormal spaces (a reasonable thought in view of the subclinical edema so common incancer pateints) has been suggested by results obtained inmy laboratory (27) and by others (99). Definitive proof is notat hand. Nephrotic syndromes and protein-losing enteropathies have been well described in patients with cancer (62,98, 100), but such abnormal losses are so infrequent compared to hypoalbuminemia that they cannot be taken as ageneral explanation.

The central point, which still needs to be established , is towhat extent is hypoalbuminemia secondary to poor nutrition and to what extent is it due to the specific effects of thetumorperse. That poor intake might not be the only explanation for hypoalbuminemia is supported by the observation on occasion of patients in whom the loss of nearly 50%of body weight and a substantial reduction in midarm circumference coexist with normal hemoglobin and serumalbumin levels.

In this context it is useful to mention the observations byGoodlad and Clark (17, 18, 46) who have shown that, withadult rats bearing Walker 256, there is a marked inhibitionof amino acid incorporation by muscle polyribosomes. Theresults are interpreted as suggesting some translation defect possibly mediated through the serum factor describedby Toporek (96). A defect in the postinitiation stage oftranslation was also described in a more recent paper byClark and Goodlad (19). These studies therefore illustratealterations in the synthesis of host protein, which are independent from nutritional intake. Whether or not these arerelevant to albumin metabolism remains to be established.

Recently, protein malnutrition in man has been studiedeffectively by Bistrian et al. and by Blackburn et al. (7-10)with a combination of anthropometric and biochemical parameters. The simplicity of the methods gives hope that

effective guidelines can be developed for quantifying overall protein depletion and for monitoring the effects of hyperalimentation.

The contribution of hypoalbuminemia to the overall mor

bidity, as long as albumin levels do not decrease below 2 g/100 ml, is hard to assess at the present time. There is noquestion that protein depletion can contribute significantlyto the overall morbidity of the cancer patient. The pathologyof protein malnutrition as it occurs within the context ofstarvation is well known. Shorter survival time; inability totolerate chemotherapy, radiotherapy, or surgery; loss ofimmunological competence (24); and altered respiratoryhomeostasis (38) have all been described in protein-depleted patients. The cumulative effects of protein depletionon the viability of the patient can therefore be overwhelming.

Glucose Depletion

The syndrome of hypoglycemia associated with tumors ofnonpancreatic origin is a well-documented entity. Since1929, when the 1st report appeared in the literature, about150 cases have been described . Nearly 50% of the tumorshave been fibrosarcomas and another 30% have been hepatomas. Nearly 90% of the tumors were growing in the retroperitoneal space or in the liver (15, 72, 85). The hypoglycemia induced by the above tumors is at variance with thetendency of most other neoplasms to impair glucose utilization in the host (104).

One of the outstanding characteristics of these tumors istheir size. The great majority of those that were weighedexceeded 1 kg. A 9-kg tumor is probably the largest of theseries. The age or sex distribution of the syndrome is notsubstantially different from that of tumors in general.

The pathogenesis of the hypoglycemia is the subject ofconsiderable controversy. The large size of the majority ofthese tumors has suggested overutilization of glucose bythe neoplasm (15). The other potential pathogenetic mecha

Caler@lntoksMar

BodyWeigMkg

70

66

62

58

54

50

Nitrogen 0lfltokeg,Idoy 4

8

12

16

20

24

2 4 6 8 10November,972

8 10 2 14 16 8 20April, 1973

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

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CANCER]

@Absorptionof Nutrients Anorexia I Altered MetabolismI Obstruction, Malabeorptlon. etc.) Hypophaglat [tHormon.s;Tozlc Factor?)

[HOST DEPLETION

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

Cachexia

Abn. Routes IIFistula,,

I HYPERALIMENTATION

4,

+ _____J

IDEATH]@ [CACHEXIA]—.MORBIDITYShorter Survival

Inadequate Homeostasts

@ Tolerance to InterventIon

@ Response to Intervention@ Immunocompetence

nism proposes secretion by the tumor of a substance orsubstances capable of producing hypoglycemia. In a number of cases, insulin-like activity has been demonstrated inthe tumor, whereas in an approximately equal number ofcases this claim could not be substantiated (25, 85).

The hypoglycemic syndrome can add significantly to themorbidity of patients. On occasion a blood glucose levelcompatible with life can be maintained only with great difficulty. The predominance of 2 types of tumors and substantially 1 general localization makes the syndrome anatomically and clinically a well-defined entity. Its pathogenesisremains to be further elucidated.

Conclusions

We have discussed manifestations of cachexia characterized by depletion of protein, fat, and carbohydrates, and wehave attempted in each case to evaluate the relative pathogenetic roles of decreased delivery of nutrients and of altered host metabolism.

Until recently the student of cachexia was limited to thedescription and the interpretation of phenomena. Theadded dimension of metabolic intervention was not available. In the 1960's the recognition that undernutrition washighly prevalent in patients hospitalized for nonneoplasticdiseases (11, 58) stimulated the development by Dudrick etal. (41) of methods of parenteral nutrition, which wereshown to be effective in repleting such individuals. Thesesame techniques are now being applied to cancer patientsand appear already to be nutritionally effective and synergistic with other modalities of cancer intervention (21, 40).Their application to cancer patients will do more than replete the patient. They will finally allow (having wholly reversed the consequences of poor intake) adequate identification of the nonnutritional effects of cancer, if indeedthese effects exist (Chart 4).

The question of parasitization of the host by the tumor willcome under proper perspective by observing the growth ofcancer in the well-fed host. A number of studies in animal

models have implied that cancer grows best in a well-fedhost (6, 42, 68, 74, 88). This fear of stimulating tumorgrowth has in the past been a deterrent (in the minds ofsome) to the institution of hyperalimentation to cancer patients. It seems unlikely that such fear is justified. In theanimal models studied, the tumor biomass exceeds 30% ofthe host, a condition which makes parasitization an important factor but which is not applicable to man in whomtumor mass rarely exceeds 5% of the host. Moreover, theimproved therapeutic effects that can be obtained in wellfed patients (21) will probably prove conclusive in showingthe beneficial effects of hyperalimentation.

It is probable (in the mind of this reviewer) that distanteffects of tumors will still be observable in well-fed patients.It is hoped that recognition of these effects will finally giveimpetus to the search and isolation of those chemical mediators of tumor aggression, the existence of which wasbroadly hinted at in our discussion. The technology for thistask can be borrowed initially from the investigations of thechemical mediators of inflammation and of lymphocyte factors. The unambiguous demonstration of the existence oftumor toxins and the definition of their role might well bethe significant breakthrough in oncology.

References

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