Pathophysiology of Cancer Cachexia: Current Understanding and Areas for Future Research1

[CANCER RESEARCH (SUPPL.) 42, 721S-726S, February 1982]

William D. DeWys

Nutrition Section, Clinical Investigations Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205

Abstract use may also be an important variable (32). Food consumption may be considered to be insufficient either in absolute terms or Weight loss and failure to gain weight normally in cancer in terms relative to an increased energy use. Also to be consid patients are attributable to negative energy balance and altered ered when evaluating the relative adequacy of food intake are metabolism. Energy balance is negative because of decreased individual variations in caloric requirements for weight gain (27) intake, increased expenditure, or both. Changes in carbohy and homeostatic adjustment to reduced caloric intake. In nor drate metabolism include glucose uptake and lactate produc mal subjects, a forced reduction in caloric intake leads to a tion by tumor, relative hypoinsulinism, and relative insulin re reduction in caloric expenditure; but in cancer patients, this sistance. Alterations in protein metabolism include preferential normal adaptation may be blunted or blocked (3). uptake of amino acids by the tumor, decreased synthesis of There are relatively few studies of energy balance in cancer some host tissue proteins such as muscle tissue, and increased patients and no detailed studies of energy balance in children synthesis of other host proteins. Lipid metabolism is seemingly with cancer. In adults, a report by Warnold ef al. (32) is less affected. These metabolic changes result in muscle wast probably the best available study. They estimated caloric intake ing in adult cancer patients and growth failure in pediatrie and expenditure over a 24-hr period and compared the results cancer patients. Host tissues are catabolized to meet the with controls having roughly comparable activity. They found nutritional demands of the tumor, and nutritional death may both decreased energy intake and increased energy expendi ensue. ture in the cancer patients compared with controls. The energy expenditure averaged 1980 kcal/24 hr, well within the range Weight loss in adult patients and weight loss or failure to gain of normal caloric intake, while energy intake averaged 1340 weight normally in children are frequent adverse effects of kcal/24 hr. One illustrative case from that series was a patient cancer (15). Weight loss or the failure to gain weight normally who was studied while his tumor was present and again after must represent disturbed coupling between energy intake and its surgical removal. When the tumor was present, his energy energy expenditure. In the normal coupling of these 2 pro intake was 1390 kcal/day, and his expenditure was 3330 cesses, if energy expenditure is increased (such as by in kcal/day. During the second study, 20 weeks after surgery, creased activity), energy intake increases. Conversely, if en he was in caloric balance with an intake of 2270 kcal/day and ergy intake is decreased (such as in a voluntary reduction of an expenditure of 2190 kcal/day. If we consider the second caloric intake), homeostatic processes, such as a lowering of study as representative of his normal metabolic state, then the metabolic rate, result in reduced caloric expenditure. initial study showed both reduced intake and increased expen In cancer patients, either reduced caloric intake or increased diture. caloric expenditure or a combination of the 2 results in negative Many studies of caloric expenditure are deficient due to energy balance, cessation of growth, and weight loss. In some technical or other considerations. Patients have been studied patients, factors causing reduced intake such as interference by indirect calorimetry (O2 consumption and CO2 production) with normal gastrointestinal function may be apparent, but in often for only limited periods of time, and the data obtained many patients no apparent cause of decreased intake can be have then been extrapolated to 24 hr of expenditure. Errors in discerned. In some patients, such as in a patient with fever, sampling and analyses and the magnification of these errors increased energy expenditure may be obvious, but in most by extrapolation must be considered when interpreting the patients, increased expenditure escapes clinical detection. results from indirect calorimetry. Energy expenditure in cancer In this paper, I will review current understanding of energy patients should be studied using direct calorimetry (measuring balance in cancer patients. However, negative energy balance body heat production) for periods of at least 24 hr to encom is only one determinant of cancer cachexia; therefore, I will pass the usual diurnal cyclic variations in metabolism. Also also review alterations in metabolism in cancer patients which patients should be studied at a caloric intake of their choice contribute to our understanding of cancer cachexia. and at a caloric intake commensurate with their energy expen diture. The latter would evaluate whether increasing the energy intake results in a further increase in energy expenditure. Energy Balance These studies would resolve the question of whether energy The role of insufficient food consumption as a cause of balance is easily obtainable or is elusive. This kind of study weight loss or growth failure in a cancer patient seems indis would also provide a clue as to whether patients have reduced putable. However, evidence suggests that increased energy their caloric intake as a means of reducing their caloric expen diture (see below). ' Presented at the Pediatrie Cancer and Nutrition Workshop, December 11 Energy balance should also be studied under conditions of an activity level of the patient's choice and at an increased and 12, 1980, Bethesda. Md.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1982 American Association for Cancer Research. W. D. DeWys level. It will be of interest to know whether the increase in has shown that increased carbohydrate intake results in a caloric expenditure with exercise is similar in cancer patients further increase in lactate production. It is known that infusion and in normal controls. The pattern of decreased activity in of lactate into normal volunteers elicits sensations of nausea. cancer patients is not well understood. A possible explanation Thus, it is possible that, if a cancer patient eats a normal-sized is that cancer patients may decrease their activity to reduce meal, lactate production may increase, a feeling of nausea may their energy expenditure and thus diminish their energy deficit. ensue, and the learned response may be to eat less to avoid this sequence. Psychophysical studies in cancer patients can Increased Energy Expenditure elucidate this possibility.

The increased energy expenditure of cancer patients in Mobilization of Energy Stores cludes energy expenditure within the tumor and energy de mands placed on the host by the presence of the tumor. The When energy expenditure exceeds energy intake, energy energy requirements within the tumor will be discussed below stores must be utilized in accordance with principles of ther in terms of carbohydrate and protein metabolism. The energy modynamics. Short-term deficits are met by mobilization of requirements of a tumor affect energy expenditure by host glycogen to form glucose, but glycogen stores are limited and organ systems. If increased amounts of food need to be in are soon depleted. Body fat and body protein are then mobi gested and digested, this may increase energy utilization within lized to meet energy requirements. In simple starvation, most the digestive system. Circulation of blood through the tumor of the energy requirements are drawn from body fat, and may increase energy utilization by the heart. Increased energy critical organs adapt to use of lipids and lipid metabolites as an expenditure results in increased oxygen consumption and in energy source (3). However, in cancer cachexia, there is an creased carbon dioxide production, and this may increase the increased need for glucose for use by the tumor (see below), work of breathing. and muscle protein is broken down to provide the carbon skeletons for glucogenesis. Reduced Energy Intake Carbohydrate Metabolism The reduced caloric intake in cancer patients is not well understood. Alterations in taste and smell sensation have been Carbohydrates provide a major source of the energy require documented in cancer patients (6, 7, 23), but the relationship ments for tumor metabolism. The magnitude of glucose uptake between these alterations and reduced caloric intake is not by a tumor-bearing limb has been studied in perfusion experi clear-cut. In several studies, reduced caloric intake seemed to ments and averaged 160 mg/min in patients with soft-tissue correlate with these sensory abnormalities (5); but in a multi- sarcoma (24). If this level of uptake were constant over 24 hr, variate analysis currently in progress, the association is of the average tumor would take up 230 g of glucose. Glucose borderline statistical significance.2 uptake was proportionate to tumor size and was approximately Hypothalamic food intake control centers have been studied 1.4 g/24 hr/g of tumor (24). This level of glucose uptake (230 with the general conclusion that these centers are not abnormal g/24 hr) by tumor agrees quite well with the increased glucose in the cancer-bearing host (21). Bernstein (2) has recently turnover of 170 g/24 hr observed by Holroyde (11 ) in studies drawn attention to learned aversions related to chemotherapy of whole-body glucose metabolism in weight-losing cancer as a possible factor in reduced intake. It is likely that learning patients. Holroyde, however, did not find glucose turnover to processes play a large role in controlling food intake. People be proportionate to tumor size, perhaps reflecting greater learn to prefer certain foods because of pleasant tastes, smells, heterogeneity in his study population. ect., during eating and because of pleasant internal feelings Glucose is metabolized in tumor tissue predominantly via which follow eating of these foods. If eating of specific foods is anaerobic glycolysis (31). This predominance of anaerobic followed by unpleasant sensations, one learns to avoid those metabolism over aerobic metabolism persists even if tumor foods. Normally, there is a slight increase in body heat produc cells are well oxygenated in tissue culture, and it is explained tion following eating, and this is perceived as pleasant. How by concentrations of enzymes which control cellular metabo ever, excessive body heat production is unpleasant, and if lism. eating a certain amount of food resulted in an unpleasant One consequence of this anaerobic metabolism is the degree of heat production, a learned reduction in food intake release into the circulation of lactate by tumor cells. Lactate is might result. I postulate that the increased energy expenditure transported via the circulation and is metabolized by the liver in cancer patients includes an increased energy expenditure in and kidney to produce glucose in an energy-requiring process. response to energy intake and that intake of a normal-sized This cycle from glucose to lactate back to glucose, known as meal results in an unpleasant amount of body heat production. the Cori cycle, has been estimated to account for a 10% The patient then learns to eat less in order to avoid this increase in energy expenditure in the tumor-bearing host (34). unpleasant sequela of eating. This hypothesis is testable using Arterial blood levels of lactate increase only slightly in the continuous calorimetry to study the heat produced following a presence of a tumor,3 reflecting the considerable ability of the meal of the patient's choice or a high-calorie meal. liver and kidney to metabolize lactate. However, in the presence Biochemical changes following eating might also lead to of extensive liver damage, such as with extensive liver mÃ©tas learned alterations in eating behavior. Lactate production is tases, lactic acidosis may develop. As discussed above, a increased in cancer patients (see below) and Holroyde (11)3 question for future study is the role of lactate production in 2 W. D. DeWys. unpublished observations. producing anorexia. 3 C. P. Holroyde, personal communication. Another aspect of carbohydrate metabolism which may be

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1982 American Association for Cancer Research. Pathophysiology of Cancer Cachexia relevant to cachexia is abnormality of glucose tolerance (28). It is of interest to compare muscle metabolism in cancer- In this study by Smith ef a/., cancer patients had a mean blood bearing hosts with that in pair-fed controls (imitating the de glucose in excess of 160 mg/100 ml 2 hr after a standard p.o. creased food intake of tumor bearers). Pair-fed controls show glucose load. Over the interval from 1 to 4 hr after glucose decreased muscle protein synthesis to the same level as do P.O., cancer patients had statistically elevated blood glucose tumor bearers (29)." However, pair-fed controls show de values compared to controls. Plasma insulin rose at a slower creased breakdown of muscle protein in contrast to increased rate in cancer patients, but the eventual maximum concentra breakdown of muscle protein in the cancer-bearing host tissues tions were identical. However, the insuliniglucose ratio was (16). lower in cancer patients, suggesting a relative hyporesponsive- The pathophysiology of these alterations in muscle tissue ness of insulin release by islet cells. can be in part explained by changes in muscle enzyme levels. There is also evidence for insulin resistance in cancer pa Enzyme activities in muscle tissues of tumor-bearing animals tients. In a study of glucose loading p.o. (5 g every 15 min), the and humans show depression of key enzymes of anabolism steady-state level of glucose was higher in cancer patients than and increases in activity of catabolic enzymes, such as ca- in controls, while both groups had comparable insulin lev thepsin D. The increased activity of catabolic enzymes in els (26, 28). Also, in a study in which exogenous insulin muscle tissue from cancer patients could be correlated with was administered while endogenous insulin production was increased protein degradation compared to normal controls blocked, blood glucose was approximately twice as high in (15). Amino acids released from skeletal muscle are used for cancer patients as in controls, while comparable steady-state tumor protein synthesis and for gluconeogenesis to provide insulin levels were achieved providing further evidence for glucose for tumor metabolism (24). The result is progressive insulin resistance (27). muscle wasting in the cancer patient. Future studies should include further evaluation of insulin resistance using the recently developed glucose clamp and Lipid Metabolism insulin clamp techniques. The mechanism(s) of insulin resist ance should be a focus of future research. Lipid metabolism is generally normal in cancer patients. Fasting free fatty acid levels are usually normal (11, 26), and Protein Metabolism they fall appropriately in response to insulin (19, 25). However, free fatty acid oxidation was suppressed to a lesser extent by Abnormalities in protein metabolism in cancer patients in glucose loading of cancer patients than that seen in normal clude the flow of amino acids into the tumor for synthesis of controls (33). This decreased suppression of free fatty acid protein, reduction of synthesis of some host proteins, and an oxidation probably reflects utilization of glycerol for the accel increased synthesis of other host proteins. The flow of amino erated gluconeogenesis in the cancer patient (25). acids into tumors has been documented in animal models (8) Seemingly at odds with these observations of Waterhouse and in humans (24). The human studies measured arteriove- which support increased utilization of free fatty acids are ob nous differences in a tumor-bearing limb in the postabsorptive servations by Axelrod and Costa (1 ) which suggest decreased state. In the tumor-free limb of these patients, there was release mobilization of fat in cancer patients. In Axelrod's studies of of all amino acids. The tumor-bearing limb released less of the effect of a 4-day fast, controls show a progressive rise in every amino acid and, overall, released less than one-half of free fatty acids during fasting, reflecting release from lipid the quantity of amino acids released by the control limb. This stores. Cancer patients show a slower rise in fatty acids, reduced release from the tumor-bearing limb reflects the net suggesting decreased mobilization of lipid. A progressive rise effect of amino acid uptake by tumor tissue and amino acid in plasma ketones is noted in both groups with no difference release by normal tissue in that limb (24). between them. Synthesis of muscle proteins is generally depressed in can In searching for an explanation for decreased lipid mobili cer patients. Plasma amino acids in cancer patients are altered zation, Axelrod and Costa (1 ) have studied serial changes in with decreases in some amino acids (4). However, decreased hormones known to affect lipid metabolism. They have found muscle protein synthesis is not simply due to alterations in the that the cancer patients have decreased levels of triiodothyro- precursor pool. When protein synthesis is measured in cultures nine. During fasting, triiodothyronine levels fall in both controls of tissues taken from cancer patients, the depressed synthesis and cancer patients, but differences between them continue is only partially corrected by an addition of an excess of amino for the duration of the fast. In interpreting these observations acids (16) or insulin (19). on plasma triiodothyronine levels, one must consider that a While synthesis of muscle proteins is depressed, synthesis decrease in triiodothyronine levels is one of the homeostatic of other host proteins may be increased. The liver seems to be responses to reduced caloric intake. Thus, the low levels of protected from catabolic protein balance in the tumor-bearing triiodothyronine could reflect a response to antecedent hypo- host (17, 18, 30), and liver size remains normal or increases. caloric intake rather than an effect of cancer. This area requires The liver normally accounts for 20 to 25% of total oxygen further study. consumption; therefore, continued hepatic protein synthesis may be an important factor in energy balance in cancer patients (34). When the characteristics of protein synthesis in the liver Body Composition of tumor bearers are analyzed further, it is seen that synthesis Observations on body composition, are relevant to this dis of liver structural proteins is normal, while synthesis of secre tory proteins such as acute-phase reactants is increased (22)." cussion of lipid metabolism. Cohn ef al. (5), using neutron activation and whole-body counting, have estimated body fat ' L. Ekman. personal communication. and muscle compartments in cancer patients and age-matched

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controls. They have noted relatively equal depletion of body fat kcal/g growth. Based on a targeted weight gain of 0.9 g/kg/ and body muscle in cancer patients who have lost weight. If day, this converts to 0.4 to 1.1 kcal/kg body weight. In addi one thinks in terms of conservation of body function, mobili tion, one must allow for the metabolic requirements of activity zation of body fat and preservation of body muscle would be which will be an addition of about 50% of basal metabolic advantageous. However, in the cancer patients, the abnormal requirements for moderate activity and a stress allowance for ities of protein metabolism discussed above with normal or the requirements of the tumor and the effects of treatment. decreased lipid mobilization result in depletion of muscle re If either the caloric or nitrogen requirements are not met in serves concurrent with relative preservation of body fat. the cancer patient, the first effect will probably be interference with growth. Growth of soft tissue may be affected out of Nutritional Requirements for Growth proportion to skeletal growth, and the weight:height ratio will fall below normal averages. With further decline in caloric Nutritional requirements for growing children must include intake, there may be insufficient energy for activity, and the maintenance requirements, requirements for growth, and re child may become apathetic and listless. With decline in protein quirements for stress. Maintenance requirements for protein intake below growth requirements, the dynamic resynthesis of can be derived from nitrogen balance studies in which nitrogen muscle may decline and further decrease activity. With contin balance is correlated with nitrogen intake. As one increases ued inadequacies of caloric or nitrogen intake, host tissues will nitrogen intake from suboptimal to optimal, nitrogen balance be catabolized to meet the needs of the tumor and the needs changes from negative to positive. The nitrogen intake at which of vital host functions such as circulation and respiration. nitrogen balance crosses the zero intercept is taken as a Eventually, these too may fail and nutritional death may ensue. measure of maintenance requirements. Several studies of this design lead to a suggestion of 140 mg/kg/day for maintenance References for calculation of protein requirements for infants and children 1. Axelrod. L.. and Costa, G. The contribution of fat loss to weight loss in (9, 12-14). Losses through the skin, hair, and nails can be cancer. Nutr. Cancer, 2. 81 -83, 1980. measured and, allowing for individual variation, one arrives at 2. Bernstein, I. L. Physiological and psychological mechanisms of cancer an estimate of 18 mg/kg for these losses (12). The protein anorexia. Cancer Res. (Suppl.), 42: 715s-720s, 1982. 3. Brennan, M. F. Uncomplicated starvation versus cancer cachexia. Cancer requirements for growth can be calculated based on the protein Res., 37: 2359-2364. 1977. content of normal weight gain and the efficiency of protein 4. Clark, E. F., Lewis, A. M., and Waterhouse. C. Peripheral amino acid levels utilization (12). Protein for growth represents about 20 to 25% in patients with cancer. Cancer (Phila.) 42: 2909-2913, 1978. 5. Cohn, S. H., Gartenhaus, W., Sawitsky, A., Rai, K.. Ellis. K. J., Yasumura, of the protein requirements of an infant. Finally, in a cancer S., and Vartsky, D. Compartmental body composition of cancer patients by patient, we must include a "stress allowance" for the require measurement of total body nitrogen, potassium, and water. Metab. Clin. Exp., 30. 222-229, 1981. ments of the tumor and the stress effects of treatment. The 6. DeWys, W. D. Taste abnormalities and caloric Intake In cancer patients: a magnitude of this stress allowance is entirely speculative (Table review. J. Hum. Nutr., 32: 447-453, 1978. 7. DeWys, W. D., and Walters, K. Abnormalities of taste sensation in cancer 1). patients. Cancer (Phila.), 36. 1888-1896, 1975. Caloric requirements can also be analyzed into component 8. Fenninger, L. D.. and Wider, G. B. Energy and nitrogen metabolism in parts. Caloric requirements for basal metabolism can be cal cancer. Adv. Cancer Res., 2. 229-253, 1954. culated from the value suggested by Fleish of 53 kcal per sq m 9. Fomon, S. J.. DeMaeyer, F. M., and Owen, G. N. Urinary and fecal excretion of endogenous nitrogen by infants and children. J. Nutr., 85: 235-246. body surface area per hr or 1270 per sq m per 24 hr (Table 2) 1965. (10). Synthesis of protein is an energy-requiring process esti 10. Guyton, A. C. 1976 Textbook of Medical Physiology, Ed. 5. p. 954. Phila mated at 3 to 8 kcal for each g of protein synthesized (20). If delphia: W. B. Saunders Co., 1976. 11. Holroyde, C. P., Gabuzda, T. G., Putnam, R. C., Paul, P., and Reinchard, G. each g of growth is composed of 0.15 g protein, 0.6 g water, A. Altered glucose metabolism in metastatic carcinoma. Cancer Res., 35: and 0.25 g fat, then each g growth would require 0.45 to 1.2 3710-3714, 1978. 12. Huang, P. C., LJn. C. P., and Hsu, J. Y. Protein requirements of normal infants at the age of about 1 year: maintenance nitrogen requirements and obligatory nitrogen losses. J. Nutr.. 110: 1727-1735, 1980. Table 1 13. Joint FAO/WHO Expert Committee on Energy and Protein Requirements. Estimation of protein requirements for infants and children Energy and protein requirements. WHO Technical Report Series 522, Ge neva: WHO, 1973. Nitrogen 14. Kaye, R., Barness, L. A., Valyasevi, A., and Knapp, J. Nitrogen balance (mg/kg/day) studies of plant proteins in infants. In: Meeting Protein Needs of Infants and Children, pp. 297-312. Washington, D. C.: National Academy of Sciences- Maintenance requirement 140 National Research Council (Publication 843), 1961. Loss in skin, hair, and nails 18 15. Kisner, D. L., and DeWys, W. 0. Anorexia and cachexia in malignant disease. Requirment for growth" 43 In. G. R. Newell and N. M. Ellison (eds.), Nutrition and Cancer: Etiology and Stress allowance (? tumor) 20% 40 Treatment, pp. 355-365. New York: Raven Press. 1981. Total requirement 241 16. Lundholm, K.. Bylund, A. C., Holm. T., and Schersten, T. Skeletal muscle metabolism in patients with malignant tumor. Eur. J. Cancer, 72: 465-473, Total protein requirement (241 x 6.25) = 1.5 g/kg/day 1976. '' Based on a daily weight gain of 0.9 g/kg with 15% of this gain as protein 17. Lundholm, K.. Ekman, L., Edstrom, S., Karlberg, !.. Jagenburg, R., and Schersten, T. Protein synthesis in liver tissue under the influence of a and a correction for efficiency of protein utilization. methylcholanthrene induced sarcoma in mice. Cancer Res., 39: 4657- 4661, 1979. 18. Lundholm. K., Ekman, L., Karlberg, I., Edstrom, S.. and Schersten. T. Table 2 Comparison of hepatic cathepsin D activity in response to tumor growth and Estimation of energy requirements for a child with cancer to caloric restriction in mice. Cancer Res.. 40: 1680-1685. 1980. 19. Lundholm. K.. Holm, G.. and Schersten. T. Insulin resistance in patients with Basal metabolic requirements 1270kcal/sq m/24 hr cancer. Cancer Res.. 38: 4665-4670, 1978. Growth requirements 0.4-1.1 kcal/kg 20. Milward. D. J.. and Garlick. P. J. The energy cost of growth. Proc. Nutr. Activity allowance Add 50% Soc., 35: 339-349, 1976. Stress allowance {? tumor) Add 20% 21. Morrison, S. D. Control of food intake in cancer cachexia: a challenge and

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a tool. Physiol. Behav., 77: 705-714, 1976. in man. Recent Prog. Horm. Res., 29: 457-496, 1973. 22. Narendra, G. M. The site of synthesis and functions of acute plasma proteins: 28. Smith, F. P., Kisner, D., and Schein, P. S. Nutrition and cancer prospects close relationship with the reticuloendothelial system. Med Hypotheses, 3. for clinical research. Nutr. Cancer, 2: 34-39, 1980. 63-70, 1977. 29. Stein, T. P. Cachexia, gluconeogenesis and progressive weight loss in 23. Nielsen, S. S., Theologides, A., and Vickers, Z. M. Influence of food odors cancer patients. J. Theor. Biol., 73: 51-59, 1978. on food aversions and preferences in patients with cancer. Am. J. Clin. 30. Stein, T. P., Omar-Smith, J. C., Leskiw, M. J., Wallace, H. W., and Miller, E. Nutr., 33: 2253-2261, 1980. F. Tumor-caused changes in host protein synthesis under different dietary 24. Norton, J. A., Burt, M. E . and Brennan, M. F. In vivo utilization of substrate situations. Cancer Res., 36: 3936-3940, 1976. by human sarcoma-bearing limbs. Cancer (Phila.), 45: 2934-2939, 1980. 31. Warburg, O. Metabolism of Tumors. London: Constable & Co., Ltd., 1930. 25. Ruderman, E., Toews, C., and Shafrin, E. Role of free fatty acids in glucose 32. Warnold, I., Lundholm, K., and Schersten, T. Energy balance and body homeostasis. Arch. Intern. Med., 723: 299-313, 1969. composition in cancer patients. Cancer Res., 38: 1801-1807, 1978. 26. Schein, P., Kisner, D., Haller, D.. Blecher, M., and Hamosh, M. Cachexia of 33. Waterhouse, C., and Kemperman, J. Carbohydrate metabolism in subjects malignancy: potential role of insulin in nutritional management. Cancer with cancer. Cancer Res., 31: 1273-1278. 1971. (Phila). 43: 2070-2076, 1979. 34. Young, V. R. Energy metabolism and requirements in the cancer patients. 27. Sims, E. A. H., Danforth, E., Jr., Horton, E. S., Bray, G. A., Glennon, J. A., Cancer Res., 37. 2336-2347, 1977. and Salans, L. B. Endocrine and metabolic effects of experimental obesity

Discussion parameters. Specifically, even though lactate production tended to be increased as tumor burden tended to increase, a fact which I find very Dr. Holroyde: We have been concerned, in collaboration with Dr. difficult to measure in adults with average solid tumors, this correlation George Richard, with attempting to use isotope tracer methodology to was far from clear-cut. Equally, if we look at glucose turnover rates, assess overall carbohydrate metabolism in patients with cancer ca- and we now have in excess of 200 turnover studies, Cori cycle activity chexia. Patients were not uniform as to cell type but were uniform in as measured was markedly elevated in about 30%, and these patients that all were losing weight, usually up to 15% of body weight, and none tend to be those that have the highest caloric expenditure and the of the patients were considered to be terminal at the time of study. I'd highest O2 consumption, but this is not necessarily so. A further 30% like to give an overview of glucose and lactate metabolism in normal of patients have moderately increased glucose turnover rates, and humans. The liver has glycogen stores and a supply of glucose through roughly 40% or so are normal. One can have enormous tumor burden gluconeogenesis which supplies the central nervous system, muscle and have totally normal glucose turnover rates. Equally, one can have mass, and RBC. In RBC, lactate is produced which circulates to the normal rates of caloric expenditure. The difference in those patients liver and kidney where it is converted back to glucose, giving a return who are normal versus those with elevated turnover is entirely attributed of glucose from lactate of approximately 35 g of glucose per day. This to increased glucose recycling through the Cori cycle in cancer pa gives a total turnover, that is, net production plus utilization, of 200 g. tients. Therefore, its seems that we have some subjects with normal This cycle, referred to as the Cori cycle, is energetically wasteful in turnover and therefore with presumably normal requirements, and we that it requires energy to return lactate to glucose. In our view, however, have others with extraordinarily high requirements. It is of interest to no direct measurements of the effect on overall energy metabolism can us to compare these results with those in 7-day-fasted normals. During be made, since I do not believe it is possible to calculate this given the fasting, glucose turnover rate falls. If you look at cancer patients with present state of knowledge. In one of our patients the total production anorexia or cachexia studied in the postabsorptive state, the glucose plus utilization of glucose was 365 g/day which is at least twice normal turnover may be normal or it may be markedly elevated, clearly different glucose turnover, an enormous elevation in the utilization of glucose. from controls who are starved but otherwise normal. It might, therefore, Assuming that the normal person would require 130 g for the central be attractive as a hypothesis to wonder whether even a normal glucose nervous system, 40 g for muscle, and 30 g for RBC, then we assume turnover in the face of reduced caloric intake is not inappropriately that the tumor requires on the order of 165 g/day. These data are elevated. I'd like to comment on Dr. DeWys' comments about carbohydrate consistent with the data both from animal models and from the work of Dr. Brennan using isolated limb perfusion (24). This is, in effect, an intolerance. One thing which very rapidly will inhibit gluconeogenesis extraordinarily high recycling of lactic acid, that is, glucose to lactate within the liver is insulin, so that the finding of elevated Cori cycle by anaerobic metabolism and back to glucose again as part of gluco activity in some patients would make you think they probably would be neogenesis. We have now studied in the postabsorptive state approx insensitive to insulin, either through tissue insensitivity in the liver or imately 50 patients, using either glucose or uniformly labeled lactic through a reduced secretion of insulin by the pancreas. The first has acid in order to measure Cori cycle in a cancer population. I'd like to been hypothesized, and the second I think has been reasonably proven. preface any remarks by saying that nothing about the metabolic events We have done some preliminary work and do find that, in patients with we have seen is specific for neoplasia, and there is, in all instances, a high Cori cycle activity, there is a degree of relative hypoinsulinemia rather remarkable spectrum of results. First of all, we looked at lactate relative to the prevailing glucose level at the time the study was production rates in 20 patients using ['4C>lactate, and roughly 50% of performed. Why do people have high Cori cycle activity? I think one the patients had an increase in lactate production. This I think one must assume that this is a mechanism by which enough glucose is would expect, both from in vitro data and from data on isolated tumors supplied to the host, the cancer-bearing patient, and that without using arterio-venous differences. Thus, in a cancer patient population effective gluconeogenesis glucose homeostasis could not be main who are anorectic, lactate production is increased in about 50%. When tained. One way of decreasing gluconeogenesis would be for the I say increased, this is increased as compared to normal age-matched patient to eat more, that is, to increase carbohydrate intake; but subjects, and it is important in all studies of metabolism to attempt to through anorexia, whatever the mechanism for anorexia is, this does get appropriate controls. This is a very difficult thing to do. One thing not seem to happen, and therefore one must assume that glycogen that we must do is to forbear the use of healthy young men for controls stores are probably depleted in such patients. Shapo, many years ago, because there are many known factors of metabolism which are very using infusions of epinephrine, found that a very large percentage of much dependent on the age of the subject. Carbohydrate tolerance is weight-losing cancer patients appeared to be depleted of liver glyco one such example, and it is also well known that many aspects of fat gen, and we have some ongoing studies using glucagon infusions metabolism are affected by age even in normal people. So when I use which seem to support this contention. I would like to mention glucagon controls for the purposes of this brief discussion, I'm referring to an in passing since it is an extraordinarily catabolic, naturally-occurring elderly group of volunteers without evident disease. It is of no surprise hormone which also is antagonistic to the normal actions of insulin. that we found lactate production to be increased; what was surprising Unfortunately, we do not fully understand the normal role of glucagon, to us was that there was a lack of correlation with various clinical and it has largely only been studied in normals and in patients with

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William D. DeWys

Cancer Res 1982;42:721s-725s.

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