Metabolic Abnormalities in Cancer Patients: Carbohydrate Metabolism

Nutrition and Cancer I

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Metabolic Abnormalities in Cancer Patients: Carbohydrate Metabolism Rowan T. Chlebowski, M.D., Ph.D., * and David Heber, M.D., Ph.D.t

Weight loss commonly accompanies cancer, is associated with decreased survival, and by itself may be a cause of death in many patients with malignancy. 13, 15 Although the impact of malnutrition on survival in cancer patients is evident, the ability of existing methods of nutritional intervention to influence clinical outcome is not established. It is becoming apparent, however, that for patients with advanced solid malignancies, provision of increased calories alone using current techniques of total parenteral nutrition does not significantly alter the clinical course of this condition. 6, 39, 54 An increasing body of evidence supports the concept that factors other than caloric deprivation alone underlie the weight loss and associated adverse prognosis seen in the malnourished cancer patient. 2 , 13,50,56 For example, in a series of 254 patients with advanced cancer given a standardized nutritional assessment, Grosvenor and colleagues 22 observed essentially no difference in caloric intake in 170 weight-losing patients when compared with 63 weight-stable patients (intake of 1868 ± 15 kcal per day and 1817 ± 81 kcallday, respectively). As a result, increasing attention has been directed at the role of factors other than reduced caloric intake contributing to the development of weight loss in the cancer population. *Associate

Professor of Medicine, UCLA School of Medicine, and Associate Chief, Medical Oncology Division, Harbor-UCLA Medical Center, Torrance, California tAssociate Professor of Medicine, UCLA School of Medicine, and Chief, Nutrition Division, UCLA Center for Health Sciences, Los Angeles, California Work presented in this article is supported in part by Grants CA-37320 and CA-26563 from the National Cancer Institute, NIH, by the General Clinical Research Center Grant RR00425, and by Grant RD-163 from the American Cancer Society.

Surgical Clinics of North America-Vol. 66, No.5, October 1986

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ABNORMAL CARBOHYDRATE METABOLISM IN THE CANCER PATIENT One of the earliest metabolic abnormalities described in cancer populations was glucose intolerance, proposed in 1919 as a means of identifying patients with gastrointestinal symptoms more likely to have gastric cancer than peptic ulcer disease. 44 In subsequent years the occurrence of glucose intolerance in heterogeneous populations with advanced cancer has been confirmed by a number of investigators. lO • 31, 37 The glucose intolerance seen in the cancer population is associated with a marked resistance to administered insulin, 36, 47 but the exact mechanism underlying this insulin resistance has not been well defined. However, since weight loss related to caloric deprivation in the absence of cancer can itself lead to a glucose intolerance, the insulin resistance observed may not represent a specific cancer-associated defect. Another abnormality in glucose metabolism consistently seen in cancer patients with advanced disease is an increase in glucose turnover measured with isotope tracer techniques, 7, 28, 35, 53 In the usual clinical situation in humans, glucose is synthesized from substrates such as lactate and glucogenic amino acids in response to a variety of hormonal signals to meet the energy requirements of glucose-dependent tissues such as the brain, The cyclic metabolic pathway in which glucose is converted to lactate by glycolysis and then reconverted to glucose in the liver is referred to as the Cori cycle, Gluconeogenesis, or new glucose production from a variety of substrates, requires a significant amount of energy, Thus, if pathways leading to new glucose formation are activated inappropriately and in excess, "futile cycling" and increased energy expenditure can result. 27 Initial studies largely involving heterogeneous populations of cancer patients have demonstrated .accelerated glucose turnover as well as increased recycling of glucose through lactate or alanine, 29, 52 especially in patients experiencing weight loss. More recently, as the potential importance of these observations has begun to be realized, investigators have defined these abnormalities in glucose metabolism in more homogeneous populations with specific tumor types. The results of these efforts involving patients with adenocarcinoma of the colon, non-small cell lung cancer, esophageal carcinoma, and sarcoma are summarized in Table 1. In populations of colon cancer patients with weight loss evaluated at two centers, both Holroyde and co-workers 30 and Chlebowskf demonstrated significantly delayed clearance of glucose. In 27 patients with localized sarcoma studied prior to development of weight loss, reduction in

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Table 1. Abnormalities in Carbohydrate Metabolism in Defined Cancer Populations* PRIMARY CANCER LOCATION

Colon carcinoma

NUMBER STUDIED

18

Colon carcinoma

12

Sarcoma Esophageal

27 18

Oropharyngeal Lung carcinoma (non-small cell)

6

41

FINDINGS

l' Glucose turnover and glucose intolerance l' Glucose production and recycling via lactate Early glucose intolerance l' Gluconeogenesis from alanine Markedly decreased insulin sensitivity l' Glucose turnover and glucose intolerance

AUTHORS

Chlebowski7 Holroyde et al. 30 Norton et al. 40 Burt and Brennan3 Heber et al. 24 Chlebowski et al. 7, 10

*All studies involve comparison to results obtained from concurrent cancer-free control populations, clearance of a glucose load compared with that seen in a cancer-free population was also documented by Norton and co-workers.40 This glucose intolerance was most prevalent in patients who maintained less than their ideal weight, did correlate with tumor burden, and occurred before other signs of cachexia appeared. Finally, Heber and co-workers 24 , 25 have defined a markedly abnormal first phase of insulin secretion and decreased insulin sensitivity. They used a multicompartmental model of insulin action to analyze test results of modified intravenous glucose tolerance in a population with localized squamous cell carcinoma of the head and neck Taken together, these results suggest a relatively common abnormality in glucose tolerance seen in a variety of cancers commonly associated with weight loss. In some cases, abnormalities are detected prior to the manifestation of weight loss or cachexia symptomatology. Increased oxidation of glucose and oxygen consumption52 have also been seen in cancer patients with weight loss when compared with control populations without cancer. Studies by Holroyde and Reichard 29 have suggested that the increased rate of total glucose turnover seen in cancer patients with weight loss could be accounted for by enhanced Cori cycle activity. Such an increase in glucose production as that seen in cancer patients differs from the situation in cancer-free subjects experiencing weight loss due to starvation alone, in whom a decrease in glucose turnover is observed. 29 Increased rates of glucose turnover have likewise been described in a population with localized squamous cell carcinoma of the distal esophagus by Burt and Brennan. 3 It was noteworthy that these patients with localized esophageal carcinoma also had a significantly higher rate of glucose uptake and lactate release from the forearm as compared with normal subjects. In our UCLA experience with

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colon cancer and non-small cell lung cancer patients, glucose turnover (measured by 6 3H -glucose infusion to equilibrium) was also significantly increased in these two cancer populations compared with an age-matched control group free of cancer. 7 Thus, in these two tumor types commonly associated with weight loss, abnormal glucose metabolism of a similar magnitude was seen. In addition, the abnormal glucose metabolism showed no trend toward improvement in the nonresponding lung cancer patients given chemotherapy, as studies at I-month intervals demonstrated no improvement in glucose tolerance and further increase in glucose turnover values. 10

DOES WEIGHT LOSS WITHOUT CANCER RESULT IN SIMILAR ABNORMALITIES? Metabolic results from malnourished cancer patients have been directly compared with those from a cancer-free control patient population with weight loss, composed largely of patients with prior gastric surgery or depression, by Eden and co-workers.16 Glucose turnover and recycling of glucose were measured in the fasting state and fed state following 14 days of continuous enteral nutrition in both patient populations. In each condition, glucose turnover and recycling of glucose were significantly higher in cancer patients with weight loss than in a cancer-free population with comparable weight loss. These data suggest that the elevated glucose flux in cancer disease is specifically related to the presence of the neoplasm either directly or through resultant production of circulating substances rather than as a consequence of the malnutrition per se. The importance of the liver in this condition is supported by reports describing increased gluconeogenesis in livers isolated from rats bearing tumors at other sites,46 increased enzymes of gluconeogenesis in tumor-bearing rats,23 and increased energy expenditure in hepatocytes isolated from rats with tumors at distant sites. 43 Taken together, these data support an important remote effect of cancer on glucose metabolism in the liver. The observations documenting increased glucose turnover rates and increased rates of gluconeogenesis from alanine or lactate are supported by studies of circulatory amino acid levels in patients with cancer. 12. 13. 25 Amino acids released from muscle breakdown represent another potential substrate for gluconeogenesis. This topic is discussed in greater detail by Kurzer and Meguid in "Cancer and Protein Metabolism" in this issue. Clark and associates 12 have studied peripheral arterial and venous blood concentrations of amino acids after an overnight fast in four groups of subjects: (1) malnourished

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cancer patients; (2) cancer patients without weight loss; (3) malnourished subjects without cancer; and (4) normal adults. Glucogenic amino acids were decreased in both malnourished cancer patients and malnourished subjects without cancer, a characteristic finding for chronic starvation. However, branched-chain amino acids remain normal in cancer cachexia. The authors interpreted these findings as showing an increased rate of gluconeogenesis in patients with weight loss and cancer. Heber and colleagues 25 have determined amino acid levels in 29 patients with non-small cell lung cancer. Serum alanine levels were significantly (p < 0.05) lower in lung cancer patients (218 ± nmoVml) than in age-matched controls (298 ± nmollml). Isoleucine levels were statistically higher among cancer patients, but there was no difference in total levels of branched-chain amino acids. These data suggest that in the host with lung cancer alanine is being released at a normal or enhanced rate and utilized more rapidly for the production of glucose. The preceding data related to glucose turnover and amino acid levels suggest that futile cycling of carbohydrates via energy-wasting pathways in the liver contributes to the problem of the development of cancer cachexia. As a result, an increasing number of investigators have raised the hypothesis first outlined by Gold in 196820 that abnormal accelerated pathways of glucose metbolism represent a point of possible therapeutic intervention in cancer patients with weight loss.

CONSEQUENCES OF ENERGY EXPENDITURE WITH ABNORMAL CARBOHYDRATE METABOLISM The potential energy consequences of increased glucose turnover in populations of weight-losing cancer patients have been evaluated by Eden and associates. 16 They estimated that the increased glucose flux observed corresponds to 42 per cent of the daily glucose intake in the cancer patient population. This amount of glucose represents a potential loss of 520 mg of body lipids per kilogram per day if the incomplete oxidation of glucose were to be substituted by complete oxidation of lipids. This alteration in cancer host metabolism was then calculated to lead to a loss of 0.9 kg of body fat per month. Although such an elevation in energy expenditure would be moderate, resulting in an increase in energy expenditure of 250 to 300 kcal per day, over the long term such cumulative effects may be important in the development of weight loss seen in a cancer patient population, especially in the face of a relative reduction in caloric intake.

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In fact, increases in energy expenditure of a magnitude similar to those postulated by Eden and associates 16 have been observed in a variety of cancer patient populations studied using indirect caloremetry.1, 2,14,32,45,51 In these studies, a pattern of moderate increase in energy expenditure in a subset of patients having a variety of primary cancers has been reported. In some diseases, such as gastrointestinal malignancies, only a minority of patients (26 per cent) are found to be hypermetabolic with resting energy expenditure greater than 110 per cent of predicted. 14 In other diseases such as small cell carcinoma of the lung, a more consistent increase in resting energy expenditure has been observed in the majority of patients with this condition. 45 Chemotherapy per se and use of either total parenteral nutrition45 or enteral nutritional support 16 do not reduce the elevations of resting energy expenditure seen in these cancer populations. In patients with small cell lung cancer, however, complete response to chemotherapy reduced resting energy expenditure and increased caloric intake, whereas the contrary was true in nonresponders.45 In addition, tumor resection has resulted in a normalization of energy expenditure in some populations. 1 The results suggest that for at least some cancer patients an increased energy demand may contribute to the development of their weight loss.

ETIOLOGY OF ABNORMAL CARBOHYDRATE METABOLISM IN CANCER The variable nature of the energy expenditure seen in the cancer-bearing host and the Similarity of the stress reaction to the cancer-bearing situation in terms of influence on several metabolic parameters suggest that biologic agents or products produced in the host in response to the tumor are responsible for the metabolic alterations seen in the cancer patient with weight 10ss.49 Factors such as interferon, tumor necrosis factor, and interleukin38, 49, 55 have been reported to result in some of the metabolic changes seen in both stress and the cancer-bearing states. It is intriguing to think that the adverse prognosis associated with weight loss in the cancer patient may also be related in some fashion to the production of these biologic factors by the host in response to the tumor. However, other authors have suggested that a requirement for essential amino acids by the tumor is responsible for the changes in glucose metabolism seen in cancer cachexia. 33 At present, there are not enough data to decide between such potentially competing hypotheses for the etiology of cancer cachexia development. Larger studies are

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needed to assess impact of decreased calories, increased energy expenditure, and abnormal metabolism not only on weight loss but also on adverse clinical outcome in carefully defined, more homogeneous cancer populations before this question can be definitively answered. In any event, major changes in the usual counter-regulatory hormones controlling glucose metabolism such as insulin, cortisol, and growth hormone are not observed in conjunction with the abnormal glucose metabolism seen in the cancer patient populations. 16• 26 This is noteworthy since infusion of such counter-regulatory agents in amounts paralleling blood levels found clinically during the injury response has been shown to result in increased gluconeogenesis. 18 Testosterone, which might be expected to have more influence on protein rather than on glucose metabolism, is found in lower levels in many male cancer patients. 9 Only limited information on catecholamine circulatory levels under these conditions has been reported. Thus, although the data are somewhat preliminary, a consensus view is that counter-regulatory hormonal changes are not responsible for the characteristic changes in carbohydrate metabolism seen in cancer patients.

APPROACHES TO REVERSING ABNORMAL CARBOHYDRATE METABOLISM IN CANCER As identified previously, the progressive and consistent abnormality in glucose turnover seen in patients with cancer cachexia represents a possible point of therapeutic intervention.2O Consideration of the gluconeogenic pathway shows it to be amenable to interruption at the phosphoenolpyruvate carboxykinase (PEPCK) reaction. The enzyme that catalyzes the Gonversion of oxaloacetate to phosphoenolpyruvate is PEPCK. Hydrazine sulfate is a noncompetitive inhibitor of PEPCK and inhibits in vitro gluconeogenesis in animal systems. 42 Early clinical evaluation of this agent as a potential therapy for cancer cachexia suggested some benefit in terms of subjective parameters in cancer populations. 19• 21 Therefore, to more definitively characterize the effects of hydrazine sulfate in the cancer-bearing host, we initiated a randomized, placebo-controlled, double-blind study to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer patients with weight loss. Patients with metastatic cancer were eligible for study if they had lost 10 per cent or more of their usual body weight. All patients had an initial 3-day in-patient metabolic evaluation, including an-

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thropometrics, standard oral glucose tolerance testing, and glucose turnover determination. After 28 days of treatment with capsules containing either a placebo or hydrazine sulfate given in a dose of 60 mg, three times per day, the metabolic evaluation was repeated. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Use of hydrazine sulfate resulted in a significant improvement in glucose tolerance and a significant reduction in glucose production in cancer patients compared with those receiving placebo. 11 Use of hydrazine sulfate was well tolerated; less than 10 per cent of patients experienced difficulty with lightheadedness or nausea during the period ofhydrazine administration. We have subsequently expanded the number of patients having both pre- and post-therapy metabolic evaluation while receiving hydrazine and have identified a statistically significant association (p < 0.05) between improved glucose tolerance and weight stabilization while they were on hydrazine treatment. 8 Our most recent experience involving a population of 101 heavily pretreated patients given either hydrazine or placebo therapy demonstrated a significant effect of hydrazine in terms of weight maintenance and appetite improvement. 8 Interestingly, although caloric intake was somewhat higher in the hydrazine-treated patients, the difference was not statistically significant. However, the increased caloric intake was more commonly associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81 per cent versus 53 per cent, respectively, p > 0.05). Thus it appeared that administration of hydrazine sulfate resulted in maintenance of body weight in patients with cancer by increasing the efficacy of the ingested caloric intake. The favorable influence of hydrazine sulfate on nutritional status in cancer patients with weight loss that we observed agrees with prior single-arm studies involving Russian and American patients with cancer. 19. 21 In both series, over 50 per cent of patients demonstrated some improvement largely measured by subjective parameters. However, not all clinical studies of hydrazine sulfate have shown benefit. In three small trials of hydrazine sulfate (all entering less than 30 patients) in which reduction in tumor size was used as a major therapeutic endpoint, little benefit was reported. 34, 41,48 Only in our experience at UCLA has hydrazine sulfate been prospectively evaluated against placebo control populations and has influence on caloric intake been determined. In any event, whether such improvement in metabolic and/or nutritional indices associated with hydrazine sulfate use will translate into improvement in important parameters of clinical outcome such as overall survival will require further prospective clinical trials.

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Several other therapies are receiving evaluation as potential approaches to the abnormal glucose metabolism seen in the cancer population. Use of insulin to suppress this abnormal metabolic picture has been proposed by Schein and co-workers,47 but no clinical reports using this approach have been published. A phase I agent, 3-mercaptopicolinic acid, developed as an oral hypoglycemic for use in diabetes mellitus, has been used to inhibit gluconeogenesis with resultant hypoglycemia development in a cancer-bearing man. 5 In these efforts, the highest of three doses of 3-mercaptopicolinic acid (114 mg per kg) resulted in marked hypoglycemia and lactic acidema, which was consistent with inhibition of gluconeogenesis at the PEPCK level. Interestingly, the authors administered glycerol to provide a substrate for use by the host but not by neoplastic tissue in the hopes of using hypoglycemia with glycerol infusion as a direct antineoplastic therapy. A final approach to reversing the abnormal glucose metabolisms seen in the cancer-bearing population has involved use of higher rates of glucose administration with techniques of total parenteral nutrition. In one report, administration of total parenteral nutrition resulted in improvement in the abnormal glucose metabolism and reduction inthe accelerated glucose turnover. 4 However, experience at our own institution with patients with head and neck cancer receiving either a weight-maintaining regimen of Traumacal calculated on the basis of 125 per cent of basal energy expenditure or an anabolic regimen calculated at 225 per cent of basal energy expenditure showed no long-term effect of caloric provision on production rates of whole-body glucose. Whether this discrepancy in results represents the specific agent used to provide the calories, the intensity of the glucose calories provided, or the differences in primary tumor types remains to be established. In conclusion, weight loss in the patient with a variety of cancers is associated with poor prognosis. Consistent abnormalities of carbohydrate metabolism are seen in patients with cancer cachexia and appear to represent derangements in host metabolism induced by the cancer. At present, investigations are under way at our own institution and others throughout the country aimed at defining the relationships among glucose metabolism, altered energy expenditure, caloric intake, weight loss, and clinical outcome for patients with a variety of advanced cancers. The ultimate goal of these efforts is to identify potential therapeutic strategies designed to improve the currently poor clinical outcome for the cancer patient with weight loss.

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REFERENCES 1. Arbeit, J. M., Lees, D. E., Corsey, R., et al.: Resting energy expenditure in controls and cancer patients with localized and diffuse disease. Ann. Surg., 200:292-298, 1984. 2. Bozetti, F., Pagnoni, A. M., and Del Vecchio, M.: Excessive caloric expenditure as a cause of malnutrition in patients with cancer. Surg. Gynecol. Obstet., 150:229-234, 1980. 3. Burt, M. E., and Brennan, M. F.: Nutritional support of the patient with esophageal cancer. Semin. Oncol., 11:127-135, 1984. 4. Burt, M. E., Gorschboth, C. M., and Brennan, M. F.: A controlled prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient. Cancer, 49:1092-1105, 1982. 5. Burt, M. E., Peters, M., Brennan, M. G., et al.: Hypoglycemia with glycerol infusion as antineoplastic therapy: A hypothesis. Surgery, 97:231-234, 1985. 6. Chlebowski, R. T.: Critical evaluation of the role of nutritional support with chemotherapy. Cancer, 55:268-272, 1985. 7. Chlebowski, R. T.: Abnormal glucose metabolism in patients with advanced cancer. In Heber, D. (moderator): Malnutrition and Cancer: Mechanism and Therapy. Nutr. Int., 1986, in press. 8. Chlebowski, R. T., Grosvenor, M., Scrooc, M., et al.: Influence of hydrazine sulfate on food intake and weight maintenance in patients with cancer. Proc. Am. Soc. Clin. Oncol., 4(abstract):C-I029, 1985. 9. Chlebowski, R. T., and Heber, D.: Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Cancer Res., 42:2495-2498, 1982. 10. Chlebowski, R. T., Heber, D., and Block, J. B.: Serial assessment of glucose metabolism in patients with cancer cachexia. Clin. Res., 30(abstract):69A, 1982. 11. Chlebowski, R. T., Heber, D. Richardson, B., et al.: Influence ofhydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res., 44:857-861, 1984. 12. Clark, E. F., Lewis, A. M., and Waterhouse, C.: Peripheral amino acid levels in patients with cancer. Cancer, 42:2909-2913, 1978. 13. Costa, G., Lane, W. W., Vincent, R. G., et al.: Weight loss and cachexia in lung cancer. Nutr. Cancer, 2:98-103, 1981. 14. Dempsey, D. T., Feurer, 1. D., Knox, L. S., et al.: Energy expenditure in malnourished gastrointestinal cancer patients. Cancer, 53:1265-1273, 1984. 15. DeWys, W. D., Begg, C., Lavin, P. T., et al.: Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am. J. Med., 69:491-498, 1980. 16. Eden, E" Edstrom, S., Bennegard, K., et al.: Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res., 44:1717-1724, 1984. 17. Furst, P., Bergstrom, J., Hellstrom, B., et al.: Amino acid metabolism in cancer. In Kluthe, R., and Lohr, G. (eds.): Nutrition and Metabolism in Cancer. New York, Thieme-Stratton, 1981, pp. 75-189. 18. Gelfand, R., Matthews, D. E., Bier, D. M., et al.: Role of counterregulatory hormones in the catabolic response to stress. J. CHn. Invest., 74:2238-2248, 1984. 19. Gershanovich, M. L., Danova, L. A., Ivin, B. A., et al.: Results of clinical study of antitumor action of hydrazine sulfate. Nutr. Cancer, 3:7-12, 1982. 20. Gold, J.: Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology, 22:185-207, 1968. 21. Gold, J.: Use of hydrazine sulfate in terminal and preterminal cancer patients. Oncology, 32:1-10, 1975. 22. Grosvenor, M., Madriaga, M., Bulcavage, L., et al.: Symptoms influencing food intake in cancer populations: Correlations with primary site, caloric intake, and nutritional status. [Abstract.] Proc. Am. Soc. CHn. Oncol., 5:1002, 1986. 23. Gutman, A., Thilo, E., and Brian, S.: Enzymes of gluconeogenesis in tumor-bearing rats. Isr. J. Med. Sci., 5:998-1001, 1969. 24. Heber, D., Byerley, L. 0., Chi, J., et al.: Pathophysiology of malnutrition in the adult cancer patient. Cancer, 1986 (in press).

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25. Heber, D., Byerley, L. 0., and Chlebowski, R. T.: Metabolic abnormalities in the cancer patient. Cancer, 55:225-233, 1985. 26. Heber, D., Chlebowski, R. T., Ishibashi, D. E., et al.: Abnormalities in glucose and protein metabolism in non-cachectic lung cancer patients. Cancer Res., 42:4815-4819, 1982. 27. Hers, G. G., and Hue, L.: Gluconeogenesis and related aspects of glycolysis. Ann. Rev. Biochem., 53:617-653, 1983. 28. Holroyde, C. P., Gabuzda, G., Putnam, R. C., et al.: Altered glucose metabolism in metastatic cancer. Cancer Res., 35:3710-3714, 1975. 29. Holroyde, C. P., and Reichard, G. A.: Carbohydrate metabolism in cancer cachexia. Cancer Treat. Rep., 65(Suppl. 5):61-65, 1981. 30. Holroyde, C. P., Skutches, C. L., Boden, G., et al.: Glucose metabolism in cachectic patients with colorectal cancer. Cancer Res., 44:5910-5913, 1984. 31. Jasani, B., Donaldson, L. J., Tatcliffe, J. G., et al.: Mechanism of impaired glucose tolerance in patients with neoplasia. Br. J. Cancer, 38:286-292, 1978. 32. Knox, L.S., Crosby, L. 0., Feurer, I. D., et al.: Energy expenditure in malnourished cancer patients. Ann. Surg., 197:152-162, 1983. 33. Lazo, P. A.: Tumour-host metabolic interaction and cachexia. FEBS Lett., 187:189-194, 1985. 34. Lerner, H. J., and Regelson, W.: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat. Rep., 60:959-960, 1976. 35. Lundholm, K., Edstrom, S., Karlberg, I., et al.: Glucose turmJver, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients. Cancer, 50:1142-1150, 1982. 36. Lundholm, K., Holm, G., and Schersten, T.: Insulin resistance in patients with progressive malignant disease. Cancer Res., 39:1968-1972, 1979. 37. Marks, P. A., and Bishop, J. S.: The glucose metabolism of patients with malignant disease and of normal subjects as studied by means of an intravenous glucose tolerance test. J. Clin. Invest., 36:254-264, 1957. 38. Mayer, D., Hetrick, K., Riggs, C., et al.: Weight loss in patients receiving recombinant leukoyte A interferon. Cancer Nurs., 7:53-56, 1984. 39. Nixon, D. W.: Hyperalimentation in the undernourished cancer patient. Cancer Res., 42(Suppl.):727s-728s, 1982. 40. Norton, J. A., Maher, M., Wesley, R., et al.: Glucose intolerance in sarcoma patients. Cancer, 54:3022-3027, 1984. 41. Ochoa, M., Wittes, R., and Krakoff, I.: Trial ofhydrazine sulfate (NSC-1500l4) in patients with cancer. Cancer Chemother. Rep., 59:1151-1153, 1975. 42. Ray, P. D., Hanson, R. L., and Lardy, H. A.: Inhibition by hydrazine of gluconeogenesis in the rat. J. BioI. Chem., 245:690-696, 1970. 43. Roh, M. S., Ekman, L. G., Jeevanandam, M., et al.: Elevated energy expenditure in hepatocytes from tumor-bearing rats. J. Surg. Res., 38:407-415, 1985. 44. Rohdenberg, G. L., Bernhard, A., and Krehbiel, 0.: Sugar tolerance in cancer. J.A. M.A., 72:1528-1529, 1919. 45. Russell, D. M., Shike, M., Marliss, E. B., et al.: Effects of total parenteral nutrition and chemotherapy on the metabolic derangements in small cell lung cancer. Cancer Res., 44:1706-1711, 1984. 46. Schearer, J., Caldwell, M., and Crosby, L. 0.: Tumor effects on gluconeogenesis in the isolated perfused rat liver. J.P.E.N., 7:105-109, 1983. 47. Schein, P. S., Kisner, D., Haller, D., et al.: Cachexia of malignancy: Potential role of insulin in institutional management. Cancer, 49:2070-2076, 1979. 48. Spemulli, E., Wampler, G. L., and Regelson, W.: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother. Pharmacol., 3:121-124, 1979. 49. Torti, F. M., Dieckman, B., Beutler, B., et al.: A macrophage factor inhibits adipocyte gene expression: An in vitro model of cachexia. Science, 229:867-869, 1985. 50. van Eys, J.: Nutrition and cancer: Physiological interrelationships. Ann. Rev. N utr., 5:435-461, 1985. 51. Warnhold, I., Lundholm, K., and Schersten, T.: Energy balance and body composition in cancer patients. Cancer Res., 38:1801-1807, 1978. 52. Waterhouse, C.: Oxidation and metabolic interconversion in malignant cachexia. Cancer Treat. Rep., 65(Suppl. 5):61-66, 1981.

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53. Waterhouse, C., Jeanpretre, N., and Keilson, J.: Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res., 39:1968-1972, 1979. 54. Weiner, R. S., Kramer, B. S., Clamon, G. H., et al.: Effects of intravenous hyperalimentation during treatment in patients with small-cell lung cancer. J. Clin. Oncol., 3:949-957, 1985. 55. Yang, R. D., Moldgiver, L. L., Sakamoto, A., et al.: Leukocyte endogenous mediator alters protein dynamics in rats. Metabolism, 32:654-660, 1983. 56. Young, V. R.: Energy metabolism and requirements in the cancer patient. Cancer Res., 37:2336--2341, 1977. Division of Medical Oncology Harbor-UCLA Medical Center 1000 West Carson Street Torrance, California 90509