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Body Compositional Changes in Cancer Patients
Nutrition and Cancer I
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Body Compositional Changes in Cancer Patients Kent C. Lundholm, M.D. *
The statistical significance of undernutrition in the morbidity and mortality associated with cancer disease is well recognized. 25 Cachexia has been reported as the most important cause of death in heterogeneous groups of patients with solid tumors, exceeded only by pulmonary complications. 36 Cachexia seems to be of particular importance for clinical outcome in patients with breast, stomach, and colorectal carcinoma. However, it is still unknown whether such patients die of malnutrition itself or whether severe malnutrition is only a closely correlated phenomenon and death is due to other causative changes. Experiments in our laboratory have demonstrated that severely malnourished tumor-bearing animals do not die simply from depletion of energy stores despite loss of approximately 25 per cent of their carcass weight. 12 Thus, it is likely that death in clinical cancer, which is generally associated with considerably smaller tumor burdens than found in experimental models, is due to one or more specific metabolic derangements rather than to just overall undernutrition. However, without a doubt, severe malnutrition in cancer patients causes considerable dysfunction, such as muscular weakness, mental depression, and abnormal fatigue, leading to a decreased quality of life. In view of this, it is important in future investigations to be able to correlate alterations in nutritional status (body composition) with changes in function and overall quality of life. Despite numerous reports that cancer patients suffer from a variety of nutritional disorders and that such alterations are highly correlated to increased morbidity and mortality mathematically, we still lack definitive proof that reversal of or protection from developing malnutrition in cancer patients will improve clinical outcome and func*Associate Professor, Department of Surgery I, Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden
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tion. Although several reproducible, convenient, and reliablemethods are available for assessing nutritional status, measurements of body composition remain the cornerstone in both basic research and clinical attempts to evaluate the consequences of metabolic host relationships and different treatment modalities in cancer.
MEASUREMENT OF BODY COMPOSITION In animal research, the classic method for assessing body composition is biochemical extraction of the cadaver components, which is a highly reliable and reproducible method, particularly in small animals in which the whole carcass can be processed. Although results of direct analysis of human carcass have been reported, the classic clinical methods have generally relied on measurements of total body potassium, body water, weight, height, and creatinine excretion in urine. 13, 24 Body potassium can be measured either by injecting isotopic potassium9 or by measuring the 1.46 MeV natural gamma radiation (40K ) from the body by whole body spectroscopy. 30 The total amount of body potassium is then calculated, assuming that the relationship between radioactive and nonradioactive potassium is constant. In measurements of body water, injections of stable or radioactively labeled water have generally been used. Body water is then calculated from the equilibrium volume of label. Although this method has been reported to be very reproducible with an excellent coefficient of variation « 1%),7 it is not quite the experience of the method in our hands. In some investigations, labeled, uncharged molecules such as urea have been used for measurements of body water. 32 Body water has also been calculated from body potassium, assuming that intracellular water concentration is around 160 mmol of potassium per liter of cell water. 31 In general, the isotopic dilution methods give lower values of body water compared with the direct measurement by evaporation of tissues to absolute dryness. This discrepancy may occur because too short equilibration times are employed and all water is known not to be available for instantaneous exchange. However, when used in a highly standardized manner, the isotopic techniques can be used for estimating total body water, particularly in longitudinal and group-comparing studies. The effectiveness of the more recent nuclear methods has been demonstrated in studies on humans. Analytic neutron activation procedures, now in routine use in several institutions, allow direct quantification of body nitrogen, sodium, phosphorus, chloride, and calcium with a p~ecision at the level of ± 4 per cent. 1, 8, 15, 33 Body
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potassium can be analyzed in a whole body counter at the level of ± 3 per cent or better. Body oxygen has also been analyzed by some groups, with procedures similar to those for the determination of hydrogen, nitrogen, and body carbon, by means of prompt gamma analysis following neutron activation. One obvious limitation with the nuclear methods, which involves radiation procedures, may be its limited applicability in growing individuals and perhaps in fertile subjects. A limited number of comparative studies of body protein determination by in vivo neutron activation and carcass analysis of nitrogen have been performed in rats and pigs. 22 , 29 The rat experiments demonstrated that the technique is sufficiently precise to measure 0.14 gm of nitrogen, which corresponds to the nitrogen accretion over 2 days in a growing rat. Simultaneous chemical measurements by destructive carcass analysis in comparable groups of animals could resolve changes at the level of 0.37 gm of nitrogen. This high-resolution power can be compared with the changes in nitrogen excretion in healthy, voluntarily starving individuals, which is initially 6 to 7 gm of nitrogen and later 2 to 2.5 gm of nitrogen per day after 20 days on a protein-free diet. 14 Therefore, neutron activation is sensitive enough to measure body nitrogen at the level of chemical methods and is even better in the clinical situation when accounting for the difficulties in collecting urine and stool as well as the uncertainties in estimating the loss of epithelial debris. The amount of nitrogen corresponding to the power of neutron activation method thus corresponds to a resolution of 4 to 5 gm of muscle mass. This would be compared to the degree of accuracy that we generally use for measurements of body weight by standard balances, which are generally not better than 100 gm of muscle mass in most clinical circumstances. However, the critical control experiments with regard to nutrition have not been reported so far. Such experiments might include the infusions of plasma proteins or the consumption of a protein-rich diet and then the determination of whether prompt gamma neutron activation could detect accurately the acute changes in the nitrogen pool of the body. Unless such experiments are undertaken, demonstrating the sensitivity of the method, we must regard as circumstantial evidence that increased botein is obtained in response to nutrition of cancer patients. 1, 31
BODY COMPOSITION IN CANCER PATIENTS A nearly universal prevalence of protein-calorie malnutrition has been reported in advanced cancer, with unpredictable losses of
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adipose tissue, visceral protein, and skeletal muscle, from patient to patient. 26 In the report, the creatinine to height index was claimed to be the most sensitive indicator of protein-calorie undernutrition: 88 per cent of the patients had a creatinine to height index less than 80 per cent of standard, whereas only 42 per cent and 23 per cent of these patients had values less than 80 per cent of standard for triceps skinfold and mid-arm muscle area, respectively. In these patients weight loss correlated significantly to triceps skinfold, midarm muscle area, and creatinine to height index but not to serum albumin concentrations. These results agree with those in a more recent study by Shike and colleagues, who found that serum protein levels (including albumin) were normal in patients with small-cell lung cancer suffering from malnutrition as assessed by the creatinineheight index and total body nitrogen measurement. 3l The combination of normal albumin concentration with a significantly impaired body composition in some cancer patients is particularly noteworthy, since plasma albumin has been found to be a powerful indicator of undernutrition and a predictor of morbidity in both cancer and noncancer patients in other studies. 16. 34 The explanation for these discrepancies among reports may be that certain diseases in themselves may lead to depressed albumin synthesis or that increased albumin leakage occurs in certain patients, especially those with gastrOintestinal cancer.16 Another explanation may simply be that depressed albumin concentration is a later phenomenon than loss of lean body mass. In this context, it should be emphasized that most patients reported by Nixon and colleagues26 had received tumor treatment before or concomitant with nutritional assessment, although tumor treatment was not given during the week that measurements were performed. In a recent study, we have reported that plasma albumin concentrations less than 35 gm per L are associated with the onset' of a low T3 syndrome, an indication of adaptive changes in energy metabolism in both cancer and noncancer patients.28 In a recent study on a group of completely untreated malnourished cancer patients, we have reported that loss of body fat was the most pronounced alteration in body composition, which is in accord with findings in experimental cancer. 12, 35 Untreated cancer patients primarily mobilize neutral fat for energy production, in agreement with significantly lower respiratory quotients in lung cancer patients and in patients with different types of solid tumors. 1S, 23 In contrast to these results, Cohn and colleagues recently reported that the loss of body weight by patients with solid tumors primarily consisted of the loss of muscle mass with less loss of body fat.5 Even in severe wasting, the authors concluded that the patients appear to retain significant amounts of body fat, although it was probably not possible
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to assess to what extent the remaining body fat represented phospholipids. Changes in body fat are generally derived by subtracting lean body mass from body weight. This calculation cannot discriminate between neutral fat and phospholipids. A cell or tissue can be depleted of most of its neutral fat without any disturbance in function, but membrane lipids cannot be decreased much, if at all, if cell integrity is to be maintained. Thus, measurements of the changes in neutral fat content should be related to the amounts of neutral fat in the individual prior to treatment or morbidity, if alterations in neutral fat content are to be evaluated precisely. A normal-weight individual with large amounts of lean tissue mass and small amounts of storage fat thus cannot be expected to lose large amounts of fat because a considerable amount of membrane lipids must remain. This kind of problem has not been sufficiently accounted for when changes in body composition are judged in clinical studies and particularly in studies on cancer patients, in which it is often claimed that the range of body fat loss is quite variable. In the studies in which Cohn and colleagues reported that skeletal muscle was predominantly lost, they also observed that visceral proteins were spared to a considerable extent. 5 The nonmuscle tissue, including the visceral fraction, did not decrease but actually appeared to increase in size when compared with that of normal populations. In a more recent report in which longitudinal studies were performed, changes in body composition were analyzed in terms of lean body mass and its constituents, protein, water, and fat. 6 Weight loss was found to reflect primarily the loss offat, water, potassium, and only to a minor extent the protein component of lean body mass, as assessed by direct measurement of body nitrogen. These seemingly contradictory results may, however, be due to truly different study populations in the two investigations. However, a considerable number of the patients were reported to be the same in the two studies, but one experimental condition reported longitudinal measurements and the other represented a single point: measurement. That some of the discrepancies between these two studies as well as between other reports are also dependent on methodologic problems cannot be excluded. It is important to remember that compartment analysis is generally based on derived results relying on assumed prerequisites. 7 Generally only body potassium and water have been measured and, in some investigations, body nitrogen, too. Compartment derivation of body cell mass, lean body mass, muscle mass, and so on thus requires that the relationships between potassium and nitrogen, potassium and water, and muscle and creatine are comparatively normal even in conditions of malnutrition and severe metabolic disturbances. In normal individuals, the ratio between total body nitrogen and total body
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potassium has been reported to be around 13.5 ± 1.1 based on independent measurements of nitrogen and potassium. 1, 5 In cancer patients suffering from progressive wasting, this ratio is significantly higher. 5 This increase may be interpreted to indicate the proportionately larger loss of muscle mass than of average body cell mass. 5 , 7 However, an alternative explanation may be that cancer-induced malnutrition is associated with the preferential loss of intracellular potassium. In many cancer patients, loss of body potassium reflects both a loss of lean tissue, in particular, skeletal muscles, and an intracellular depletion of potassium. In cancer patients, decreased intracellular potassium concentration has been supported recently by direct measurements. In studies on lung cancer patients, Shike and colleagues reported that 4 weeks of parenteral nutrition increased body fat and potassium but not nitrogen, as assessed by neutron activation. 31 In addition, we have recently completed studies on well-nourished young males with testicular carcinoma in whom body potassium was measured before initiation of aggressive cytostatic treatment. Within the first week of treatment, body potassium decreased by 18 per cent (unpublished results). The decrease in body potassium could be prevented by daily parenteral infusion of potassium-containing nutritional solutions. However, over the weeks, potassium supplementation could not prevent the insidious decline in body potassium, which most likely reflected a decrease in lean body mass, particularly skeletal muscle. Direct measurements of arm muscle area, nitrogen excretion, creatinine-height index, and 3-methylhistidine excretion confirmed that muscle mass was actually decreased. A reduced whole body oxygen consumption, when performed in the resting condition, is an excellent indication of lean body mass and does reflect a loss of lean tissues. 17 When considering changes in body potassium, one must obviously take into account the duration of alterations in nutritional state or rehabilitation. It is likely that chronic and long-standing alterations in body potassium reflect loss of muscle mass, whereas short-term alterations (days to weeks?) can reflect changes in the intracellular potassium concentration as well. Results indicating improvement of lean body mass must, therefore, always be suspected to reflect only replenishment of the intracellular pools of potassium unless further direct measurements of body nitrogen or protein status do not indicate replenishment of the nitrogen pool as well. We have previously reported increased body potassium following enteral and parenteral nutrition in cancer patients in combination with positive nitrogen balance. 2, 3, 10, 20 Such combined evidence of net synthesis of lean tissues in cancer patients is suggested to demonstrate repletion of muscle mass. We cannot, however, disregard the possibility that positive nitrogen balance primarily reflects
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BODY COMPOSITIONAL CHANGES IN CANCER PATIENTS .2000r------------,-------,--------, AMINO ACID BALANCE
GLUCOSE BALANCE
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Figure 1. Amino acid and energy balance across the leg after an overnight fast (B) and following 2 weeks of enteral nutrition (E). The results support the conclusion that enteral feeding does not promote a resynthesis of lean body mass as measured over peripheral compartments in either malnourished cancer patients or malnourished patients without cancer. Fat and glycogen stores are, however, improved, as the patients were in net glucose and FFA balance in response to feeding. All patients received a formula diet consisting of 35 to 40 kcallkgJday, and the protein intake was approximately 0.2 g N/kgJday. The diet was infused 24 hours a day via a nasogastric tube. (From Bennegard, K., Lindmark, L., Eden, E., et al.: Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res., 44:386-393, 1984; with permission.)
the repletion of visceral proteins, in particular plasma proteins, while accumulation of potassium may reflect rather an intracellular replenishment. Simultaneous measurements of muscle RNA from biopsy material before and after nutrition, in combination with increased body potassium, support the conclusion that repletion of muscle tissue is possible in cancer patients. However, this may demand a particularly high load of calories and nitrogen levels that may be detrimental for the patient in other regards. 10 In contrast to our earlier investigations, our more recent studies support the suggestion that a considerable proportion of weight-losing cancer patients do not replenish protein content in peripheral tissues, particularly muscle tissue. This is indicated by the fact that they do not switch to positive amino acid balance over the leg in the fed state (Fig. 1).3 This is true even after 2 weeks on conventional enteral feeding through a nasogastric tube, with an intake of calories and nitrogen adequate for repletion of muscle tissue according to the estimated whole body needs of the patients. Such problems in artificial nutrition may explain the lack of evidence for nitrogen accumulation in cytostatic-treated lung cancer patients on adjunctive nutritional support. 31 However, an alternative explanation to the lack of protein
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accretion in the patients reported on by Shike and colleagues may be that cytostatic drugs block protein synthesis but not the resynthesis of fat and its deposition into lipid storage. This latter explanation, however, is not relevant for any of our own studies, as they included patients only before tumor treatment. Several studies have addressed the question of whether elevated energy expenditure or anorexia explains wasting of body composition in cancer. It is quite clear that elevated energy expenditure occurs in numerous weight-losing cancer patients,18, 35 although some authors have failed to detect such differences. 4 Such discrepancies may be due to differences in investigative approaches, with regard to the use of reference patients and the degree of sensitivity, stability, and reproducibility of the technology used to measure energy expenditure. Burke and colleagues could not demonstrate an elevated expenditure of energy in cancer patients with early onset of weight loss, and they were therefore prone to explain body compositional changes by other mechanisms, such as qualitative alterations in food intake and perhaps increased malabsorption. 4 Their weight-losing cancer patients showed some alterations in selection of food composition, with the main defect being energy deficiency, as protein intake was usually well maintained. There was also a positive correlation between protein and energy intake versus changes in lean body mass in patients with benign disease, which was lacking in the cancer patients. This lack of an expected correlation in the cancer patients could be explained by such alterations as increased energy expenditure, although not demonstrated by specific alterations in intermediary metabolism, particularly in the synthetic machinery of muscle protein, or by specific derangements in food selection or impaired absorption of enteric nutrients. However, most investigators have been unable to demonstrate any major alterations in gastrointestinal absorption in cancer patients, although slight steatorrhea has been observed in occasional patients. This lack of evidence for a systematic finding of malabsorption may, however, be because methods that are too insensitive have been applied in most studies. Some evidence is available that cancer patients may select food differently, although such findings do not seem to be occurring regularly. Such a discrepancy may also be due to the fact that malignancies are not a uniform entity or disease. In addition to our own results, demonstrating a less than normal resynthesis of major body compartments, such as skeletal muscles, it has been reported that some cancer patients do not replete normal body composition as evaluated from studies on nitrogen and ion balances during parenteral nutrition. 27 In line with the preceding discussion, it has been investigated whether cancer patients lose body components differently as com-
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pared with patients suffering from benign wasting. 37 If so, this should lead to a significant alteration of body composition over a considerable period compared with patients suffering from body wasting because of reasons other than malignancy. Evidence to support this hypothesis has been reported in a comparative study between small groups of patients. 37 It was concluded that body composition in cancer cachexia differs from that in cachexia caused by benign inflammatory disease, in that lean tissue appears to be better conserved in the cancer group. However, it is more likely that these differences represent the result of comparing two populations that probably differ in the time course of the disease progression and state of malnutrition and not any true differences in underlying metabolism. Of course, some well-defined metabolic differences may be possible to demonstrate between such populations if they are compared in different phases of disease progression. A more preserved lean body mass in cancer patients would theoretically indicate a more preserved protein balance, perhaps because of a lower demand for gluconeogenesis. However, increased gluconeogenesis and depressed synthesis of muscle protein are both well-recognized alterations in patients with progressive wasting due to cancer and in conditions of partial or complete starvation. 11, 19,21 Therefore, body compositional changes can only reflect the end result of different net alterations over a certain period of time. Body composition analyses are not a tool to use in evaluating underlying disorders of metabolism, but they remain the most important technique for evaluating the therapeutic net results and for defining the degree of malnutrition in groups of patients.
SUMMARY Noninvasive and spectroscopic techniques already available and under further development in several laboratories will in the near future give us a greater amount of detailed information on changes in body compartments in disease and in response to therapeutic efforts. Such techniques should have the ability to measure directly components in an organ or tissue in contrast to most present and previous techniques that generally rely on derivation of components from a few direct measurements. Such derivations are unfortunately dependent on assumptions that are not possible to control in several circumstances.
REFERENCES 1. Beddoe, A. H., and Hill, C. L.: Clinical measurement of body composition using in vivo neutron activation analysis. J.P.E.N., 9:504-520, 1985.
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2. Bennegard, K., Eden, E., Schersten, T., et al.: Metabolic response of whole body and peripheral tissues to enteral nutrition in weight-losing cancer and noncancer patients. Gastroenterology, 85:92-99, 1983. 3. Bennegard, K., Lindmark, L., Eden, E., et al.: Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res., 44:386--393, 1984. 4. Burke, M., Bryson, E. 1., and Kark, A. E.: Dietary intakes, resting metabolic rates, and body composition in benign and malignant gastrointestinal disease. Br. Med. J., 26:211-215, 1980. 5. Cohn, S. H., Gartenhaus, W., Sawitsky, A., et al.: Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water. Metabolism, 30:222-229, 1981. 6. Cohn, S. H., Gartenhaus, W., Vartsky, D., et al.: Body composition and dietary intake in neoplastic disease. Am. J. Clin. Nutr., 34:1997-2004, 1981. 7. Cohn, S. H., Vartsky, D., Yasumura, S., et al.: Indexes of body cell mass: Nitrogen versus potassium. Am. J. Physiol., 244:E305-E310, 1983. 8. Conway, J. M., Norris, K. H., and Bodwell, C. E.: A new approach for the estimation of body composition: Infrared interactance. Am. J. Clin. Nutr., 40:1123-1130, 1984. 9. Corsa, L., and Olney, J. M.: The measurement of exchangeable potassium in man by isotope dilution. J. Clin. Invest., 29:1280-1290, 1950. 10. Eden, E., Bennegard, K., Bylund-Fellenius, A.-C., et al.: Whole-body energy metabolism and metabolic capacity of skeletal muscles in malnourished patients before and after total parenteral nutrition. Hum. Nutr. Clin. Nutr., 37C:185-196, 1983. 11. Eden, E., Edstrom, S., Bennegard, K., et al.: Glucose flux in relation to energy expenditure during fasting and in the fed state in malnourished cancer and non-cancer patients. Cancer Res., 44:1718-1724, 1984. 12. Eden, E., Lindmark, L., Karlberg, 1., et al.: Role of whole-body lipids and nitrogen as limiting factors for survival in tumor-bearing mice with anorexia and cachexia. Cancer Res., 43:3707-3711, 1983. 13. Forbes, G. B., and Bruining, G. J.: Urinary creatinine excretion and lean body mass. Am. J. Clin. Nutr., 29:1359-1366, 1976. 14. Forbes, G., and Drenick, E. J.: Loss of body nitrogen on fasting. Am. J. Clin. Nutr., 32:1570-1574, 1979. 15. Garrow, J. S.: New approaches to body composition. Am. J. Clin. Nutr., 35:1152-1158, 1982. 16. Harvey, K. B., Moldawer, L. L., Bistrian, B. R., et al.: Biological measures for the formulation of hospital prognostic index. Am. J. Clin. Nutr., 34:2013-2022, 1981. 17. Kinney, J. M., Lister, J., and Moore, F. D.: Relationship of energy expenditure to total exchangeable potassium. Ann. N.Y. Acad. Sci., 110:711-722, 1963. 18. Lindmark, L., Bennegard, K., Eden, E., et al.: Resting energy expenditure in malnourished patients with and without cancer. Gastroenterology, 87:402-408, 1984. 19. Lundholm, K., Bylund, A.-C., Holm, J., et al.: Skeletal muscle metabolism in patients with malignant tumor. Eur. J. Cancer, 12:465-473, 1976. 20. Lundholm, K., Edstrom, S., Ekman, L., et al.: Metabolism in peripheral tissues in cancer patients. Cancer Treat. Rep., 65:79-83, 1981. 21. Lundholm, K., Edstrom, S., Karlberg, 1., et al.: Glucose turnover, gluconeogenesis from glycerol and estimation of net glucose cycling in cancer patients. Cancer, 50:1142-1150, 1982. 22. McNeil, K. G., Mernagh, J. R., Jeejeebhoy, K. N., et al.: In vivo measurements of body protein based on the determination of nitrogen by prompt analysis. Am. J. Clin. Nutr., 32:1955-1961, 1979. 23. McR. Russell, D., 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. 24. Moore, F. D., Olesen, K. H., McMurrey, J. D., et al.: The Body Cell Mass and Its Supporting Environment: Body Composition in Health and Disease. Philadelphia, W. B. Saunders, 1963. 25. Mullen, J. L., Buzby, G. P., Waldman, M. T., et al.: Prediction of operative morbidity and mortality by preoperative nutritional assessment. Surg. Forum, 30:80-82, 1979. 26. Nixon, D. W., Heymsfield, S. B., Cohen, A. E., et al.: Protein-calorie undernutrition in hospitalized cancer patients. Am. J. Med., 68:683-690, 1980.
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27. Nixon, D. W., Lawson, D. H., Kutner, M., et al.: Hyperalimentation of the cancer patient with protein-calorie undernutrition. Cancer Res., 41:2038-2045, 1981. 28. Persson, H., Bennegard, K., Lundberg, P.-A., et aI.: Thyroid hormones in conditions of chronic malnutrition. Ann. Surg., 201:45-52, 1985. 29. Preston, T., Reeds, P. J., East, B. W., et al.: A comparison of body protein determination in rats by in vivo neutron activation and carcass analysis. CHn. Sci., 68:349--355, 1985. 30. SharaR, A., Pearson, D., and Oxby, C. B.: Multi-element analysis of the human body using neutron activation. Phys. Med. BioI., 28:203--214, 1983. 31. Shike, M., McR. Russell, D., Detsky, A. S., et al.: Changes in body composition in patients with small-cell lung cancer. The effect of total parenteral nutrition as an adjunct to chemotherapy. Ann. Intern. Med., 101:303--309, 1984. 32. Steffensen, K. A.: Some determinations of the total body water in man by means of intravenous injections of urea. Acta Phys. Scand., 13:282--290, 1947. 33. Vartsky, D., Ellis, K. J., and Cohn, S. H.: In vivo measurement of body nitrogen by analysis of prompt gammas from neutron capture. J. NucI. Med., 20:1158-1165, 1979. 34. Warnold, I., and Lundholm, K.: Clinical significance of preoperative nutritional status in 215 noncancer patients. Ann. Surg., 199:299--305, 1983. 35. Warnold, I., Lundholm, K., and Schersten, T.: Energy balance and body composition in cancer patients. Cancer Res., 38:1801-1807, 1978. 36. Warren, S.: The immediate causes of death in cancer. Am. J. Med. Sci., 184:610--615, 1932. 37. Watson, W. S., and Sammon, A. M.: Body composition in cachexia resulting from malignant and non-malignant diseases. Cancer, 46:2041-2046, 1980. Department of Surgery I Sahlgrenska Hospital University of Gothenburg S-413 45 Gothenburg Sweden
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Body Compositional Changes in Cancer Patients Kent C. Lundholm, M.D. *
The statistical significance of undernutrition in the morbidity and mortality associated with cancer disease is well recognized. 25 Cachexia has been reported as the most important cause of death in heterogeneous groups of patients with solid tumors, exceeded only by pulmonary complications. 36 Cachexia seems to be of particular importance for clinical outcome in patients with breast, stomach, and colorectal carcinoma. However, it is still unknown whether such patients die of malnutrition itself or whether severe malnutrition is only a closely correlated phenomenon and death is due to other causative changes. Experiments in our laboratory have demonstrated that severely malnourished tumor-bearing animals do not die simply from depletion of energy stores despite loss of approximately 25 per cent of their carcass weight. 12 Thus, it is likely that death in clinical cancer, which is generally associated with considerably smaller tumor burdens than found in experimental models, is due to one or more specific metabolic derangements rather than to just overall undernutrition. However, without a doubt, severe malnutrition in cancer patients causes considerable dysfunction, such as muscular weakness, mental depression, and abnormal fatigue, leading to a decreased quality of life. In view of this, it is important in future investigations to be able to correlate alterations in nutritional status (body composition) with changes in function and overall quality of life. Despite numerous reports that cancer patients suffer from a variety of nutritional disorders and that such alterations are highly correlated to increased morbidity and mortality mathematically, we still lack definitive proof that reversal of or protection from developing malnutrition in cancer patients will improve clinical outcome and func*Associate Professor, Department of Surgery I, Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden
Surgical Clinics of North America-Vol. 66, No.5, October 1986
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tion. Although several reproducible, convenient, and reliablemethods are available for assessing nutritional status, measurements of body composition remain the cornerstone in both basic research and clinical attempts to evaluate the consequences of metabolic host relationships and different treatment modalities in cancer.
MEASUREMENT OF BODY COMPOSITION In animal research, the classic method for assessing body composition is biochemical extraction of the cadaver components, which is a highly reliable and reproducible method, particularly in small animals in which the whole carcass can be processed. Although results of direct analysis of human carcass have been reported, the classic clinical methods have generally relied on measurements of total body potassium, body water, weight, height, and creatinine excretion in urine. 13, 24 Body potassium can be measured either by injecting isotopic potassium9 or by measuring the 1.46 MeV natural gamma radiation (40K ) from the body by whole body spectroscopy. 30 The total amount of body potassium is then calculated, assuming that the relationship between radioactive and nonradioactive potassium is constant. In measurements of body water, injections of stable or radioactively labeled water have generally been used. Body water is then calculated from the equilibrium volume of label. Although this method has been reported to be very reproducible with an excellent coefficient of variation « 1%),7 it is not quite the experience of the method in our hands. In some investigations, labeled, uncharged molecules such as urea have been used for measurements of body water. 32 Body water has also been calculated from body potassium, assuming that intracellular water concentration is around 160 mmol of potassium per liter of cell water. 31 In general, the isotopic dilution methods give lower values of body water compared with the direct measurement by evaporation of tissues to absolute dryness. This discrepancy may occur because too short equilibration times are employed and all water is known not to be available for instantaneous exchange. However, when used in a highly standardized manner, the isotopic techniques can be used for estimating total body water, particularly in longitudinal and group-comparing studies. The effectiveness of the more recent nuclear methods has been demonstrated in studies on humans. Analytic neutron activation procedures, now in routine use in several institutions, allow direct quantification of body nitrogen, sodium, phosphorus, chloride, and calcium with a p~ecision at the level of ± 4 per cent. 1, 8, 15, 33 Body
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potassium can be analyzed in a whole body counter at the level of ± 3 per cent or better. Body oxygen has also been analyzed by some groups, with procedures similar to those for the determination of hydrogen, nitrogen, and body carbon, by means of prompt gamma analysis following neutron activation. One obvious limitation with the nuclear methods, which involves radiation procedures, may be its limited applicability in growing individuals and perhaps in fertile subjects. A limited number of comparative studies of body protein determination by in vivo neutron activation and carcass analysis of nitrogen have been performed in rats and pigs. 22 , 29 The rat experiments demonstrated that the technique is sufficiently precise to measure 0.14 gm of nitrogen, which corresponds to the nitrogen accretion over 2 days in a growing rat. Simultaneous chemical measurements by destructive carcass analysis in comparable groups of animals could resolve changes at the level of 0.37 gm of nitrogen. This high-resolution power can be compared with the changes in nitrogen excretion in healthy, voluntarily starving individuals, which is initially 6 to 7 gm of nitrogen and later 2 to 2.5 gm of nitrogen per day after 20 days on a protein-free diet. 14 Therefore, neutron activation is sensitive enough to measure body nitrogen at the level of chemical methods and is even better in the clinical situation when accounting for the difficulties in collecting urine and stool as well as the uncertainties in estimating the loss of epithelial debris. The amount of nitrogen corresponding to the power of neutron activation method thus corresponds to a resolution of 4 to 5 gm of muscle mass. This would be compared to the degree of accuracy that we generally use for measurements of body weight by standard balances, which are generally not better than 100 gm of muscle mass in most clinical circumstances. However, the critical control experiments with regard to nutrition have not been reported so far. Such experiments might include the infusions of plasma proteins or the consumption of a protein-rich diet and then the determination of whether prompt gamma neutron activation could detect accurately the acute changes in the nitrogen pool of the body. Unless such experiments are undertaken, demonstrating the sensitivity of the method, we must regard as circumstantial evidence that increased botein is obtained in response to nutrition of cancer patients. 1, 31
BODY COMPOSITION IN CANCER PATIENTS A nearly universal prevalence of protein-calorie malnutrition has been reported in advanced cancer, with unpredictable losses of
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adipose tissue, visceral protein, and skeletal muscle, from patient to patient. 26 In the report, the creatinine to height index was claimed to be the most sensitive indicator of protein-calorie undernutrition: 88 per cent of the patients had a creatinine to height index less than 80 per cent of standard, whereas only 42 per cent and 23 per cent of these patients had values less than 80 per cent of standard for triceps skinfold and mid-arm muscle area, respectively. In these patients weight loss correlated significantly to triceps skinfold, midarm muscle area, and creatinine to height index but not to serum albumin concentrations. These results agree with those in a more recent study by Shike and colleagues, who found that serum protein levels (including albumin) were normal in patients with small-cell lung cancer suffering from malnutrition as assessed by the creatinineheight index and total body nitrogen measurement. 3l The combination of normal albumin concentration with a significantly impaired body composition in some cancer patients is particularly noteworthy, since plasma albumin has been found to be a powerful indicator of undernutrition and a predictor of morbidity in both cancer and noncancer patients in other studies. 16. 34 The explanation for these discrepancies among reports may be that certain diseases in themselves may lead to depressed albumin synthesis or that increased albumin leakage occurs in certain patients, especially those with gastrOintestinal cancer.16 Another explanation may simply be that depressed albumin concentration is a later phenomenon than loss of lean body mass. In this context, it should be emphasized that most patients reported by Nixon and colleagues26 had received tumor treatment before or concomitant with nutritional assessment, although tumor treatment was not given during the week that measurements were performed. In a recent study, we have reported that plasma albumin concentrations less than 35 gm per L are associated with the onset' of a low T3 syndrome, an indication of adaptive changes in energy metabolism in both cancer and noncancer patients.28 In a recent study on a group of completely untreated malnourished cancer patients, we have reported that loss of body fat was the most pronounced alteration in body composition, which is in accord with findings in experimental cancer. 12, 35 Untreated cancer patients primarily mobilize neutral fat for energy production, in agreement with significantly lower respiratory quotients in lung cancer patients and in patients with different types of solid tumors. 1S, 23 In contrast to these results, Cohn and colleagues recently reported that the loss of body weight by patients with solid tumors primarily consisted of the loss of muscle mass with less loss of body fat.5 Even in severe wasting, the authors concluded that the patients appear to retain significant amounts of body fat, although it was probably not possible
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to assess to what extent the remaining body fat represented phospholipids. Changes in body fat are generally derived by subtracting lean body mass from body weight. This calculation cannot discriminate between neutral fat and phospholipids. A cell or tissue can be depleted of most of its neutral fat without any disturbance in function, but membrane lipids cannot be decreased much, if at all, if cell integrity is to be maintained. Thus, measurements of the changes in neutral fat content should be related to the amounts of neutral fat in the individual prior to treatment or morbidity, if alterations in neutral fat content are to be evaluated precisely. A normal-weight individual with large amounts of lean tissue mass and small amounts of storage fat thus cannot be expected to lose large amounts of fat because a considerable amount of membrane lipids must remain. This kind of problem has not been sufficiently accounted for when changes in body composition are judged in clinical studies and particularly in studies on cancer patients, in which it is often claimed that the range of body fat loss is quite variable. In the studies in which Cohn and colleagues reported that skeletal muscle was predominantly lost, they also observed that visceral proteins were spared to a considerable extent. 5 The nonmuscle tissue, including the visceral fraction, did not decrease but actually appeared to increase in size when compared with that of normal populations. In a more recent report in which longitudinal studies were performed, changes in body composition were analyzed in terms of lean body mass and its constituents, protein, water, and fat. 6 Weight loss was found to reflect primarily the loss offat, water, potassium, and only to a minor extent the protein component of lean body mass, as assessed by direct measurement of body nitrogen. These seemingly contradictory results may, however, be due to truly different study populations in the two investigations. However, a considerable number of the patients were reported to be the same in the two studies, but one experimental condition reported longitudinal measurements and the other represented a single point: measurement. That some of the discrepancies between these two studies as well as between other reports are also dependent on methodologic problems cannot be excluded. It is important to remember that compartment analysis is generally based on derived results relying on assumed prerequisites. 7 Generally only body potassium and water have been measured and, in some investigations, body nitrogen, too. Compartment derivation of body cell mass, lean body mass, muscle mass, and so on thus requires that the relationships between potassium and nitrogen, potassium and water, and muscle and creatine are comparatively normal even in conditions of malnutrition and severe metabolic disturbances. In normal individuals, the ratio between total body nitrogen and total body
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potassium has been reported to be around 13.5 ± 1.1 based on independent measurements of nitrogen and potassium. 1, 5 In cancer patients suffering from progressive wasting, this ratio is significantly higher. 5 This increase may be interpreted to indicate the proportionately larger loss of muscle mass than of average body cell mass. 5 , 7 However, an alternative explanation may be that cancer-induced malnutrition is associated with the preferential loss of intracellular potassium. In many cancer patients, loss of body potassium reflects both a loss of lean tissue, in particular, skeletal muscles, and an intracellular depletion of potassium. In cancer patients, decreased intracellular potassium concentration has been supported recently by direct measurements. In studies on lung cancer patients, Shike and colleagues reported that 4 weeks of parenteral nutrition increased body fat and potassium but not nitrogen, as assessed by neutron activation. 31 In addition, we have recently completed studies on well-nourished young males with testicular carcinoma in whom body potassium was measured before initiation of aggressive cytostatic treatment. Within the first week of treatment, body potassium decreased by 18 per cent (unpublished results). The decrease in body potassium could be prevented by daily parenteral infusion of potassium-containing nutritional solutions. However, over the weeks, potassium supplementation could not prevent the insidious decline in body potassium, which most likely reflected a decrease in lean body mass, particularly skeletal muscle. Direct measurements of arm muscle area, nitrogen excretion, creatinine-height index, and 3-methylhistidine excretion confirmed that muscle mass was actually decreased. A reduced whole body oxygen consumption, when performed in the resting condition, is an excellent indication of lean body mass and does reflect a loss of lean tissues. 17 When considering changes in body potassium, one must obviously take into account the duration of alterations in nutritional state or rehabilitation. It is likely that chronic and long-standing alterations in body potassium reflect loss of muscle mass, whereas short-term alterations (days to weeks?) can reflect changes in the intracellular potassium concentration as well. Results indicating improvement of lean body mass must, therefore, always be suspected to reflect only replenishment of the intracellular pools of potassium unless further direct measurements of body nitrogen or protein status do not indicate replenishment of the nitrogen pool as well. We have previously reported increased body potassium following enteral and parenteral nutrition in cancer patients in combination with positive nitrogen balance. 2, 3, 10, 20 Such combined evidence of net synthesis of lean tissues in cancer patients is suggested to demonstrate repletion of muscle mass. We cannot, however, disregard the possibility that positive nitrogen balance primarily reflects
1019
BODY COMPOSITIONAL CHANGES IN CANCER PATIENTS .2000r------------,-------,--------, AMINO ACID BALANCE
GLUCOSE BALANCE
FFA BALANCE
w
'" ;'!
.1000
::> '"
o o
-
we;
~H ~
w
-1000
'"
E
B
-2 000 '---------"-B_ _ _ _ _----'_ _ _ _ _-'-_ _ _ _-----' ~ Cancer patients
o
Controls
Figure 1. Amino acid and energy balance across the leg after an overnight fast (B) and following 2 weeks of enteral nutrition (E). The results support the conclusion that enteral feeding does not promote a resynthesis of lean body mass as measured over peripheral compartments in either malnourished cancer patients or malnourished patients without cancer. Fat and glycogen stores are, however, improved, as the patients were in net glucose and FFA balance in response to feeding. All patients received a formula diet consisting of 35 to 40 kcallkgJday, and the protein intake was approximately 0.2 g N/kgJday. The diet was infused 24 hours a day via a nasogastric tube. (From Bennegard, K., Lindmark, L., Eden, E., et al.: Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res., 44:386-393, 1984; with permission.)
the repletion of visceral proteins, in particular plasma proteins, while accumulation of potassium may reflect rather an intracellular replenishment. Simultaneous measurements of muscle RNA from biopsy material before and after nutrition, in combination with increased body potassium, support the conclusion that repletion of muscle tissue is possible in cancer patients. However, this may demand a particularly high load of calories and nitrogen levels that may be detrimental for the patient in other regards. 10 In contrast to our earlier investigations, our more recent studies support the suggestion that a considerable proportion of weight-losing cancer patients do not replenish protein content in peripheral tissues, particularly muscle tissue. This is indicated by the fact that they do not switch to positive amino acid balance over the leg in the fed state (Fig. 1).3 This is true even after 2 weeks on conventional enteral feeding through a nasogastric tube, with an intake of calories and nitrogen adequate for repletion of muscle tissue according to the estimated whole body needs of the patients. Such problems in artificial nutrition may explain the lack of evidence for nitrogen accumulation in cytostatic-treated lung cancer patients on adjunctive nutritional support. 31 However, an alternative explanation to the lack of protein
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accretion in the patients reported on by Shike and colleagues may be that cytostatic drugs block protein synthesis but not the resynthesis of fat and its deposition into lipid storage. This latter explanation, however, is not relevant for any of our own studies, as they included patients only before tumor treatment. Several studies have addressed the question of whether elevated energy expenditure or anorexia explains wasting of body composition in cancer. It is quite clear that elevated energy expenditure occurs in numerous weight-losing cancer patients,18, 35 although some authors have failed to detect such differences. 4 Such discrepancies may be due to differences in investigative approaches, with regard to the use of reference patients and the degree of sensitivity, stability, and reproducibility of the technology used to measure energy expenditure. Burke and colleagues could not demonstrate an elevated expenditure of energy in cancer patients with early onset of weight loss, and they were therefore prone to explain body compositional changes by other mechanisms, such as qualitative alterations in food intake and perhaps increased malabsorption. 4 Their weight-losing cancer patients showed some alterations in selection of food composition, with the main defect being energy deficiency, as protein intake was usually well maintained. There was also a positive correlation between protein and energy intake versus changes in lean body mass in patients with benign disease, which was lacking in the cancer patients. This lack of an expected correlation in the cancer patients could be explained by such alterations as increased energy expenditure, although not demonstrated by specific alterations in intermediary metabolism, particularly in the synthetic machinery of muscle protein, or by specific derangements in food selection or impaired absorption of enteric nutrients. However, most investigators have been unable to demonstrate any major alterations in gastrointestinal absorption in cancer patients, although slight steatorrhea has been observed in occasional patients. This lack of evidence for a systematic finding of malabsorption may, however, be because methods that are too insensitive have been applied in most studies. Some evidence is available that cancer patients may select food differently, although such findings do not seem to be occurring regularly. Such a discrepancy may also be due to the fact that malignancies are not a uniform entity or disease. In addition to our own results, demonstrating a less than normal resynthesis of major body compartments, such as skeletal muscles, it has been reported that some cancer patients do not replete normal body composition as evaluated from studies on nitrogen and ion balances during parenteral nutrition. 27 In line with the preceding discussion, it has been investigated whether cancer patients lose body components differently as com-
BODY COMPOSITIONAL CHANGES IN CANCER PATIENTS
1021
pared with patients suffering from benign wasting. 37 If so, this should lead to a significant alteration of body composition over a considerable period compared with patients suffering from body wasting because of reasons other than malignancy. Evidence to support this hypothesis has been reported in a comparative study between small groups of patients. 37 It was concluded that body composition in cancer cachexia differs from that in cachexia caused by benign inflammatory disease, in that lean tissue appears to be better conserved in the cancer group. However, it is more likely that these differences represent the result of comparing two populations that probably differ in the time course of the disease progression and state of malnutrition and not any true differences in underlying metabolism. Of course, some well-defined metabolic differences may be possible to demonstrate between such populations if they are compared in different phases of disease progression. A more preserved lean body mass in cancer patients would theoretically indicate a more preserved protein balance, perhaps because of a lower demand for gluconeogenesis. However, increased gluconeogenesis and depressed synthesis of muscle protein are both well-recognized alterations in patients with progressive wasting due to cancer and in conditions of partial or complete starvation. 11, 19,21 Therefore, body compositional changes can only reflect the end result of different net alterations over a certain period of time. Body composition analyses are not a tool to use in evaluating underlying disorders of metabolism, but they remain the most important technique for evaluating the therapeutic net results and for defining the degree of malnutrition in groups of patients.
SUMMARY Noninvasive and spectroscopic techniques already available and under further development in several laboratories will in the near future give us a greater amount of detailed information on changes in body compartments in disease and in response to therapeutic efforts. Such techniques should have the ability to measure directly components in an organ or tissue in contrast to most present and previous techniques that generally rely on derivation of components from a few direct measurements. Such derivations are unfortunately dependent on assumptions that are not possible to control in several circumstances.
REFERENCES 1. Beddoe, A. H., and Hill, C. L.: Clinical measurement of body composition using in vivo neutron activation analysis. J.P.E.N., 9:504-520, 1985.
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2. Bennegard, K., Eden, E., Schersten, T., et al.: Metabolic response of whole body and peripheral tissues to enteral nutrition in weight-losing cancer and noncancer patients. Gastroenterology, 85:92-99, 1983. 3. Bennegard, K., Lindmark, L., Eden, E., et al.: Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res., 44:386--393, 1984. 4. Burke, M., Bryson, E. 1., and Kark, A. E.: Dietary intakes, resting metabolic rates, and body composition in benign and malignant gastrointestinal disease. Br. Med. J., 26:211-215, 1980. 5. Cohn, S. H., Gartenhaus, W., Sawitsky, A., et al.: Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water. Metabolism, 30:222-229, 1981. 6. Cohn, S. H., Gartenhaus, W., Vartsky, D., et al.: Body composition and dietary intake in neoplastic disease. Am. J. Clin. Nutr., 34:1997-2004, 1981. 7. Cohn, S. H., Vartsky, D., Yasumura, S., et al.: Indexes of body cell mass: Nitrogen versus potassium. Am. J. Physiol., 244:E305-E310, 1983. 8. Conway, J. M., Norris, K. H., and Bodwell, C. E.: A new approach for the estimation of body composition: Infrared interactance. Am. J. Clin. Nutr., 40:1123-1130, 1984. 9. Corsa, L., and Olney, J. M.: The measurement of exchangeable potassium in man by isotope dilution. J. Clin. Invest., 29:1280-1290, 1950. 10. Eden, E., Bennegard, K., Bylund-Fellenius, A.-C., et al.: Whole-body energy metabolism and metabolic capacity of skeletal muscles in malnourished patients before and after total parenteral nutrition. Hum. Nutr. Clin. Nutr., 37C:185-196, 1983. 11. Eden, E., Edstrom, S., Bennegard, K., et al.: Glucose flux in relation to energy expenditure during fasting and in the fed state in malnourished cancer and non-cancer patients. Cancer Res., 44:1718-1724, 1984. 12. Eden, E., Lindmark, L., Karlberg, 1., et al.: Role of whole-body lipids and nitrogen as limiting factors for survival in tumor-bearing mice with anorexia and cachexia. Cancer Res., 43:3707-3711, 1983. 13. Forbes, G. B., and Bruining, G. J.: Urinary creatinine excretion and lean body mass. Am. J. Clin. Nutr., 29:1359-1366, 1976. 14. Forbes, G., and Drenick, E. J.: Loss of body nitrogen on fasting. Am. J. Clin. Nutr., 32:1570-1574, 1979. 15. Garrow, J. S.: New approaches to body composition. Am. J. Clin. Nutr., 35:1152-1158, 1982. 16. Harvey, K. B., Moldawer, L. L., Bistrian, B. R., et al.: Biological measures for the formulation of hospital prognostic index. Am. J. Clin. Nutr., 34:2013-2022, 1981. 17. Kinney, J. M., Lister, J., and Moore, F. D.: Relationship of energy expenditure to total exchangeable potassium. Ann. N.Y. Acad. Sci., 110:711-722, 1963. 18. Lindmark, L., Bennegard, K., Eden, E., et al.: Resting energy expenditure in malnourished patients with and without cancer. Gastroenterology, 87:402-408, 1984. 19. Lundholm, K., Bylund, A.-C., Holm, J., et al.: Skeletal muscle metabolism in patients with malignant tumor. Eur. J. Cancer, 12:465-473, 1976. 20. Lundholm, K., Edstrom, S., Ekman, L., et al.: Metabolism in peripheral tissues in cancer patients. Cancer Treat. Rep., 65:79-83, 1981. 21. Lundholm, K., Edstrom, S., Karlberg, 1., et al.: Glucose turnover, gluconeogenesis from glycerol and estimation of net glucose cycling in cancer patients. Cancer, 50:1142-1150, 1982. 22. McNeil, K. G., Mernagh, J. R., Jeejeebhoy, K. N., et al.: In vivo measurements of body protein based on the determination of nitrogen by prompt analysis. Am. J. Clin. Nutr., 32:1955-1961, 1979. 23. McR. Russell, D., 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. 24. Moore, F. D., Olesen, K. H., McMurrey, J. D., et al.: The Body Cell Mass and Its Supporting Environment: Body Composition in Health and Disease. Philadelphia, W. B. Saunders, 1963. 25. Mullen, J. L., Buzby, G. P., Waldman, M. T., et al.: Prediction of operative morbidity and mortality by preoperative nutritional assessment. Surg. Forum, 30:80-82, 1979. 26. Nixon, D. W., Heymsfield, S. B., Cohen, A. E., et al.: Protein-calorie undernutrition in hospitalized cancer patients. Am. J. Med., 68:683-690, 1980.
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27. Nixon, D. W., Lawson, D. H., Kutner, M., et al.: Hyperalimentation of the cancer patient with protein-calorie undernutrition. Cancer Res., 41:2038-2045, 1981. 28. Persson, H., Bennegard, K., Lundberg, P.-A., et aI.: Thyroid hormones in conditions of chronic malnutrition. Ann. Surg., 201:45-52, 1985. 29. Preston, T., Reeds, P. J., East, B. W., et al.: A comparison of body protein determination in rats by in vivo neutron activation and carcass analysis. CHn. Sci., 68:349--355, 1985. 30. SharaR, A., Pearson, D., and Oxby, C. B.: Multi-element analysis of the human body using neutron activation. Phys. Med. BioI., 28:203--214, 1983. 31. Shike, M., McR. Russell, D., Detsky, A. S., et al.: Changes in body composition in patients with small-cell lung cancer. The effect of total parenteral nutrition as an adjunct to chemotherapy. Ann. Intern. Med., 101:303--309, 1984. 32. Steffensen, K. A.: Some determinations of the total body water in man by means of intravenous injections of urea. Acta Phys. Scand., 13:282--290, 1947. 33. Vartsky, D., Ellis, K. J., and Cohn, S. H.: In vivo measurement of body nitrogen by analysis of prompt gammas from neutron capture. J. NucI. Med., 20:1158-1165, 1979. 34. Warnold, I., and Lundholm, K.: Clinical significance of preoperative nutritional status in 215 noncancer patients. Ann. Surg., 199:299--305, 1983. 35. Warnold, I., Lundholm, K., and Schersten, T.: Energy balance and body composition in cancer patients. Cancer Res., 38:1801-1807, 1978. 36. Warren, S.: The immediate causes of death in cancer. Am. J. Med. Sci., 184:610--615, 1932. 37. Watson, W. S., and Sammon, A. M.: Body composition in cachexia resulting from malignant and non-malignant diseases. Cancer, 46:2041-2046, 1980. Department of Surgery I Sahlgrenska Hospital University of Gothenburg S-413 45 Gothenburg Sweden