Nutritional Support in the Cancer Patient JOHN M.
DALY, M.D., KURT HOFFMAN, M.D., MICHAEL LIEBERMAN, M.D., PABLO LEON, M.D., H. P. REDMOND, M.D., JIAN SHOU, M.D., AND MICHAEL H. TOROSIAN, M.D.
From the Division
of Surgical Oncology and
the
Department of Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
a13 proposed that tumor peptides acting through neuroendocrine cells and neuroreceptors alter metabolic pathways. Nakahara9 described a &dquo;toxohormone&dquo; (75,000
Progressive weight loss and malnutrition occurs commonly in cancer patients’-’ and is a major source of morbidity and mortality.’,’ Antineoplastic therapy has a varying impact on the nutritional status of the host, adding to the cachectic state caused by the tumor itself and leading to a more profound nutritional depletion’ and increased morbidity. Malnourished cancer patients should be evaluated prior to initiation of antineoplastic treatment and intervention performed to improve nutritional status. The term &dquo;cancer cachexia&dquo; describes a group of symptoms and signs-inanition, anorexia, weakness, tissue wasting, and organ dysfunction. Cachexia, common in patients with advanced metastatic disease, also occurs in patients with localized disease. DeWys et al3 noted substantial weight loss in 40% of patients with breast cancer and in 80% of patients with gastric or pancreatic carcinoma. The relationship of cachexia to tumor burden, disease stage, and cell type is inconsistent, however, and no single theory satisfactorily explains the cachectic state. A variety of etiologic factors can occur simultaneously or sequentially to produce cachexia. Anorexia is a major contributing factor in the development of the cachectic state. Often, loss of appetite is an important symptom of an underlying neoplasm. Several physiologic derangements have been cited as possible reasons for anorexia. Abnormalities in taste perception, such as reduced threshold for sweetness and for sour and salty flavors, have been demonstrated by DeWys and Walters.’ Deficiencies in zinc and other trace elements may contribute to altered taste sensation. Patients with hepatic metastases accompanied by some degree of hepatic insufficiency may develop anorexia and nausea as a result of difficulty in clearing lactate produced by the tumor’s anaerobic metabolism of glucose. Substances released by the tumor or by the host’s monocytes (cachectin) in response to the tumor may act on the feeding center in the hypothalamus and cause anorexia. Recent studies have demonstrated the presence of cachectin in the plasma of tumor-bearing rodents which correlated with the onset of anorexia. Many studies have been conducted to elucidate the specific metabolic processes that affect nutrient intake in cancer patients. Lucke et al8 noted the presence of a humoral factor that produces in the non-tumor-bearing rat characteristics of the tumor-bearing state. DeWys et
dalton protein) capable of mimicking the cancerous state when injected into normal animals. Rats given cachectin intraperitoneally for 5 days demonstrated decreased dietary intake with a corresponding decline in host body weight.l° When subsequently inoculated with tumor, these rats survived for a significantly longer period than control animals not pretreated with cachectin. Thus, endogenously produced cachectin may be a mediator in the development of cachexia in the tumor-bearing host. Recently, Krause et all’ postulated that abnormalities in the central nervous system metabolism of serotonin may be responsible for the anorexia associated with the tu-
mor-bearing
state.
The local effect of the tumor itself is another factor that may reduce food intake, especially when the tumor arises from or impinges on the alimentary tract. Patients with cancer of the oral cavity, the pharynx, or the esophagus may have reduced intake because of odynophagia or dysphagia. Patients with gastric cancer often have reduced gastric capacity or partial gastric outlet obstruction leading to an early feeling of fullness, nausea, and vomiting. Intestinal tumors may result in partial obstruction or blind-loop syndrome and interfere with nutrient
absorption. Psychologic factors such as depression, grief, or anxiety resulting from the disease or its treatment may lead to poor appetite, abnormal eating behavior, and learned food aversions and thus, a diminished or unbalanced dietary intake. Extensive changes in energy, carbohydrate, lipid, and protein metabolism have been demonstrated in cancer patients.12,13 Increased energy expenditure and inefficient energy utilization are frequently cited causes of malnutrition in tumor-bearing hostS.14,15 Young&dquo; reviewed a number of clinical studies and concluded that resting metabolism was not consistently elevated in cancer patients, though increased resting energy expenditure was noted in leukemia and lymphoma patients. Warnold et ap6 demonstrated that increases in resting metabolic rate paralleled advancing disease and reduced nutrient intake. Shike et all’ demonstrated that basal energy expenditure was elevated in patients with small cell lung carcinoma. In those who responded to chemotherapy, there was a significant decrease in basal energy expenditure while nonresponding patients exhibited no change. In 1983, Knox et all&dquo; measured energy
244S Downloaded from pen.sagepub.com at Glasgow University Library on June 28, 2015
245S and found that only 41 °l of cancer patients had a normal resting energy expenditure while decreased and increased resting energy expenditure was observed in 33% and 26% of patients, respectively. Similarly, Heber et a119°2° found no clear evidence of hypermetabolism in noncachetic lung cancer patients. They argued that since malnourished patients normally decrease basal metabolic rate as an adaptation to starvation, even normal predicted metabolic rates are inappropriately elevated in malnourished cancer patients. Shaw et a121 argued that the alteration in metabolic rate depends on the type of tumor. An elevated rate of energy expenditure was noted in sarcoma-bearing patients and this abnormality was associated with increased Cori cycle activity, glucose turnover, reduced glucose oxidation, and increased protein catabolism. Inefficient energy utilization by the tumor-bearing host may occur because of several mechanisms. Holroyde and Reichard14 reported increased Cori cycle activity in patients with malignancy. This futile cycle in which glucose is converted to lactic acid and subsequently reconverted to glucose by hepatocytes is an energy-wasting process. The highest level of Cori cycle activity was observed in patients with the greatest energy expenditure and weight loss. Young&dquo; has suggested that increased rates of protein turnover also result in significant energy losses. This is due to the failure of normal adaptation to starvation. In noncancer patients, muscle protein breakdown is gradually replaced by fatty acids, which are converted to ketone bodies to be used for energy by peripheral tissues and eventually up to 95% of energy utilization by the brain. This results in decreased glucose utilization with secondary sparing of muscle protein. In cancer patients these adaptive mechanisms do not occur, resulting in increased glucose production and protein catabolism. Although cancer patients have normal levels of circulating insulin and glucose, they have impaired insulin sensitivity. Glucose intolerance is documented by hyperglycemia and delayed clearance of blood glucose in cancer patients after oral or intravenous glucose administration. 14,19,22 Glucose intolerance is, in part, due to decreased tissue sensitivity to insulin but may also involve an attenuated insulin secretion to exogenous glucose. 21,11 Cancer patients also exhibit increased gluconeogenesis from alanine and lactate. Using [14C]alanine, Waterhouse et a124 found that the apparent increased gluconeogenesis from alanine reflected a very rapid glucose turnover. Feedback control of glucose production may be impaired as gluconeogenesis and Cori cycle activity are not inhibited by glucose administration in the cancer
expenditure
found that fatty acids are the major substrates in patients with progressive malignant disease. Increased plasma clearance of fatty acids and exogenously administered fat emulsions in cancer patients have been demonstrated 21-11 in both the fasting and fed states. Frequently, cancer patients fail to suppress lipolysis after glucose administration and continue to oxidize fatty acids. Several abnormalities of protein metabolism occur in cancer patients,30,31 including host nitrogen depletion, decreased muscle protein synthesis, and the occurrence of abnormal plasma aminograms. Nitrogen balance is often negative in patients with progressive malignancy.32 Amino acid trapping by tumor cells has been demonstrated clinically and experimentally. In a study of sarcoma-bearing limbs, Norton et ap3 found that affected limbs released less than 50% of the amount of amino acids released from tumor-free limbs. Evidence obtained with whole body protein studies using [15 N]glycine indicate that cancer patients have increased protein turnover, a circumstance that contributes to increased energy
expenditure.33 Additional changes associated with cachexia include in body composition such as increased extracellular fluid and total body sodium and decreased intracellular fluid and total body potassium. Cohn et aV4 using prompt y-neutron activation to evaluate total body nitrogen and a whole body counter to measure 4°K, found that total body potassium was diminished out of proportion to total body nitrogen. On the basis of this finding they concluded that endogenous nutrient losses in cancer patients were predominantly in the skeletal muscle compartment since muscle comprises 45% of total body nitrogen and 85% of total body potassium. Antineoplastic therapy invariably affects the host, by mechanical and physiologic alterations due to operation or at the cellular level with chemotherapy or radiation therapy.6 Their effects may add to the cachexia of malignancy and result in a more substantial nutritional deficiency. Operative therapy is the primary treatment modality of many cancers, particularly those of the gastrointestinal tract. The immediate metabolic responses to surgery include increased nitrogen losses and energy requirements.35,36 However, because cancer patients tend to have significant weight loss prior to surgery, their ability to cope with stress is impaired, 3-,.:18 resulting in increased morbidity and mortality. The increased catecholamine, glucagon, and cortisone levels result in hy-
changes
permetabolism, weight loss, negative nitrogen balance, and retention of sodium and
water.
Antineoplastic chemotherapy may profoundly alter the
patient.
nutritional state of the host. These effects may be direct
Alterations in lipid metabolism in cancer patients include changes in whole body composition and increased lipid mobilization.25,26 Decreases in total body fat are common among these patients and are most likely related to insulin deficiency. As well as increased lipolysis, there is also increased oxidation of fatty acids. The by-products of lipolysis-glycerol and fatty acids-serve as substrates for gluconeogenesis and energy production, respectively, ‘ during periods of nutrient deprivation. Waterhouse 27
by interfering with host cell metabolism or DNA synthesis and cellular replication or indirect by producing nausea, vomiting, changes in taste sensation, and learned food aversions. Most agents have in common the ability to stimulate the chemoreceptor trigger zone in the brain. resulting in nausea and vomiting. The rapidity of turnover of cells in the mucosa of the alimentary tract makes it especially vulnerable to chemotherapy, resulting in stomatitis, ulceration, and decreased absorptive capacity.
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246S These effects result, in turn, in decreased intake and absorption of nutrients and further predispose the cancer patient to malnutrition. The bone marrow is another organ with a high cell turnover. Toxicity is manifested by anemia, leukopenia, and thrombocytopenia. Neutropenia is, in turn, associated with an increased risk of
sepsis. Radiation therapy may affect the nutritional state of by its effects on the gastrointestinal tract. The severity of the injury is related to the dose of radiation and the volume of tissue treated. The effects of radiation therapy may be classified as early or late. Early effects are transient and are manifested by diarrhea, bleeding,
the host
nausea, vomiting, weight loss, mucositis, xerostomia, alterations in taste, and food aversions. Late effects include intestinal strictures, fistulae, and malabsorption. The clinical relevance of severe malnutrition has been demonstrated by increased morbidity and mortality and poor treatment tolerance in malnourished, tumor-bearing individuals.4,5,39 In 1932, Warren4° found that malnutrition was a major contributing factor to death in cancer patients. The protein-calorie malnutrition produced by the cancer-bearing state leads not only to obvious weight loss, but also to visceral and somatic protein depletion resulting in compromise of enzymatic, structural, and mechanical functions. Impairment of
immunocompetence4u42
and increased susceptibility to infection frequently result. The effect on immune function may be further exacerbated by chemotherapy.43 Moreover, poor wound healing, increased wound infections, prolonged postoperative ileus, and longer hospital stay have all been linked to poor nutritional status in cancer patients. Meguid et a144 demonstrated that in patients undergoing colorectal cancer operations, the return to adequate oral food intake was significantly delayed in patients classified as malnourished based on preoperative assessment. In that study the morbidity and mortality in malnourished patients was 52% and 12%, respectively, compared with 31% and 6% in well-nourished patients. In animal studies, both humoral and cellular immune responses are depressed with severe protein restriction. In 1978, Daly et a142 demonstrated that only 30% of tumor-bearing rats had a delayed hypersensitivity response to intradermal purified protein derivative after 2 weeks on an oral, protein-free diet. Protein repletion with 7 days of total parenteral nutrition (TPN) or oral ad libitum feeding restored the immune response in 91% and 78% of rats, respectively. In 1974, Law et al38 found reduced titers of antibodies, IgM-producing cells, reduced lymphocyte response to mitogens, and decreased delayed hypersensitivity in rats after 6 weeks on protein-free nutrition. In patient studies, there is evidence of increased morbidity and mortality associated with depressed immunocompetence. Harvey et a14~ reported on a group of 161 cancer
32
patients receiving nutritional support. Of these, anergic prior to therapy. In 27 of these patients
were
anergy was reversed and three of this group died. Of the five patients who remained anergic, all died. Daly et al4s found that 51 % of anergic patients undergoing cancer
treatment had restoration of skin test sponse to TPN.
reactivity in
re-
Sixteen randomized, prospective trials have evaluated the effects of preoperative TPN on clinical outcome in cancer patients. In 1987, Detsky et al 17 reviewed 14 trials utilizing meta-analysis techniques to evaluate their results. They concluded that &dquo;routine use of perioperative TPN in unselected patients having major surgery is not justified, however, this intervention may be helpful in subgroups of these patients who are at high risk.&dquo; Based upon these previous reports and those subsequently published, there is common agreement that perioperative TPN should be utilized in certain subgroups of patients who may benefit. In 1979, Heatley et a148 studied 74 gastric cancer patients who either received preoperative TPN for 7-10 days or served as controls. TPN patients had fewer wound infections and lost less body weight perioperatively than corresponding control patients. Muller et a149 studied 125 patients with gastrointestinal cancer who were randomized to receive 10 days of pre66) or standard diet (n operative TPN (n 59). Postoperative major morbidity and mortality were significantly lower in the TPN group. Muller et al reported an extension of their work which included three groups: control, TPN (amino acids/glucose), and TPN (amino acids/glucose/lipid emulsion) patients. Significant differences were noted for weight change and increased protein and immune parameters as well as major complications and mortality comparing the TPN (amino acid/glucose) patients and controls. The trial was changed before completion by stopping the TPN (amino acids/glucose/lipid emulsion) group because of greater complications in this group. Studies by Starker et al50 and Bellantone et a151 included patients with benign and malignant disease. In the former study, 59 malnourished patients were divided into three groups based on initial response to TPN. 50 Patients received TPN for a period ranging from 5 days to 6 weeks. The authors noted a high morbidity and mortality in those patients who remained hypoalbuminemic after 1 week of TPN. Their data suggest that a prolonged period of TPN decreased postoperative complications. This observation suggests the importance of administering preoperative TPN until nutritional deficits have been corrected. Foschi et all studied 64 patients who underwent preoperative catheter biliary division for obstructive jaundice with or without preoperative TPN. The nutritionally repleted group had significantly fewer major complications (18% us 47%) and mortality (3.5% vs. 12.5%) compared with control =
=
patients. A multi-institutional prospective randomized trial evaluating TPN in surgical patients has been completed (Buzby, GP, personal communication). Two hundred thirty-one TPN and 228 control patients were studied. Mortality rates and major complications were similar for both groups. A higher incidence of infectious complications was noted in the TPN group while a higher noninfectious complication rate occurred in controls. In the subgroup of patients with severe malnutrition, measured by subjective global assessment and nutritional index,
Downloaded from pen.sagepub.com at Glasgow University Library on June 28, 2015
247S TPN significantly reduced overall major complications from 47% to 21%-26%. In summary, clinical trials of perioperative TPN in cancer patients have demonstrated improved nutritional status as reflected by gain in body weight and improvement in serum protein levels, immune function, and nitrogen balance. Effects on clinical outcome remain less well defined. Preoperative TPN has resulted in a significant reduction in postoperative complications and reduced mortality, in the severely malnourished high-risk
preoperative
group, when TPN is administered for an adequate length of time. Failure to demonstrate improved outcome with TPN in other trials may accurately reflect the limited value of TPN. It is also possible that in these patients, the complications associated with TPN and the increased risk of nosocomial infections due to an increased duration of hospitalization may negate any benefit and may result in net harm. In severely malnourished patients
undergoing high-risk major operative procedures,
those modalities of treatment. Animal studies indicate that protein depletion increases toxicity and lethality of chemotherapy.53 Furthermore, TPN or increased dietary protein reduces toxicity in animals compared with those fed regular or protein-depleted diets.54 In the 1970s clinical reviews correlated malnutrition with a poor prognosis in patients with metastatic disease receiving chemotherapy. This suggested that nutritional support would increase therapeutic benefit and many trials using TPN as adjunctive therapy were initiated. Chlebowski55 reviewed recent randomized trials and found no clear evidence that TPN alleviated chemotherapy-related toxicity or enhanced tumor response in humans (Table I). Although randomized trials have failed to demonstrate an adjunctive role for TPN or a reduction in side effects, nutritional therapy is an important supportive measure. cancer
patients who
are otherwise not because of inanition to undergo continuing chemotherapy and potentially achieved disease remission. Some workers have demonstrated reduced mortalitv and increased tumor response rates in patients receiving extensive radiation therapy with adjunctive TPN compared with patients not receiving nutritional support. 5 t3. -i However, these studies were carried out in small groups of patients. Donaldson58 reviewed these and other prospective trials in 1984 and failed to show that nutritional support reduced the complication rates or improved local cancer control and survival. This suggests that TPN or enteral feedings are important support measures in patients undergoing a planned course of radiation therapy but do not sensitize the tumor to irradiation or prevent gastrointestinal side effects.
permit
candidates for
some
treatment
pre-
operative TPN appears to have a beneficial role. A narrow margin of therapeutic safety exists for chemotherapeutic drugs and adequate levels of radiation therapy and cachexia may reduce the therapeutic index of
TABLE I Randomized trials of TPN and chemotherapy in
It may
patients
CONCLUSION
Cancer patients are frequently malnourished at the time of diagnosis. These patients develop anorexia and reduced nutritional intake. Specific abnormalities in substrate metabolism and energy expenditure have been detected in patients and in tumor-bearing animals. Protein catabolism, increased lipolysis, and glucose availability help to create a milieu favorable to tumor growth at the expense of the host. There is evidence that the tumor effects these changes through neurohumoral mechanisms. There is little doubt that malnutrition associated with cancer has a negative prognostic effect and can contribute directly to the demise of the patient as well as increase postoperative morbidity and decrease the tumor response and patient tolerance to all modalities of treatment. Nutritional therapy is an important supportive measure for the patient undergoing antineoplastic treatment. It increases the well-being of the patient and may permit the administration of more intensive therapies. There is no conclusive evidence that adequate nutritional support preferentially feeds the tumor and results in increased tumor growth in humans. There is good evidence that effective nutritional repletion can reduce postoperative complications and mortality rates after surgery in severely malnourished patients. Weight gain is possible and immune status may be improved but definite improvement in tumor response rates and patient survival following chemotherapy or radiotherapy remains unproven.
Modified from Chlebowski.55 NED, no evidence of disease. * Trials suggesting adverse effect of TPN to chemotherapy.
In the future, more specific manipulation of substrates and hormones administered to the host may provide improved results. Clinical trials of arginine supplementation to enteral feeding hale shown rapid return of lymphocyte proliferation to normal following operation. Use of glutamine supplementation in TPN may reduce the stomatitis and enteritis associated with multidrug chemotherapy. Finally, use of growth hormone or tumor necrosis factor antibodies may beneficially affect the metabolism of endogenous and exogenous substrates.
Downloaded from pen.sagepub.com at Glasgow University Library on June 28, 2015
248S on
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488, 1972 3. DeWys WE, Begg C, Lavin PT, et al: Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 69:491497, 1980 4. Copeland EM, Daly JM, Dudrick SJ: Nutrition as an adjunct to cancer treatment in the adult. Cancer Res 37:2451-2456, 1977 5. Smale BF, Mullen JL, Buzby GP, et al: The efficacy of nutritional assessment and support in cancer surgery. Cancer 47:2375-2381, 1981 6. McAnena OJ, Daly JM: Impact of antitumor therapy on nutrition. Surg Clin North Am 66:1213-1228, 1986 7. DeWys WD, Walters K: Abnormalities of taste sensation in cancer patients. Cancer 36:1888-1896, 1975 8. Lucke B, Borwick M, Zeckwer I: Liver catalase activity in parabiotic rats with one partner tumor bearing. J Natl Cancer Inst
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9. Nakahara W: A chemical basis for tumor host relations. J Natl Cancer Inst 24:77-86, 1960 10. Stovroff MC, Norton JA: Cachectin: A mediator of cancer cachexia. Surg Forum 38:413-415, 1987 11. Krause R, Humphreys C, von Meyenfeldt M, et al: A central mechanism for anorexia in cancer: A hypothesis. Cancer Treat Rep 65(suppl 5):15-21, 1981 12. Brennan MF: Uncomplicated starvation versus cancer cachexia. Cancer Res 37:2359-2364, 1977 13. Brennan MF: Total parenteral nutrition in the cancer patient. N Engl J Med 305:375-381, 1981 14. Holroyde CP, Reichard A: Carbohydrate metabolism in cancer cachexia. Cancer Treat Rep 65(suppl):55-59, 1981 15. Young VR: Energy metabolism and requirements in the cancer patient. Cancer Res 37:2336-2347, 1977 16. Warnold I, Lundholm K, Schersten T: Energy balance and body composition in cancer. Cancer Res 38:1801-1807, 1978 17. Shike M, Russel D, Detsky A, et al: Changes in body composition in patients with small cell lung cancer: The effect of TPN as an adjunct to chemotherapy. Ann Intern Med 101:303-309, 1984 18. Knox LS, Crosby LO, Feurer ID, et al: Energy expenditure in malnourished cancer patients. Ann Surg 197:152-162, 1983 19. Heber D, Chlebowski RT, Ishibashi DE, et al: Abnormalities in glucose and protein metabolism in noncachectic lung cancer patients. Cancer Res 42:4815-4819, 1982 20. Heber D, Byerley LO, Chi J, et al: Pathophysiology of malnutrition in the adult cancer patient. Cancer 58(suppl):1867-1873, 1986 21. Shaw JM, Humberstone DM, Wolfe RR: Energy and protein metabolism in sarcoma patients. Ann Surg 207:283-289, 1988 22. Schein PS, Kesner D, Haller D, et al: Cachexia of malignancy: Potential role of insulin in nutritional management. Cancer
184:610-615, 1932
28:1148-1155, 1975 42.
Dudrick SJ, Copeland EM: Effects of protein depletion cell mediated immunity in experimental animals. Ann Surg
Daly JM, on
188:791-796, 1978 AB, Brunstetter FH, Kemmere WT, et al: Cellular immune competence of breast cancer patients receiving chemotherapy. Arch Surg 107:531-535, 1983 44. Meguid MM, Mughal MM, Debonis D, et al: Influence of nutritional status on the resumption of adequate food intake in patients recovering from colorectal cancer operation. Surg Clin North Am 66:1167-1176, 1986 45. Harvey KB, Bath A Jr, Blackburn GL: Nutritional assessment and Cancer patient outcome during oncological therapy. 43. Cosimi
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47. 48.
49.
43(suppl):2065-2069, 1979 Daly JM, Dudrick SJ, Copeland EM: Intravenous hyperalimentation : Effect on delayed cutaneous hypersensitivity in cancer patients. Ann Surg 192:587-592, 1980 Detsky AS, Baker JP, O’Rourke K, et al: Perioperative parenteral nutrition: A meta-analysis. Ann Intern Med 107:195-203, 1987 Heatley RV, Williams RHP, Lewis MH: Preoperative intravenous feeding: A controlled trial. Postgrad Med J 55:541-545, 1979 Muller JM, Brenner U, Dienst C, et al: Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet 1:6871, 1982
PM, LaSala PA, Askanazi J, et al: The influence of preoperative total parenteral nutrition upon morbidity and mortality. Surg Gynecol Obstet 162:569-574, 1986 Bellantone R, Doglietto G, Bossola M, et al: Preoperative parenteral nutrition of malnourished surgical patients. Acta Chir Scand 22:249-251, 1988 Foschi D, Cavagna G, Callioni F, et al: Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. Br J Surg 73:716-719, 1986 Flanigen-Roat DT, Milholland RJ, Ip MM: Effect of a high-protein low-carbohydrate diet on toxicity and antitumor activity of 5-
50. Starker
51.
PA, Bishop JS: 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 26:254-264,
52.
1957 24. Waterhouse C, Jeanpretre N, Keilson J: Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res
53.
23. Marks
39:1968-1972, 1979
and turnover in normal and malnourished patients with and without known cancer. Ann Surg 194:123-128, 1981 Cohn SH, 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, 1980 Stein JP, Buzby GP: Protein metabolism in surgical patients. Surg Clin North Am 61:519-527, 1981 Brennan MF: Metabolic response to surgery in the cancer patient. Cancer 43:2053-2064, 1979 Buzby GP, Muller JL, Matthews DC, et al: Prognostic nutritional index in gastrointestinal surgery. Am J Surg 139:160-167, 1980 Law DK, Dudrick SJ, Abdou NI: The effects of protein-calorie malnutrition on immunocompetence of the surgical patient. Surg Gynecol Obstet 139:257-266, 1974 Nixon DW, Heymsfield SB, Cohen AE, et al: Protein undernutrition in hospitalized cancer patients. Am J Med 68:683-690, 1980 Warren S: The immediate cause of death in cancer. Am J Med Sci
41. Bistrian BR, Blackburn DL, Scrimshaw NS, et al: Cellular immunity in semistarved states in hospitalized adults. Am J Clin Nutr
43:2070-2076, 1979
25. Lundholm K, Edstron S, Ekman L, et al: Metabolism in peripheral tissues in cancer patients. Cancer Treat Rep 65(suppl):79-83, 1981 26. Brennan M: Cancer cachexia and rate of whole body lipolysis. Metabolism 35:304-310, 1986 27. Waterhouse C, Kemperman JH: Carbohydrate metabolism in subjects with cancer. Cancer Res 31:1273-1278, 1971 28. Edmonson JH: Fatty acid mobilization and glucose metabolism in patients with cancer. Cancer 19:277-280, 1966 29. Waterhouse C: Nutritional disorders in neoplastic diseases. J Chronic Dis 16:637-644, 1963 30. Brennan MF, Burt ME: Nitrogen metabolism in cancer patients. Cancer Treat Rep 65(suppl):67-78, 1981 31. Blackburn GL, Maini BS, Bistrian BR, et al: The effect of cancer
nitrogen, electrolyte and mineral metabolism. Cancer Res
36:3936-3940, 1976 32. Moley JF, Aamodt R, Rumble W, et al: Body cell mass in cancer bearing and anorexic patients. JPEN 11:219-222, 1987 33. Norton JA, Stein TP, Brennan MF: Whole body protein synthesis
fluorouracil in mice. J Natl Cancer Inst 74:705-710, 1985 54. Souchon EA, Copeland EM, Watson P, et al: Intravenous hyperalimentation as an adjunct to cancer chemotherapy with 5-fluorouracil. J Surg Res 19:451-454, 1975 55. Chlebowski RT: Effect of nutritional support on the outcome of antineoplastic therapy. Clin Oncol 5:365-379, 1986 56. Bothe A Jr, Valerio D, Bistrian BR, et al: Randomized control trial of hospital nutritional support during abdominal radiotherapy. JPEN 3:292, 1979 57. Valerio D, Overett L, Malcolm, et al: Nutritional support of cancer patients receiving abdominal and pelvic radiotherapy. Surg Forum
29:145-148, 1978 58. Donaldson SS: Nutritional support therapy. JPEN 8:302-309, 1984
Downloaded from pen.sagepub.com at Glasgow University Library on June 28, 2015
as
an
adjunct
to
radiation
DALY, M.D., KURT HOFFMAN, M.D., MICHAEL LIEBERMAN, M.D., PABLO LEON, M.D., H. P. REDMOND, M.D., JIAN SHOU, M.D., AND MICHAEL H. TOROSIAN, M.D.
From the Division
of Surgical Oncology and
the
Department of Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
a13 proposed that tumor peptides acting through neuroendocrine cells and neuroreceptors alter metabolic pathways. Nakahara9 described a &dquo;toxohormone&dquo; (75,000
Progressive weight loss and malnutrition occurs commonly in cancer patients’-’ and is a major source of morbidity and mortality.’,’ Antineoplastic therapy has a varying impact on the nutritional status of the host, adding to the cachectic state caused by the tumor itself and leading to a more profound nutritional depletion’ and increased morbidity. Malnourished cancer patients should be evaluated prior to initiation of antineoplastic treatment and intervention performed to improve nutritional status. The term &dquo;cancer cachexia&dquo; describes a group of symptoms and signs-inanition, anorexia, weakness, tissue wasting, and organ dysfunction. Cachexia, common in patients with advanced metastatic disease, also occurs in patients with localized disease. DeWys et al3 noted substantial weight loss in 40% of patients with breast cancer and in 80% of patients with gastric or pancreatic carcinoma. The relationship of cachexia to tumor burden, disease stage, and cell type is inconsistent, however, and no single theory satisfactorily explains the cachectic state. A variety of etiologic factors can occur simultaneously or sequentially to produce cachexia. Anorexia is a major contributing factor in the development of the cachectic state. Often, loss of appetite is an important symptom of an underlying neoplasm. Several physiologic derangements have been cited as possible reasons for anorexia. Abnormalities in taste perception, such as reduced threshold for sweetness and for sour and salty flavors, have been demonstrated by DeWys and Walters.’ Deficiencies in zinc and other trace elements may contribute to altered taste sensation. Patients with hepatic metastases accompanied by some degree of hepatic insufficiency may develop anorexia and nausea as a result of difficulty in clearing lactate produced by the tumor’s anaerobic metabolism of glucose. Substances released by the tumor or by the host’s monocytes (cachectin) in response to the tumor may act on the feeding center in the hypothalamus and cause anorexia. Recent studies have demonstrated the presence of cachectin in the plasma of tumor-bearing rodents which correlated with the onset of anorexia. Many studies have been conducted to elucidate the specific metabolic processes that affect nutrient intake in cancer patients. Lucke et al8 noted the presence of a humoral factor that produces in the non-tumor-bearing rat characteristics of the tumor-bearing state. DeWys et
dalton protein) capable of mimicking the cancerous state when injected into normal animals. Rats given cachectin intraperitoneally for 5 days demonstrated decreased dietary intake with a corresponding decline in host body weight.l° When subsequently inoculated with tumor, these rats survived for a significantly longer period than control animals not pretreated with cachectin. Thus, endogenously produced cachectin may be a mediator in the development of cachexia in the tumor-bearing host. Recently, Krause et all’ postulated that abnormalities in the central nervous system metabolism of serotonin may be responsible for the anorexia associated with the tu-
mor-bearing
state.
The local effect of the tumor itself is another factor that may reduce food intake, especially when the tumor arises from or impinges on the alimentary tract. Patients with cancer of the oral cavity, the pharynx, or the esophagus may have reduced intake because of odynophagia or dysphagia. Patients with gastric cancer often have reduced gastric capacity or partial gastric outlet obstruction leading to an early feeling of fullness, nausea, and vomiting. Intestinal tumors may result in partial obstruction or blind-loop syndrome and interfere with nutrient
absorption. Psychologic factors such as depression, grief, or anxiety resulting from the disease or its treatment may lead to poor appetite, abnormal eating behavior, and learned food aversions and thus, a diminished or unbalanced dietary intake. Extensive changes in energy, carbohydrate, lipid, and protein metabolism have been demonstrated in cancer patients.12,13 Increased energy expenditure and inefficient energy utilization are frequently cited causes of malnutrition in tumor-bearing hostS.14,15 Young&dquo; reviewed a number of clinical studies and concluded that resting metabolism was not consistently elevated in cancer patients, though increased resting energy expenditure was noted in leukemia and lymphoma patients. Warnold et ap6 demonstrated that increases in resting metabolic rate paralleled advancing disease and reduced nutrient intake. Shike et all’ demonstrated that basal energy expenditure was elevated in patients with small cell lung carcinoma. In those who responded to chemotherapy, there was a significant decrease in basal energy expenditure while nonresponding patients exhibited no change. In 1983, Knox et all&dquo; measured energy
244S Downloaded from pen.sagepub.com at Glasgow University Library on June 28, 2015
245S and found that only 41 °l of cancer patients had a normal resting energy expenditure while decreased and increased resting energy expenditure was observed in 33% and 26% of patients, respectively. Similarly, Heber et a119°2° found no clear evidence of hypermetabolism in noncachetic lung cancer patients. They argued that since malnourished patients normally decrease basal metabolic rate as an adaptation to starvation, even normal predicted metabolic rates are inappropriately elevated in malnourished cancer patients. Shaw et a121 argued that the alteration in metabolic rate depends on the type of tumor. An elevated rate of energy expenditure was noted in sarcoma-bearing patients and this abnormality was associated with increased Cori cycle activity, glucose turnover, reduced glucose oxidation, and increased protein catabolism. Inefficient energy utilization by the tumor-bearing host may occur because of several mechanisms. Holroyde and Reichard14 reported increased Cori cycle activity in patients with malignancy. This futile cycle in which glucose is converted to lactic acid and subsequently reconverted to glucose by hepatocytes is an energy-wasting process. The highest level of Cori cycle activity was observed in patients with the greatest energy expenditure and weight loss. Young&dquo; has suggested that increased rates of protein turnover also result in significant energy losses. This is due to the failure of normal adaptation to starvation. In noncancer patients, muscle protein breakdown is gradually replaced by fatty acids, which are converted to ketone bodies to be used for energy by peripheral tissues and eventually up to 95% of energy utilization by the brain. This results in decreased glucose utilization with secondary sparing of muscle protein. In cancer patients these adaptive mechanisms do not occur, resulting in increased glucose production and protein catabolism. Although cancer patients have normal levels of circulating insulin and glucose, they have impaired insulin sensitivity. Glucose intolerance is documented by hyperglycemia and delayed clearance of blood glucose in cancer patients after oral or intravenous glucose administration. 14,19,22 Glucose intolerance is, in part, due to decreased tissue sensitivity to insulin but may also involve an attenuated insulin secretion to exogenous glucose. 21,11 Cancer patients also exhibit increased gluconeogenesis from alanine and lactate. Using [14C]alanine, Waterhouse et a124 found that the apparent increased gluconeogenesis from alanine reflected a very rapid glucose turnover. Feedback control of glucose production may be impaired as gluconeogenesis and Cori cycle activity are not inhibited by glucose administration in the cancer
expenditure
found that fatty acids are the major substrates in patients with progressive malignant disease. Increased plasma clearance of fatty acids and exogenously administered fat emulsions in cancer patients have been demonstrated 21-11 in both the fasting and fed states. Frequently, cancer patients fail to suppress lipolysis after glucose administration and continue to oxidize fatty acids. Several abnormalities of protein metabolism occur in cancer patients,30,31 including host nitrogen depletion, decreased muscle protein synthesis, and the occurrence of abnormal plasma aminograms. Nitrogen balance is often negative in patients with progressive malignancy.32 Amino acid trapping by tumor cells has been demonstrated clinically and experimentally. In a study of sarcoma-bearing limbs, Norton et ap3 found that affected limbs released less than 50% of the amount of amino acids released from tumor-free limbs. Evidence obtained with whole body protein studies using [15 N]glycine indicate that cancer patients have increased protein turnover, a circumstance that contributes to increased energy
expenditure.33 Additional changes associated with cachexia include in body composition such as increased extracellular fluid and total body sodium and decreased intracellular fluid and total body potassium. Cohn et aV4 using prompt y-neutron activation to evaluate total body nitrogen and a whole body counter to measure 4°K, found that total body potassium was diminished out of proportion to total body nitrogen. On the basis of this finding they concluded that endogenous nutrient losses in cancer patients were predominantly in the skeletal muscle compartment since muscle comprises 45% of total body nitrogen and 85% of total body potassium. Antineoplastic therapy invariably affects the host, by mechanical and physiologic alterations due to operation or at the cellular level with chemotherapy or radiation therapy.6 Their effects may add to the cachexia of malignancy and result in a more substantial nutritional deficiency. Operative therapy is the primary treatment modality of many cancers, particularly those of the gastrointestinal tract. The immediate metabolic responses to surgery include increased nitrogen losses and energy requirements.35,36 However, because cancer patients tend to have significant weight loss prior to surgery, their ability to cope with stress is impaired, 3-,.:18 resulting in increased morbidity and mortality. The increased catecholamine, glucagon, and cortisone levels result in hy-
changes
permetabolism, weight loss, negative nitrogen balance, and retention of sodium and
water.
Antineoplastic chemotherapy may profoundly alter the
patient.
nutritional state of the host. These effects may be direct
Alterations in lipid metabolism in cancer patients include changes in whole body composition and increased lipid mobilization.25,26 Decreases in total body fat are common among these patients and are most likely related to insulin deficiency. As well as increased lipolysis, there is also increased oxidation of fatty acids. The by-products of lipolysis-glycerol and fatty acids-serve as substrates for gluconeogenesis and energy production, respectively, ‘ during periods of nutrient deprivation. Waterhouse 27
by interfering with host cell metabolism or DNA synthesis and cellular replication or indirect by producing nausea, vomiting, changes in taste sensation, and learned food aversions. Most agents have in common the ability to stimulate the chemoreceptor trigger zone in the brain. resulting in nausea and vomiting. The rapidity of turnover of cells in the mucosa of the alimentary tract makes it especially vulnerable to chemotherapy, resulting in stomatitis, ulceration, and decreased absorptive capacity.
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246S These effects result, in turn, in decreased intake and absorption of nutrients and further predispose the cancer patient to malnutrition. The bone marrow is another organ with a high cell turnover. Toxicity is manifested by anemia, leukopenia, and thrombocytopenia. Neutropenia is, in turn, associated with an increased risk of
sepsis. Radiation therapy may affect the nutritional state of by its effects on the gastrointestinal tract. The severity of the injury is related to the dose of radiation and the volume of tissue treated. The effects of radiation therapy may be classified as early or late. Early effects are transient and are manifested by diarrhea, bleeding,
the host
nausea, vomiting, weight loss, mucositis, xerostomia, alterations in taste, and food aversions. Late effects include intestinal strictures, fistulae, and malabsorption. The clinical relevance of severe malnutrition has been demonstrated by increased morbidity and mortality and poor treatment tolerance in malnourished, tumor-bearing individuals.4,5,39 In 1932, Warren4° found that malnutrition was a major contributing factor to death in cancer patients. The protein-calorie malnutrition produced by the cancer-bearing state leads not only to obvious weight loss, but also to visceral and somatic protein depletion resulting in compromise of enzymatic, structural, and mechanical functions. Impairment of
immunocompetence4u42
and increased susceptibility to infection frequently result. The effect on immune function may be further exacerbated by chemotherapy.43 Moreover, poor wound healing, increased wound infections, prolonged postoperative ileus, and longer hospital stay have all been linked to poor nutritional status in cancer patients. Meguid et a144 demonstrated that in patients undergoing colorectal cancer operations, the return to adequate oral food intake was significantly delayed in patients classified as malnourished based on preoperative assessment. In that study the morbidity and mortality in malnourished patients was 52% and 12%, respectively, compared with 31% and 6% in well-nourished patients. In animal studies, both humoral and cellular immune responses are depressed with severe protein restriction. In 1978, Daly et a142 demonstrated that only 30% of tumor-bearing rats had a delayed hypersensitivity response to intradermal purified protein derivative after 2 weeks on an oral, protein-free diet. Protein repletion with 7 days of total parenteral nutrition (TPN) or oral ad libitum feeding restored the immune response in 91% and 78% of rats, respectively. In 1974, Law et al38 found reduced titers of antibodies, IgM-producing cells, reduced lymphocyte response to mitogens, and decreased delayed hypersensitivity in rats after 6 weeks on protein-free nutrition. In patient studies, there is evidence of increased morbidity and mortality associated with depressed immunocompetence. Harvey et a14~ reported on a group of 161 cancer
32
patients receiving nutritional support. Of these, anergic prior to therapy. In 27 of these patients
were
anergy was reversed and three of this group died. Of the five patients who remained anergic, all died. Daly et al4s found that 51 % of anergic patients undergoing cancer
treatment had restoration of skin test sponse to TPN.
reactivity in
re-
Sixteen randomized, prospective trials have evaluated the effects of preoperative TPN on clinical outcome in cancer patients. In 1987, Detsky et al 17 reviewed 14 trials utilizing meta-analysis techniques to evaluate their results. They concluded that &dquo;routine use of perioperative TPN in unselected patients having major surgery is not justified, however, this intervention may be helpful in subgroups of these patients who are at high risk.&dquo; Based upon these previous reports and those subsequently published, there is common agreement that perioperative TPN should be utilized in certain subgroups of patients who may benefit. In 1979, Heatley et a148 studied 74 gastric cancer patients who either received preoperative TPN for 7-10 days or served as controls. TPN patients had fewer wound infections and lost less body weight perioperatively than corresponding control patients. Muller et a149 studied 125 patients with gastrointestinal cancer who were randomized to receive 10 days of pre66) or standard diet (n operative TPN (n 59). Postoperative major morbidity and mortality were significantly lower in the TPN group. Muller et al reported an extension of their work which included three groups: control, TPN (amino acids/glucose), and TPN (amino acids/glucose/lipid emulsion) patients. Significant differences were noted for weight change and increased protein and immune parameters as well as major complications and mortality comparing the TPN (amino acid/glucose) patients and controls. The trial was changed before completion by stopping the TPN (amino acids/glucose/lipid emulsion) group because of greater complications in this group. Studies by Starker et al50 and Bellantone et a151 included patients with benign and malignant disease. In the former study, 59 malnourished patients were divided into three groups based on initial response to TPN. 50 Patients received TPN for a period ranging from 5 days to 6 weeks. The authors noted a high morbidity and mortality in those patients who remained hypoalbuminemic after 1 week of TPN. Their data suggest that a prolonged period of TPN decreased postoperative complications. This observation suggests the importance of administering preoperative TPN until nutritional deficits have been corrected. Foschi et all studied 64 patients who underwent preoperative catheter biliary division for obstructive jaundice with or without preoperative TPN. The nutritionally repleted group had significantly fewer major complications (18% us 47%) and mortality (3.5% vs. 12.5%) compared with control =
=
patients. A multi-institutional prospective randomized trial evaluating TPN in surgical patients has been completed (Buzby, GP, personal communication). Two hundred thirty-one TPN and 228 control patients were studied. Mortality rates and major complications were similar for both groups. A higher incidence of infectious complications was noted in the TPN group while a higher noninfectious complication rate occurred in controls. In the subgroup of patients with severe malnutrition, measured by subjective global assessment and nutritional index,
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247S TPN significantly reduced overall major complications from 47% to 21%-26%. In summary, clinical trials of perioperative TPN in cancer patients have demonstrated improved nutritional status as reflected by gain in body weight and improvement in serum protein levels, immune function, and nitrogen balance. Effects on clinical outcome remain less well defined. Preoperative TPN has resulted in a significant reduction in postoperative complications and reduced mortality, in the severely malnourished high-risk
preoperative
group, when TPN is administered for an adequate length of time. Failure to demonstrate improved outcome with TPN in other trials may accurately reflect the limited value of TPN. It is also possible that in these patients, the complications associated with TPN and the increased risk of nosocomial infections due to an increased duration of hospitalization may negate any benefit and may result in net harm. In severely malnourished patients
undergoing high-risk major operative procedures,
those modalities of treatment. Animal studies indicate that protein depletion increases toxicity and lethality of chemotherapy.53 Furthermore, TPN or increased dietary protein reduces toxicity in animals compared with those fed regular or protein-depleted diets.54 In the 1970s clinical reviews correlated malnutrition with a poor prognosis in patients with metastatic disease receiving chemotherapy. This suggested that nutritional support would increase therapeutic benefit and many trials using TPN as adjunctive therapy were initiated. Chlebowski55 reviewed recent randomized trials and found no clear evidence that TPN alleviated chemotherapy-related toxicity or enhanced tumor response in humans (Table I). Although randomized trials have failed to demonstrate an adjunctive role for TPN or a reduction in side effects, nutritional therapy is an important supportive measure. cancer
patients who
are otherwise not because of inanition to undergo continuing chemotherapy and potentially achieved disease remission. Some workers have demonstrated reduced mortalitv and increased tumor response rates in patients receiving extensive radiation therapy with adjunctive TPN compared with patients not receiving nutritional support. 5 t3. -i However, these studies were carried out in small groups of patients. Donaldson58 reviewed these and other prospective trials in 1984 and failed to show that nutritional support reduced the complication rates or improved local cancer control and survival. This suggests that TPN or enteral feedings are important support measures in patients undergoing a planned course of radiation therapy but do not sensitize the tumor to irradiation or prevent gastrointestinal side effects.
permit
candidates for
some
treatment
pre-
operative TPN appears to have a beneficial role. A narrow margin of therapeutic safety exists for chemotherapeutic drugs and adequate levels of radiation therapy and cachexia may reduce the therapeutic index of
TABLE I Randomized trials of TPN and chemotherapy in
It may
patients
CONCLUSION
Cancer patients are frequently malnourished at the time of diagnosis. These patients develop anorexia and reduced nutritional intake. Specific abnormalities in substrate metabolism and energy expenditure have been detected in patients and in tumor-bearing animals. Protein catabolism, increased lipolysis, and glucose availability help to create a milieu favorable to tumor growth at the expense of the host. There is evidence that the tumor effects these changes through neurohumoral mechanisms. There is little doubt that malnutrition associated with cancer has a negative prognostic effect and can contribute directly to the demise of the patient as well as increase postoperative morbidity and decrease the tumor response and patient tolerance to all modalities of treatment. Nutritional therapy is an important supportive measure for the patient undergoing antineoplastic treatment. It increases the well-being of the patient and may permit the administration of more intensive therapies. There is no conclusive evidence that adequate nutritional support preferentially feeds the tumor and results in increased tumor growth in humans. There is good evidence that effective nutritional repletion can reduce postoperative complications and mortality rates after surgery in severely malnourished patients. Weight gain is possible and immune status may be improved but definite improvement in tumor response rates and patient survival following chemotherapy or radiotherapy remains unproven.
Modified from Chlebowski.55 NED, no evidence of disease. * Trials suggesting adverse effect of TPN to chemotherapy.
In the future, more specific manipulation of substrates and hormones administered to the host may provide improved results. Clinical trials of arginine supplementation to enteral feeding hale shown rapid return of lymphocyte proliferation to normal following operation. Use of glutamine supplementation in TPN may reduce the stomatitis and enteritis associated with multidrug chemotherapy. Finally, use of growth hormone or tumor necrosis factor antibodies may beneficially affect the metabolism of endogenous and exogenous substrates.
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248S on
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as
an
adjunct
to
radiation
