Journal of Parenteral and Enteral Nutrition

There is, at present, considerable interest in the possible role for the proinflammatory cytokines, tumor necrosis factor-α, interleukin-1, interleukin-6, and interferon-γ in the pathogenesis of cancer cachexia. Indirect evidence for such a role is based on the observation that chronic administration of many of these cytokines, either alone or in combination, can reproduce the myriad of host responses seen in experimental and human cancer cachexia. Elevated plasma levels of tumor necrosis factor-α, interleukin-1, and inteferon-γ have rarely been detected in patients or experimental animals with cancer, although interleukin-6 levels appear to correlate with tumor progression in animal models. The strongest evidence for a causal role for cytokines has come from rodent studies in which tumor-bearing animals have been passively immunized with antibodies directed against individual cytokines. Several groups have shown modest but significant improvements in food intake and lean tissue retention with antibodies directed against tumor necrosis factor-α, interleukin-1, interleukin-6, and interferon-γ. However, there has been no consistent finding that one cytokine is universally involved in cancer cachexia in histologically distinct tumor models. One ominous finding in several tumor models has been that the endogenous production of cytokines appears to support tumor growth. Such findings raise the intriguing possibility that these cytokines, although contributors to tissue wasting and anorexia, may also serve the tumor as either direct or indirect cell growth factors. We conclude, however, that because of redundancy in the cytokine network and differential cytokine production in histologically distinct tumors, efforts to block the development of cancer cachexia with anticytokine therapies will require the inhibition of several proinflammatory cytokines simultaneously. (Journal of Parenteral and Enteral Nutrition16:43S-49S, 1992)

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-γ and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment. (Journal of Parenteral and Enteral Nutrition16:50S-55S)

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10 6 methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia. (Journal of Parenteral and Enteral Nutrition 16:56S-59S, 1992)

Many common metastatic cancers are associated with marked weight loss at the time of diagnosis. Anorexia clearly plays a major role in weight loss in the cancer patient, but cannot explain all of the weight loss noted. Malnourished patients with localized cancers under metabolic ward conditions fail to gain weight when given apparently adequate calories for anabolism, thus suggesting that these patients are hypermetabolic. Increased whole body protein breakdown, increased lipolysis, and increased gluconeogenesis have been repeatedly demonstrated in malnourished cancer patients. Protein and glucose metabolism are closely linked, and both are regulated by a number of the same hormones and metabolites. For example, when increased glucose production in malnourished cancer patients is inhibited pharmacologically, protein catabolism is proportionally decreased. Studies of glucose, growth hormone, cortisol, and insulin secretion following an oral glucose load in well-nourished cancer patients are consistent with insulin resistance but no other hormonal abnormalities. Malnourished cancer patients have elevated levels of growth hormone that are further stimulated by arginine and insulin infusion. No abnormalities of thyroid function were noted in cancer patients. Current studies are underway to determine the mechanisms and effects of progestational steroids and cytokines on both food intake and intermediary lipid metabolism. (Journal of Parenteral and Enteral Nutrition 16:60S-64S, 1992)

The goal of this investigation was to identify the metabolic abnormalities in a group of colon cancer patients before and during 5-fluorouracil chemotherapy. Twenty-two colon cancer patients were prospectively enrolled into a Clinical Research Center for measurement of counter regulatory hormones, fasting hepatic glucose production (HGP), intravenous glucose tolerance test, plasma leucine appearance (LA), and leucine oxidation (LO). Both the cancer group and the normal volunteers were matched for nutrition status (109 ± 5% of ideal body weight us 104 ± 4%, mean ± SEM, respectively) and history of weight loss (6.3 ± 2.6 kg vs 4.4 ± 4.8). Plasma growth hormone was significantly elevated in the colon cancer patients (3.22 ± 0.62 ng/mL us 0.73 ± 0.18, p < .05) despite the fact that insulin-like growth factor-1 levels were not different. Plasma glucose, insulin, cortisol, glucagon, epinephrine, and norepinephrine levels were not significantly different than those of the normal volunteers. Fasting HGP rates were slightly but not significantly elevated in the group of colon cancer patients compared with the normal volunteers (2.09 ± 0.11 mg/kg per minute us 1.79 ± 0.10, p = .10). Plasma LA was not significantly elevated in the colon cancer group (63.3 ± 3.0 μmol/kg per hour vs 57.7 ± 4.2; p = .25). Five days of continuous 5-fluorouracil chemotherapy was associated with a significant elevation in both the fasting glucose level (97 ± 3 mg/dL vs 106 ± 5, p < .05), and HGP (2.09 ± 0.11 mg/kg per minute us 2.27 ± 0.10; p < .05). The increased fasting glucose value was associated with an increase in the insulin response to the intravenous glucose tolerance test. LA was not affected by the chemotherapy infusion (63.3 ± 3.0 μmol/kg per hour us 58.4 ± 3.0). In contrast, LO was significantly increased (11.5 ± 1.1 μmol/kg per hour us 13.0 ± 1.0, p < .05) and leucine incorporation into protein was significantly decreased (51.2 ± 2.7 μmol/kg per hour us 45.4 ± 2.7, p < .05) while the patients received chemotherapy. Evaluating all the the counter-regulatory hormone measurements demonstrated a significant correlation between the mean HGP and growth hormone levels (r = .446; p < .05). Twenty-four-hour growth hormone pulse frequency in a patient with diffuse carcinoma was 2.5 times the normal rate compared with a sex-and weight-matched normal volunteer. The HGP rate was increased from 1.7 mg/kg per minute to 2.12 mg/kg per minute in the cancer patient. Further work is in progress to identify the possible association between growth hormone physiology and the elevation in fasting HGP observed in cancer patients. (Journal of Parenteral and Enteral Nutrition 16:675-71S)

Controversy exists regarding the use of nutrition support in the cancer patient. Although nutrition support can clearly improve host nutritional status and restore immunoconfidence, the efficacy of nutrition support to reduce morbidity and mortality associated with antineoplastic therapy is questionable. A potential concern with the use of nutrition support in the tumor-bearing host is stimulation of primary tumor growth and metastasis. Numerous animal studies clearly demonstrate that oral and parenteral nutrition can significantly stimulate tumor cell proliferation and distant metastasis. Although cellular kinetic studies in humans have shown alterations after parenteral nutrition, objective measures of tumor growth, metastasis and tumor protein synthesis have not been affected by parenteral nutrition. This chapter summarizes the research and clinical work regarding the effect of nutrients on tumorigenesis, primary tumor growth, and metastasis in both animal and human tumors. ( Journal of Parenteral and Enteral Nutrition16:72S-75S)

The notion that tumors act as "nitrogen traps" has led to the belief that nutrition support of the cancer-bearing patient can enhance tumor growth. Proponents of this theory consider the provision of energy and essential nutrients as well as the influence of hormones and growth factors as responsible for this effect. On the other hand, nutrition administration in the debilitated cancer patient may improve antitumor host defense mechanisms and reduce tumor growth. This paper reviews methodologic issues related to the study of nutrition and cancer growth with emphasis on in vivo methods for measuring tumor protein turnover and cytokinetics. Using this combined approach, we previously demonstrated that dietary fat may significantly regulate tumor growth during chronic feeding as well as with short-term intravenous nutrition support in experimental models. Although the mechanism of this effect remains unclear, we have reasoned that by altering arachidonic acid metabolism and prostaglandin synthesis, ω-3 fatty acids could change tumor protein breakdown rates and inhibit the proliferation potential of these tumors. Acknowledging alternative hypotheses, we now present cytokinetic evidence that intracellular protein degradation may regulate tumor cell proliferation. Additional studies relating dietary fat, tumor protein metabolism and tumor proliferation potential are currently in progress. We propose that the effect of nutrition administration on tumor growth is complex and involves several regulatory systems. Thus, based on available evidence, an a priori tumor-enhancing effect for nutrition support is clearly not warranted. Intracellular protein breakdown and host defense mechanisms, both of which are energy dependent, are important loci at which nutrition and tumor growth regulation could interact. Results from experimental tumor models have indicated that specific dietary fats, such as fish oil and structured lipids, may be used favorably in the nutrition support of the cancer patient. (Journal of Parenteral and Enteral Nutrition16:76S-82S, 1992)

Dose intensification of chemotherapy is thought to increase survival. With recent advances in hemopoietic cell modulators such as granulocyte colony stimulating factor, the limiting toxicity of intensifying chemotherapeutic regimens has become the severity of the associated enterocolitis. In animal models, glutamine protects the host from methotrexate-induced enterocolitis. This study evaluates the effects of a glutamine-supplemented diet on the tumoricidal effectiveness of methotrexate. Sarcoma-bearing Fisher 344 rats (n = 30) were pair-fed an isocaloric elemental diet containing 1% glutamine or an isonitrogenous amount of glycine beginning on day 25 of the study. Rats from each group received two intraperitoneal injections of methotrexate (5 mg/kg) or saline on days 26 and 33 of the study. On day 40, rats were killed, tumor volume and weight were recorded, and tumor glutaminase activity and tumor morphometrics were measured. Blood was taken for arterial glutamine content, complete blood count, and blood culture. The gut was processed for glutaminase activity and synthesis phase of the deoxyribonucleic acid. In rats receiving methotrexate, the tumor volume loss was nearly doubled when glutamine was added to the diet. Significant differences in tumor glutaminase activity and morphometrics were not detected. The toxicity to the host was ameliorated. Significantly increased synthesis phase of deoxyribonucleic acid of the whole jejunum, decreased bacteremia, "sepsis," and mortality were demonstrated. Glutamine supplementation enhances the tumoricidal effectiveness of methotrexate while reducing its morbidity and mortality in this sarcoma rat model. (Journal of Parenteral and Enteral Nutrition16:83S-87S, 1992)

The endpoints used as outcome variables in clinical cancer treatment trials, including nutrition intervention studies, should contain items that are meaningful to the patient. Variables to consider are appetite, food intake, physical performance, psychological and social functioning, response to cancer therapies, survival time, nutrition status, associated morbidity, and costs. Ideally, the design and conduct of nutrition trials should be carried out by a multidisciplinary team comprising medical oncologists, physician specialists in nutrition, dietitians, and social scientists. Anorexia has not been a focus of nutrition support trials in the past partly because of the lack of effective strategies to reverse it. Anorexia is one important cause of cancer starvation, and it also causes patient discomfort. This paper describes outcome variables that include patient derived subjective factors such as anorexia, and outlines new strategies to reverse anorexia. Pharmacologic strategies tested to reverse anorexia include corticosteroids, anabolic steroids, cyproheptadine, hydrazine sulfate, cannabinoids, and megestrol acetate. Of these, only the latter has been consistently well tolerated and effective, with significant improvements in appetite and food intake demonstrated in large-scale, randomized, controlled trials involving more than 600 cancer patients. Dose-response studies have demonstrated increasing efficacy with increasing doses of megestrol acetate from 160 to 800 mg/day. Doses in excess of 800 mg/day are not currently recommended. The mechanisms of action of megestrol acetate involve both behavioral and metabolic effects, and its impact on energy expenditure, appetite, body composition, endocrine function, and lipid metabolism is the subject of ongoing research. Such effects as well as new information on the role of various cytokines provide opportunities to test new therapies to renourish the cancer patient not by way of forced feeding, but by reversing the systemic effects of malignancies that impair renutrition. (Journal of Parenteral and Enteral Nutrition16:885-925, 1992)

The clinical outcome for 1362 patients with active cancer managed on home parenteral nutrition (HPN) is compared with that of 122 patients with radiation enteritis ("cured" cancer) and 416 patients with Crohn's disease. This longitudinal clinical information was reported to the North American Home Parenteral and Enteral Nutrition Registry (Oley Foundation/A.S.P.E.N. joint project) between 1985 and 1989. The data shows that the number of active cancer patients on this therapy is increasing 13% per year. The annual survival rate is 25% for patients with active cancer, as compared with 88% for patients with radiation enteritis and 95% for patients with Crohn's disease. Although 50% of all active cancer patients starting HPN are dead within 6 to 9 months, the prognosis is somewhat better in children, and 20% of these active cancer patients appear to do well, returning to full oral nutrition and experiencing complete rehabilitation. These are presumed to be patients with a potentially curable cancer requiring super-aggressive treatment, which causes temporary severe gastrointestinal dysfunction. Adult active cancer patients have the same rehospitalization rate for HPN complications (once per year) as radiation enteritis and Crohn's disease patients. However, their rehospitalization rate for non-HPN complications is four times higher. This article reviews the factors that may explain the growth of HPN in active cancer patients and discusses some of the unanswered clinical questions that urgently need to be addressed to more effectively determine the appropriateness or inappropriateness of HPN management in the active cancer setting. (Journal of Parenteral and Enteral Nutrition16:93S-99S, 1992)

Cancer patients have the highest incidence of protein-calorie malnutrition seen in hospitalized patients, with significant malnutrition occurring in more than 30% of cancer patients undergoing major upper gastrointestinal procedures. Clinically significant malnutrition occurs as a result of diminished nutrient intake, increased nutrient losses, and tumor-induced derangements in host metabolism. In the absence of adequate exogenous nutrients, the body utilizes endogenous substrates to satisfy the ongoing requirements of both host and tumor for energy and protein. In those patients with malignant obstruction of the gastrointestinal tract, the tumor itself may induce diminished nutrient intake. Present day treatment modalities including gastrointestinal resection, chemotherapy, and radiotherapy compound these metabolic derangements, further increasing the risk of postoperative morbidity and death. The presence of malnutrition in cancer patients has prognostic importance. In a review of more than 3000 cancer patients, DeWys and colleagues identified significantly improved survival in those patients without weight loss compared with those had lost 6% of their body weight (Am J Med 69:491-497, 1980). Other investigators have noted increased postoperative morbidity and mortality associated with malnutrition. Early hypotheses suggested that reversal of weight loss would improve survival. The development and refinements of enteral and parenteral nutrition have provided the opportunity for studying the relationship between nutritional supplementation and postoperative prognosis. Nutrition support is therefore often instituted to improve nutritional status and thereby reduce the risks of postoperative complications. This article addresses the beneficial role of preoperative nutrition therapy in cancer patients. (Journal of Parenteral and Enteral Nutrition16:100S-105S, 1992)

Nutrition interventions with cancer patients may produce benefits beyond those typically evaluated, such as increased appetite, food intake, and weight gain. Other benefits include enhanced mood, improved sense of well-being, and increased socialization because of an increased ability to eat in public or with family. Along with the target benefits of nutrition interventions, these "untargeted" benefits have come to be clustered under the general rubric of health-related quality of life. All medical treatments, including nutrition interventions, can be evaluated in terms of their total effect upon health-related quality of life. However, demonstrating health outcome benefits of nutrition interventions can be very difficult. This difficulty is at two levels: conceptual and practical. Conceptual difficulties can be overcome by refining and clarifying the definition and measurement of health-related quality of life. Practical difficulties are more diverse and must be tackled on a point-by-point basis, depending upon the unique characteristics of the disease being treated, the intervention being tested, and the context of the trial. This paper offers some guidelines and recommendations for overcoming many of the more commonly confronted barriers to successful demonstration of health outcome benefits from clinical nutrition trials with cancer patients. (Journal of Parenteral and Enteral Nutrition16:106S-111S, 1992)

Many studies have assessed the benefits of nutrition support in cancer patients. Except for studies directed at the treatment of severe malnutrition, most clinical trials have failed. Although prospective randomized controlled clinical trials (Phase III) remain the most reliable means of evaluating the efficacy of therapy, the available literature reports only results from small trials (Phase II to III), most of which appear to be contradictory and none of which conclusively answer the question being considered. To address this gap in knowledge, tools such as meta-analysis have been adapted from the field of statistics. Meta-analysis involves pooling results across several studies and provides a more precise estimate of treatment effect than can each individual study. However, clinical trials selected for meta-analysis, although broadly similar, can differ significantly in terms of therapies used and clinical populations studied. Major cancer types with differing effects on food intake and malnutrition (eg, the mechanical obstruction in head and neck cancer vs the cytokine-induced metastases associated with lung, ovarian, colon, and breast cancer) cannot be subject to the same analytic criteria. In this paper, the current state of clinical outcome trials in nutrition and cancer is examined, and the desired design for future studies is proposed. Research priorities include the conduct of Phase II clinical trials that use as outcome measures quality of life, performance status, and survival to identify optimal cancer-specific and patient-specific nutrition support. The next round of Phase III efficacy studies should establish the appropriate use of nutrition support in cancer therapy. (Journal of Parenteral and Enteral Nutrition16: 112S-116S, 1992)