Introduction
Loss of weight and appetite predict a poor prognosis for cancer patients. In an 1811 treatise, John Abernathy described a patient with a tumor, "which made him look very sickly and grow very thin, and caused some persons to deem the disease cancerous."[1] Abernathy went on to say that "the derangement of the constitution was as violent as the local disease, and in about a week, the patient died."
Spurred by such early observations, DeWys and others formally analyzed the impact of weight loss on cancer prognosis.[2] In a multi-institutional, retrospective, Eastern Cooperative Oncology Group evaluation of 3,047 patients from 12 different clinical trials, these investigators found that loss of more than 5% of premorbid weight predicted a poor prognosis for cancer patients. Independent of tumor stage, tumor histology, and patient performance status, this weight loss not only predicted a poor outcome but was associated with a trend toward lower chemotherapy response rates.
Along similar lines, Chang recently reviewed the prognostic effect of various cancer symptoms.[3] He summarized studies showing that loss of appetite also predicts a poor outcome for cancer patients. Taken together, these three publications demonstrate a strong association between cancer-associated anorexia/weight loss and an early demise.
Couple these prognostic data with the observation that cancer-associated anorexia and weight loss are highly prevalent, and the magnitude of the problem enlarges. Tchekmedyian and others examined the prevalence of cancer-associated weight loss and anorexia in an ambulatory oncology setting.[4] Among 644 consecutive patients, evidence of diminished appetite, compromised oral intake, or weight loss greater than 5% of premorbid weight occurred in more than half of patients. Additionally, 54% of patients were underweight in direct comparisons between patients’ actual weight and calculated ideal weight. These prevalence rates are likely to be even higher among nonambulatory cancer patients in the late stages of advanced disease. In short, cancer-associated anorexia and weight loss are common and carry a notable adverse prognostic impact.
Treatment Options
Almost 200 years after Abernathy’s description of his patient with a "derangement of the constitution," weight loss continues to plague cancer patients. Yet, treatment has yielded only modest success. Clinical efforts have primarily focused on energy repletion by means of either a direct increase in caloric intake or mitigation of anorexia. Only more recently have treatment efforts targeted maintenance of lean tissue. Below, we summarize treatment approaches for cancer-associated weight loss and anorexia and the rationale for their use, as they pertain to (1) caloric supplementation, (2) orexigenic agents, and (3) agents targeted at maintenance of lean tissue.
Role of Caloric Supplementation
At first glance, caloric repletion seems the optimal approach to the treatment of cancer-associated weight loss. After all, since weight loss is the result of an energy deficit, an increase in caloric intake would appear to tilt the scales in favor of weight stability and, thereby, generate clinical benefit for cancer patients. Studies have suggested, however, that increased caloric intake might help cancer patients in only a few specific circumstances: (1) perioperatively, (2) in the setting of stem cell or bone marrow transplantation, and (3) during treatment for head and neck cancer.
The data to support these indications are discussed below (Table 1). Otherwise, caloric supplementation either has not been tested or has proven to be detrimental.
Perioperative Nutritional Support: First, two studies suggest perioperative nutritional support benefits patients prior to major surgery, counterbalanced by one recent meta-analysis on total parenteral nutrition in general. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group trial examined 395 malnourished patients who were randomized to receive no fewer than 7 days of standard preoperative total parenteral nutrition vs no nutritional supplementation.[5] All patients were considered surgical candidates prior to study enrollment, and 65% had cancer.
Within this study, the 24 patients who were considered severely malnourished, as suggested by low scores on the Nutrition Risk Index, appeared to benefit from perioperative nutritional support. These patients manifested fewer noninfectious complications—such as anastomotic leak, bronchopleural fistula, and others—when compared to severely malnourished patients who did not receive nutritional support. Such benefits were not observed among patients with mild or moderate malnutrition.
Similarly, in the second trial, Fan et al evaluated 124 malnourished patients with hepatocellular carcinoma prior to surgery.[6] Many of these patients were only mildly malnourished, with only 20% having sustained a loss of > 10% of their premorbid weight. In this placebo-controlled, randomized trial, patients who received total parenteral nutrition sustained an overall reduction in postoperative morbidity. There was also a reduction in the use of diuretics in the postoperative setting. Although neither of these studies showed a survival advantage with total parenteral nutrition, they did demonstrate a decrease in morbidity.
In contrast to these two studies, a recent meta-analysis, which included 26 randomized trials and a total of 2,211 patients, concluded that the use of total parenteral nutrition in surgical or critically ill patients did not improve mortality or complication rates.[7] Although not all studies in this meta-analysis included cancer patients, the comprehensiveness of the analysis and the fact that some cancer patients were included suggest that the use of total parenteral nutrition for cancer patients perioperatively should be weighed carefully prior to implementation.
Taken together, these data support caloric supplementation in the perioperative setting among cancer patients with severe malnutrition or in patients with a potentially resectable hepatocellular carcinoma, although such recommendations remain controversial.
Enteral and Parenteral Nutrition: Secondly, nutritional supplementation potentially helps patients in the setting of stem cell rescue after high-dose chemotherapy. Both enteral and parenteral nutrition appear to be beneficial.
In one of the earliest and largest studies examining total parenteral nutrition in the transplant setting, Weisdorf et al evaluated 137 patients who were well nourished at the initiation of their transplant procedure.[8] The majority of these patients (93%) had been diagnosed with cancer, predominantly leukemia. After stratification on the basis of age and type of transplant (autologous vs allogeneic), patients were randomized to receive either total parenteral nutrition or intravenous fluids with 5% dextrose(Drug information on dextrose), electrolytes, minerals, trace elements, vitamins, and no lipids. Both treatment arms were initiated prophylactically—ie, prior to patients showing evidence of malnutrition. Because a decline in nutritional status became evident during the clinical course of these patients, 61% in the control arm crossed over to the total parenteral nutrition arm.
In a direct comparison of the two study arms, overall survival, time to cancer relapse, and disease-free survival were significantly improved in the total parenteral nutrition arm. In contrast, the incidence of graft-vs-host disease, time to engraftment, and time to bacteremia were not significantly different between the two arms. In effect, this study suggests that total parenteral nutrition confers some benefit in this setting when administered prophylactically.
Head and Neck Cancer: Thirdly, studies in patients with head and neck cancer also suggest a role for nutritional supplementation, although these studies are far less compelling than the studies cited above. In one preliminary trial, 40 patients with inoperable nasopharyngeal or oropharyngeal squamous cell carcinoma were randomized to receive either oral nutrition or intensive nasogastric tube feedings during radiation treatment.[9] The latter provided more calories.
Although no statistical differences were observed between the two groups with respect to tumor response rates or survival, a slightly greater percentage of patients who received the tube feedings—8 of 13 tube-fed patients vs 5 of 11 orally fed patients—returned to their regular activities after a 6-month follow up period. These data might be viewed as exploratory in nature, but they nevertheless suggest that aggressive oral nutrition might confer clinical benefit to head and neck cancer patients during aggressive therapy.
Similarly, another randomized trial by Nayel and others found that aggressive oral feeding resulted in completion of radiation without interruption in 11 of 11 patients who received it. In contrast, radiation therapy was interrupted in 5 of 12 patients who did not receive aggressive oral feeding.[10] These data suggest that aggressive feeding might provide short- and long-term benefits to head and neck cancer patients.
Advanced Cancer: In contrast to the specific clinical indications sited above, trials in chemotherapy patients with advanced cancer have not demonstrated favorable outcomes with aggressive caloric supplementation. In one such study, Ovesen et al evaluated 105 cancer patients who were receiving chemotherapy.[11] Patients were randomized to either nutritional counseling or no nutritional counseling. Although the former group consumed significantly more calories than the latter group, tumor response rates, patient survival, and quality of life did not differ significantly between the two groups.
Several clinical trials in which patients with advanced cancer received total parenteral nutrition also failed to demonstrate a favorable impact of nutritional supplementation. Some of these studies actually noted increased rates of infection or other detrimental effects with the use of total parenteral nutrition.
Recommendations: In 1989, a review of these studies led to a consensus statement from the American College of Physicians (ACP) on total parenteral nutrition in cancer patients receiving chemotherapy.[12] More than 10 years later, the ACP has not revised their original statement:
The routine use of parenteral nutrition for patients undergoing chemotherapy should be strongly discouraged, and, in deciding to use such therapy in individual patients whose malnutrition is judged to be life threatening, physicians should take into account the possible exposure to increased risk.
How do we reconcile the results of the foregoing studies, some of which suggest clinical benefits with nutritional supplementation in cancer patients, and others of which do not? Moreover, since not all groups of cancer patients have been formally studied with respect to implementation of adjunctive nutritional therapy, how do we decide when to use such supportive measures and when not to?
Two empiric guidelines, derived from the studies cited above, might help answer these questions. Cancer patients who seem to benefit from caloric supplementation fall into both of the following categories: (1) patients who are either notably malnourished or at risk of becoming so during cancer treatment; and (2) patients who have potentially curable disease or look forward to the promise of a long disease-free period after cancer treatment.
In summary, reasonable justification can be found for administering adjunctive nutritional therapy to cancer patients prior to an attempt at resecting the primary tumor, prophylactically during stem cell or bone marrow transplantation, and during radiation treatment for head and neck cancer. With malignancies such as potentially curative locally advanced esophageal cancer treated with concomitant chemotherapy and radiation, the use of adjunctive nutritional therapy remains of speculative value and must be decided on a case-by-case basis. In contrast, little justification exists for the use of adjunctive nutritional treatment, such as total parenteral nutrition, in patients receiving chemotherapy for advanced cancer.
