Cancer Cachexia

Definitions and Epidemiology

This chapter specifically focuses on patients with incurable, treatment-refractory metastatic cancer. These distinctions of incurability and refractory disease are important. First, previous studies have shown that in the setting of potentially curable cancer, severe malnutrition can be treated with nutrition support with improvement in outcomes. However, such is not the case in patients with incurable disease. Although this latter group of patients may appear “malnourished,” caloric repletion clearly does not lead to improved outcomes and in fact leads to a variety of complications that arise directly from implementing nutrition support. Indeed, as far back as 1989 the American College of Physicians provided a position paper on parenteral nutrition in cancer patients who are receiving chemotherapy; this paper stated, “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.”

To our knowledge, this position statement has not been revised, emphasizing ongoing concerns for providing nutrition support to cancer patients who are at or near the end of life. Baldwin and colleagues conducted a systematic review and meta-analysis that included 13 randomized, controlled studies with 1414 patients with cancer in an effort to assess the role of oral nutritional supplementation. Although enteral nutrition appeared to have beneficial effects on some aspects of quality of life (e.g., emotional functioning, dyspnea, loss of appetite, and global quality of life), it had no effect on mortality (relative risk, 1.06; 95% confidence interval [CI], 0.92–1.22; P = .43; I ² = 0%; P (heterogeneity) = .56). As noted, the studies within this meta-analysis were fraught with clinical and statistical heterogeneity, but nonetheless these investigators concluded that cachectic patients with cancer or those at risk for cachexia do not appear to gain a survival advantage with oral nutritional support. Once again, the fact that these patients with advanced cancer may appear “malnourished” does not translate into clear benefit from increased calories.

Second, tumor response is often associated with symptom improvement. Geels and colleagues showed that among patients with metastatic breast cancer, a higher proportion (91.7%) with a complete or partial response manifested an improvement in anorexia and that none of the patients with a complete response or partial response described a worsening of appetite. Although these results did not reach statistical significance, they point to a phenomenon to which many oncologists can readily attest: tumor response leads to improvements in baseline symptoms in many patients with cancer. Hence this chapter focuses on a commonly seen group of cancer patients who are cachectic and who experience symptoms and signs that are refractory to cancer treatment and caloric repletion.

From an epidemiologic standpoint, is cachexia truly a concern for patients, their families, and health care providers? A classic article from the Eastern Cooperative Oncology Group demonstrates that it is. Dewys and colleagues used prospectively gathered data from 12 cancer cooperative group trials that included more than 3000 patients and showed that weight loss of more than 5% was a powerful predictor of early demise in both univariate and multivariate analyses. Examining body mass index (BMI) in over 21,000 patients who received first-line chemotherapy for metastatic colorectal cancer, Renfro and others showed that low BMI was associated with worse progression-free survival and overall survival with an L -shaped risk pattern that emerged as the BMI approached 28 kg/m ² . Put simply, patients with a BMI of 18.5 kg/m ² had a 50% greater risk of death compared with obese patients. Finally, emphasizing the importance of lean tissue, Martin and others examined cross-sectional muscle on computed tomography (CT) scans at the third lumbar vertebra in over 1400 patients with cancer. Those patients who manifested myopenia, as determined by a skeletal muscle index, had a hazard ratio of death of 1.34 (95% CI, 1.18–1.52; P < .001) compared with patients without myopenia. The foregoing findings emphasize the important interplay among weight loss, body composition, and survival in patients with advanced incurable cancer.

A similar prognostic association is observed with patient-reported loss of appetite. Quinten and colleagues examined 30 randomized controlled trials from the European Organisation for Research and Treatment of Cancer from 1986 through 2004, including more than 1800 cancer patients who described varying degrees of appetite loss. Survival and appetite were tied together; patients who had maintained their appetite had a more favorable median survival compared with patients with loss of appetite. Hence not only is weight loss a strong predictor of poor outcome in patients with metastatic cancer, but the same can be said for loss of appetite.

To date, most research has underscored the fact that cancer itself is the main culprit when it comes to losing weight in the setting of advanced malignancy. Several studies point to the predisposition of patients with cancer to the loss of lean tissue with some slight preservation of adipose tissue, a clinical scenario that stands in stark contrast to what one observes in classic cases of starvation, in which adipose tissue wastes and lean tissue is relatively preserved. Recently, however, findings of a series of studies suggest that some of the newer cancer agents lead to the direct wasting of lean tissue, despite their role in sometimes improving patient survival. For example, Antoun and colleagues undertook a secondary analysis of data from a placebo-controlled, double-blind trial in metastatic renal cell cancer patients who were treated with sorafenib. The findings of these investigators, who used retrospective analyses of CT images, were surprising. As expected, at study entry, muscle wasting was observed in 72% of patients with a BMI below 25 and in 34% of patients with a BMI above 25. However, although patients in the placebo group had stable body weight during 6 months with no major changes in body composition, patients who received sorafenib lost on average 2.1 kg of weight over 6 months and 4.2 kg over 1 year. Moreover, patients treated with sorafenib lost skeletal muscle progressively at 6 months (a decrease of 4.9%; P = .01) and 12 months (a decrease of 8.0%; P = .01), and statistically significant decrements in muscle mass were observed even in comparisons against the placebo arm. Some decrease in muscle mass has also been observed with bevacizumab, presumably via similar pathways. Further research in this area is indicated, given the variety of emerging, new antineoplastic agents.