What Therapies Are Effective in Improving Anorexia and Weight Loss in Cancer?

Introduction and Scope of the Problem

The onset of involuntary weight loss is often the first clinical sign of the presence of malignant disease. In cancers that are incurable by currently available therapies, significant weight loss can be seen in any palliative care setting.

The estimated prevalence of cancer cachexia is variable. Given the prevalence of obesity in Westernized countries, the marked shift in body weight renders the definition of clinically significant weight loss in patients with cancer a moving target. In the United States, it has been estimated that cancer cachexia may affect 430,000 people annually. The prevalence of cancer cachexia varies depending on the type of malignancy, with the greatest frequency of weight loss (approximately 50% to 85% of patients) observed in gastrointestinal (e.g., pancreatic and colorectal) and lung cancers at diagnosis and before initiation of chemotherapy. Weight loss is known to be part of the disease trajectory of all incurable malignancies, which contribute to an estimated 10 million deaths per year worldwide.

Cachexia has been recognized since ancient times as an adverse effect of cancer. It is associated with reduced physical function, reduced tolerance to anticancer therapy, and reduced survival. The evident physical wasting and loss of appetite that patients commonly experience, particularly in advanced stages of cancer, coupled with the poor efficacy of nutritional supplementation to reverse cachexia, impart a substantial burden of distress on the patient and family. Often family members hold a strong belief that increased caloric intake can enhance patient quality of life and prolong survival, and patients are often distressed when family members insist on offering food. Thus the progression of cancer cachexia and associated physical wasting can have profound effects on the family environment, including distress, frustration, and heightened anxiety regarding outcomes of the disease.

Relevant Pathophysiology

Cancer cachexia is a complex multidimensional problem for which there has been no generally agreed upon classification system or treatment algorithm. Several international consensus groups have worked to develop a conceptual framework for the cause-based diagnosis of cancer-associated malnutrition and cachexia. The motivation for these efforts was concern that multiple, often discordant, definitions for these terms are found in the literature and that lack of uniformly accepted definitions, diagnostic criteria, and classification has impeded advancement in both clinical trials and clinical practice.

The efforts of these groups create a jumping-off point for the diagnosis, staging, and intervention for cancer cachexia, with agreement on the following key elements, all contributing to the complex syndrome of anorexia and cachexia in cancer patients (see Fig. 22.1 for a visual representation of the interplay of these factors):

• 1.

  The specific erosion of skeletal muscle (i.e., lean tissue) is the physiologically and nutritionally important element of weight loss. Connected with this point is the important finding that many cancer patients whose body weight is normal, overweight, or even obese may harbor very significant muscle wasting. This severe muscle wasting (also known as sarcopenia) is an occult condition, and while hidden behind a mantle of adipose tissue, is related to reduced survival and increased toxicity of systemic antineoplastic therapy. The presence of occult muscle wasting necessitates objective measures of skeletal muscle mass in the clinical assessment of patients with cancer.

• 2.

  The pathophysiology of cachexia is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The degree to which food intake is decreased and metabolism is increased is a characteristic of a given patient, disease type, and stage. Clinically practicable tools for assessment of reduced caloric intake are available, including several validated for patient report.

• 3.

  Reduced food intake is attributable to primary anorexia, as well as other symptoms affecting oral intake. A clinical distinction is to be made between alterations occurring in the brain, such as decreased central drive to eat, and secondary causes of impaired food intake (e.g., stomatitis, constipation, decreased upper gastrointestinal motility [causing early satiety and nausea], dyspnea, pain, and suboptimal dietary habits), which should be recognized early because they might prove readily reversible.

• 4.

  Hypercatabolism aggravates weight loss and is provoked by tumor burden, systemic inflammation, and other catabolic factors. Tumor burden may reach a mass sufficient to result in a quantitatively significant energy expenditure; however, other systemic changes may occur, such as increased sensitivity to lipolytic factors or resistance to the normal anabolic actions of insulin that underlie weight loss. A growing list of catabolic effector molecules are suggested to drive cachexia, and these are tumor derived and/or generated by the tumor-induced activation of the immune system. Proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, interferon-γ, and tumor necrosis factor (TNF)-α, may be primary catabolic triggers of skeletal muscle loss. Other tumor-derived molecules such as growth and differentiation factor (GDF)-15 may bring into play distinct mechanisms for suppression of food intake. These metabolic changes define the reason that cachexia, unlike simple malnutrition, cannot be fully reversed by conventional nutritional support; some of these metabolic factors are potentially reversible with specific targeted therapy. Finally, antineoplastic agents may act as catabolic effectors. In particular, several targeted therapies promote weight loss and skeletal muscle catabolism. This is suggested to occur because pathways of muscle anabolism and of tumor cell proliferation share common elements.

• 5.

  Clinical progression of malnutrition and cachexia occurs over time. Given the interaction between the disease, its treatment, and nutritional status, a staging system to what is essentially a progressive and cumulative problem of depletion should be applied. This is an exceedingly important point in relation to therapy and in recognition of cancer cachexia as a continuum. Fearon and colleagues proposed three stages of clinical relevance: precachexia, cachexia, and refractory cachexia. Because the underlying metabolic abnormalities responsible for the eventual clinical manifestations of cachexia are likely present before overt weight loss, it seems reasonable to identify cachexia in its earliest stages (precachexia) with a view to delay or prevent the onset of cachexia. On the other end of the spectrum, cachexia can be clinically refractory as a result of very advanced disease (the presence of rapidly progressive cancer unresponsive to anticancer therapy). This stage is associated with profound anorexia and active catabolism or the presence of factors that render active management of weight loss no longer possible or appropriate. Refractory cachexia is characterized by a low performance status (World Health Organizations cancer performance status score 3 or 4) and a life expectancy of less than 3 months. Thus cachexia may be viewed in this context as an end-of-life condition that is managed primarily through palliative approaches in the refractory phase, whereas cachexia may be present early in the progression of cancer and approachable by nutritional and cancer-directed treatment.

Summary of Evidence Regarding Treatment Recommendations

Treatment recommendations for cancer cachexia must be based on its stage and cause. Management of precachexia is based on early identification, preventive intervention, and monitoring for progression to cachexia. Clinical practice guidelines emphasize screening for cachexia in all patients. Cachexia requires multimodal management based on its presentation, with priority also given to the reversal of symptoms contributing to low dietary intake. In the instance of refractory cachexia, palliation of symptoms and psychosocial support come to the forefront. Of note, the most extensively studied therapies are compounds that palliate the profound anorexia in advanced cancer, progestins, and corticosteroids (see later discussion).

Multiple systematic reviews are available concerning the causes and pharmacological therapies for cancer-associated anorexia and weight loss in adult patients. Few studies meet criteria for scientific rigor (e.g., randomized, controlled design), a clear sign that research is needed to better understand which therapies for anorexia and cachexia are truly beneficial in patients with advanced cancer. Randomized clinical trials of therapies for cancer cachexia frequently have been conducted in populations well within the 3 months preceding death. Missing data, due to attrition and death, greatly limit the interpretation of such studies. Only two classes of drugs (progestins and corticosteroids) have been found in these reviews to have sufficient evidence to support their use in cancer cachexia, although the data on these therapies are also of mixed quality with results that do not always demonstrate clear benefit.