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Therapies for cachexia: new ammo against an inveterate foe?

Cachexia is a devastating condition that frequently develops across a large spectrum of chronic illnesses. The most important disease in this regard is cancer, as up to 80% of patients with solid tumors, particularly those of the gastrointestinal tract, become cachectic in late stages of the disease.1 This is not surprising, because tumors tend to adapt to available sources of energy and divert these away from peripheral tissues, yielding tissue starvation. Patients with other diseases who tend to develop cachexia in the course of their disease include those with chronic obstructive pulmonary disease, heart failure, chronic kidney disease, rheumatoid arthritis, and AIDS. The magnitude of different diseases explains why therapeutic approaches to cachexia per se have remained difficult in recent years. Indeed, therapies must embrace not only the specific type of tissue that is lost, i.e. fat tissue or muscle tissue, but also need to consider disease-specific aspects like anorexia, inflammation, or anabolic/catabolic dysbalances. Recent therapeutic approaches show that interventions may be useful already when muscle is lost only, i.e. even before weight loss becomes apparent.2

The last two years have seen some progress in this regard as studies have reported promising results. Several clinical trials have used the appetite stimulant megestrol acetate and have tried to boost its effectiveness with adjunct treatments like thalidomide,3 formoterol,4 or L-carnitine.5 The most promising study was done using megestrol acetate together with thalidomide, as this study in 102 patients with cancer was not only the largest, but also because the combination therapy yielded improvements in body weight, quality of life, serum levels of pro-inflammatory cytokines, and hand grip strength that were more pronounced in the combination therapy group than in the group that received megestrol acetate only.3 A novel first-in-class monoclonal antibody against interleukin-1α has shown increases in lean mass within 8 weeks of treatment.6 This study is of particular interest, because targeting single cytokines has become less fashionable in recent years and the recent study therefore tells us that this approach stays interesting. Nutritional support remains an interesting target and has been studied recently in patients on maintenance haemodialysis,7 however, an endpoint of increases in serum albumin levels has scientific merit, but it is too far from what could be translated into improvements in quality of life or improved exercise capacity. Research into ghrelin, a peptide mainly derived from the fundus of the stomach that regulates appetite, has recently received tremendous research activity. Anamorelin, a ghrelin receptor agonist was tested in a clinical trial of 226 patients with cancer and yielded increases in body weight after 12 weeks of treatment;8 although no significant effect was noted with regards to hand grip strength. Finally, anabolics have seen some research activity over the last 2 years. Enobosarm is a selective androgen receptor modulator that was used in a clinical trial in 159 male and postmenopausal women with cancer and weight loss of at least 2% of body weight.9 After 6 months of treatment, enobosarm application was associated with a significant increase in lean mass. Finally, 16 weeks of treatment with espindolol, a novel anabolic/catabolic transforming agent, showed beneficial effects with regards to body weight and hand grip strength among 87 patients with cancer cachexia.10

Several studies have been undertaken over the last years to alter the course of body wasting, particularly in patients with cancer cachexia. Results are promising, but far from having beneficial effects on survival. Improvements in body weight are not necessarily associated with increases in lean mass. Increases in lean mass, i.e. muscle mass, are not necessarily associated with improvements in muscle strength or quality of life. Substances that directly act on skeletal muscle are most promising in this regard.

Stephan von Haehling MD PhD DIC FESC,
Consultant Cardiologist, Associate Professor of Medicine, Department of Cardiology and Pneumology, University of Göttingen Medical School.


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