Anorexia and cachexia are devastating results of cancer and commonly coexist in patients with advanced disease.1 Although both are multifactorial in origin, anorexia often manifests as decreased appetite and food intake, whereas cachexia is characterised by loss of bodyweight and lean body mass.2 Weight loss in patients with cancer cachexia is due to a variable combination of decreased oral intake and metabolic change, leading to negative protein and energy balance.3 Patients with cancer cachexia frequently experience decreased quality of life, reduced chemotherapy tolerance, reduced physical functioning, and shortened survival.3, 4, 5, 6 Between 50% and 80% of patients with advanced cancer develop cachexia, with highest incidence reported in patients with lung and gastrointestinal cancer.7
Despite the high prevalence of cancer cachexia, few therapeutic options exist and there is no standard of care for its management. The cause of the condition is multifactorial, and a single-modality approach is unlikely to reverse all aspects of the syndrome and result in durable clinical benefits. Indeed, cachexia is thought to require a comprehensive intervention, including nutrition, exercise, and drugs. However, development of an evidence base for individual treatments is necessary to ultimately build an effective multimodality intervention.1 To address both nutrition and symptom burden, an ideal drug would improve anorexia and enhance food intake while also stimulating anabolism, thus overcoming the catabolic drive associated with cachexia and increasing lean body mass and bodyweight. Although several available drugs can improve patients' appetite or increase their bodyweight, none can substantially affect lean body mass and its key functional element, skeletal muscle.8, 31 Additionally, corticosteroids and progestational drugs, which are the most commonly used drugs in patients with anorexia, have substantial adverse events and potential toxic effects, which can include catabolism and muscle wasting.9, 10
Research in context
Evidence before this study
Although cachexia has long been recognised as a substantial source of morbidity and mortality in patients with cancer, treatment options are scarce. We did a literature review with PubMed from Jan 3, 2005, to Jan 3, 2015, with the terms “cancer” and “cachexia” and/or “anorexia” and “weight loss”, confirming the absence of evidence supporting the use of approved medications for the treatment of cancer cachexia. A systematic review of the treatment of cancer-associated anorexia concluded that progestins and corticosteroids are effective in increasing patients' appetite and weight, but had no effect on cachexia. Two Cochrane Database reviews of megestrol acetate, the most commonly used progestin for cancer-associated anorexia and cachexia, similarly concluded that use of megestrol acetate is associated with improvement in appetite and only slight weight gain. However, the more recent review noted that oedema, thromboembolic events, and death were frequent complications of megestrol acetate, and recommended that patients are informed of the risks associated with the drug. A comprehensive literature review of treatment options in cancer cachexia concluded that there are no available drugs for the treatment of cancer cachexia.
Added value of this study
We show in two international phase 3 clinical trials that patients with advanced non-small-cell lung cancer and cachexia who received anamorelin consistently increased lean body mass as well as bodyweight over the 12-week study period. Importantly, patients also had an improvement in their anorexia–cachexia symptoms.
Implications of all the available evidence
Anamorelin is an effective and well tolerated drug for the treatment of patients with advanced non-small-cell lung cancer and cachexia, and might be a novel treatment for such patients.
Anamorelin is an orally active, high-affinity, selective ghrelin-receptor agonist.11 Ghrelin is the natural ligand for the G-protein-coupled ghrelin receptor, which when activated has anabolic and appetite-stimulating effects.12 These effects are partly mediated through transient increases in growth hormone and insulin-like growth factor (IGF-1). Several double-blind, randomised phase 2 studies13, 14, 15 in patients with advanced cancer have shown that anamorelin is safe and efficacious in increasing patients' lean body mass, bodyweight, and appetite.
In theory, an effective treatment for cancer-associated muscle wasting, a key component of the cachexia, should improve muscle mass and, as a consequence, increase muscle strength. However, muscle wasting in patients with cancer is complex, arising from diverse factors such as age-related sarcopenia, cancer therapy, and comorbidity, in addition to the tumour. Moreover, muscle strength might not only be related to muscle mass, but also to other factors, such as persisting systemic inflammation and associated fatigue. A previous phase 2 study13 with anamorelin showed a significant effect on handgrip strength over a 12-week treatment period, whereas a subsequent phase 2 study did not.15 In the absence of an alternative internationally agreed standard for muscle strength and function, we assessed the efficacy with lean body mass and handgrip strength as co-primary endpoints and safety of anamorelin compared with placebo in two international, double-blind, phase 3 studies in patients with advanced non-small-cell lung cancer and cachexia.