The relationship between muscle mass and function in cancer cachexia: smoke and mirrors?

Randomized clinical trials of cancer cachexia interventions are based on the premise that an increase in the muscle mass of patients is associated with consequent improvements in muscle function, and ultimately, quality of life. However, recent trials that have succeeded in demonstrating increases in lean body mass have been unable to show associated increases in patient physical function. In this review, we examine the potential causes for this lack of association between muscle mass and function in cancer cachexia, paying particular attention to those factors that may be at play when using body composition analysis techniques involving cross-sectional imaging. Moreover, we propose a new population-specific model for the relationship between muscle mass and physical function in patients with cancer cachexia.

The ROMANA 1 and 2 trials of anamorelin (a novel ghrelin agonist) and the POWER 1 and 2 trials of enobosarm (a selective androgen receptor modulator) were able to demonstrate improvements in patient lean body mass, but not the functional co-primary endpoints of handgrip strength and stair climb power, respectively. We report similar confirmatory findings in other studies, and describe potential reasons for these observations.

The relationship between muscle mass and muscle function is complex and unlikely to be linear. Furthermore, the relationship is influenced by the techniques used to assess nutritional endpoints [e.g. computed tomography (CT)]; the nature of the chosen physical function outcome measures; and the sex and severity of the recruited cachectic patients. Such factors need to be considered when designing intervention trials for cancer cachexia with functional endpoints.