TREATING CANCER CACHEXIA

Currently, there is no licensed treatment and no standard of care for cancer cachexia. Putting this in the context of a condition which impairs the delivery of anti-cancer therapy (through increased side-effects, treatment delays, dose reductions),^[1] causes marked distress to patients and their families and is associated with reduced survival, there remains an urgency to progress the research agenda in cancer cachexia.^[2]

Currow et al. are to be commended for rising to this challenge and herein they present long-term safety and efficacy data on the ghrelin agonist, anamorelin.^[3]Preceding this trial, two large double blind placebo controlled randomised trials (ROMANA 1 and 2) have reported that anamorelin improves lean body mass and symptoms of cancer cachexia.^[4] The present safety extension study (ROMANA 3) also reinforces the fact that anamorelin is well tolerated with prolonged use (24 weeks) and continues to improve body weight. Therefore, in the search for the holy grail that is a treatment of cancer cachexia, the present study and the accompanying body of work examining anamorelin are encouraging.

Discussion with the regulators are ongoing with relation to a licence for anamorelin based on the fact that the co-primary end points were not met; indeed whilst there was an improvement in lean body mass, the accompanying end point assessing function (hand grip strength) was not met.^[4] Independent of this, however, the programme of work examining anamorelin, through early and late phase trials, will evolve with a focus on body weight, appetite and quality of life.

This challenge of developing a treatment of cancer cachexia is likely to continue to deter major pharma from entering this arena. Indeed, in the last three decades, the failure to develop treatments for cancer cachexia is in part due to the lack of engagement from pharmaceutical companies. Like the developers of anamorelin, there have been others who admirably have developed treatments for cancer cachexia that have not been realised into the clinical setting, for reasons which include clinical end points not being met.

For example, the selective androgen receptor modulator Enobosarm underwent clinical trials and reported beneficial effects on lean body mass but failed to show any consistent benefit on functional outcomes (using stair climb power or hand grip strength).^[5] Whilst as cachexia researchers we can press regulators for appropriate guidance and consensus on optimal end points for cachexia trials, experts in this field have to provide the most informed information about measures of function that are both clinically meaningful and valid in patients with advanced cancer.^[6]Researchers also need to be mindful that changes in muscle mass will not necessarily equate to changes in function. Using a measure of function such as hand grip strength or stair-climb may not be optimal end points in cachexia trials as they can be affected by numerous other cancer and non-cancer-related factors, rather than just due to loss of muscle and/or muscle function. The critical area of clinical end points requires more thought. It may be that a more patient-centred approach to muscle function, with a focus on Activities of Daily Living, rather than hand grip strength would be a more clinically useful end point. Similarly, a realistic measure of physical activity could be measured in clinical trials using a research grade accelerometer, such as the Actigraph.

It also follows that without robust characterisation of the clinical phenotype in cancer cachexia studies, including as a minimum, stratification for the systemic inflammatory response (SIR), results will be challenging to interpret. Indeed, in the ROMANA trials, the median time from diagnosis to trial entry was ~8 months. In the population studied (stage III or IV non-small cell lung cancer) this group of patients would be in the late stages of their illness and as such may have cachexia which is refractory to treatment. To optimise the treatment of cancer cachexia, any interventions should be initiated as early as possible to maximise any benefits and attenuate the development of cachexia.

We must also be mindful that it is challenging to conduct clinical trials in cancer cachexia when debate continues regarding the definition and classification.^[7,8]Recently, Vanhoutte et al. have further advocated the role of the SIR in the genesis of cachexia.^[9] This is congruent with evidence of the association of the SIR in quality of life in advanced cancer and its relationship to physical function.^[10] In the design of future trials in cachexia, the SIR should be a key stratification factor and may identify subgroups where treatments may be more effective.^[11]

There are, however, grounds for optimism and the study by Currow et al. demonstrates progress in researching a treatment of cachexia. The complex pathophysiology of cancer cachexia will almost certainly require therapy that targets the multiple mechanisms of cancer cachexia; termed multimodal therapy.^[12,13] To treat cancer cachexia optimally, it could be argued that a foundation of optimal cachexia care is needed using multimodal therapy which targets the SIR, reduced food intake and decreased physical function. A phase II trial examining such an approach has recently been conducted and the encouraging findings mean that a phase III trial is underway.^[14] It could be argued that novel agents such as anamorelin may have maximal benefits when used in combination with a background of optimal cachexia care. This may provide the best platform for novel therapies to reach their true potential.