Selective Androgen Receptor Modulators In Cancer Cachexia
[The changes for FDA Approval are far from certain. GTXi is betting on those that will die, no hope of life, NONE, NADA , ZIP. (Also, the attempt to use a SARM that is not tarnished with the name Anabolic Steroid. It is noteworthy that Oxandrolone is approved for wasting.) Therefore, any untoward side-effects will be offset by QoL. The most significant side-effect being hypogonadism after stopping the SARM, which will lead to a condition that only magnifies and exacerbates the cancer cachexia. The plan is they will take the drug until they die. The QoL change measured being at most marginally significant and more likely unimportant in end-of-life planning. Overall, IMO, a bust.]
Fearon KH. Selective androgen receptor modulators in cancer cachexia? The Lancet Oncology.
Selective androgen receptor modulators in cancer cachexia? : The Lancet Oncology
Although osteoporosis has been a dominant target for novel therapeutics for the past two decades, much interest now surrounds that other component of the musculoskeletal system, namely skeletal muscle. This interest has been spurred by increased understanding of the molecular biology of skeletal muscle fuelled partly by the nascent science of sports medicine. Equally a strong imperative exists for such research in view of the daunting demographics of age-related sarcopenia.
Adults older than 40 years lose 1% of their muscle mass per year; the number of individuals older than 80 years is projected to double over the next 20 years and in this population age-related muscle loss is predicted to be a major source of physical disability, poor quality of life, and death.
Most patients with cancer are older than 65 years and therefore many will already have some degree of pre-existent age-related sarcopenia. Equally, modern multimodal cancer therapy often consists of a continuum of months or years of cycles of chemotherapy combined with surgery and radiotherapy. Even a short course of chemotherapy can result in loss of kilograms of skeletal muscle.
When these effects compound pre-existing age-related sarcopenia and are accompanied by cancer-induced muscle loss a substantial proportion of patients with advanced disease can be rendered profoundly myopenic. Evidence suggests that such crucial loss of skeletal muscle mass is associated with increased chemotoxicity, reduced tolerance of therapy, and reduced overall survival.
In adults, muscle mass is maintained partly by the anabolic effects of androgens (eg, dehydroepiandrosterone and testosterone). Androgens act via the androgen receptor and increase muscle protein synthesis via several signal transduction pathways. Male hypogonadism is noted frequently in advanced cancer but the epidemiological evidence linking it independently to cachexia or fatigue is awaited. Non-steroidal selective androgen receptor modulators are a class of drug that act mainly on androgen receptors in skeletal muscle and bone and aim to avoid potentially undesirable effects in prostate, skin, and other organs, including liver.
It is against this background that the phase 2 trial by Adrian Dobs and colleagues of a first-in-class oral selective androgen receptor modulator (enobosarm, GTx-024; GTx, Memphis, TN, USA) should attract much interest. A diverse cohort (n=159) of patients with cancer (lung cancer, colorectal cancer, lymphoma, breast cancer, or chronic lymphocytic leukaemia) with a range of stage of disease (II—IV) were randomly assigned to enobosarm 1 mg, enobosarm 3 mg, or placebo once daily for 16 weeks.
The drug was well tolerated and resulted in a significant gain of lean body mass (enobosarm 1 mg median 1.5 kg, range ?2.1 to 12.6, p=0•0012; enodosarm 3 mg median 1.0 kg, ?4.8 to 11.5, p=0•046) measured by dual-energy x-ray absorptiometry compared with baseline measurement. Change in total lean body mass within the placebo group was not significant (0•02 kg, ?5•8 to 6•7, p=0•88). The gain in lean muscle was associated with improved physical function as judged by shortened time and increased power in the 12 step stair climb test.
Limitations include small sample size, heterogeneity of cancer type, and the issue that a proportion of patients entered into the study might have been disease-free and therefore could not be deemed to have cancer cachexia. Moreover, the nature of other supportive care in both the treatment and control groups was not well defined.
Importantly, management of cancer-associated muscle loss is unlikely to be optimum without a multimodal approach. A study by Temel and colleagues in advanced lung cancer has emphasised that optimum symptom control by early introduction of palliative care can even translate into a survival advantage. Patients need active management of nutrition-effect symptoms. Nearly 50% of patients with advanced cancer have a daily protein intake below the best level for protein synthesis.
Equally, clinicians generally recognise that in patients with cancer, systemic inflammation is likely to drive both muscle loss and overall sickness behaviour. Failure to address inflammation could lead to sustained muscle loss and failure to use the muscle that remains. Levels of physical activity are often much reduced in advanced cancer. Exercise is the best physiological intervention for muscle maintenance. A 6 week supervised exercise intervention in advanced cancer is both feasible and effective in reduction of fatigue. However, the effects of this intervention alone on overall quality of life remain difficult to detect. Home-based training is likely to be a more achievable intervention; however, it is probably best focused on keeping people active and targeting physical function, as opposed to fitness or capacity, which require closer supervision.
The trial by Dobs and colleagues hopefully opens a new era of therapy for the management of muscle loss in patients with cancer. The result of phase 3 trials with this drug (NCT01355484, NCT01355497) and other promising agents are anxiously awaited. The oncology community needs to consider how to optimise the benefits of such treatments. An urgent need exists to establish a validated classification system for cancer cachexia and to establish what is best supportive care (nutrition, exercise, anti-inflammation) so that novel anabolic or anticatabolic agents can be used rationally and to best effect.
