Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment

Abstract

The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

Figures

Figure 1

Proteasome inhibitory activity in serum samples of 14 patients with early symptoms of cancer cachexia treated with n-3 fatty acid supplements.

References

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

A classic manuscript that proposes the definition and comprehensive discussion of the CC syndrome. This review is comprehensive review that compares the catabolic actions of tumour necrosis factor-alpha (TNF-alpha) and proteolysis-inducing factor (PIF) and their involvement in human cancer cachexia. This excellent review summarizes current thinking relating to inflammation, cachexia and prognosis in cancer patients, with particular emphasis on studies relating to recent therapeutic advances This article reviews the enzymatic cascade involved in ubiquitin-mediated degradation, describes some of the structural motifs identified by the conjugating machinery, and summarize recent developments in the involvement of the system in the pathogenesis of selected disease states, including CC. This review provides a pragmatic approach to the treatment of cachexia, stating the goal must be to stabilise cachexia and prevent or delay further decline and established the need to evaluate strategies to counteract both hypermetabolism and reduced dietary intake and the importance of improving not only survival but function and quality of life of cancer patients. This review provides a comprehensive evidence-base and makes a case for multimodal approaches for the design of complex intervention studies in the management of cancer cachexia. This article discusses several cancer-related skeletal muscle wasting mechanisms and proposes how physical activity might attenuate muscle wasting by counteracting some of these mechanisms. This is a phase III randomized study which includes all the agents currently used to treat CC and examines several safety and efficacy endpoints of cancer cachexia: lean body mass (LBM), resting energy expenditure (REE), fatigue; and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines.