Cancer cachexia: Developing multimodal therapy for a multidimensional problem

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Abstract

Cancer cachexia is a multi-factorial syndrome that encompasses a spectrum from early weight loss (pre-cachexia) to a state of severe incapacity incompatible with life. The molecular basis of the syndrome in animal models (based on host–tumour cell interaction, the neuro-hormonal control of appetite and the hypertrophy/atrophy pathways that govern muscle-wasting) has provided a new raft of biomarkers and therapeutic targets. Key defining features of cachexia in humans (weight loss, reduced food intake and systemic inflammation) now provide not only a framework for classification but also a rationale for targets for therapeutic intervention. The role of age and immobility in muscle-wasting also provides a rationale for the nature of nutritional support in cachexia. There is now a substantive evidence that multimodal approaches that address these key issues can stabilise and even improve the nutritional status, function and quality of life of at least a proportion of advanced cancer patients. Novel biomarkers for patient stratification and more specific techniques for the estimation of muscle mass and physical activity level herald a new era in trial design. The current evidence-base justifies new enthusiasm for the design of complex intervention studies in the management of cancer cachexia.

Introduction

Progress in the treatment of cancer cachexia has been slow. Contributory factors include the lack of a clear definition for cachexia, the multi-factorial nature of the condition, the lack of validated biomarkers, primitive clinical trial design and a paucity of interest by pharmaceutical/government sponsors of research. At present, the oncology community is divided between the majority who believe that weight loss is an inevitable consequence of progressive tumour growth versus a small minority who think that there is potential to significantly influence the patients’ nutritional status (and thereby improve the quality and the quantity of life) independent of tumour status. The former look to better ways of controlling tumour growth whilst the latter await well-conducted randomised trials on which to find an evidence-base to enact the change in clinical practice. The aim of this article is to determine whether there are grounds for optimism.

Section snippets

Classification of cachexia

It would be surprising to find that progress had been made in the treatment of a condition for which there was no clear definition. Sadly, there is no agreed classification of cancer cachexia. What can be said is that cachexia is a multidimensional syndrome that affects every compartment of the body and is most easily recognised in its advanced form by the severe loss of subcutaneous fat and skeletal muscle. Attempts by clinical trialists to define cachexia have focused generally at an earlier

Prevalence and impact of cachexia

Approximately one-quarter of all deaths in Western Society are due to cancer. Half of all patients with cancer lose some body weight; one-third lose more than 5% of their original body weight and up to 20% of all cancer deaths are caused directly by cachexia (through immobility, cardiac/respiratory failure).2, 3 The incidence of weight loss upon diagnosis varies greatly according to the tumour site. The highest prevalence of weight loss is seen amongst patients with solid tumours, e.g. gastric,

Pathophysiology of cachexia

Cancer patients lose weight as a result of reduced food intake (secondary to anorexia), abnormal metabolism or a combination of the two. For patients whose weight loss is predominantly due to anorexia, artificial nutritional support can be very successful. In this situation, the problem arises in balancing the use of invasive techniques against the preservation of the quality of life, in an individual whose lifespan is quite limited. However, this is not the situation in most cancer patients.

Biomarkers of cachexia

For the purposes of intervention trial design, there are a variety of novel biomarkers (Fig. 4) and end-points that should be considered. This area is developing rapidly and thus the following discussion is not exhaustive.

Novel end-points in cachexia intervention studies

Regulatory authorities are interested generally in a drug or treatment influencing favourably both body composition and physical function prior to licensing it for the treatment of cachexia. Until recently, it has been difficult for clinical investigators to provide accurate information on both domains. However, recent progress has opened new avenues.

Treatment options

Clearly, the best way to cure cachexia is to cure the cancer and a clear focus on optimal oncological management is important. It is also vital to recognise that comprehensive general medical management of the patient is essential to assess and treat secondary factors that might contribute to anorexia or metabolic decline. Thus, the pancreatic cancer patient with ongoing cholangitis, steatorrhoea or unrecognised diabetes is not going to respond to anti-cachexia therapy until he receives

Conclusions

There is an urgent need for further development of a formal definition of the cachexia spectrum and robust biomarkers of pre-cachexia and patient-oriented outcomes for cachexia randomised intervention trials. Recent advances in pathophysiology emphasise the need for improved food intake (especially protein), exercise and use of anti-inflammatory agents. Not all patients will respond equally. However, multimodal strategies to tackle both food intake and metabolic change have been demonstrated to

Conflict of interest statement

None declared.

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