Cancer cachexia results in significant morbidity and mortality. It is very common among patients with advanced lung cancer, with an estimated incidence of between 36 and 76% (1–3), and its presence is associated with worse outcomes (4, 5).
Patients with cancer cachexia experience a number of distressing symptoms, functional impairment and decreased tolerance of cancer treatment (6, 7). Cancer cachexia is described as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment (4).
In recent years there has been a significant increase in research in the field of cachexia resulting in greater understanding of pathophysiology and an appreciation that cancer cachexia represents a continuum of pre-cachexia, cachexia and refractory cachexia (4, 8). Although its pathophysiology remains incompletely understood, it is known to be multifactorial in nature and characterised by a negative protein and energy balance and abnormal metabolism (4, 9). A number of different pathways have been associated with, and contribute to, the pathogenesis of cancer cachexia including the secretion of inflammatory cytokines such as tumour necrosis factor-α (TNFα), proteolysis-inducing factor (PIF), lipolysis and lipid-mobilising factor (LMF), as well as abnormalities in glucose, fat and protein metabolism, and abnormalities in mitochondrial energy metabolism which contribute to tissue catabolism, all promoting cancer cachexia (8).
This increased understanding of the pathology behind the development of cachexia has led to some promising new angles of investigation of potential therapeutic agents. It has long been recognised that cancer cachexia cannot be reversed by nutritional support alone (9). However, despite a large number of randomised clinical trials of investigational agents including, amongst others, progestins (10), cannabinoids (11), corticosteroids (12), non-steroidal anti-inflammatory drugs (NSAIDs) (13) and thalidomide (14), there is currently no effective treatment for cancer cachexia in clinical use. It is possible that this, in part, is because clinical trials of investigational agents for cancer cachexia often recruit patients with very advanced disease or refractory cachexia. These patients have severe muscle wasting, catabolism and a low performance status and are unlikely to benefit from any cachexia therapy. This frequently results in poor recruitment and high dropout rates. In this situation, it is possible that a potentially effective agent has been unable to demonstrate clinical efficacy due to trial design. One promising agent has recently emerged however, anamorelin, which has demonstrated benefit in patients with advanced non-small cell lung cancer (NSCLC)-associated cachexia (15–17), although it still remains to be adopted into routine clinical care.
At the time of the NOURISH trial’s inception, an agent with a strong biological rationale for use in cancer cachexia was β-hydroxy β-methyl butyrate (HMB) in combination with arginine and glutamine (HMB/Arg/Gln). The oral nutritional supplement was initially reported to improve wound healing via improved protein and collagen synthesis (18). β-hydroxy β-methyl butyrate is an active metabolite of the amino acid leucine that may improve muscle protein turnover (19). Arginine may synergise with HMB to attenuate muscle loss (20), with studies suggesting glutamine can upregulate muscle protein synthesis (21). All three components of this amino acid rich supplement may work together to decrease muscle damage from reactive oxygen species and pro-inflammatory cytokines (20–22). Of relevance to NOURISH, clinical studies suggested HMB/Arg/Gln supports maintenance of lean body mass (LBM) in older, healthy adults (23). A large randomised trial of 472 patients with advanced cancer and who experienced 2–10% weight loss were given HMB/Arg/Gln or placebo for eight weeks (24). Although, no significant difference in LBM was observed at the end of treatment, a trend towards higher LBM in the intervention arm compared to placebo was noted. These data supported an earlier smaller randomised trial where 49 patients with advanced cancer and weight loss greater than 5% were administered HMB/Arg/Gln or control (25); a significant increase in fat-free mass (FFM) in the intervention arm was observed (1.6 kg +/- 0.94; P < 0.05). Both trials however experienced a high dropout rate; only 37% and 18% completing the trial, respectively. Therefore, further investigation specifically in advanced lung cancer was warranted.
We postulated that to test the effectiveness of an intervention it not only needed to be given early in the disease process before the onset of refractory cachexia but also in conjunction with attention to nutritional support, exercise support, symptom control and appropriately targeted anticancer therapy. It was important that this supportive therapy was deliverable within everyday clinical practice. We identified the Macmillan Durham Cachexia Pack (MDCP) as a vehicle with which to deliver a standardised symptom control programme (26, 27). The MDCP was a resource developed in 2007 by a Durham-based team with support from professionals around the UK. It provided an evidence-based guide for healthcare professionals to assess and manage common symptoms and problems seen in patients with anorexia-cachexia syndrome. The pack also contained a number of leaflets to help patients and their families deal with the emotional and psychological impact of the condition, however, efficacy of the packs use by clinicians remains unpublished. The MDCP used during the NOURISH trial has been included in Supplementary Appendix 1.
The NOURISH trial was, therefore, a randomised phase II trial designed as a pilot to detect a signal that dietary supplementation with HMB/Arg/Gln, on a background of structured nutritional and symptom support, delays the onset of cachexia in patients with advanced lung cancer sufficiently to justify further investigation in a larger phase III trial. Unlike previous trials before it, patients recruited into NOURISH were not required to have weight loss or other symptoms of cachexia. This paper reports the results from the NOURISH trial, which despite the limited data, can still contribute to the pool of evidence in this important clinical area.