Cancer cachexia - adopting a systems wide approach.

PURPOSE OF REVIEW: Cancer cachexia results in the death of approximately 2 million people worldwide annually. Despite the impact of this devastating condition, there is limited therapy and no standard of care. Although multiple definitions exist, confusion remains as a true understanding of the biology has not yet been achieved and distinct phases of cachexia have not been examined. Research has mainly focused on weight loss and muscle wasting, but cachexia is increasingly recognized as a multiorgan disorder involving adipose tissue, liver, brain, gut and heart, with systemic inflammation a central unifying feature. RECENT FINDINGS: In this review, we will discuss some of the extra-muscular features and multisystem interactions in cachexia, and describe how moving our focus beyond muscle can lead to a greater understanding of the mechanisms and clinical features seen in cachexia. SUMMARY: We describe the need for robust characterization of patients with cachexia, to allow clinical phenotypes and multisystem mechanisms to be untangled, and to enable the implementation of multimodal treatment strategies.

Advance care planning in primary care for patients with gastrointestinal cancer: feasibility randomised trial.

BACKGROUND: Advance (anticipatory) care planning (ACP) requires discussions between patients and healthcare professionals about planning for future deterioration in health. ACP improves care coordination but uptake is limited and often deferred. AIM: To assess the feasibility and acceptability to patients, carers, and GPs of a primary care ACP intervention for people with incurable oesophageal, gastric, or pancreatic cancer. DESIGN AND SETTING: A 12-month feasibility randomised controlled trial (RCT) in a Scottish Cancer Network. METHOD: Patients aged ≥18 years starting palliative oncology treatment were randomised 1:1 to an ACP intervention or standard care. Patients in the intervention group received an oncologist letter supporting them to request a GP review along with a patient information leaflet about ACP. Pre-specified analyses with masking included trial recruitment and retention, ACP completion, and quality-of-life questionnaires (EuroQol EQ-5D-5L and ICECAP Supportive Care Measure) at baseline, 6, 12, 24, and 48 weeks. Qualitative interviews with purposive sampling explored patient, carer, and GP experiences. RESULTS: Of 99 eligible participants (269 screened), 46% were recruited (n = 46) and randomised; 25 to intervention and 21 to control. By 12 weeks, 45% (n = 9/20) of the individuals in the intervention and 59% (n = 10/17) in the control group had a documented ACP plan. By 24 weeks, 30% (n = 14) had died; in the remaining participants quality of life was maintained at 24 weeks except for physical symptoms. Social norms associating ACP with dying were prevalent among 23 participants interviewed. No psychological or clinical harms were identified. CONCLUSION: An RCT of ACP for people with incurable cancer in primary care is feasible. Patient, carer, and GP attitudes and behaviours determined acceptability and timing of care planning.

Neuromuscular junctions are stable in patients with cancer cachexia.

Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.

The emerging role of anamorelin hydrochloride in the management of patients with cancer anorexia-cachexia.

Cancer cachexia affects many patients with advanced cancer. This multifactorial syndrome, which involves loss of muscle mass and body weight, profoundly affects patients' physical functioning and quality of life. Pharmacologic interventions that target weight loss and also improve patient-reported measures are required. Anamorelin hydrochloride is an oral ghrelin receptor agonist for the treatment of cancer anorexia-cachexia that stimulates release of growth hormone and insulin-like growth factor 1, and improves food intake and body weight. Phase II and III trials have demonstrated that anamorelin increases body muscle and fat composition, and improves patient-reported appetite and quality of life. Anamorelin shows promise as an anabolic agent with benefits maintained over time, without the virilizing side effects of other anabolic medications.

The dermcidin gene in cancer: role in cachexia, carcinogenesis and tumour cell survival.

PURPOSE OF REVIEW: The diverse protein products of the dermcidin gene are relevant to immunity, cancer cell progression and cancer cachexia. This article evaluates recent developments/controversies around dermcidin. RECENT FINDINGS: Dermcidin has recently been shown to act as a survival/proliferation factor in hepatoma and prostate cancer cell lines. Recent studies suggest that the Y-P30 subunit of the dermcidin polypeptide offers a survival advantage in such cancer cells. Nevertheless, the relevance of Y-P30 to cancer growth in vivo, and mechanisms of action remain unknown. In mice, tumour cells appear to glycosylate the Y-P30 subunit, transforming it into a potent skeletal muscle proteolysis-inducing factor. Recent work has described a receptor and signal transduction pathways for murine glycosylated proteolysis-inducing factor. The absence of classical N-glycosylation sites in the human proteolysis-inducing factor peptide and the lack of specific tools for the detection of the key carbohydrate moieties conferring the proteolysis-inducing activity, however, remain barriers to confirming glycosylated proteolysis-inducing factor as a pro-cachectic factor in humans. SUMMARY: There is a growing body of evidence illustrating dermcidin as an oncogene and Y-P30 as a survival factor. The biology of murine proteolysis-inducing factor as a pro-cachectic factor continues to evolve; however, its role in human biology remains speculative.

Neoadjuvant chemotherapy for carcinoma of the oesophagus and oesophago-gastric junction: a six-year experience.

BACKGROUND: Oesophageal cancer is a major clinical problem with a generally poor prognosis. As a result there has been interest in combining surgery with neoadjuvant chemotherapy to try and improve outcomes, although the current evidence for benefit is inconsistent. We aimed to compare, in a non-randomised study, the post-operative complication rate and short and long-term survival of patients who underwent surgical resection for carcinoma of the oesophagus and types I and II carcinoma of the oesophago-gastric junction with or without neo-adjuvant chemotherapy. METHODS: Details of all resections for oesophageal/junctional (types I and II) adenocarcinoma or squamous cell carcinoma between April 2000 and July 2006 were collected prospectively. Data from patients with T3 and/or N1 disease who underwent either neoadjuvant chemotherapy (NAC) or not (non-NAC) were compared. Data were analysed using Kaplan-Meier plots, Mann-Whitney U-test, Cox Regression modelling, and Chi-squared test with Yates' correction where sample sizes <10. RESULTS: 167 patients were included (89 NAC and 78 non-NAC). The in-hospital post-operative mortality rate of the NAC group (n = 2 deaths; 2.2%) was significantly lower (p = 0.045) than the non-NAC group (n = 6 deaths; 7.7%). Most deaths were due to cardio-respiratory complications; however, there was no significant difference in rates of chest infections, anastomotic leaks, wound infections, re-operations, readmission to ITU or overall complications between the two groups. Although both the two-year survival rate (60.7%) and long-term survival of NAC patients (median survival = 793 days; 95% CI = 390-1196) was greater than non-NAC patients (two-year survival rate = 48.7%; median survival = 554 days; 95% CI = 246-862 respectively), these differences were not statistically significant. CONCLUSION: This non-randomised study demonstrated that NAC was associated with a significant reduction in post-operative inpatient mortality rate. Whether this can be explained by a decreased co-morbidity in NAC patients or a protective phenomenon associated with NAC remains unclear. This study also demonstrated a greater two-year survival rate and overall median survival time following NAC but this was not statistically significant.