Exercise and nutritional rehabilitation in patients with incurable cancer
Hall, Charlie Christopher
BACKGROUND: Cancer treatments are evolving, so that in many cases cancer is becoming a chronic disease. Rehabilitation is a cornerstone in the management of many chronic diseases, however, it is not yet a routine component of cancer care, in spite of this being advocated (Tiberini R, 2015, Alfano et al., 2016). There is limited evidence for the core components of a rehabilitation programme for patients with incurable cancer. The progressive decline in function and nutritional status in these patients would support an approach that targets these factors. The multi-modal therapeutic approach proposed to treat cancer cachexia, which incorporates exercise and nutrition (Fearon, 2008, Solheim, 2018), has the potential to be adapted as a rehabilitation programme for patients with any type of incurable cancer. However, the feasibility of such a programme remains to be tested. AIMS: The aims of this thesis were: firstly, to examine the evidence for combined exercise and nutritional interventions in patients with incurable cancer. A phase II, randomised controlled feasibility trial of an exercise and nutritional rehabilitation programme (ENeRgy) versus standard care was designed and undertaken for patients with incurable cancer. Assessing the primary (feasibility) and secondary (exploratory) endpoints of this trial constitute the second and third aims of this thesis. METHODS: A systematic review was undertaken to assess existing evidence for combined exercise and nutritional interventions for patients with incurable cancer. The internationally recognised Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria were applied to rank evidence relating to patient-important outcomes, detailed in chapter two. The ENeRgy trial was undertaken as detailed in chapter three. Eligible participants came from two Edinburgh Hospice community palliative care teams or the Edinburgh tertiary Oncology centre. Participants were ≥18 years of age; Karnofsky Performance Status (KPS) ≥ 60; had a diagnosis of incurable cancer (defined as metastatic or locally advanced cancer not amenable to curative treatment); and were not undergoing anti-cancer therapy. Participants were randomised in a 1:1 ratio to receive an eight-week exercise and nutritional rehabilitation programme (intervention arm) or standard care (control arm). The primary endpoints examined feasibility of the trial and compliance with interventions, while secondary endpoints examined recruitment, retention, participant and carer quality of life (QoL) including sleep parameters. Physical activity measures included mean daily step count measured by physical activity monitor (PAM), two minute walk test (TMWT), timed up and go test (TUG), Life Space Assessment (LSA) and KPS. Nutritional status was measured using weight, the abridged Patient Generated Subjective Global Assessment (aPG-SGA) questionnaire and a ten point verbal scale assessment of nutritional intake (AveS). Overall survival was also measured. All endpoints were assessed at trial baseline (week 0), midpoint (week 5) and endpoint (week 9). RESULTS: Systematic Review: There are a limited number of published clinical trials examining combined exercise and nutritional rehabilitation in patients with incurable cancer. However, the existing evidence suggests there are multiple beneficial effects: the highest quality body of evidence pertained to improvements in physical function and depression: graded as moderate (B). Improvements in QoL and fatigue were graded as low (C), and the least quality of evidence (very low, D) related to improvements in overall function and nutrition/ weight. ENeRgy Trial: Forty-five people (28 males) were recruited over 15 months with an attrition rate of 36% (n=16) with a higher rate of attrition in the control arm (41% vs. 30%). Attrition was mainly due to deterioration in health and no participants withdrew due to the intervention being overly burdensome. Twenty-one participants had a GI or thoracic malignancy and the median [inter-quartile range, IQR] age was 78 years [69-84]. Trial procedures were well tolerated and at least 76% of participants in the treatment arm complied with >80% of the trial interventions. There were no significant differences in participant QoL, with the exception of emotional functioning which remained significantly higher in the intervention arm [P=0.006]. A non-significant improvement in carer QoL was seen in the intervention arm compared to the control arm. There was a non-significant increase in weight in the intervention arm compared to a loss in the control arm (P=0.184). There were no significant differences in step count (P=0.55), TUG (P=0.78), TMWT (P=0.48) and LSA (P=1.0), a-PG-SGA scores (P=0.249), AveS (P=0.398), KPS scores or survival between trial arms. CONCLUSIONS: Results of the systematic review suggest that there are multiple benefits to be gained for patients with incurable cancer from combined exercise and nutritional rehabilitation programmes, most notably in terms of physical function and mood. This ostensibly could result in improvements in QoL, but adequately powered trials are lacking. Results from the ENeRgy trial demonstrate that delivering an exercise and nutritional rehabilitation programme in a hospice outpatient setting is feasible in terms of patient recruitment and compliance with interventions, despite attrition. Furthermore there are potential benefits, including improvements in emotional functioning, carer quality of life and weight, which require a larger phase three trial to fully elucidate. Funding for the follow- on phase three trial ‘ENeRgise’ is currently being sought and the results of this trial could lead to fundamental changes in the way we approach rehabilitation in Palliative Medicine.