The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients: a randomised controlled trial (The EMPOWER Trial).

BACKGROUND: The EMPOWER trial aimed to assess the effects of a 9-week exercise prehabilitation programme on physical fitness compared with a usual care control group. Secondary aims were to investigate the effect of (1) the exercise prehabilitation programme on psychological health; and (2) neoadjuvant chemoradiotherapy (NCRT) on physical fitness and psychological health. METHODS: Between October 2013 and December 2016, adults with locally advanced rectal cancer undergoing standardised NCRT and surgery were recruited to a multi-centre trial. Patients underwent cardiopulmonary exercise testing (CPET) and completed HRQoL questionnaires (EORTC-QLQ-C30 and EQ-5D-5L) pre-NCRT and post-NCRT (week 0/baseline). At week 0, patients were randomised to exercise prehabilitation or usual care (no intervention). CPET and HRQoL questionnaires were assessed at week 0, 3, 6 and 9, whilst semi-structured interviews were assessed at week 0 and week 9. Changes in oxygen uptake at anaerobic threshold (VO2 at AT (ml kg-1 min-1)) between groups were compared using linear mixed modelling. RESULTS: Thirty-eight patients were recruited, mean age 64 (10.4) years. Of the 38 patients, 33 were randomised: 16 to usual care and 17 to exercise prehabilitation (26 males and 7 females). Exercise prehabilitation significantly improved VO2 at AT at week 9 compared to the usual care. The change from baseline to week 9, when adjusted for baseline, between the randomised groups was + 2.9 ml kg -1 min -1; (95% CI 0.8 to 5.1), p = 0.011. CONCLUSION: A 9-week exercise prehabilitation programme significantly improved fitness following NCRT. These findings have informed the WesFit trial (NCT03509428) which is investigating the effects of community-based multimodal prehabilitation before cancer surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914068 . Registered 1 August 2013.

The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients (The EMPOWER Trial): study protocol for a randomised controlled trial.

BACKGROUND: The standard treatment pathway for locally advanced rectal cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Neoadjuvant CRT has been shown to decrease physical fitness, and this decrease is associated with increased post-operative morbidity. Exercise training can stimulate skeletal muscle adaptations such as increased mitochondrial content and improved oxygen uptake capacity, both of which are contributors to physical fitness. The aims of the EMPOWER trial are to assess the effects of neoadjuvant CRT and an in-hospital exercise training programme on physical fitness, health-related quality of life (HRQoL), and physical activity levels, as well as post-operative morbidity and cancer staging. METHODS/DESIGN: The EMPOWER Trial is a randomised controlled trial with a planned recruitment of 46 patients with locally advanced rectal cancer and who are undergoing neoadjuvant CRT and surgery. Following completion of the neoadjuvant CRT (week 0) prior to surgery, patients are randomised to an in-hospital exercise training programme (aerobic interval training for 6 to 9 weeks) or a usual care control group (usual care and no formal exercise training). The primary endpoint is oxygen uptake at lactate threshold ([Formula: see text] at [Formula: see text]) measured using cardiopulmonary exercise testing assessed over several time points throughout the study. Secondary endpoints include HRQoL, assessed using semi-structured interviews and questionnaires, and physical activity levels assessed using activity monitors. Exploratory endpoints include post-operative morbidity, assessed using the Post-Operative Morbidity Survey (POMS), and cancer staging, assessed by using magnetic resonance tumour regression grading. DISCUSSION: The EMPOWER trial is the first randomised controlled trial comparing an in-hospital exercise training group with a usual care control group in patients with locally advanced rectal cancer. This trial will allow us to determine whether exercise training following neoadjuvant CRT can improve physical fitness and activity levels, as well as other important clinical outcome measures such as HRQoL and post-operative morbidity. These results will aid the design of a large, multi-centre trial to determine whether an increase in physical fitness improves clinically relevant post-operative outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914068 (received: 7 June 2013). SPONSOR: University Hospital Southampton NHS Foundation Trust.

The effect of neoadjuvant chemoradiotherapy on whole-body physical fitness and skeletal muscle mitochondrial oxidative phosphorylation in vivo in locally advanced rectal cancer patients--an observational pilot study.

BACKGROUND: In the United Kingdom, patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy. However, the effects of this on physical fitness are unclear. This pilot study is aimed to investigate the effect of neoadjuvant chemoradiotherapy on objectively measured in vivo muscle mitochondrial function and whole-body physical fitness. METHODS: We prospectively studied 12 patients with rectal cancer who completed standardized neoadjuvant chemoradiotherapy, recruited from a large tertiary cancer centre, between October 2012 and July 2013. All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy. Data were analysed and reported blind to patient identity and clinical course. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise (ml.kg-1.min-1), and the post-exercise phosphocreatine recovery rate constant (min-1), a measure of muscle mitochondrial capacity in vivo. RESULTS: Median age was 67 years (IQR 64-75). Differences (95%CI) in all three primary variables were significantly negative post-NACRT: Oxygen uptake at estimated anaerobic threshold -2.4 ml.kg-1.min-1 (-3.8, -0.9), p = 0.004; Oxygen uptake at Peak -4.0 ml.kg-1.min-1 (-6.8, -1.1), p = 0.011; and post-exercise phosphocreatine recovery rate constant -0.34 min-1 (-0.51, -0.17), p<0.001. CONCLUSION: The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms, no doubt multifactorial, may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy. This may have implications for targeted interventions to improve physical fitness pre-surgery. TRIAL REGISTRATION: Clinicaltrials.gov registration NCT01859442.