The effects of neoadjuvant chemoradiotherapy and a structured exercise training programme on phusical fitness and in vivo mitochrondrial function in advanced rectal cancer patients

Outcomes after major surgery depend partly on patients’ physiological tolerance to iatrogenic trauma. Objectively measured fitness assessments (cardiopulmonary exercise testing; CPET) show a link between poor fitness and poor surgical outcome, especially in major colorectal surgery. However evidence on fitness of surgical patients undergoing neoadjuvant chemoradiotherapy (NACRT) and/or preoperative exercise training is lacking. This thesis focuses on the physiological effects of NACRT and a preoperative structured responsive exercise training programme (SRETP) on objectively measured physical fitness using cardiopulmonary exercise testing, and the related effects on mitochondrial function using 31-phosphorus magnetic resonance spectroscopy (31P MRS) in operable advanced rectal cancer patients. First, CPET variables (oxygen uptake ( o2) at estimated lactate threshold ( L) and at peak exercise) were measured in advanced rectal cancer patients pre and post-NACRT and were followed up to 1 year postoperatively. A reduction in o2 at L and o2 at Peak exercise was observed (-1.5 and -1.4 ml.kg-1.min-1 respectively; p<0.0001), both significantly associated with in-hospital complications. This is the first direct evidence that the benefits of NACRT in tumour downsizing may be partly offset by increased perioperative risk due to a reduction in physical fitness. A SRETP was then constructed, and a feasibility and tolerability study carried out. The SRETP improved physical fitness within 6 weeks following NACRT ( o2 at L +3.3 ml.kg-1.min-1 and o2 Peak by +5.8 ml.kg-1.min-1), enough to reverse the deleterious effects of NACRT. A 98% adherence proves the SRETP both feasible and tolerable, with no adverse events encountered. Next, locally advanced rectal cancer patients were recruited to an interventional pilot study scheduled to undergo standardised NACRT and a 6-week SRETP (exercise group n=22) or a control period (n=13). A significant benefit in o2 at L of +2.12 ml.kg-1.min-1 (p<0.0001) in the exercise group was observed. This study reinforces the benefits of prehabilitation with exercise training to improve physical fitness after the deleterious effects of NACRT prior to the added insult of major surgery. Lastly, patients were randomized to the SRETP or to negative control after undergoing standardized NACRT, serial measures of whole body fitness and in vivo mitochondrial function by 31P MRS (measuring the rate constant of phosphocreatine recovery, kPCr). Significant reductions in o2 at L (-2.36 ml.kg-1.min-1) were observed with NACRT, after which the SRETP improved fitness ( o2 at L +3.85 ml.kg-1.min-1). A significant reduction in kPCr of -0.34 was found with NACRT, improved by +0.66 after SRETP. These novel, clinically relevant findings show a significant decline in fitness with NACRT in an advanced rectal cancer cohort, reversible by a tailored exercise intervention post-NACRT. Concomitant changes in muscle mitochondrial function may account for this acute loss in fitness. The improvement in mitochondrial function observed with exercise, might indicate that a structured intervention immediately after NACRT is necessary to rescue and reverse NACRT’s deleterious effect on mitochondrial function and fitness in this patient cohort.