Exercise prehabilitation in colorectal cancer: establishing mechanisms of adaptation to advance optimisation and stratification.

Bowel cancers, such as colon or rectal, are a leading cause of death, especially in those over the age of 60 years. However, if caught early, these cancers also present an opportunity for curative treatment. There is however a required period of less than 31 days from diagnosis of cancer to resection with curative intent, and this limits the window of opportunity to physically prepare patients for their surgery. Despite often successful surgery, the burden of cancer (which some patients may have been harbouring for a long time) and the physiological insult of surgery each negatively impact surgical recovery with both short- and long-term consequences (e.g., increased hospital length of stay and hampered return to normal activities, respectively). Declines in cardiorespiratory fitness ((CRF); the fitness of the heart and lungs) and losses of skeletal muscle mass and function, both of which can be enhanced through different types of exercise training, each contribute strongly to poor clinical (i.e., surgical complications and overall survival) and patient-centred (i.e., quality of life) outcomes in these patients. However, despite this knowledge, the underpinning mechanisms of why these aspects of physiology decline with colorectal cancer, and how colorectal cancer impacts responses to exercise training remain unknown. As such, a first aim of this proposal is to investigate multiple facets of cardiorespiratory and skeletal muscle biology in patients with colorectal cancer compared to sex and age-matched controls. The second aim surrounds surgical "prehabilitation". Constituting exercise in the preoperative period, prehabilitation is a means by which to counter deleterious changes in the cardiorespiratory system. Promisingly, previous research has shown that cardiorespiratory adaptation can be achieved in less than 31-days with an exercise modality known as high-intensity interval training (HIIT). Notably however, HIIT (nor traditional aerobic exercise (i.e., prolonged moderate intensity jogging or cycling)) does not appear able to robustly enhance skeletal muscle mass or function in colorectal cancer patients and this is a major barrier to achieving optimal physical condition in preparation for surgery. To address this, we propose a trial of HIIT versus HIIT plus resistance exercise training ((RET; weights-based training), which we will call ReHIIT) in colorectal cancer patients. We hypothesise that adding RET to HIIT will present major benefits by achieving gains in both muscle mass and CRF, and will test this using a statistical method whereby improvements in these two separate aspects are combined to give a numerical value of improvement in 'overall health'. Crucially, we will also conduct laboratory investigations of muscle, blood and urine samples to determine the underlying mechanisms of declines in cardiorespiratory and skeletal muscle status with colorectal cancer, and the impact of colorectal cancer on the effectiveness of prehabilitation. These laboratory investigations will include measures of: i) muscle protein turnover (i.e., cell growth and breakdown), ii) blood vessel remodelling, and iii) circulating proteins. We will also build mathematical models to predict which patients will likely best respond to either type of prehabilitation (HIIT or ReHIIT) to help inform future personalised-medicine approaches.

Bowel cancers are a leading cause of death, but also present opportunity for curative treatment. From diagnosis of colorectal cancer, there is a mandated period of <31 days before resection with curative intent. Yet despite often successful surgery, the burden of cancer and the physiological insult of surgery negatively impact recovery with both short- and long-term consequences e.g., increased hospital stay and hampered return to normal activities. Declines in cardiorespiratory fitness (CRF) in addition to skeletal muscle wasting and dysfunction contribute strongly to worse clinical and patient-centred outcomes, albeit through poorly understood mechanisms. As such, a first aim of this proposal is to investigate cardiovascular and skeletal muscle physiology during colorectal cancer burden compared to age-matched controls. The second aim surrounds "prehabilitation". Constituting exercise in the preoperative period, prehabilitation is a means by which to counter deleterious changes in the cardiorespiratory system; adaptations that can be achieved in <31-days with high-intensity interval training (HIIT). However, neither HIIT, nor traditional aerobic exercise, robustly enhance skeletal muscle mass or function; a major barrier to optimising physical condition. To address this, we propose a trial of HIIT vs. HIIT+resistance exercise training (RET). We hypothesise that RET adjuvant to HIIT will confer major benefit in terms of achieving gains in both muscle mass, function and CRF, and will test this using composite statistical powering. Crucially, we also propose complementary metabolic and molecular investigations to determine the mechanisms underlying loss of muscle mass and function and interactions with cancer (cf. controls) and prehabilitation, including: i) muscle protein turnover, ii) vascular remodelling, and iii) metabolomic/proteomic signatures. We will also build Bayesian models of responsiveness to prehabilitation to inform personalised-medicine approaches.