ExeNTrO: Exercise During Neoadjuvant Chemoradiation Treatment to Improve Rectal and

Strong evidence from randomized controlled trials (RCT) showed that physical exercise during chemotherapy or radiotherapy benefits physical fitness, muscle mass, muscle strength, fatigue, and health-related quality of life (HRQoL). Additionally, exercise may counteract treatment-related side effects and help prevent treatment modifications, which might improve survival. To date, the majority of RCTs examining the effects of exercise during cancer treatment have been conducted in patients with breast cancer or prostate cancer who were treated with curative intent. Due to differences in treatment trajectories and side effects, generalisability of these findings to patients with other types of cancer is limited. Additionally, widespread implementation of exercise in clinical cancer care is hampered by the lack of knowledge of the exercise effects on clinical outcome, e.g. tumour recurrence, progression and cancer-specific survival. Also, the causality and underlying physiological and biological mechanisms linking exercise to clinical outcome are largely unknown. This knowledge is essential to understand the potential and limitations of exercise as integral part of cancer care and to further optimize exercise interventions. Pre-clinical studies have shown that exercise can directly impact tumour growth and function as sensitizer for anticancer treatment. However, it is unclear whether these results can be translated to patients.

Standard treatment for patients with esophageal cancer and for a part of the patients with rectal cancer includes neoadjuvant chemoradiation treatment (NCRT), followed by a 6 - 12 weeks or 8 - 10 weeks waiting period prior to surgical resection, respectively. NCRT might reduce tumour size and even induce a pathological complete response. However, pathological complete response rate after NCRT is relatively low for these patient populations: 15-20% for rectal cancer and 30% for esophageal cancer. A part of patients with rectal cancer are treated with radiotherapy (50 Gray in 25 fractions of 2 Gray) for five weeks combined with the oral chemotherapy capecitabine. NCRT for patients with esophageal cancer includes radiotherapy (41.4 Gray in 23 fractions for 5 days a week) combined with the intravenous chemotherapies paclitaxel and carboplatin once a week for 5 weeks. Besides the curative value of NCRT it may cause severe treatment-related side effects including diarrhoea, fatigue, haematological toxicity, and neuropathy. Exercise training may counteract side effects such as fatigue, neutropenia, neuropathy, and gastrointestinal problems (e.g. nausea) while simultaneously improving physical fitness and HRQoL. Exercise frequency, intensity, timing and type may impact the effects of the intervention. For example, aerobic exercise at higher intensities may provide larger cardiovascular benefits, but may result in more gastrointestinal side effects. Therefore, it is important to study whether exercise is feasible during neoadjuvant chemoradiation, and whether exercise frequency, intensity, and timing can induce different effects. Thus, more knowledge is needed on the feasibility and effectivity of exercise prescriptions in patients with rectal or esophageal cancer, and the robustness of the potential exercise-induced effects across patient populations. Improving neoadjuvant treatment in these patients populations might enable more organ saving surgeries, and increase survival rates.

Potential mechanisms of exercise training influencing clinical and pathological response In addition to the well-established influence of physical exercise on physical fitness and the HRQoL in patients with cancer, pre-clinical studies showed that exercise training can directly influence tumour growth. To illustrate, studies in rodents revealed a few possible mechanisms by which exercise training can influence tumour physiology, including exercise-induced immune reactions, and alterations in vascularisation and perfusion of the tumour. Studies in mice showed exercise-induced immune reactions, stimulated by the release of epinephrine and the cytokine interleukin-6 (IL-6). IL-6 and epinephrine can initiate an immune response which mobilises, activates and redistributes natural killer (NK) cells. These processes have shown to stimulate the infiltration of activated NK cells in the tumour and to reduce tumour growth. Secondly, in mouse-models, exercise training showed to induce a 'normalisation' of the intratumoural vasculature, reducing hypoxia and thereby improving the chemotherapeutic and radiotherapeutic efficiency. Both pathways might contribute to a more rapid tumour regression. Due to differences between animal models and humans, including feasible exercise levels, tumour characteristics, metabolic rates and potential comorbidities, it is unclear whether these results can directly be translated to (wo)men.

The number of studies in patients investigating mechanistic pathways of exercise-induced tumour changes are scarce. Long-term exercise training as well as acute exercise bouts are characterised by specific physiological responses leading to immediate and chronic adaptations. Exploratory studies on exercise during neoadjuvant chemotherapy in patients provided initial support for the hypothesis that exercise can modulate several host- and tumour related pathways. These studies showed that exercise influenced circulating systemic factors, such as vascular endothelial growth factor (VEGF), Tumour Necrosis factor (TNF)-α, interleukins (ILs), and intracellular adhesion molecule (ICAM)-1. Due to the exercise-induced release of circulating systemic anti-inflammatory cytokines and angiogenic factors, aerobic training might improve immune activation in patients. Indeed, studies investigating the immune system showed that acute exercise induces a mobilisation of NK cells (and an improved NK-cell cytotoxicity in patients with cancer. In addition, data from our METRIC pilot trial in 14 patients with breast or colon cancer, showed that a 9-week exercise intervention during chemotherapy preserved NK-cell functionality (degranulation and cytotoxicity) compared to a reduction in the usual care control group, with a 10% difference between groups.

To our knowledge there are only two clinical trials in patients who investigated the influence of exercise training on tumour perfusion and vascularisation. In the study of Jones et al. among women with breast cancer, only limited data was available for perfusion assessments due to the relatively high proportion of patients with pathological complete responses. The study of Florez Bedoya et al. in patients with pancreatic cancer showed an increased number of vessels, elongated vessels, open vessels and an increased microvascular density in the tumour of patients who received an exercise intervention compared to historic control samples. Studies assessing changes in immune activation in the blood as well as intra-tumoural vascularisation and immune infiltration after exercise training during NCRT are non-existent in patients with rectal or esophageal cancer.