Exercise during Neoadjuvant chemoradiation Treatment to improve rectal and esophageal cancer Outcome - pilot trial.

Patients with primary rectal or esophageal carcinoma are often treated with
neoadjuvant chemoradiation therapy (NCRT) for 5 weeks, followed by a waiting
period (8 - 10 weeks for rectal cancer and 6 - 12 weeks for esophageal cancer).
This treatment aims to reduce the tumour size and stage prior to surgical
resection. However, Pathological complete response rate after NCRT is
relatively low for these patient populations: 15-20% for rectal cancer and 30%
for esophageal cancer. Additionally, many patients face severe side effects
during NCRT, reducing their physical function and health-related quality of
life (HRQoL).
Strong evidence from randomized controlled trials (RCT) showed that
physical exercise during chemotherapy or radiotherapy benefits physical
fitness, muscle mass, muscle strength, fatigue, and HRQoL. Moreover, exercise
may counteract treatment-related side effects and help prevent treatment
modifications, which might benefit 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 rectal and esophageal
carcinoma receiving NCRT is limited. Additionally, exercise type, timing,
intensity, and duration 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 different exercise frequency,
intensity, and timing can induce different effects on underlying physiological
mechanisms.
Observational studies in patients with breast, colorectal or prostate
cancer showed that physical activity and fitness were positively associated
with cancer-specific survival, however, the causality and underlying mechanisms
linking exercise to clinical outcome are largely unknown. These mechanisms are
essential to understand the potential and limitations of exercise as integral
part of cancer care, and to further optimize exercise prescriptions.
Pre-clinical studies showed that both a chronic exercise intervention as well
as an acute exercise bout can impact the tumour microenvironment via several
underlying mechanisms. Studies focusing on these mechanisms have shown that
exercise can directly impact tumour growth via normalising tumour vasculature,
increasing perfusion, reducing hypoxia, and thereby increasing sensitivity for
anticancer treatment. Furthermore, exercise can induce a mobilisation,
activation and redistribution of natural killer (NK) cells which leads to a
better infiltration of activated NK cells in the tumour. Moreover, studies in
healthy participants showed that one bout of exercise can already largely
mobilise immune cells including NK cells and T cells. Nevertheless, it is
unclear whether these results can be translated to patients with cancer. A
recent study in patients with esophageal cancer showed that patients with more
circulating T cells prior NCRT are more likely to have a pathological complete
response. Hence, exercise prior to each radiotherapy session may mobilise
immune cells including T cells and thereby enhance radiotherapy response. A
study in patients receiving NCRT would provide an opportunity to directly
assess the effects of exercise on the tumour in situ.
A phase II randomised controlled exercise trial in patients with rectal
cancer showed that exercise is feasible during NCRT and may enhance tumour
regression. Similarly, feasibility of an exercise trail in patients with
esophageal cancer was shown, including a non-randomised exercise trial which
suggests an improved tumour regression in the exercise group. Additionally, a
RCT in patients with non-small cell lung cancer showed that aerobic exercise
prior to each radiotherapy session was feasible. None of these studies included
evaluations of underlying mechanisms of action, nor did they compare different
exercise programs.
Knowledge on the feasibility of different exercise programs and
variability in immune activation, immune cell infiltration and vascularisation
is essential to design a future well-powered RCT examining exercise
intervention efficacy. Increasing the efficacy of neoadjuvant treatment in
these patient populations would benefit organ-conserving surgery and survival.

To 1) evaluate feasibility and fidelity of a three-arm RCT containing a
twice-weekly exercise intervention supervised by a first-line (oncology)
physiotherapist and a 5-day weekly in-hospital exercise intervention versus
usual care in patients with rectal cancer or esophageal cancer receiving NCRT,
and 2) generate preliminary data on the variability in exercise responses on
immune function, immune infiltration, and vascularisation of the tumour, and
the composition and function of the microbiome.

pilot randomized controlled trial

Participants will be randomized in one of three study arms: 1) AE + RE - group;
combined moderate-to-high intensity aerobic exercise (AE) and resistance
exercise (RE) twice a week supervised by a specially trained first-line
physiotherapist, and a home-based moderate intensity aerobic exercise session
once a week; 2) ExPR - group; in-hospital exercise intervention consisting of
30 min moderate intensity aerobic exercise within one hour prior to every
radiotherapy session (five times a week); and 3) UC - group; a control group
that receives usual care.

Patients will visit the hospital three times for study measurements. These
visits will be combined with regular preoperative hospital visits as much as
possible. Prior to the start of the treatment and randomisation, blood samples
will be taken and a fitness test will be performed (T0). These measurements
will be repeated directly after completion of the NCRT (T1) and within a week
before surgery (T2). The risks of the blood drawing and fitness tests are
negligible. Both a biopsy at diagnosis and the removal of the tumour will be
performed as part of usual care. The ExPR exercise intervention will be
combined with regular radiotherapy appointments. The safety of the exercise
intervention during radiotherapy or chemotherapy has been well documented.