Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05686213 |
| Other study ID # |
NL81016.091.22 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2022 |
| Est. completion date |
March 1, 2024 |
Study information
| Verified date |
November 2022 |
| Source |
Radboud University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goals of this study is 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.
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.
The main study parameters will be the feasibility in terms of trial participation rate and
attendance, and intervention fidelity (e.g. extend of and reasons for adaptations to the
exercise intervention). The secondary study parameters are the average effect sizes and
measures of variability on immune function, infiltration and vascularisation. Measurements
will take place at baseline, directly after finishing NCRT, and within a week before surgery.
Description:
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.
Another potential mechanism through which exercise may affect tumour response to NCRT in
patients with rectal cancer is an altered microbiome. At the pathology department of
Radboudumc, dr. Boleij and Prof. dr. Nagtegaal examine the mucosal and fecal microbiome in
relation to colorectal cancer development and disease progression using in situ detection
techniques and feces collections at multiple timepoints during disease trajectories. Exercise
may have a positive effect on the microbiome, by modifying the microbiota and increases
health-beneficial gut bacteria populations. An insight in changes in the microbiome after an
exercise intervention during NCRT might provide valuable information about the tumour
micro-environment. Hence, in this pilot study we want to exploratively include the collection
of feces in patients with rectal cancer.
Besides the effects of exercise training after multiple sessions, pre-clinical studies showed
that the induced effects of one exercise bout might already interfere with mechanisms
underlying cancer progression and treatment response. Potential mechanisms for this acute
phenomenon include mild hyperthermia, augmented tumour perfusion, reduced tumour hypoxia, and
enhanced immune mobilisation. Even after one exercise bout these mechanisms may enhance
tumour oxygenation and immunity, which could potentially, driven by accumulative effects of
repeated acute exercise, result in improved radiotherapy efficacy.
An acute bout of exercise in healthy participants induces a large transient increase in
peripheral blood lymphocyte counts, including NK cells and CD8+ T cells. In addition, an
acute exercise bout can increase NK-cell cytotoxicity with 50 - 100%. Lymphocyte numbers
return to below pre-exercise values 1-2 hours after exercise, possibly reflecting a
redistribution of immune cells to peripheral tissue, which could be beneficial for immune
surveillance. It was shown that acute exercise in healthy individuals selectively mobilises
memory CD8+ T cells. Notably, Goedegebuure et al. showed that esophageal cancer patients
enriched with circulating CD8+ memory T cells prior to the start of treatment were more
likely to have a pathological complete response after NCRT. Also, high levels of CD8+ memory
T cell infiltration in the tumour are associated with a good prognosis in both esophageal and
colorectal cancer.
Besides the immune activation, pre-clinical studies showed that acute exercise might impact
the tumour perfusion and hypoxia. As reported above, several pre-clinical studies report more
patent and perfused vessels after exercise training, resulting in a larger and more
homogeneously perfused tumour area. An acute reduction in hypoxia might make the tumour more
sensitive to the radiotherapy. In addition, exercise-induced hyperthermia of the human body
might induce vasodilatation, increase perfusion and make the tumour more permissible for
immune cells. Consequently, linking the immune effects and perfusion effects of acute
exercise to radiotherapy efficacy reveals the possibility of acute exercise as
radiosensitizer. A close timing of an exercise session directly prior a radiotherapy session
might be beneficial for the radiotherapy response. Exercise prior to a radiotherapy session
was proven to be feasible and safe in patients with non-small cell lung carcinoma.
The feasibility and safety of an exercise intervention during NCRT in patients with rectal
cancer and esophageal cancer has been evaluated in previous studies. High adherence rates and
no adverse events related to the exercise intervention were reported in these studies, and
most reported barriers were willingness to participate and recruitment of patients. We
foresee that close collaborations with our multidisciplinary research team (e.g. clinical
researchers, clinicians,specially trained physiotherapists, tumour immunologist, pathologist)
and alignment of measurements with routine clinical practice will reduce these barriers.
These previous studies explored the effects of exercise interventions during neoadjuvant
therapy on physical activity, fitness, HRQoL, and post-operative complications. Additionally,
exploratory studies detected that exercise during NCRT in patients with rectal cancer and
esophageal cancer might lead to an augmented tumour regression. However, both in patients
with rectal and esophageal cancer, there is only one RCT investigating the feasibility of a
supervised exercise intervention during NCRT, and none of the currently performed studies
included investigations of underlying mechanisms of action.
To our knowledge there is only one RCT evaluating the feasibility of aerobic exercise prior
to each radiotherapy session during concomitant chemoradiotherapy (24). This small trial in
patients with locally advanced non-small cell lung cancer showed that pre-radiotherapy
exercise was safe and feasible.
We aim to conduct a three-arm pilot RCT in patients with rectal or esophageal cancer, while
simultaneously collecting data on the underlying mechanisms through which exercise can
influence tumour microenvironment. This pilot will investigate the feasibility of 1) AE + RT;
an exercise intervention consisting of two exercise sessions per week combining
moderate-to-high aerobic exercise (AE) and resistance exercise (RE) supervised by a
first-line specially educated physiotherapist, and one home-based moderate intensity aerobic
exercise session per week, 2) ExPR; in-hospital exercise intervention consisting of 30 min
moderate intensity aerobic exercise sessions within one hour prior to every radiotherapy
session (five times a week). Both interventions are similar in terms of weekly exercise
volume. Simultaneously, this pilot will gather preliminary data on measures of variability on
the potential efficacy of exercise on immune function, immune infiltration and
vascularisation of both exercise interventions. Additionally, we will evaluate the acute
immune response of one exercise session in patients in the ExPR group.
Knowledge on the feasibility and preliminary results of the underlying mechanisms of exercise
regimes will be a first step towards improved supportive care for patients with rectal and
esophageal cancer receiving neoadjuvant chemoradiation. If the preliminary results on
underlying mechanisms are promising, we aim to write a grant application to set up a
sufficiently powered multi-centre randomized controlled trial in cooperation with other large
medical centres (e.g. Erasmus MC, Amsterdam UMC), focusing on the effects of exercise on
tumour responses and underlying mechanisms.
