Trial Title:
ExeNTrO: Exercise During Neoadjuvant Chemoradiation Treatment to Improve Rectal and Esophageal Cancer Outcome - Pilot Trial
NCT ID:
NCT05686213
Condition:
Oncology
Conditions: Official terms:
Neoplasms
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Unknown status
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Supportive Care
Masking:
None (Open Label)
Intervention:
Intervention type:
Behavioral
Intervention name:
combined aerobic exercise + resistance exercise intervention (AE + RE)
Description:
The AE + RE intervention group will be offered a supervised exercise program which
includes both aerobic and resistance exercise. Exercise sessions will take place twice a
week with a duration of 60 minutes. The training load will be tailored to a patient's
individual fitness level throughout the intervention. Patient will be asked to be
physically active on an additional day in the week on their own (for at least 30 minutes
at moderate intensity) according to the ACSM guidelines for patients with cancer.
Arm group label:
combined aerobic exercise + resistance exercise intervention (AE + RE)
Intervention type:
Behavioral
Intervention name:
Aerobic exercise prior to daily radiotherapy sessions (ExPR)
Description:
Patients in the ExPR in-hospital exercise intervention group will be offered an aerobic
exercise program at moderate intensity. The exercise sessions will take place 5 days a
week (only weekdays), and will have a duration of 30 minutes including a warming-up (5
min) and cooling-down (5 min). Total exercise volume will be aimed at 150 min per week.
The sessions will take place within an hour before the daily radiotherapy session.
Arm group label:
Aerobic exercise prior to daily radiotherapy sessions (ExPR)
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.
Detailed 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Diagnosed with rectal or esophageal cancer
- Patients with rectal or esophageal cancer need to be scheduled for treatment with
neoadjuvant chemoradiation therapy
- Oral capecitabine combined with concurrent radiotherapy (50 Gy in 25 fractions)
for rectal cancer
- CROSS regimen (carboplatin, paclitaxel with concurrent 41.4 Gy in 23 fractions
radiation) for esophageal cancer
- Aged > 18 years
- Provided written informed-consent
Exclusion Criteria:
- Unable to perform basic activities of daily living such as walking or biking
- Presence of other disabling co-morbidity that might hamper or endanger physical
exercise e.g. heart failure, chronic obstructive pulmonary disease, orthopaedic
conditions and neurological disorders
- Presence of cognitive disorders or severe emotional instability (e.g.,
Schizophrenia, Alzheimer, alcohol addiction)
- Immunodeficiency (primary or secondary)
- Insufficient mastery of the Dutch language
- Participation in another exercise and/or dietary intervention study at the same
time.
- Already participating in structured vigorous aerobic and/or resistance exercise ≥ 2
times per week comparable to our intervention and planning to continue this
throughout the period of neoadjuvant chemoradiation.
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Radboud Institute for Health Science
Address:
City:
Nijmegen
Country:
Netherlands
Status:
Recruiting
Contact:
Last name:
Isa Mast, MSc
Phone:
024-3613416
Email:
isa.mast@radboudumc.nl
Contact backup:
Last name:
IKS integraal kwaliteitssysteem
Investigator:
Last name:
Laurien Buffart, Dr
Email:
Principal Investigator
Start date:
September 1, 2022
Completion date:
March 1, 2024
Lead sponsor:
Agency:
Radboud University Medical Center
Agency class:
Other
Source:
Radboud University Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05686213
