Clinical trial NCT04754672: Aerobic Fitness or Muscle Mass Training to Improve Colorectal Cancer Outcome
Official title: Aerobic Fitness or Muscle Mass Training to Improve Colorectal Cancer Outcome (AMICO). The Effects of Exercise on Chemotherapy Dose Modification and Progression Free Survival in Patients With Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Colorectal Cancer
Chemotherapeutic Toxicity
Survivorship
Lifestyle
Keywords: Exercise
Muscle strength
Cardiorespiratory fitness
Colorectal cancer
Chemotherapy dose modification
Progression free survival
Bayesian adaptive trial
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: UMC Utrecht
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Rijnstate Hospital
name: Jeroen Bosch Ziekenhuis
name: Flevoziekenhuis
name: Catharina Ziekenhuis Eindhoven
name: Meander Medical Center
name: Ziekenhuis Amstelland
name: Amphia Hospital
name: Spaarne Gasthuis
name: Canisius-Wilhelmina Hospital
name: Amsterdam UMC, location VUmc
name: The Netherlands Cancer Institute
First posted: 2021-02-15
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised controlled trial
Primary purpose: SUPPORTIVE_CARE

Brief summary: Evidence from randomized controlled trials shows that exercise during cancer treatment benefits physical fitness, fatigue and quality of life. Since the effect of exercise on clinical outcome is currently unknown, exercise is not included as integral part of standard cancer care. Moreover, evidence regarding the optimal exercise prescription in terms of type and dose is lacking.

To maintain quality of life in patients receiving palliative treatment with chemotherapy, toxicity-induced modifications in the prescribed chemotherapy dose are common. Such modifications - occurring in 40% of patients with metastatic colorectal cancer - may reduce benefit of treatment. The investigators hypothesize that exercise prevents chemotherapy dose modifications by reducing toxicity and enhancing psychological strength. Additionally, based on studies in rodents and preliminary data in patients with cancer, the researchers hypothesize that exercise has beneficial effects on the functionality of the natural killer cells, which play an important role in the innate immune defense against cancer. Both, fewer dose modifications and improved immune function may improve progression-free survival.

This study is a three-armed trial comparing resistance exercise, aerobic interval exercise and usual care in patients with metastatic colorectal cancer to select the optimal exercise prescription for preventing chemotherapy dose modifications. The trial will use a Bayesian adaptive multi-arm multi-stage design with several interim analyses after which an ineffective study arm can be dropped early. This novel design makes the trial more efficient and reduces patients' exposure to suboptimal study arms.

Evidence regarding the exercise effects on i) clinical outcome, ii) the optimal exercise prescription, and iii) the underlying mechanisms, elucidates the potential of exercise to boost benefit from chemotherapy treatment. This evidence provides leads to improve progression-free survival and quality of life of patients suffering from one of the leading causes of cancer death worldwide.

Detailed description: First-line treatment of metastatic colorectal cancer (mCRC) generally includes the chemotherapies fluoropyrimidines in combination with oxaliplatin and/or irinotecan, known as doublet or triplet chemotherapy. A previous study showed that over 40% of patients with metastatic colorectal cancer required dose modifications (including dose reductions, treatment delays or discontinuation) within the first three months of palliative treatment, and around 30% was admitted to hospital due to chemotherapy-related toxicity. Toxicity-induced dose modifications and hospitalization may reduce benefit of treatment. In patients with metastatic colorectal cancer, reductions in muscle mass and lower physical activity levels (\<9 metabolic equivalent of task hours/week) were found to be associated with more dose-limiting toxicity and shorter (progression-free) survival. However, the causality and underlying mechanisms linking physical activity and exercise to cancer outcome have not been elucidated. The immune system (by increased infiltration of activated natural killer cells into the tumour) might play a role as was shown in studies with rodents. In addition, studies among patients showed that exercise may counteract a variety of treatment toxicities (e.g. neutropenia, neuropathy, gastrointestinal side effects, fatigue), but optimal exercise type and dose are unknown.

In addition to the above-mentioned biophysiological effects by which exercise may prevent dose modifications, several studies demonstrated the positive effects of exercise during cancer treatment on quality of life. A recent study on patients' perceptions indicated that exercise helped patients to better cope with cancer treatments, as it gave them psychological strength (i.e. empowerment and resilience) next to physical strength. The investigators hypothesize that exercise reduces treatment-related toxicity and thereby reduces chemotherapy dose modifications and improves progression free survival.

randomised controlled trials are the gold standard for ascertaining treatment efficacy. Studying differences in effects on chemotherapy dose modifications between different exercise programs requires a multi-arm randomised controlled trial. Due to complex logistics and high costs, the conduct of a traditional adequately powered multi-arm exercise trial is difficult with available patients and resources. Therefore, a Bayesian adaptive flexible multi-arm multi-stage design will be used which allows for a number of interim analyses after which a treatment arm can be dropped early if it falls outside the pre-defined futility/efficacy boundaries. This reduces patients' exposure to suboptimal interventions and increases trial efficiency.

This study aims to examine whether:

1. Exercise prevents chemotherapy dose modifications via reduced toxicity and enhanced psychological strength, and which exercise program yields largest benefits.
2. Exercise improves immune function (e.g. functionality of natural killer cells).
3. Benefits of exercise on dose modifications and immune function improves progression-free survival.

Eligibility criteria: Inclusion Criteria:

* mCRC with indication for palliative chemotherapy
* scheduled for treatment with first-line doublet or triplet chemotherapy, according to the national guideline
* able and willing to give written informed consent.

Exclusion Criteria:

* life expectancy \<6 months
* unable to perform basic activities of daily living such as walking or biking
* presence of cognitive disorders or severe emotional instability (e.g., Schizophrenia, Alzheimer, alcohol addiction);
* presence of other disabling co-morbidities that might hamper physical exercise (e.g. heart failure (NYHA classes 3 and 4), chronic obstructive pulmonary disease (COPD, gold 3 and 4), orthopaedic conditions and neurological disorders (e.g., hernia, paresis, amputation, active rheumatoid arthritis);
* insufficient mastery of the Dutch language;
* presence of serious cardiovascular or cardiopulmonary conditions (e.g. unstable angina, arrhythmia or valve disease) such that exercise safety is at risk, as judged by the treating physician.
* Already participating in structured vigorous aerobic and/or resistance exercise ≥ 2 times per week comparable to our intervention

Primary outcomes:
measure: Chemotherapy dose modifications
timeFrame: between baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch. Cycle duration is 2 or 3 weeks.
measure: Progression free survival
timeFrame: between baseline and time to progression (up to 2 years)
Secondary outcomes:
measure: NK-cell functionality
timeFrame: change from baseline to 6th treatment cycle or treatment switch (Cycle duration is 3 weeks)
measure: Hospitalization
timeFrame: during treatment (6 treatment cycles of 3 weeks per cycle or 8 treatment cycles of 2 weeks per cycle)
measure: Treatment-related toxicity
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Aerobic fitness
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Maximum short exercise capacity
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Muscle strength
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Muscle mass
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Health-related quality of life
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Fatigue
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Resilience
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Empowerment
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
measure: Physical activity
timeFrame: change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)
Other outcomes:
Locations:
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Breda
country: Netherlands
facility: Ziekenhuis Amphia
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Utrecht
country: Netherlands
facility: UMCU
Study officials:
References: