Aerobic Fitness or Muscle Mass Training to Improve Colorectal Cancer Outcome (AMICO)

Radboud University Medical Center

Status: Enrolling

Conditions: Lifestyle; Survivorship; Chemotherapeutic Toxicity; Colorectal Cancer

Treatments: Behavioral: Continuous aerobic and resistance exercise intervention; Behavioral: Continuous aerobic and aerobic interval exercise intervention

Study type: Interventional

Funder types: Other

Identifiers

NCT04754672

09150171910017 (Other Grant/Funding Number)

NL72482.091.20 (Other Identifier)

2020-6867

Details and patient eligibility

About

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.

Full 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.

Enrollment: 228 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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228 participants in 3 patient groups

Continuous aerobic and resistance exercise (AE+RE)

Experimental group

Description:

Two 60 min moderate-to-high intensity exercise sessions per week supervised by a physiotherapist. Continuous aerobic exercise: 15-20 min continuous aerobic exercise (e.g. walking) of moderate intensity (Borg 13-14 'somewhat hard'). Resistance exercise (25 min): 6 exercises targeting large muscle groups vertical row, squat, bench press, pull over, abdominal crunch, and lunge. 2 sets of 10 repetitions at 70-80% of 1 RM. To ensure adequate training load over time, tests are repeated every 3/4 weeks aligned with the chemotherapy cycle. One additional (third) session from home at moderate intensity for at least 30 min. A brochure with exercise guidelines is provided.

Treatment:

Behavioral: Continuous aerobic and resistance exercise intervention

Continuous aerobic and aerobic interval exercise (AE+AI)

Experimental group

Description:

Continuous aerobic exercise: 15-20 min continuous aerobic exercise (e.g. walking) of moderate intensity (Borg 13-14 'somewhat hard'). Aerobic interval (25 min): cycling with high intensity intervals alternated with recovery intervals. Intensity of the interval: between 85% and 95% of estimated maximum heart rate, adjusted to Borg 16-18 'hard - very hard'. In between the intervals, light intensity cycling will be performed for active recovery at 30% of Wmax estimated from Steep ramp test and adjusted to Borg \< 12. One additional (third) session from home at moderate intensity for at least 30 min. A brochure with exercise guidelines is provided.

Treatment:

Behavioral: Continuous aerobic and aerobic interval exercise intervention

Usual care control group

No Intervention group

Description:

Patients in the usual care group receive care as usual. In addition, a brochure with exercise guidelines for cancer survivors is provided