Aerobic Fitness or Muscle Mass Training to Improve Colorectal Cancer Outcome

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.

• Continuous aerobic and resistance exercise intervention (Behavioral), also known as AE+RE: Continuous aerobic and resistance exercises intervention
• Continuous aerobic and aerobic interval exercise intervention (Behavioral), also known as AE+AI: Continuous aerobic and aerobic interval exercise intervention

Primary outcomes

• Chemotherapy dose modifications [between baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch. Cycle duration is 2 or 3 weeks.]: Number of patients requiring dose modifications (i.e. dose reductions, treatment delay, discontinuation or switch)
• Progression free survival [between baseline and time to progression (up to 2 years)]: From date of randomization until the date of first documented progression

Secondary outcomes

• NK-cell functionality [change from baseline to 6th treatment cycle or treatment switch (Cycle duration is 3 weeks)]: degranulation and cytotoxicity of NK-cells on peripheral blood mononuclear cells
• Hospitalization [during treatment (6 treatment cycles of 3 weeks per cycle or 8 treatment cycles of 2 weeks per cycle)]: Number of patients requiring hospitalisation assessed from medical records
• Treatment-related toxicity [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: severity of treatment-related toxicity assessed with the Common Terminology Criteria for Adverse Events
• Aerobic fitness [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Astrand-Rhyming test
• Maximum short exercise capacity [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Steep ramp test
• Muscle strength [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: indirect 1 repetition maximum for leg press
• Muscle mass [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Computed Tomogrophy scans
• Health-related quality of life [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: European Organization for Research and Treatment of Cancer Quality of Life Questionaire Core 30. Score from 0-100, higher scores indicate better functioning
• Fatigue [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: European Organization for Research and Treatment of Cancer Quality of Life Questionaire- Fatigue 12. Score 0-100, higher scores indicate higher levels of fatigue
• Resilience [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Resilience Evaluation Scale, score 0-40, higher scores indicate better resilience
• Empowerment [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Self-efficacy-28, score 4-28, higher scores indicate better empowerment
• Physical activity [change from baseline to 3rd/4th and 6th/8th treatment cycle or treatment switch (cycle duration is 2 or 3 weeks)]: Short QUestionnaire to ASsess Health enhancing physical activity, higher scores indicate higher physical activity levels

Sex: All, ages: 18 Years to any

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

• Results publication: Brouwer CG, Tusscher MRT, de Roos BM, Gootjes EC, Buffart TE, Versteeg KS, Mast IH, Streppel MM, Werter IM, May AM, Verheul HMW, Buffart LM; AMICO Consortium. Experiences of patients with metastatic colorectal cancer participating in a supervised exercise intervention during chemotherapy. Support Care Cancer. 2025 Jan 8;33(2):82. doi: 10.1007/s00520-024-09101-1. PMID 39779537