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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.

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.

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

Continuous aerobic and resistance exercises intervention

Continuous aerobic and resistance exercise intervention

Continuous aerobic and aerobic interval exercise intervention

Laurien M Buffart, PhD

D. Sommeijer, MD

H.M. Otten, MD

A.A. v Zweeden, MD

T.E. Buffart, MD

K.S. Versteeg, MD

K. Bolhuis, MD

R. Koornstra, MD

I. Werter, MD

M. Streppel, MD

M. Wumkes, MD

G.J. Creemers, MD

A. Beeker, MD

L. Buffart, Dr.

E. Gootjes, MD

J.J.B. Janssen, MD

A. May, Prof.

J. Roodhart, Dr.

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.

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.

Treatment allocation is concealed. Baseline assessments prior to group allocation.

Aerobic Fitness or Muscle Mass Training to Improve Colorectal Cancer Outcome

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

IPD will be shared via the POLARIS consortium see PROSPERO registry CRD42013003805 or paper: Buffart et al. Systematic Reviews 2013; 2: 75.

Number of patients requiring dose modifications (i.e. dose reductions, treatment delay, discontinuation or switch)

From date of randomization until the date of first documented progression

degranulation and cytotoxicity of NK-cells on peripheral blood mononuclear cells

Number of patients requiring hospitalisation assessed from medical records

severity of treatment-related toxicity assessed with the Common Terminology Criteria for Adverse Events

indirect 1 repetition maximum for leg press

European Organization for Research and Treatment of Cancer Quality of Life Questionaire Core 30. Score from 0-100, higher scores indicate better functioning

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 Evaluation Scale, score 0-40, higher scores indicate better resilience

Self-efficacy-28, score 4-28, higher scores indicate better empowerment

Short QUestionnaire to ASsess Health enhancing physical activity, higher scores indicate higher physical activity levels

Spots Global Cancer Trial Database for continuous aerobic and aerobic interval exercise intervention