NEJM: First Phase 3 Clinical Trial Confirms Exercise Can Fight Cancer, Comparable to Anti-Cancer Drugs

Colorectal cancer is the third most commonly diagnosed cancer worldwide (nearly 2 million new cases annually, second only to lung and breast cancer) and the second leading cause of cancer death (nearly 1 million deaths annually, second only to lung cancer). The standard treatment for stage III or high-risk stage II colon cancer patients includes 3-6 months of adjuvant chemotherapy with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin), CAPOX (capecitabine + oxaliplatin), or fluoropyrimidine monotherapy after surgery. Despite these treatments, 20%-40% of patients still experience recurrence. Moreover, surgery and adjuvant chemotherapy cause side effects that impair quality of life and reduce physical function. For this patient group, interventions are needed that can both improve survival and enhance quality of life.

Preclinical studies have shown that exercise can slow cancer progression (including colon cancer). Additionally, observational studies indicate that colorectal cancer patients (including stage III colon cancer) who increase recreational physical activity after treatment have reduced risks of cancer recurrence and death. Possible mechanisms for these associations include exercise effects on metabolic growth factors, inflammation, and immune function. Although these findings suggest exercise may help extend cancer patients' lives, the methodological limitations of observational studies mean there is a lack of Level 1 evidence (highest level of evidence), so the conclusions remain uncertain.

On June 1, 2025, researchers from Queen's University, University of Alberta, and other institutions in Canada published a clinical research paper titled Structured Exercise after Adjuvant Chemotherapy for Colon Cancer in the prestigious international medical journal New England Journal of Medicine (NEJM).

This phase 3 randomized controlled trial (RCT) showed that structured exercise significantly improved disease-free survival (DFS) and overall survival (OS) in post-surgery colon cancer patients, with effects comparable to some adjuvant drug therapies. This study is the first phase 3 trial with long-term follow-up to demonstrate a causal benefit of exercise for colon cancer patients after surgery. It not only provides Level 1 evidence for exercise as an adjuvant cancer therapy but also suggests mechanisms by which exercise may reduce tumor recurrence or death risk.

Whether exercise interventions can substantially improve cancer patient prognosis requires confirmation by phase 3 clinical trials. To address this gap in clinical practice, the research team launched the CHALLENGE phase 3 randomized controlled trial in 2009, enrolling stage III or high-risk stage II colon cancer patients who had completed adjuvant chemotherapy. Patients were randomized to a structured exercise intervention group or a usual care health education control group.

In this paper, the research team reported final results on disease-free survival (primary endpoint), overall survival, patient-reported physical function, objective physical performance and fitness, and moderate-to-vigorous recreational physical activity (MVPA), among other key secondary endpoints.

The trial was conducted at 55 medical centers in Canada and Australia, enrolling 889 stage III or high-risk stage II colon cancer patients who had undergone curative surgery and 3-6 months of adjuvant chemotherapy, with 2-6 months elapsed since chemotherapy completion. Patients were randomized 1:1 to either the “structured exercise intervention group” (445 patients) or the “usual health education control group” (444 patients). The control group received only a comprehensive health education booklet, while the exercise group completed a 3-year exercise program under certified fitness coach supervision or guidance.

The structured exercise intervention comprised three phases:

• Phase 1 (0-6 months): Patients attended a mandatory face-to-face behavioral support session every two weeks (12 sessions), 12 supervised exercise sessions, and 12 recommended supervised exercise sessions.
• Phase 2 (7-12 months): Patients attended a behavioral support session every two weeks (12 sessions, face-to-face or remote), and 12 recommended supervised exercise sessions.
• Phase 3 (12-36 months): Patients attended a behavioral support session once monthly (24 sessions, face-to-face or remote), and 24 recommended supervised exercise sessions.

The exercise program aimed to increase recreational aerobic activity by at least 10 metabolic equivalent task (MET) hours per week from baseline within the first 6 months, then maintain or further increase activity over the next 2.5 years. The focus was on promoting at least moderate-intensity aerobic exercise, such as brisk walking for 1 hour (approximately 4 MET-hours).

Over 3 years, the exercise group’s MVPA was 5.2–7.4 MET-hours/week higher than the control group; maximal oxygen consumption was 1.3–2.7 mL/(kg·min) higher; and the 6-minute walk distance was 13–30 meters longer.

During a median follow-up of 7.9 years, the exercise group had significantly longer DFS and OS than the health education group. The exercise group reduced the risk of disease recurrence, new primary cancers, or death by 28%, with a 5-year DFS rate of 80.3% versus 73.9% in the control group. The risk of death was reduced by 37%, with an 8-year OS rate of 90.3% versus 83.2% in controls.

Regarding safety, 351 patients (82.0%) in the structured exercise group and 352 patients (76.4%) in the control group experienced at least one adverse event. Musculoskeletal adverse events occurred in 18.5% of the exercise group and 11.5% of controls, but only 8 cases (10%) in the exercise group were deemed directly related to exercise, mostly mild sprains. Postoperative exercise should be conducted under rehabilitation therapist guidance to avoid sudden high-intensity activity and should progress gradually.

Why can exercise help fight cancer?

1. Immune enhancement: Exercise mobilizes immune cells to precisely clear micrometastases.
2. Metabolic regulation: Exercise helps reduce insulin and inflammatory factors (e.g., IL-6), cutting tumor growth signals.
3. Microenvironment remodeling: Exercise increases blood flow shear stress, inhibiting tumor metastasis to liver and lungs.

In summary, this phase 3 randomized controlled trial with long-term follow-up provides Level 1 evidence (highest evidence grade) that exercise interventions can significantly improve disease-free and overall survival after colon cancer surgery, at very high cost-effectiveness, with benefits comparable to some expensive targeted drugs. Exercise also improves physical function and quality of life and has good safety. This study provides a solid evidence base for the importance of exercise as adjuvant therapy, supporting integration of personalized exercise prescriptions with routine postoperative care and wider implementation in oncology centers.

Reference

[1]. Kerry S. Courneya, Ph.D., Janette L. Vardy, M.D., Ph.D., Christopher J. O’Callaghan, D.V.M., Ph.D., Sharlene Gill, M.D., Christine M. Friedenreich, Ph.D., Rebecca K.S. Wong, M.B., Ch.B., Haryana M. Dhillon, Ph.D., +20 , for the CHALLENGE Investigators. Structured Exercise after Adjuvant Chemotherapy for Colon Cancer. DOI: 10.1056/NEJMoa2502760. url: https://www.nejm.org/doi/full/10.1056/NEJMoa2502760