– Published in NEJM June 1, 2025
The CHALLENGE trial (Canadian Cancer Trials Group CO.21) represents a pivotal, international, multicenter, randomized phase 3 study that investigated the impact of a structured physical activity program on colon cancer survivors who completed adjuvant chemotherapy. With growing evidence that physical activity improves quality of life and may reduce cancer recurrence risk, the CHALLENGE trial was designed to assess whether a structured exercise intervention could significantly enhance disease-free survival (DFS) and overall survival (OS) in patients with high-risk stage II or stage III colon cancer.
Background and Rationale
Colon cancer survivors face a considerable risk of recurrence following initial treatment. While adjuvant chemotherapy reduces this risk, recurrence rates remain significant. Observational studies suggest that higher levels of physical activity post-treatment are associated with better outcomes, including lower recurrence and mortality rates. However, these studies could not establish causality due to their design limitations. The CHALLENGE trial was conceived to rigorously evaluate, through randomization, whether structured exercise could lead to improved long-term cancer outcomes.
Study Design
The trial enrolled 962 participants across 55 sites in Canada and Australia. After excluding ineligible patients, 889 were randomized (442 to exercise intervention, 447 to health education control). Eligible participants had completed adjuvant chemotherapy for high-risk stage II or stage III colon cancer within the past 60 to 180 days, were disease-free at baseline, and reported low levels of physical activity (<150 minutes per week of moderate to vigorous intensity). Importantly, they had to demonstrate adequate physical function.
Patients were randomized 1:1 to:
- Structured Exercise Program: A 3-year behavioral support intervention designed to achieve ≥10 MET-hours/week of recreational aerobic exercise (equivalent to brisk walking 3–4 times per week for 45–60 minutes). It included supervised sessions, home-based activity, and behavioral counseling based on the Theory of Planned Behavior.
- Health Education Group: This group received standard survivorship health education materials but no structured exercise programming.
The primary endpoint was disease-free survival, defined as time to cancer recurrence, a new primary cancer, or death from any cause. Secondary endpoints included overall survival, physical activity levels, fitness, health-related quality of life, and adverse events.
Baseline Characteristics
Participants had a median age of 62 years; approximately 45% were female. Most had stage III disease (about 90%) and received standard adjuvant chemotherapy regimens, including oxaliplatin-based therapy. Baseline physical activity levels were uniformly low across groups, averaging under 6 MET-hours/week. Baseline cardiorespiratory fitness, as measured by submaximal treadmill testing and the 6-minute walk test, was also similar.
Key Results
1. Disease-Free Survival (DFS)
After a median follow-up of 7.9 years, the structured exercise group demonstrated significantly better DFS:
- Hazard Ratio (HR): 0.72 (95% CI, 0.55–0.94), indicating a 28% reduction in the risk of recurrence, new primary cancer, or death.
- 5-year DFS rate: 80.3% in the exercise group vs. 73.9% in the control group (absolute difference of 6.4%).
This result provides strong evidence that structured exercise can lower the risk of disease recurrence or death in this patient population.
2. Overall Survival (OS)
The overall survival data showed a 37% relative reduction in the risk of death:
- HR: 0.63 (95% CI, 0.43–0.94).
- 8-year OS rate: 90.3% for the exercise group vs. 83.2% for the control group (absolute difference of 7.1%).
Though not the primary endpoint, the improvement in OS further supports the value of the exercise intervention.
3. Physical Activity and Fitness
Participants in the exercise group significantly increased their activity levels:
- Average increase of 5.2 to 7.4 MET-hours/week more than controls during the intervention period.
- Improvements in 6-minute walk distance (an indicator of functional capacity).
- Gains in cardiorespiratory fitness, as assessed by submaximal exercise tests.
These improvements were sustained across the 3-year intervention, demonstrating adherence and lasting behavioral change.
4. Health-Related Quality of Life (HRQOL)
Self-reported measures of physical functioning, fatigue, and mental health showed improvements in the intervention group. While these were secondary endpoints, they are clinically important in survivorship care.
Safety and Adverse Events
While the exercise program was generally safe, adverse events were somewhat more common in the intervention group:
- Musculoskeletal events: Occurred in 18.5% of exercise participants vs. 11.5% in controls. These were primarily minor injuries (e.g., joint pain, muscle strain).
- Serious Adverse Events (Grade ≥3): 15.4% in the exercise group vs. 9.1% in controls.
- Only 10% of musculoskeletal events were directly attributed to the exercise protocol.
These findings underscore the need for individualized and professionally guided exercise programs to minimize risk.
Adherence and Program Delivery
Program adherence was reasonable considering the length and complexity of the intervention:
- Participants completed a median of 65% of planned behavioral sessions.
- Physical activity goals were achieved or exceeded by a large proportion of participants by year 1.
- Remote and in-person delivery formats were both used, and flexible options helped improve participation.
These results demonstrate that a structured exercise intervention is feasible on a broad scale, even in a diverse cancer population.
Study Limitations
- Event Rate: Lower-than-expected recurrence and death rates may have affected power, although the final results remained statistically significant.
- Enrollment Duration: The 9-year recruitment period reflects logistical challenges and may affect generalizability.
- Selection Bias: Participants may have been healthier or more motivated than the broader population of colon cancer survivors.
- Blinding: Neither participants nor staff were blinded to group assignment, though outcome adjudicators were.
Despite these limitations, the robustness of the findings lends confidence in their validity.
Implications and Conclusions
The CHALLENGE trial provides compelling evidence that a structured, behavioral exercise intervention can improve disease-free and overall survival in colon cancer survivors following adjuvant chemotherapy. These findings are clinically significant and support the integration of exercise into survivorship care plans.
Key implications include:
- Exercise as a Core Element of Survivorship Care: Exercise is no longer just a lifestyle recommendation—it is a potential therapeutic tool.
- System-level Integration: Health systems and cancer centers should invest in structured exercise programs and trained professionals (e.g., exercise physiologists, physical therapists).
- Scalability and Accessibility: Programs must be adaptable to remote delivery and tailored to diverse patient needs to ensure equitable access.
- Further Research: While this trial focused on colon cancer, the approach should be evaluated in other cancer types.
In conclusion, the CHALLENGE trial confirms that exercise is not only safe and feasible for colon cancer survivors, but it also offers meaningful survival benefits. This landmark study elevates the role of structured physical activity from a supportive care measure to a potentially life-saving intervention.
