Structured Exercise After Chemotherapy Improves Survival in Colon Cancer: Results from the CHALLENGE Trial

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Study Was Conducted
• The Structured Exercise Program
• How Exercise and Fitness Were Measured
• How the Data Were Analyzed
• Who Participated in the Study
• How Well Patients Followed the Exercise Program
• Key Findings: Survival Results
• Physical Functioning and Fitness Results
• Side Effects and Safety
• What These Results Mean for Patients
• Limitations of the Study
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In a randomized trial of 889 patients with stage III or high-risk stage II colon cancer who had completed chemotherapy, a 3-year structured exercise program improved disease-free survival compared with health-education materials alone.
• At a median follow-up of 7.9 years, 5-year disease-free survival was 80.3% in the exercise group versus 73.9% in the health-education group, a difference of 6.4 percentage points.
• Overall survival also favored the exercise group: 8-year overall survival was 90.3% versus 83.2%, a difference of 7.1 percentage points.
• Musculoskeletal adverse events were more common in the exercise group (18.5% vs. 11.5%), so patients should discuss exercise plans with their healthcare team.
• The program focused on aerobic exercise of at least moderate intensity, such as brisk walking, aiming to increase activity by at least 10 MET-hours per week; benefits were seen even with declining adherence.

Background: Why This Research Matters

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Standard treatment for stage III or high-risk stage II colon cancer includes surgery followed by 3 to 6 months of chemotherapy. The chemotherapy regimens used include FOLFOX (5-fluorouracil and oxaliplatin), CAPOX (capecitabine and oxaliplatin), or a single-drug fluoropyrimidine.

Despite these treatments, cancer returns in 20 to 40% of patients. Surgery and adjuvant chemotherapy (treatment given after the main treatment) also cause side effects that reduce quality of life and physical functioning. New interventions are needed that improve both survival and quality of life for this patient population.

Laboratory studies have shown that exercise can slow the growth of cancer, including colon cancer. Observational studies follow people over time without assigning them to treatments. These studies have found that patients with colorectal cancer who do more recreational physical activity after treatment have a lower risk of cancer recurrence and death. This includes patients with stage III colon cancer.

Possible biological reasons for this benefit include the effects of exercise on metabolic growth factors, inflammation, and immune function. However, these observational findings cannot prove that exercise causes better outcomes. They are limited by the ways observational studies are designed. Definitive evidence from a randomized trial was lacking.

To fill this research gap, the Canadian Cancer Trials Group launched the CO.21 Colon Health and Lifelong Exercise Change (CHALLENGE) trial. This was a phase 3 randomized trial comparing health-education materials alone versus health-education materials plus a 3-year structured exercise program. The trial enrolled patients with colon cancer who had completed adjuvant chemotherapy. The researchers previously reported that the exercise program successfully changed exercise behavior. This article reports the final results for disease-free survival (the primary endpoint) and key secondary endpoints.

How the Study Was Conducted

This was a phase 3 randomized trial conducted at 55 centers. Patients were eligible if they had complete surgical removal of stage III or high-risk stage II colon cancer. High-risk stage II was defined as a T4 tumor with removal of fewer than 12 lymph nodes and poorly differentiated histologic findings (cancer cells that look very abnormal under a microscope).

All patients had completed adjuvant chemotherapy within the past 2 to 6 months. They had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. The ECOG scale ranges from 0 (fully active) to 5 (death), so a score of 0 or 1 means patients were fully active or able to do light work.

Patients also had to be exercising less than the equivalent of 150 minutes per week of moderate-to-vigorous intensity activity at the time of enrollment. They had to be able to complete at least two stages of a submaximal treadmill test (walking at a casual pace for 6 minutes) or the 6-minute walk test.

Eligible patients were stratified (grouped) according to trial center, disease stage, body-mass index (BMI; 27.5 or below versus above 27.5), and ECOG performance-status score (0 or 1). They were then randomly assigned in a 1:1 ratio to either the exercise group or the health-education group.

Patients in the health-education group received general health-education materials promoting physical activity and healthy nutrition, plus standard surveillance (regular monitoring for cancer recurrence). Patients in the exercise group received the same materials plus an exercise guidebook developed for colon cancer survivors and support from a certified physical activity consultant for 3 years.

The Structured Exercise Program

The exercise support program was guided by the Theory of Planned Behavior and used 17 evidence-based techniques for behavioral change. The program was delivered over three phases.

Phase 1 (first 6 months): Patients attended 12 mandatory in-person behavioral-support sessions scheduled every 2 weeks. They also attended 12 mandatory supervised exercise sessions plus 12 recommended supervised exercise sessions during alternate weeks.

Phase 2 (months 7 through 12): Patients attended 12 mandatory behavioral-support sessions every 2 weeks. These sessions could be in person or remote by telephone or video. A supervised exercise session was included if the patient attended in person.

Phase 3 (the last 2 years): Patients attended 24 mandatory monthly behavioral-support sessions. These could be in person or remote. A supervised exercise session was included if the patient attended in person.

The goal of the exercise program was to increase recreational aerobic exercise from baseline by at least 10 metabolic equivalent task (MET) hours per week during the first 6 months. Patients were then asked to maintain or further increase that amount during the final 2.5 years.

The focus was on aerobic exercise of at least moderate intensity, such as brisk walking. Brisk walking has an intensity of approximately 4 METs. MET values indicate the intensity of an activity, not the time spent. Brisk walking for one hour has a value of 4 MET-hours. Patients could choose the type, frequency, intensity, and duration of aerobic exercise.

How Exercise and Fitness Were Measured

The researchers assessed recreational physical activity over the past month at baseline and every 6 months during the intervention. They used the Total Physical Activity Questionnaire. Moderate-to-vigorous physical activity was calculated based on activities with MET values of 3 or more.

Cardiorespiratory fitness (how well the heart and lungs supply oxygen during exercise), body weight and circumferences, and objective physical functioning were assessed at baseline, at 6 months, and at 1, 2, and 3 years.

Cardiorespiratory fitness was assessed using a submaximal, multistage, modified Balke treadmill protocol. A validated formula was used to predict the maximum volume of oxygen consumption (VO2 max), which is a measure of aerobic fitness. Waist and hip circumferences were measured with an anthropometric measuring tape. Objective physical functioning was assessed with the Seniors' Fitness Test, which includes a 6-minute walk test.

Physical activity and fitness assessments were discontinued in patients who had a disease event (cancer recurrence, new primary cancer, or death).

Disease-free survival (the primary endpoint) was assessed in the intention-to-treat population. This means all patients were analyzed according to the group they were assigned to, regardless of whether they completed the program. Disease-free survival was defined as the time from randomization to the first event. Events included recurrent (local or distant) colon cancer, a new primary colorectal cancer, a second primary cancer, or death from any cause.

Overall survival was defined as the time from randomization to death from any cause.

The prespecified quality-of-life outcome was physical functioning as reported by the patient. This was assessed using the physical-functioning subscale on the 36-Item Short Form (SF-36) survey every 6 months during the intervention and at years 4 and 5. Patients who had a disease event were included in this assessment. Higher scores on the physical-functioning subscale indicate better functioning.

Adverse events were monitored for 36 months after randomization using the Common Terminology Criteria for Adverse Events, version 3.0. Data were reported for patients according to the intervention they actually received (as-treated population). Musculoskeletal adverse events were of special interest.

How the Data Were Analyzed

The trial was designed to detect a hazard ratio of 0.75 for disease-free survival. A hazard ratio is a measure of how much a treatment reduces the risk of an event. A hazard ratio of 0.75 means the treatment group had 25% fewer events. This corresponded to an increase in 3-year disease-free survival from an expected 75% in the health-education group to 80.6% in the exercise group.

The researchers calculated that 380 events of disease recurrence, new primary cancer, or death would provide 80% power to determine a result at a two-sided alpha value of 0.05. Power is the probability of detecting a real difference if one exists. An alpha value of 0.05 means there is a 5% chance of a false-positive result.

The trial planned to randomize 962 patients during a 3-year period. The required number of events was expected to be observed 4 to 5 years after the last patient was randomly assigned.

Four interim analyses were planned:

1. One assessing the feasibility of recruiting patients to the trial
2. One assessing the feasibility of a change in exercise behavior
3. Two assessing the efficacy of the intervention after approximately one third of the target number of events (125 patients) and approximately two thirds of the target number (250 patients)

The feasibility of change in exercise behavior was confirmed in May 2015, and these results were published with permission of the data and safety monitoring committee. The first interim efficacy analysis was completed in November 2019. At that time, the committee recommended that the trial continue.

Because of slow recruitment and a lower-than-expected pooled-event rate, the committee approved a request to set an accrual deadline of December 31, 2023. The target for declaring a clinical data-cutoff date for the final statistical analysis was set for the end of 2024, conditional on the occurrence of at least 200 confirmed events. With at least 200 events in the final analysis, the trial would have 80% power to detect a hazard ratio of 0.67. This corresponds to an increase in 3-year disease-free survival from 75% in the health-education group to 82.5% in the exercise group at a two-sided 0.05 level.

Registration of patients stopped on December 21, 2023. The final patient underwent randomization on January 24, 2024. A clinical data-cutoff date was declared on August 29, 2024, with 224 events confirmed. The final analysis was performed on a locked database on January 24, 2025.

The researchers summarized time-to-event variables using Kaplan-Meier plots. They compared survival between intervention groups primarily by a two-sided log-rank test with adjustment for stratification factors assessed at the time of randomization, except for the trial center. The annual incidence of events was calculated by dividing the observed number of events by person-years of follow-up. All reported 95% confidence intervals are two-sided. The widths of the confidence intervals for secondary endpoints have not been adjusted for multiplicity and thus may not be used in place of hypothesis testing.

Who Participated in the Study

Between 2009 and 2024, a total of 889 patients at 55 sites (mostly in Canada and Australia) were randomly assigned to the exercise group (445 patients) or the health-education group (444 patients).

The median age of the patients was 61 years (range, 19 to 84). Just over half (51%) were women. Most patients (90%) had stage III disease. The most common chemotherapy regimen was FOLFOX, received by 61% of patients.

At baseline, patients reported participating in 11.5 MET-hours per week of moderate-to-vigorous physical activity. They had a predicted maximum volume of oxygen consumption of 30.7 ml per kilogram of body weight per minute. They walked 530 meters in 6 minutes. The trial groups were well balanced with respect to their characteristics at baseline.

Additional baseline characteristics included:

• Median weight: 81.2 kg (interquartile range, 69.5 to 96.2)
• Median body-mass index: 28.5 (interquartile range, 25.4 to 32.5)
• Obesity: 37.8% of patients
• ECOG performance-status score of 0 (fully active): 72.8% of patients
• ECOG performance-status score of 1: 27.2% of patients
• Current smokers: 4.7% of patients
• Ever smoked: 46.9% of patients
• Major medical problem: 58.6% of patients
• Hypertension: 24.4% of patients
• High cholesterol level: 14.7% of patients
• Diabetes or hyperglycemia: 11.1% of patients
• Cardiac history: 8.8% of patients
• Depression or anxiety: 8.2% of patients
• High-risk stage II adenocarcinoma: 9.8% of patients
• Stage III adenocarcinoma: 90.2% of patients

The median interval from diagnosis to trial randomization was 1.0 years (interquartile range, 0.8 to 1.1). The median interval from chemotherapy to trial randomization was 3.9 months (interquartile range, 3.1 to 5.3).

Geographic regions of enrollment were:

• Canada: 61.1% of patients
• Australia: 32.8% of patients
• Other sites: 6.1% of patients (United Kingdom, 5 sites with 30 patients; France, 1 site with 10 patients; United States, 3 sites with 9 patients; Israel, 1 site with 5 patients)

How Well Patients Followed the Exercise Program

Adherence to the exercise program varied by phase and by type of session.

Phase 1 (first 6 months):

• 83% adherence for the 12 mandatory behavioral-support sessions
• 79% adherence for the 12 mandatory supervised exercise sessions
• 20% adherence for the 12 recommended supervised exercise sessions

Phase 2 (months 7 through 12):

• 68% adherence for the 12 mandatory behavioral-support sessions
• 54% adherence for the 12 recommended supervised exercise sessions

Phase 3 (months 13 through 36):

• 63% adherence for the 24 mandatory behavioral-support sessions
• 44% adherence for the 24 recommended supervised exercise sessions

Completion rates for the measures of physical activity and fitness were similar in the exercise group and the health-education group. Completion rates were 94 to 99% at baseline and 54 to 63% at 36 months.

Patients in the exercise group achieved and maintained larger improvements than those in the health-education group over the entire 3-year intervention. The between-group differences ranged from 5.2 to 7.4 MET-hours per week for moderate-to-vigorous physical activity. For predicted maximum volume of oxygen consumption, the between-group difference was 1.3 to 2.7 ml per kilogram per minute. For 6-minute walk distance, the between-group difference was 13 to 30 meters. Minimal between-group differences were observed for body weight.

Key Findings: Survival Results

At a median follow-up of 7.9 years, disease-free survival was significantly longer in the exercise group than in the health-education group. The hazard ratio for disease recurrence, new primary cancer, or death was 0.72 (95% confidence interval [CI], 0.55 to 0.94; P = 0.02). This means the exercise group had a 28% lower risk of these events compared with the health-education group.

The 5-year disease-free survival was 80.3% in the exercise group and 73.9% in the health-education group. This is a difference of 6.4 percentage points (95% CI, 0.6 to 12.2). In other words, about 80 out of 100 patients in the exercise group were alive without cancer recurrence at 5 years, compared with about 74 out of 100 patients in the health-education group.

Results also support longer overall survival in the exercise group than in the health-education group. The hazard ratio for death was 0.63 (95% CI, 0.43 to 0.94). This means the exercise group had a 37% lower risk of death compared with the health-education group.

The 8-year overall survival was 90.3% in the exercise group and 83.2% in the health-education group. This is a difference of 7.1 percentage points (95% CI, 1.8 to 12.3). In other words, about 90 out of 100 patients in the exercise group were alive at 8 years, compared with about 83 out of 100 patients in the health-education group.

Physical Functioning and Fitness Results

Completion rates for the SF-36 survey were similar in the two trial groups. They exceeded 96% at baseline and 78% at 36 months.

Patients in the exercise group achieved and maintained larger improvements than those in the health-education group over the entire 3-year intervention. This was true for moderate-to-vigorous physical activity, predicted maximum volume of oxygen consumption, and 6-minute walk distance. Minimal between-group differences were observed for body weight.

Side Effects and Safety

Musculoskeletal adverse events (side effects related to muscles and bones) occurred more often in the exercise group than in the health-education group. These events occurred in 18.5% of patients in the exercise group versus 11.5% of patients in the health-education group.

What These Results Mean for Patients

This is the first phase 3 randomized trial to show that a structured exercise program can improve disease-free survival in patients with colon cancer who have completed adjuvant chemotherapy.

The exercise program was initiated soon after adjuvant chemotherapy. The program lasted 3 years and resulted in significantly longer disease-free survival. The findings are also consistent with longer overall survival.

For patients with colon cancer who have completed chemotherapy, these results suggest that participating in a structured exercise program may reduce the risk of cancer recurrence and death. The exercise program focused on aerobic exercise of at least moderate intensity, such as brisk walking. Patients could choose the type, frequency, intensity, and duration of aerobic exercise.

The benefits were seen even though adherence to the program declined over time. During the first 6 months, 83% of patients attended the mandatory behavioral-support sessions and 79% attended the mandatory supervised exercise sessions. By the final phase, 63% attended the mandatory behavioral-support sessions and 44% attended the recommended supervised exercise sessions. This suggests that even imperfect adherence to an exercise program can provide meaningful benefits.

The exercise group experienced more musculoskeletal adverse events than the health-education group. Patients considering an exercise program should discuss this risk with their healthcare team. However, the survival benefits were substantial and the adverse events were manageable.

Limitations of the Study

The trial had a lower-than-expected pooled-event rate. This means fewer cancer recurrences or deaths occurred in the overall study population than the researchers originally anticipated. This required the trial to be extended and the final analysis to be conducted with 224 events rather than the originally planned 380 events.

Adherence to the exercise program declined over the 3-year intervention. During the first 6 months, adherence to mandatory supervised exercise sessions was 79%. By the final phase, adherence to recommended supervised exercise sessions was 44%. The results may have been even stronger if adherence had been maintained at higher levels.

The confidence intervals for secondary endpoints have not been adjusted for multiplicity. This means the results for secondary endpoints, such as overall survival, should be interpreted with caution. The width of the confidence intervals may not be used in place of hypothesis testing.

The trial enrolled patients who were exercising less than 150 minutes per week of moderate-to-vigorous intensity activity at baseline. The results may not apply to patients who are already highly physically active.

The trial enrolled patients with stage III or high-risk stage II colon cancer who had completed adjuvant chemotherapy. The results may not apply to patients with other stages of colon cancer or to patients who have not received chemotherapy.

Recommendations for Patients

Based on the results of this trial, patients with colon cancer who have completed adjuvant chemotherapy should consider participating in a structured exercise program. The program should focus on aerobic exercise of at least moderate intensity, such as brisk walking.

The goal should be to increase recreational aerobic exercise by at least 10 MET-hours per week during the first 6 months. This is equivalent to about 2.5 hours of brisk walking per week. Patients should then aim to maintain or further increase that amount over time.

Patients should discuss their exercise plans with their healthcare team. This is especially important for patients with musculoskeletal conditions or other medical problems. The exercise group in this trial experienced more musculoskeletal adverse events than the health-education group.

Patients should also be aware that adherence to the exercise program declined over time in this trial. Even if patients cannot maintain perfect adherence, the results suggest that some exercise is better than none. Patients should aim to stay as active as possible and seek support from certified physical activity consultants or other healthcare professionals.

Patients should continue with standard surveillance for cancer recurrence. The exercise program was provided in addition to standard surveillance, not instead of it.

Frequently Asked Questions

I finished chemotherapy for colon cancer. Could a structured exercise program help me live longer without the cancer coming back?

In a randomized trial of 889 patients with stage III or high-risk stage II colon cancer who had completed chemotherapy, a 3-year structured exercise program improved disease-free survival compared with health-education materials alone. At a median follow-up of 7.9 years, 5-year disease-free survival was 80.3% with exercise versus 73.9% without. Overall survival also favored the exercise group. Discuss exercise plans with your healthcare team.

What exactly did the exercise program involve?

The 3-year program combined behavioral support with supervised exercise. In the first 6 months, patients attended 12 mandatory in-person behavioral-support sessions every 2 weeks, plus 12 mandatory and 12 recommended supervised exercise sessions. Later phases used monthly sessions, which could be in person or remote. The goal was to increase recreational aerobic exercise by at least 10 MET-hours per week, focusing on at least moderate intensity, such as brisk walking.

What does a 6.4 percentage point difference in 5-year disease-free survival mean for me?

It means that in this trial, about 80 out of 100 patients in the exercise group were alive without cancer recurrence at 5 years, compared with about 74 out of 100 in the health-education group. This difference was statistically significant. However, individual results vary, and this finding applies to patients like those enrolled: stage III or high-risk stage II colon cancer who had completed adjuvant chemotherapy.

Were there any side effects or risks from the exercise program?

Yes. Musculoskeletal adverse events, which are side effects related to muscles and bones, occurred more often in the exercise group: 18.5% versus 11.5% in the health-education group. These events were considered manageable, but patients considering an exercise program should discuss this risk with their healthcare team, especially if they have musculoskeletal conditions or other medical problems.

I am not very active right now. Could I still benefit from an exercise program?

The trial enrolled patients who were exercising less than 150 minutes per week of moderate-to-vigorous activity at baseline, so it included people who were not highly active. The results may not apply to patients who are already highly physically active. If you are currently inactive, a structured program starting with brisk walking may be appropriate, but discuss your plans with your healthcare team first.

Did patients in the trial manage to stick with the exercise program?

Adherence declined over the 3 years. In the first 6 months, 83% attended mandatory behavioral-support sessions and 79% attended mandatory supervised exercise sessions. By the final phase, 63% attended mandatory behavioral-support sessions and 44% attended recommended supervised exercise sessions. Despite this decline, benefits were still seen, suggesting that even imperfect adherence can provide meaningful benefit.

I finished chemotherapy for stage III colon cancer — when should I seek a second opinion about starting a structured exercise program?

A second opinion can help when you have completed adjuvant chemotherapy for stage III or high-risk stage II colon cancer and want to review whether a structured exercise program fits your situation. In a large randomized trial, a 3-year program focused on aerobic exercise of at least moderate intensity improved disease-free survival (80.3% vs. 73.9% at 5 years) and overall survival (90.3% vs. 83.2% at 8 years), with more musculoskeletal adverse events in the exercise group (18.5% vs. 11.5%). Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Structured Exercise after Adjuvant Chemotherapy for Colon Cancer NEJM 2025

Authors: 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., Victoria Coyle, M.B., B.Ch., Ph.D., Neil S. Chua, M.D., Derek J. Jonker, M.D., Philip J. Beale, Ph.D., Kamal Haider, M.D., Patricia A. Tang, M.D., Tony Bonaventura, M.D., Ralph Wong, M.D., Howard J. Lim, M.D., Ph.D., Matthew E. Burge, M.B., B.S., Stacey Hubay, M.D., Michael Sanatani, M.D., Kristin L. Campbell, Ph.D., Fernanda Z. Arthuso, Ph.D., Jane Turner, M.Phil., Ralph M. Meyer, M.D., Michael Brundage, M.D., Patti O'Brien, M.Sc., Dongsheng Tu, Ph.D., and Christopher M. Booth, M.D., for the CHALLENGE Investigators

Publication: New England Journal of Medicine, July 3, 2025, Volume 393, Number 1, pages 13-25

DOI: 10.1056/NEJMoa2502760

ClinicalTrials.gov number: NCT00819208

Funding: Canadian Cancer Society, Australian National Health and Medical Research Council, and Cancer Research UK

This patient-friendly article is based on peer-reviewed research.