A Standing Ovation for CHALLENGE

Every now and then, a study grabs the interest of the editors and readers of Sensible Medicine to such a degree that we seem unable to let it rest. Two weeks ago, John and I wrote separate articles about the CHALLENGE trial. Here, Dr. Blase Polite, a long-time colleague I respect immensely, points out what he sees as our errors.

Adam Cifu

I read with interest the detailed critique of the recently presented and published CHALLENGE trial offered up by Mandrola and Cifu. As an academic colorectal oncologist with 20 years of experience, I have closely followed the developments in research on the effects of exercise on colon cancer outcomes. The CHALLENGE study, eagerly awaited by the GI oncology community, represents a significant milestone and adds to the evidence from prospective cohort studies that have led many of us to already incorporate detailed exercise and diet recommendations for our colon cancer survivors. I was present at the ASCO annual meeting when the data were presented, and the standing ovation that followed (one of only 3 I have ever witnessed, including one for the HER-2 trial that Dr. Mandrola references) was a testament to the importance of these findings. Below, I provide a point-by-point rebuttal to the critiques of Drs. Mandrola and Cifu.

First, the plausibility of the results is questioned. Drs. Mandrola and Cifu suggest that the pre-test probability of success was so low that the likelihood of a false positive result is magnified. However, previous well-designed cohort exercise studies have shown similar improvements in DFS and OS, supporting the CHALLENGE study's findings. These studies demonstrated hazard ratios for DFS of 0.5-0.6 and OS hazard ratios of 0.5-0.8. The absolute improvement in the 80702 trial was 10% for both 3-year DFS and 5-year OS. These results compare favorably with the CHALLENGE study’s roughly 7% improvement. The consistency of these results across different populations and methods strengthens the plausibility of the CHALLENGE findings.

Second, Mandrola’s claim that there was no real change in exercise outcomes is nicely rebutted by Dr. Cifu. The evidence shows significant improvements in V02 max and the 6-minute walk test. Multiple studies have shown that a 1 ml/kg/min increase in V02 is associated with a 10-15% improvement in survival. The 2 ml/kg/min increase observed in the CHALLENGE study could allow patients to go from needing rest after one flight of stairs to comfortably climbing two or even three flights without stopping. The 6-minute walk test changes are equivalent to walking an additional 1-2 city blocks over 6 minutes, a meaningful improvement for older or post-chemotherapy and surgery patients.

Third, Mandrola suggests that the difference in the DFS and OS curves suggests suboptimal randomization. The difference in DFS and OS curves is consistent with successful therapies reducing recurrences. Colon cancer recurrences are highest in the first two years after treatment, and this is where the curves separate. This pattern mirrors nearly every successful chemotherapy trial, where DFS curves separate early, and OS curves continue to lag as treatments for metastatic disease improve.

Fourth, poor adherence is cited as a reason for implausibility. However, the intention-to-treat analysis still shows positive results. This suggests that the observed benefits are robust and not solely dependent on perfect adherence to the exercise regimen.

Fifth, despite the long accrual time and lowered event rate, the study maintained a power of 80%. The final trial had sufficient power to detect a hazard ratio of 0.67, corresponding to an increase in 3-year DFS from 75% in the health-education group to 82.5% in the exercise group. The risk to internal validity of this change would be to increase the risk of type II error (accepting the null hypothesis of no difference when there was in fact a difference). That the trial was still positive with the more stringent statistical criteria should be an encouraging result and not a knock on the study.

I do agree with Mandrola and Cifu that the scalability of the intervention is a challenge. The time and resources required to provide individualized support to patients are significant, and the current healthcare system is not equipped or incentivized to achieve this. However, supporting exercise goals could lower overall healthcare costs, as a robust infrastructure to help patients achieve exercise goals would be more cost-effective in the long run. The current system's incentives may favor expensive drug treatments, but the public health benefits of exercise interventions need to be loudly supported by the medical community.

The CHALLENGE study represents a significant advancement in colon cancer treatment. The findings are supported by previous research, show meaningful improvements in patient outcomes, and are robust despite challenges related to adherence and scalability. The study deserves recognition and implementation, as it offers a promising approach to improving colon cancer patients’ survival and quality of life. The entire medical community should stand up and applaud these findings.

Blase Polite, MD is a professor of medicine at the University of Chicago. He is an oncologist with expertise in the treatment of gastrointestinal malignancies, particularly colon, rectal, and anal cancers, as well as neuroendocrine tumors.

Photo Credit: Jeremy Lapak