As reported in JAMA Network Open by Sugumar et al, a systematic review and meta-analysis of randomized clinical trials comparing neoadjuvant therapies in rectal cancer showed no trial-level association between pathologic complete response and survival.
“Our study’s findings suggest a recommendation against using pathologic complete response as a surrogate endpoint for neoadjuvant therapies in rectal cancer until conclusive trial-level evidence of its association with long-term outcomes is firmly established,” the investigators commented. “Without convincing trial-level data, the adoption of pathologic complete response as a surrogate marker can lead to the approval of therapies that confer toxic effects without improving overall survival or early abandonment of therapies that may confer long-term benefit.”
Study Details
The investigators conducted a meta-analysis to identify eligible randomized clinical trials in the PubMed, EMBASE, and Cochrane databases published from database inception to January 2024. Those evaluating neoadjuvant therapies in patients with rectal cancer who underwent subsequent surgical resection and reported pathologic complete response, overall survival, and disease-free survival were included; a total of 25 trials, involving 11,882 patients, met these criteria.
Data extraction was performed by two investigators and subsequently verified by a third. The risk of bias and the certainty of the evidence were assessed using the Cochrane Risk of Bias Tool and the Grading of Recommendations Assessment, Development, and Evaluation tool, respectively. Adjusted odds and hazard ratios, along with their 95% confidence intervals [CIs], were extracted. The investigators conducted weighted linear regression analysis to evaluate the association between pathologic complete response and both overall and disease-free survival.
Key Findings
Based on meta-regression analysis, pathologic complete response was not correlated with overall (β = 0.37, 95% CI = −0.98 to 1.71; P = .57) or disease-free (β = −0.84, 95% CI = −2.55 to 0.87; P = .32) survival. The meta-analysis included two studies (8%) that were found to have a high risk of bias; upon their exclusion, a sensitivity analysis showed pathologic complete response was still not associated with overall or disease-free survival. Subgroup analysis of randomized clinical trials involving total neoadjuvant therapies was not feasible because of the limited sample size.
The investigators concluded: “In rectal cancer, the initial demonstrated patient-level association between pathologic complete response and overall survival in prior studies has already led to its more widespread use as a surrogate endpoint in rectal cancer trials using neoadjuvant therapy. [However, our analysis found] no [trial-level] correlation between pathologic complete response and improved overall survival or disease-free survival…. Establishing a trial-level association of pathologic complete response with survival in addition to patient-level association is critical because these associations do not always translate.”
Zhi Ven Fong, MD, MPH, DrPH, of Mayo Clinic, Phoenix, is the corresponding author of the JAMA Network Open article.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
