Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

SIMPLE SUMMARY: Multimodal treatment of rectal cancer is undergoing dynamic change. In phase II/III multimodal rectal cancer trials, long-term survival remains the most objective endpoint for reporting treatment efficacy, but long follow-up is required, and there is a risk that the study results will lose scientific significance over time. To address these limitations, early surrogate endpoints are increasingly used to identify treatment efficacy at an earlier timepoint. We here report the prognostic role of pCR (pathological complete response), TRG (tumor regression grade) and NAR score (neoadjuvant rectal score) for DFS (disease-free survival) in the CAO/ARO/AIO-12 trial. Surrogate markers were significant prognostic factors for DFS, but the higher pCR rate und improved TRG in trial Arm B did not lead to improved survival compared to Arm A. Therefore, early surrogate marker correlated with clinical outcome in the CAO/ARO/AIO-12 trial, but the early differences in pCR and TRG did not translate into a survival benefit. ABSTRACT: Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, Arm B:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution.