Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials

Purpose: Optimal timing of surgery after neoadjuvant chemoradiotherapy (Nad-CRT) is still controversial in locally advanced rectal cancer (LARC). The primary goal of this study was to determine the best surgical interval (SI) to achieve the highest rate of pathological complete response (pCR) and secondly to evaluate the effect on survival outcomes according to the SI. Patients and methods: Patients data were extracted from the international randomized trials: Accord12/0405, EORTC22921, FFCD9203, CAO/ARO/AIO-94, CAO-ARO-AIO-04, INTERACT and TROG01.04. Inclusion criteria were: age≥ 18, cT3–T4 and cN0–2, no clinical evidence of distant metastasis at diagnosis, Nad-CRT followed by surgery. Pearson's Chi-squared test with Yates’ continuity correction for categorical variables, the Mann–Whitney test for continuous variables, Mann–Kendall test, Kaplan–Meier curves with log-rank test, univariate and multivariate logistic regression model was used for data analysis. Results: 3085 patients met the inclusion criteria. Overall, the pCR rate was 14% at a median SI of 6 weeks (range 1–31). The cumulative pCR rate increased significantly when SI lengthened, with 95% of pCR events within 10 weeks from Nad-CRT. At univariate and multivariate logistic regression analysis, lengthening of SI (p< 0.01), radiotherapy dose (p< 0.01), and the addition of oxaliplatin to Nad-CRT (p< 0.01) had a favorable impact on pCR. Furthermore, lengthening of SI was not impact on local recurrences, distance metastases, and overall survival. Conclusion: This pooled analysis suggests that the best time to achieve pCR in LARC is at 10 weeks, considering that the lengthening of SI is not detrimental concerning survival outcomes.