Aim: To identify the optimal interval from the end of neoadjuvant chemoradiotherapy to surgery (CRT-surgery interval) based on long-term oncological outcome of locally advanced rectal cancer (LARC).

Methods: Retrospective data analysis is reported from patients diagnosed with cT3 or T4 or TxN+ rectal cancer who underwent neoadjuvant treatment and curative-intent surgery between January 2010 and December 2018. With a priority focus on the effect of interval on oncological prognosis, we used recurrence-free survival (RFS) as the primary endpoint to determine the best cutoff point of time intervals. Then, the short-term and long-term outcomes of patients from longer and shorter interval groups were compared.

Results: Data from 910 patients were analyzed, with 185 patients who achieved pCR (20.3%). The trend for increased rates of pCR for groups with a prolonged time interval was not observed (P = 0.808). X-tile determined a cutoff value of 10.5 weeks, and the population was divided into longer (> 10 weeks) and shorter (≤ 10 weeks) interval groups. The shorter interval was associated with a higher wound infection rate (4.7% vs. 1.1%, P = 0.031), but other postoperative complications did not differ between the groups. The 5-year RFS rate was significantly higher in patients in a longer group than those in the shorter weeks group (86.8% vs. 77.8%, P = 0.016). The 5-year OS rates between groups were similar (84.1% vs. 82.5%, P = 0.257). Local recurrence and lung metastases rates were higher in shorter interval group than those of longer group (local recurrence rate: 1.7% vs. 5.1%, P = 0.049; lung metastases rate: 5.7% vs. 10.7%, P = 0.047). Cox multivariate regression analysis confirmed the CRT-surgery interval (HR = 0.599, P = 0.045) to be an independent prognostic factor of RFS.

Conclusion: This study is the first, to the best of our knowledge, to define the optimal CRT-surgery interval based on RFS as the primary endpoint. Prolonging the waiting period to 10 weeks after the completion of CRT with additional chemotherapy cycles during the interval period might be a promising option to improve oncological survival in LARC patients treated with CRT and TME without compromising the surgical safety. Further randomized controlled trials investigating this are warranted to prove a clearly causality.