– COLORECTAL CANCER Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients : A Population-Based Study

Background. Neoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients. Methods. Data on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5–6 to 13–14 weeks. Kaplan–Meier curves, and logistic regression and Cox regression models were used for data analysis. Results. No significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7–8 weeks, pCR rates in LARC patients were higher after 9–10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03–2.37) and 11– 12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15–3.26). Treatment interval did not influence OS in ET or LARC patients. Conclusions. Treatment intervals of 9–12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response. In The Netherlands, rectal cancer is diagnosed in approximately 4500 patients annually. Total mesorectal excision (TME) is the gold standard in rectal cancer surgery and comprises resection of the rectal tumor together with the fatty tissue surrounding the rectum. Neoadjuvant treatment is used to improve outcome in case lymph node involvement is suspected or when the tumor extends to the mesorectal fascia on magnetic resonance imaging (MRI). For locally advanced rectal cancer (LARC), therapy consists of chemoradiation therapy (CRT) followed by TME or even beyond TME surgery. CRT consists of longcourse radiotherapy of 45–50 Gy (in fractions of 1.8– 2 Gy), with concurrent 5-fluorouracil. Treatment for early tumors (ETs) without suspicion of lymph node involvement (cT1–3N0) consists of TME surgery only; however, in a search for organ-sparing treatment modalities, CRT has also recently been applied to ET patients followed by local transanal excision. The wait-and-see approach has recently been introduced for both LARC and ET patients. Although neoadjuvant CRT has been widely implemented in the treatment of rectal cancer patients, the optimal timing of surgery after neoadjuvant therapy is as yet unclear. Surgery was previously performed 6–8 weeks Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5294-0) contains supplementary material, which is available to authorized users. The Author(s) 2016. This article is published with open access at Springerlink.com First Received: 3 February 2016; Published Online: 1 June 2016 A. J. M. Rombouts, MD e-mail: anouk.rombouts@radboudumc.nl Ann Surg Oncol (2016) 23:3593–3601 DOI 10.1245/s10434-016-5294-0 after completion of CRT; however, recent studies suggest a time-related response of the tumor to CRT. There is growing evidence that extending the treatment interval might increase the proportion of patients with a complete pathologic response (pCR). It has also been suggested that a prolongation of the treatment interval might improve overall survival (OS). A meta-analysis on this topic did not show better OS in patients with longer treatment intervals, but the amount of evidence was scarce and the authors suggested further validation of the results. The currently available literature concerning the treatment interval between CRT and surgery does not differentiate between ET and LARC patients, despite the fact that there are substantial differences in oncological outcomes. This nationwide study aimed to evaluate the effects of prolonged treatment intervals on pCR and OS in ET and LARC patients separately.