The mainstay of treatment in locally advanced rectal cancer (LARC; cT3/4; N+) is long-course neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) surgery after 6–8 weeks, with or without adjuvant chemotherapy [1, 2, 3]. Novel approaches such as total neoadjuvant therapy (TNT), whereby the bulk of chemotherapy is given prior to surgery either before (induction) or after (consolidation) standard NCRT are increasingly being used and have now been adopted into the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for rectal cancer whereby TNT is recommended as the preferred approach for stage II–III rectal cancer [4,5]. NCRT usually consists of 5-fluouracil (5-FU)-based chemoradiotherapy with a combined dose of 45–50.4 ​Gy, administered to the primary tumour and pelvic lymph nodes. The usefulness of preoperative long-course NCRT was highlighted by the landmark German CAO/ARO/AIO 94 randomized controlled trial [1].

NCRT in LARC aims to downstage the tumour and reduce tumour volume to improve local control and increase the odds of an R0 resection. A 2013 Cochrane review demonstrated significantly increased complete pathological response (pCR) rates associated with NCRT, compared to neoadjuvant radiotherapy alone [6]. Multiple observational studies have shown that patients who achieve a pCR after NCRT and TME surgery benefit from decreased local recurrence (LR) and improved survival, compared to those who do not achieve a pCR [7, 8, 9, 10]. Consequently, pCR is now regarded as a surrogate marker for recurrence-free survival in LARC [11,12]. As such, delaying the classical interval of 6–8 weeks from NCRT completion to radical TME surgery in an attempt to increase pCR rates has been trialled in several studies. The Lyon R90-01 RCT was the first randomized study comparing an interval of 2 weeks versus 6–8 weeks between NCRT and surgery and showed superior tumour downstaging in the longer interval cohort [13]. However, the French GRECCAR-6 RCT, which compared a 7- versus 11-week interval failed to show superior pCR rates but instead showed increased morbidity and inferior TME quality specimens in the 11-week group [14]. Previous meta-analyses have attempted to answer the question regarding the optimal time interval from completion of NCRT to TME surgery but they comprised mainly observational studies with confounding biases, and therefore the validity of their results is questioned [15, 16, 17]. Recently, Gambacorta et al., pooled data from seven RCT's, and concluded that a minimum of 10 weeks should be considered to achieve 95% of all pCR events [16]. A strength of the latter study was the exclusion of all non-randomized data. However, RCTs included in their dataset were designed to study other endpoints, rather than interval from NCRT to surgery and so the latter study represents a pooled analysis rather than a formal meta-analysis. For example, the included CAO/ARO/AIO 94 RCT compared the efficacy of NCRT to postoperative chemoradiotherapy which was standard of care at the time [1]. In 2019, Ryan et al. published a comprehensive meta-analysis, concluding that a minimum 8-week interval from the end of NCRT to surgery increases pCR and downstaging rates, compared to a 6–8 week interval. However, this data set included predominantly observational studies, thereby increasing the likelihood of confounding bias [15]. Additional well conducted RCTs have since been published and we aimed to appraise the existing literature and perform an updated systematic review and meta-analysis of RCTs comparing standard interval (SI, within 8 weeks), with longer interval (LI, after 8 weeks) after NCRT to surgery in LARC [14,18, 19, 20].