Effect of interval between neoadjuvant chemoradiotherapy and surgery on disease recurrence and survival in rectal cancer: long-term results of a randomized clinical trial

Abstract

Background The optimal timing of surgery following chemoradiotherapy (CRT) is controversial. This trial aimed to assess disease recurrence and survival rates between patients with locally advanced rectal adenocarcinoma (LARC) who underwent total mesorectal excision (TME) after a waiting interval of 8 weeks or less (classic interval; CI) versus more than 8 weeks (long interval; LI) following preoperative CRT. Methods This was a phase III, single-centre, randomized clinical trial. Patients with LARC situated within 12 cm of the anal verge (T3–T4 or N+ disease) were randomized to undergo TME within or after 8 weeks after CRT. Results Between January 2006 and January 2017, 350 patients were randomized, 175 to each group. As of February 2022, the median follow-up time was 80 (6–174) months. Among the 322 included patients (CI, 159; LI, 163) the cumulative incidence of locoregional recurrence at 5 years was 10.1 per cent in the CI group and 6.9 per cent in the LI group (P = 0.143). The cumulative incidence of distant metastasis at 5 years was 30.8 per cent in the CI group and 18.6 per cent in the LI group (sub-HR = 1.78; 95 per cent c.i. 1.14 to 2.78, P = 0.010). The disease-free survival (DFS) in each group was 59.7 and 69.9 per cent respectively (P = 0.157), and overall survival (OS) rates at 5 years were 73.6 versus 77.9 per cent (P = 0.476). Conclusion Incidence of distant metastasis decreased with an interval between CRT and surgery exceeding 8 weeks, but this did not impact on DFS or OS. Registration number NCT03287843 (http://www.clinicaltrials.gov).

Determining the optimal radiation‐surgery interval (RSI) for oncologic proctectomy following radiotherapy for rectal adenocarcinoma

“…19 Terzi et al 23.6% vs. 12% p = 0.02; Akgun: 18.6% vs. 10% p = 0.027). 45,46 Terzi and colleagues found no difference in morbidity between the two groups but did find a significant increase in sphincter-sparing operations in the shorter interval group (85.6% vs. 74%; p = 0.016). 45 Five meta-analyses investigated the relationship between RSI and tumor response by pooling many of the aforementioned studies.…”

“…19 Akgun and colleagues, which randomized patients to RSI of short (4-8 weeks) versus long (8-12 weeks) showed long RSI patients had lower rates of distant metastases (19% vs. 31%) but no difference in local recurrence, 5-year DFS, or 5-year OS. 46 Lefevre and colleagues, who reported in their GRECCAR-6 trial that short (7 weeks) versus long (11 weeks) RSI did not affect rates of pCR, showed no difference in local or distant recurrence and 3-year OS and DFS. 65 Similarly, four metaanalyses did not find a difference in OS with longer intervals between radiation and surgery.…”

“…Patients with locally advanced rectal cancer were randomized to shorter (Terzi: 8 weeks; Akgun: 4–8 weeks) or longer (Terzi: 12 weeks; Akgun: 8–12 weeks) RSI. Both trials found that pCR rates increased in the longer RSI patients (Terzi: 23.6% vs. 12% p = 0.02; Akgun: 18.6% vs. 10% p = 0.027) 45,46 . Terzi and colleagues found no difference in morbidity between the two groups but did find a significant increase in sphincter‐sparing operations in the shorter interval group (85.6% vs. 74%; p = 0.016) 45 .…”

“…The results of available randomized trials were split on the effect of a prolonged RSI on perioperative complications 19,21,44–46,71 . Four meta‐analyses concluded that there was no difference in perioperative complications despite a longer RSI 13,47–49 .…”

“…70 The results of available randomized trials were split on the effect of a prolonged RSI on perioperative complications. 19,21,[44][45][46]71 Four meta-analyses concluded that there was no difference in perioperative complications despite a longer RSI. 13,[47][48][49] Acknowledging the relatively small differences between short and long RSI in the published literature raises many questions when this data are extrapolated to nonoperative W&W programs where patients may fail months-to-years after radiation.…”