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Short course radiotherapy (SCRT, 25Gy in 5 fractions) followed by total mesorectal excision (TME) is the standard treatment of intermediate risk rectal cancer (T1-3(without involvement of the mesorectal fascia (MRF-))N1M0 and T3cd(MRF-)N0-1M0) in the Netherlands. A prolonged interval between SCRT and TME (4-8 weeks, SCRT-delay) resulted in a lower postoperative complication rate and a higher pathological complete response (pCR) rate than SCRT and surgery within a week (SCRT-direct surgery) in the randomized Stockholm III trial. The current study sought to confirm these associations in nationwide real-world data of Dutch rectal cancer patients.

Patients with intermediate risk rectal cancer treated with either SCRT-delay (4-12 weeks) or SCRT-direct surgery in 2018-2021 were selected from the nationwide Dutch ColoRectal Audit. The primary outcome was the general 90-day postoperative complication rate. Secondary outcomes included 90-day postoperative reintervention, ICU admittance, mortality, anastomotic leakage and pathological complete response (pCR). Baseline differences between groups were expressed as the standardized mean difference (SMD), calculated as the mean difference between groups divided by the pooled standard deviation. Confounders were eliminated using inverse probability of treatment weighting (IPTW). Outcomes were compared using log-binomial and Poisson regression.

664 patients were included in the SCRT-direct surgery and 238 in the SCRT-delay group. Before IPTW, patients in the SCRT-direct surgery group were slightly younger (67 (median, interquartile range (IQR): 58-74) versus (vs.) 68 (median, IQR: 60-77), SMD = 0.18), had a lower American Society of Anaesthesiologists (ASA) classification (ASA 1-2: 81% vs. 72%, SMD = 0.26) and were more often treated with a (low) anterior resection without an ostomy (41% vs. 28, SMD = 0.29) and less often with a (low) anterior resection with an ostomy (42% vs. 51%) or an abdominoperineal resection (17% vs. 22%) than patients in the SCRT-delay group. After IPTW, confounders were well balanced. After IPTW, the 90-day postoperative complication rate was comparable between SCRT-direct surgery and SCRT-delay (40% vs. 42%, risk ratio (RR) = 1.1 [95%confidence interval (CI): 0.9; 1.3], p=0.6). All other postoperative outcomes were similar, except for pCR, which occurred more often following SCRT-delay than following SCRT-direct surgery (10% vs. 0.3%, RR = 39 [95%CI: 11, 139], p < 0.001).

Real-world evidence could not confirm the advantage in postoperative complications of SCRT-delay compared to SCRT-direct surgery, but did confirm the increased pCR rate following SCRT-delay. SCRT-delay followed by a response assessment should be offered to patients who are interested in non-operative management. SCRT-direct surgery still seems a valid option for patients who prefer surgery.