November's Paper of the Month investigates factors contributing to the difference in higher locoregional recurrence (LRR) observed after total neoadjuvant treatment (TNT) versus chemoradiotherapy in the RAPIDO trial.
Factors influencing locoregional recurrence rates in locally advanced rectal cancer after total neoadjuvant treatment versus chemoradiotherapy in the RAPIDO trial
Ilaria Prata, Max D Tanaka, Bengt Glimelius, Iris D Nagtegaal, Regina G H Beets-Tan, Lennart K Blomqvist, Alice M Couwenberg, Boudewijn van Etten, Geke A P Hospers, Elma Meershoek-Klein Kranenbarg, Koen C M J Peeters, Hein Putter, Annet G H Roodvoets, Cornelis J H van de Velde, Per J Nilsson, Corrie A M Marijnen. BJS, Volume 112, Issue 9, September 2025, znaf190.
What is known about the subject
The use of preoperative long-course chemoradiotherapy (CRT) prior to total mesorectal excision has been shown to significantly reduce the risk of locoregional recurrence (LRR) in patients with locally advanced rectal cancer. The phase III RAPIDO trial had already demonstrated that an experimental TNT schedule - preoperative short-course radiotherapy (SCRT) followed by chemotherapy - doubled pathological complete response rates compared to the standard CRT approach, while also reducing the five-year distant metastasis (DM) rate. However, after a median follow-up time of 5.6 years, LRRs were observed more frequently in patients treated with TNT, for reasons that were unclear. This post hoc exploratory analysis of RAPIDO trial identified surgical and pathological factors associated with the higher locoregional recurrence rate after TNT.
What the study adds
The increased LRR rate was mainly in patients who underwent sphincter-preserving surgery, not abdominoperineal resection (APR). Patients who underwent sphincter-preserving surgery had a significantly higher LRR rate after TNT (12.1%) compared to after CRT (4.8%). A distal resection margin (DRM) of 10 mm or less was associated with a substantially higher cumulative incidence of LRR after TNT compared to after CRT (25.4% versus 1.8%, HR 15.51 (95% c.i. 2.02, 119.35), PInteraction = 0.014) .
Implications for colorectal practice
The results suggest that a DRM of 10 mm or less is insufficient for sphincter-preserving surgery when preceded by TNT instead of CRT, as clusters of residual tumour cells may remain scattered throughout the original tumour bed, leading to higher LRR rates. Surgeons should reconsider current resection margin standards after TNT when performing sphincter-preserving surgery. The baseline initial tumour extent (before TNT) should be taken into account when planning the surgical approach in order to avoid operating within the original tumour bed.
References
- Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:29–42
- Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH et al. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared to long-course chemoradiotherapy and surgery - a five-year follow-up of the RAPIDO trial. Ann Surg 2023;278:e766–e772