CtRO Young Researcher Award

ESTRO 2025 Congress Report

The RAPIDO trial demonstrated that a total neoadjuvant treatment (TNT) schedule with preoperative short-course radiotherapy followed by chemotherapy can reduce distant metastases of locally advanced rectal cancer compared to standard chemoradiotherapy (CRT) (1). However, a difference in locoregional recurrence rates was observed between the TNT (11%) and CRT (6%) arms. Therefore, we aimed to investigate which factors contributed to this difference.

We included 829 RAPIDO patients who underwent a local R0/1 resection. In this group, we investigated a variety of baseline, surgical and pathological factors. Notably, we only observed an increase in locoregional recurrences after TNT in patients operated on with sphincter-preserving surgery (i.e., low anterior resection or Hartmann’s procedure), while there was no difference after abdominoperineal resection. Moreover, patients in the TNT arm had more locoregional recurrences compared to the CRT arm (TNT 25% vs. CRT 2%) when the distal resection margin after sphincter-preserving surgery was ≤10mm.

In addition, we performed subgroup analyses stratified by country of inclusion. In Sweden, sphincter-preserving surgery was performed in about half of the patients in both arms, and the distal resection margin was ≤10mm in less than 10% of the patients. Interestingly, no differences in locoregional recurrences between the two arms were observed. Inversely, in the Netherlands, sphincter-preserving surgery was more common (TNT 70% and CRT 63%), and substantially more patients had a distal resection margin of ≤10mm (TNT 29% and CRT 41%). The difference between arms was the largest in this subgroup (TNT 14% vs. CRT 4%). Results of patients included in other countries resembled those of the Dutch population.

Our findings suggest that, following TNT, a short distance to the distal resection margin is an important risk factor for locoregional recurrences. In Figure 1, we propose an explanation of the underlying mechanisms. TNT generally leads to a better tumour response compared to CRT. In addition, tumours often exhibit a fragmented response pattern, leaving undetectable viable tumour clusters in the original tumour bed (2). Therefore, when surgery is performed after TNT with a short distal resection margin, there is a higher chance of resection through the original tumour bed, still containing viable tumour cells. This could, in turn, lead to an increased risk of locoregional recurrence.

A distal resection margin of at least 10mm is currently considered oncologically safe. However, this threshold is based on studies that included patients with rectal cancer receiving either CRT or no radiotherapy (3, 4). Therefore, recommendations for safe surgical margins after TNT should be reevaluated.

Figure 1. Proposed mechanisms leading to the increase in locoregional recurrences after TNT. Abbreviations: CRT = chemoradiotherapy; TNT = total neoadjuvant treatment.

 

RAPIDO study group at ESTRO 2025, Vienna. Left to right: Professor Corrie Marijnen, Ilaria Prata, Max Tanaka, Dr. Alice Couwenberg.

Ilaria Prata, MD, PhD candidate

Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands

GROW, School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands

Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands

 

Email address: i.prata@lumc.nl

LinkedIn profile: https://www.linkedin.com/in/ilaria-prata-861a841a7/

 

References

1.   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(1):29-42.

2.  Kus Ozturk S, Graham Martinez C, Sheahan K, Winter DC, Aherne S, Ryan É J, et al. Relevance of shrinkage versus fragmented response patterns in rectal cancer. Histopathology. 2023;83(6):870-9.

3.  Bujko K, Rutkowski A, Chang GJ, Michalski W, Chmielik E, Kusnierz J. Is the 1-cm rule of distal bowel resection margin in rectal cancer based on clinical evidence? A systematic review. Ann Surg Oncol. 2012;19(3):801-8.

4.  Fitzgerald TL, Brinkley J, Zervos EE. Pushing the envelope beyond a centimeter in rectal cancer: oncologic implications of close, but negative margins. J Am Coll Surg. 2011;213(5):589-95.