Immunotherapy-enhanced tumour regression in rectal cancer: should surgery be omitted?

Correspondence to: Qian Liu and Yong Yang

Qian Liu (e-mail: fcwpumch@163.com)

Department of Colorectal Surgery

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital

Chinese Academy of Medical Sciences and Peking Union Medical College

100021

Beijing

China

Yong Yang (e-mail: dr_yangyong1983@163.com)

Department of Radiation Oncology

Fujian Medical University Union Hospital

Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors (Fujian Medical University)

Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies)

Fuzhou

China

BJS, https://doi.org/10.1093/bjs/znaf057, published 22 March 2025

Funding: This research was funded by the National Key Research and Development Program (No. 2022YFC2505003).

The recent post-hoc analysis of the POLARSTAR randomized trial by Pang et al. investigated the impact of adding PD-1 blockade to neoadjuvant chemoradiotherapy (CRT) on the outcomes of total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC)1. The study convincingly demonstrates that the integration of immunotherapy significantly enhances pathological tumour regression, evidenced by increased rates of complete tumour regression grading (TRG0) and ypT0/is ypN0 status. These findings highlight the promising potential of immune checkpoint inhibition to augment neoadjuvant treatment efficacy. However, despite these encouraging pathological responses, especially in the PD-1 sequential therapy group, the trial did not explore or report on the possibility of omitting radical surgery in patients who achieved excellent tumour regression. This represents a clinically significant gap, as the growing paradigm of organ preservation in rectal cancer offers an opportunity to tailor treatment intensity based on individual response, potentially sparing selected patients from the surgery without compromising oncologic outcomes.

In contrast, the OPRA trial provides compelling evidence supporting non-operative management (NOM) for patients who achieve a clinical-complete response (cCR) following total neoadjuvant therapy (TNT)2. OPRA trial demonstrated a 3-year organ preservation rate of 77% among cCR patients, with low rates of local regrowth and favourable long-term oncologic results. Importantly, OPRA employed a rigorous three-tier clinical response grading system (complete, near-complete, incomplete response) to guide treatment decisions and optimize patient selection for a watch-and-wait approach. Similarly, the CAO/ARO/AIO-16 phase 2 trial reinforced the efficacy of intensified TNT regimens, reporting pathological complete response rates exceeding 25% with consolidation chemotherapy3. Pooled data from the OPRA and CAO/ARO/AIO-12 trials demonstrate that a selective watch-and-wait strategy after total neoadjuvant therapy yields oncologic outcomes equivalent to mandatory surgery, supporting its feasibility in patients with excellent response4. These data strongly advocate for the integration of organ-preserving strategies into contemporary treatment protocols, particularly when combined with novel immunotherapeutic agents that may further enhance tumour regression, as seen in POLARSTAR trial.

Given the substantial pathological responses observed with CRT plus PD-1 blockade, we propose that future iterations of the POLARSTAR trial consider incorporating:

Standardized post-treatment clinical evaluation protocols, including digital rectal examination, endoscopy, and high-resolution pelvic MRI, to accurately identify candidates achieving cCR or near-cCR;

Implementation of a structured watch-and-wait surveillance strategy for patients meeting defined clinical response criteria, modelled after the methodology of OPRA trial;

Prospective assessment of non-operative management outcomes, including rates of local regrowth, salvage surgery feasibility, and long-term oncologic survival.

By integrating these components, the future trial could not only advance the therapeutic efficacy of neoadjuvant immunotherapy but also pioneer a personalized, response-adapted treatment paradigm that minimizes surgical morbidity and preserves quality of life for appropriately selected patients.

We commend the authors for their significant contribution to the field of rectal cancer treatment and encourage further exploration of non-operative strategies in future trials to fully harness the promise of combined immunotherapy and chemoradiotherapy.