Impact of PD1 Blockade Added to Neoadjuvant Chemoradiotherapy on Rectal Cancer Surgery: Post-Hoc Analysis of the Randomized POLARSTAR Trial

Medicine Oncology
PD1 blockade neoadjuvant chemoradiotherapy rectal cancer surgery POLARSTAR trial

Background

Colorectal cancer is the third most common cancer type globally, with the greatest disease burden in East Asia. In China, 47% of newly diagnosed colorectal cancers are rectal cancers, of which 70% are radiologically staged as locally advanced (stage II/III) at diagnosis. For decades, neoadjuvant chemoradiotherapy (CRT) combined with total mesorectal excision (TME) has been the standard of care for locally advanced rectal cancer (LARC). However, with the advent of novel neoadjuvant treatment modalities such as total neoadjuvant therapy (TNT) and neoadjuvant immunotherapy, treatment strategies are continuously evolving.

PD1 blockade, as an immunotherapy approach, has been shown to significantly increase the pathological complete response (pCR) rate in locally advanced rectal cancer. However, its impact on TME surgery remains unclear. Therefore, this study aimed to explore the effects of adding PD1 blockade to neoadjuvant CRT on rectal cancer surgery, particularly on the successful implementation of surgery and surgical safety.

Source of the Paper

This paper was co-authored by Kai Pang, Xinzhi Liu, Hongwei Yao, and others from major colorectal cancer centers in Beijing, including Beijing Friendship Hospital and Peking University Cancer Hospital. The paper was published in 2025 in the journal BJS with the DOI 10.1093/bjs/znaf057.

Study Process

Study Subjects and Grouping

This study is a post-hoc analysis of the randomized POLARSTAR trial, conducted at eight major colorectal cancer centers in Beijing, aiming to compare the efficacy of neoadjuvant CRT combined with PD1 blockade versus CRT alone. The study enrolled patients with locally advanced rectal cancer, with a total of 186 patients randomized into three groups: CRT plus concurrent PD1 blockade (concurrent group), CRT plus sequential PD1 blockade (sequential group), and CRT alone (control group). Ultimately, 52 patients in the concurrent group, 46 in the sequential group, and 45 in the control group were included in the analysis.

Treatment Protocol

All patients underwent TME surgery after neoadjuvant treatment. Patients in the concurrent group received PD1 blockade during CRT, while those in the sequential group received PD1 blockade after completing CRT. The control group received CRT alone. The study recommended three cycles of PD1 blockade but allowed for one or two cycles.

Study Endpoints

This study focused on surgical-related endpoints, including preoperative radiological assessment indicators (e.g., objective response rate), surgery and surgical safety indicators (e.g., surgical approach, sphincter-saving plus one-stage anastomosis, TME technique, stoma formation, surgical complications, grade 3⁄4 surgical complications, 30-day readmission rate, 30-day reoperation rate, postoperative hospital stay, and postoperative urinary catheter use), and postoperative pathological indicators (e.g., clear resection margin, tumor regression grade (TRG), ypT0/is ypN0, lymphovascular invasion, perineural invasion, and neoadjuvant rectal (NAR) score).

Key Results

Preoperative Radiological Assessment

Compared to CRT alone, the radiological response rate was significantly higher in both the concurrent group (44% vs. 22%) and the sequential group (52% vs. 22%). In patients with positive lymph nodes at baseline, the down-staging rates were 70%, 59%, and 54% in the concurrent, sequential, and control groups, respectively. In patients with involved mesorectal fascia at baseline, the rates of becoming negative were 42%, 67%, and 42% in the concurrent, sequential, and control groups, respectively.

Surgery and Surgical Safety

All patients underwent TME surgery. The proportions of laparoscopic surgery were 100%, 100%, and 98% in the concurrent, sequential, and control groups, respectively. The proportions of sphincter-saving plus one-stage anastomosis surgery were 92%, 96%, and 87%, respectively. The proportions of patients without a stoma were 21%, 17%, and 11%, respectively. The surgical complication rates were 12%, 24%, and 13%, respectively, while the grade 3⁄4 surgical complication rates were 4%, 7%, and 4%, respectively. The 30-day readmission rates were 4%, 7%, and 0%, respectively, and the 30-day reoperation rates were 0% in all groups. There were no significant differences in postoperative hospital stay or postoperative urinary catheter use among the three groups.

Postoperative Pathology

The clear resection margin rates were 100%, 98%, and 96% in the concurrent, sequential, and control groups, respectively. The proportions of TRG0 were 31%, 37%, and 18%, respectively. The proportions of ypT0/is ypN0 were 33%, 39%, and 20%, respectively. The proportions of low NAR scores were 46%, 54%, and 31%, respectively. The sequential group significantly outperformed the control group in terms of TRG0, ypT0/is ypN0, and low NAR score.

Conclusion

Neoadjuvant CRT combined with PD1 blockade enhances pathological tumor regression and is beneficial to the successful implementation of TME surgery in patients with locally advanced rectal cancer. This treatment regimen does not significantly increase surgical complication rates, severe surgical complication rates, 30-day readmission rates, or 30-day reoperation rates, nor does it prolong postoperative hospital stay. Therefore, this treatment regimen is a promising neoadjuvant option and warrants further large-scale validation.

Highlights of the Study

  1. Significant Improvement in Pathological Tumor Regression: The addition of PD1 blockade to neoadjuvant CRT significantly increased the proportions of TRG0, ypT0/is ypN0, and low NAR score.
  2. Improved Surgical Outcomes: Compared to CRT alone, the combined treatment groups showed higher sphincter-saving rates and lower stoma formation rates.
  3. Good Safety Profile: The combined treatment regimen did not significantly increase surgical complication rates or severe surgical complication rates.

Research Value

This study provides clear information to surgeons that neoadjuvant CRT combined with PD1 blockade can assist in the successful implementation of TME surgery without compromising surgical safety. The study offers new insights into the treatment of locally advanced rectal cancer and lays the foundation for future larger-scale research.