Radiotherapy-free neoadjuvant strategy using sintilimab plus XELOX in locally advanced rectal cancer: A single-arm phase II trial

Abstract

BACKGROUND

Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer (LARC) and effectively reduces local recurrence; however, its survival benefit remains limited and radiotherapy is associated with substantial acute and long-term toxicities. Increasing evidence suggests that not all patients benefit equally from radiotherapy, particularly those without high-risk features such as cT4b disease, involved mesorectal fascia, or lateral lymph node metastasis. Meanwhile, immunotherapy alone shows limited efficacy in mismatch repair-proficient tumors. We hypothesized that combining chemotherapy with immunotherapy could provide a feasible radiotherapy-free neoadjuvant strategy for selected patients.

AIM

To evaluate the feasibility, efficacy, and safety of radiotherapy-free neoadjuvant sintilimab plus chemotherapy in resectable LARC.

METHODS

This multicenter, single-arm phase II trial enrolled patients with resectable LARC. Participants received 2-4 cycles of neoadjuvant sintilimab combined with XELOX, followed by total mesorectal excision. Patients with radiotherapy-mandating high-risk features were not the primary target population. Pathological response and safety were assessed. Multivariate logistic regression was used to explore predictors of major pathological response (MPR), and multiplex immunofluorescence was performed to evaluate tumor immune microenvironmental features.

RESULTS

A total of 41 patients underwent surgery, and all achieved R0 resection. The pathological complete response was observed in 11 patients (26.8%), and MPR was in 19 patients (46.3%). The objective response rates was 85.4%. T-stage and N-stage downstaging occurred in 41.5% of patients, with concurrent TN downstaging in 26.8%. Treatment-related adverse events were predominantly grade 1-2, with one case each of grade 3 immune-related rash and colitis. Multivariate analysis identified tumor size > 4 cm (odds ratio = 6.51, 95% confidence interval: 1.23-45.2; P = 0.036) and elevated baseline carcinoembryonic antigen (odds ratio = 0.12, 95% confidence interval: 0.01-0.73; P = 0.035) as independent negative predictors of MPR. Immunofluorescence analysis showed increased stromal CD8+ T-cell infiltration and reduced M2 macrophage polarization in responders.

CONCLUSION

Radiotherapy-free neoadjuvant sintilimab plus XELOX shows promising pathological responses and manageable toxicity in selected patients with LARC.

Keywords: Locally advanced rectal cancer; Immunotherapy; Sintilimab; Radiotherapy-free; Pathological complete response

Core Tip: This phase II single-arm study evaluated a radiotherapy-free neoadjuvant strategy using sintilimab plus XELOX in patients with locally advanced rectal cancer without mesorectal fascia involvement. The regimen achieved favorable pathological responses with acceptable toxicity. Tumor size > 4 cm and elevated baseline carcinoembryonic antigen levels were associated with a lower likelihood of major pathological response. Exploratory immune microenvironment analysis suggested a potential association between CD8+ T-cell infiltration and treatment response. These findings support further investigation of radiotherapy-sparing strategies in carefully selected patients.