PD-1 inhibitor and chemotherapy combined with online adaptive short-course radiotherapy as neoadjuvant therapy in mid-to-low locally advanced rectal cancer: a study protocol for a prospective, two-arm, randomized controlled phase II trial

Introduction Total neoadjuvant therapy (TNT) combining short-course radiotherapy (SCRT) with systemic chemotherapy improves local control and organ preservation in locally advanced rectal cancer (LARC). Although PD-1 inhibitors produce dramatic responses in dMMR/MSI-H tumors, the predominant pMMR/MSS subtype remains relatively resistant, and the optimal sequencing of immunotherapy within TNT for mid-to-low LARC is undefined. This trial aims to compare induction versus consolidation sequencing of sintilimab plus CAPOX with online adaptive SCRT to maximize tumor eradication and organ preservation without compromising surgical safety. Methods and analysis This prospective, two-arm, randomized phase II trial will enroll 36 participants with mid-to-low LARC (cT3–4 or N+), randomized 1:1 to induction arm (two cycles of sintilimab plus CAPOX before and after SCRT) or consolidation arm (SCRT followed by four cycles). SCRT is delivered as 30 Gy in 6 fractions using intensity-modulated radiation therapy or volumetric-modulated arc therapy, with optional online adaptive radiotherapy (MR-Linac). Systemic therapy comprises oxaliplatin, capecitabine, and sintilimab in 21-day cycles. Surgery is planned 2–4 weeks after completion of all neoadjuvant therapy. The primary endpoint is pathological complete response. Secondary endpoints include pathological tumor regression grade, 3- and 5-year overall and disease-free survival, grade 3–4 adverse events, surgical complications, and quality of life. Discussion This trial prospectively evaluates adding sintilimab to a locally intensified SCRT-CAPOX regimen and compares induction versus consolidation sequencing to determine whether either approach enhances tumor regression and organ preservation without compromising safety. Embedded translational studies explore biomarkers to inform sequence selection and personalized neoadjuvant strategies in rectal cancer. Clinical trial registration https://www.chictr.org.cn , identifier ChiCTR2500104302.