Efficacy and Safety Exploration of Short Course Radiotherapy Followed by Surufatinib and Toripalimab in Neoadjuvant Treatment of Locally Advanced Rectal Cancer (STARS-RC08)

Why is this study conducted? The purpose of this study is to improve treatment efficacy, particularly the pathological complete response rate, in patients with high-risk/extremely high-risk locally advanced rectal cancer (LARC). Recent advances have been achieved with neoadjuvant chemoradiotherapy combined with immunotherapy for rectal cancer, yet regional recurrence and distant metastasis remain persistent challenges. Developing novel therapeutic strategies for this patient population is therefore critical.

Rectal cancer management typically consists of surgery, radiation therapy, and chemotherapy. Treatment strategies are gradually shifting toward neoadjuvant chemoradiotherapy plus immunotherapy, which has demonstrated promising potential in multiple clinical trials. These trials indicate that combining short-course radiotherapy, anti-angiogenic agents, and immune checkpoint inhibitors may improve patient prognosis and increase tumor response rates. Nonetheless, the efficacy and safety of such regimens in high-risk patients require further validation.

Against this background, the study aims to evaluate a novel regimen: short-course radiotherapy followed by surufatinib and toripalimab (anti-PD-1), to increase the pathological complete response rate. The investigators also explore efficacy-associated biomarkers including RAS/BRAF status and gene expression profiles to support personalized treatment. This study seeks to optimize therapy for patients with LARC and inform future treatment approaches.

Why are participants invited to participate in this study? Participants are eligible for screening with a diagnosis of high-risk or extremely high-risk locally advanced rectal cancer that satisfies study inclusion criteria. Eligible candidates must have pathologically confirmed disease, appropriate tumor location, and no severe comorbidities or exclusionary illnesses (e.g., recurrent rectal cancer, cardiac dysfunction). Final enrollment decisions are made by study physicians based on individual clinical status.

What do participants need to do to participate in this study? Study participation requires adherence to predefined study procedures. Participants receive scheduled medical assessments, including blood tests, imaging scans, and anorectal function evaluations. During the study period, participants may complete questionnaires and provide biospecimens (e.g., blood samples) for treatment efficacy analysis. The study team defines the frequency and content of each follow-up to maintain continuous monitoring throughout treatment. Compliance with study procedures supports evaluation of regimen efficacy.

What are the risks of participating in this study?

This study applies neoadjuvant short-course radiotherapy, anti-PD-1 monoclonal antibody (toripalimab), and anti-angiogenic therapy (surufatinib). Potential risks for participants are listed below:

Risk of neoadjuvant short-course radiotherapy: Participants may develop grade ≥3 adverse events including, but not limited to, severe diarrhea, grade 3 neutropenia, and grade 3 radiation dermatitis, which may impair patient quality of life.

Risk of anti-PD-1 monoclonal antibody: Toripalimab may induce immune-related adverse events (irAEs) involving any organ system. Common irAEs include skin toxicity (papules, pruritus; incidence 30% to 40%), diarrhea and/or colitis (8% to 19%), fatigue (16% to 24%), immune-related hepatitis (5%), hypothyroidism (4% to 10%), and hyperthyroidism (4%). Approximately two-thirds of patients receiving immune checkpoint inhibitors develop irAEs of varying severity; the risk of serious adverse events cannot be overlooked.

Risk of anti-angiogenic therapy: Surufatinib may trigger adverse reactions related to its anti-angiogenic and immunomodulatory effects. Common adverse events (incidence >20%) include proteinuria, hypertension, bleeding, liver dysfunction, and diarrhea. Among grade ≥3 adverse events, hypertension (29.7%), proteinuria (14.5%), liver dysfunction (12.8%), and bleeding (4.5%) occur most frequently. Rarely, treatment-related death may result from gastrointestinal hemorrhage or cerebral hemorrhage.

Handling of research related injuries? This interventional study introduces no incremental risks beyond standard clinical diagnosis and treatment. Any harm arising from study participation will be reviewed for compensation and liability in accordance with applicable laws and regulations.