Efficacy and Safety Comparison of Short-course Radiotherapy Followed by CapeOX Chemotherapy Plus Toripalimab With or Without Concurrent Surufatinib in Neoadjuvant Therapy for Mid-to-low Localized Rectal Cancer of High-risk Criteria

Why is this study conducted? The purpose of this study is to improve the treatment efficacy, particularly the pathological complete response rate, in patients with high-risk/extremely high-risk locally advanced rectal cancer (LARC). In recent years, with the combination of neoadjuvant chemoradiotherapy and immunotherapy, some progress has been made in the treatment of rectal cancer, but there are still problems of regional recurrence and distant metastasis. Therefore, developing new treatment strategies for these patients is particularly important.

The treatment of rectal cancer usually involves surgery, radiation therapy, and chemotherapy. The current treatment methods have gradually shifted towards neoadjuvant chemoradiotherapy combined with immunotherapy, and have shown good potential in some clinical trials. These studies suggest that combining short-range radiotherapy, anti angiogenic drugs, and immune checkpoint inhibitors may play an important role in improving patient prognosis and enhancing tumor response rates. However, the efficacy and safety of these plans in high-risk patients still need further validation.

In this context, the aim of our study is to compare the efficacy and safety of neoadjuvant short-course radiotherapy followed by four cycles of CapeOX chemotherapy combined with toripalimab, with or without concurrent surufatinib, in patients with mid-to-low locally advanced rectal cancer with high-risk factors identified by MRI (including any one or more of the following: cT4, cN2, EMVI+, MRF/CRM+, or lateral lymph node metastas. This study aims to promote treatment optimization for LARC patients and provide new ideas for future treatments.

Why are you invited to participate in this study? We would like to invite you to participate in this study as you have been diagnosed with high-risk or extremely high-risk locally advanced rectal cancer, which meets the inclusion criteria of this study. Specifically, you need to meet the conditions for pathological diagnosis, have a suitable tumor location, and not have serious comorbidities or other excluded diseases (such as recurrent rectal cancer, cardiac dysfunction, etc.). The final selection will be determined by the research doctor based on your actual situation.

What do you need to do to participate in this study? Participating in this study will require you to follow a series of steps. You need to undergo regular medical examinations and evaluations, including blood tests, imaging examinations, and anorectal function assessments. During the research period, you may also need to fill out a questionnaire and provide some biological samples (such as blood samples), which will be used for the analysis of drug efficacy. The frequency and specific content of each follow-up will be informed by the research team to ensure your participation throughout the entire treatment process. I hope you can cooperate with these research steps to help us better understand the effectiveness of this treatment plan.

What are the risks of participating in this study?

This study involves the use of neoadjuvant short course radiotherapy, PD-1 monoclonal antibody (Terizumab), and anti angiogenic therapy (Sofantinib). Participants may face the following risks:

Risk of neoadjuvant short course radiotherapy: Participants may experience severe side effects (≥ grade 3), including but not limited to severe diarrhea, third degree neutropenia, and third degree radiation dermatitis. These side effects may seriously affect the quality of life of patients.

Risk of PD-1 monoclonal antibody: Terriptylimab may cause immune related adverse reactions (irAEs), which can involve any organ. The commonly known irAEs include skin toxicity (such as papules and itching, with an incidence of 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%). Overall, nearly two-thirds (about 2/3) of patients receiving immune checkpoint inhibitor therapy will experience varying degrees of irAEs, and the incidence of serious adverse events cannot be ignored.

Risk of anti angiogenic therapy: The use of sorafenib may lead to adverse reactions related to its anti angiogenic and immunomodulatory effects. Known common adverse reactions include proteinuria, hypertension, bleeding, liver dysfunction, diarrhea, etc., with an incidence rate of over 20%. Among serious adverse events (≥ grade 3), hypertension (29.7%), proteinuria (14.5%), liver dysfunction (12.8%), and bleeding (4.5%) are the most common. In rare cases, treatment-related deaths may occur due to gastrointestinal bleeding, cerebral hemorrhage, etc.

Handling of research related injuries? This study is an intervention study that does not add any additional risks beyond routine clinical diagnosis and treatment. If you suffer harm due to participating in the study, compensation or liability will be determined in accordance with relevant laws and regulations.

Inclusion criteria

• 1. Patients and their families are able to understand and willing to participate in this clinical study and sign the informed consent form; 2. Age: 18~75 years old, male or female; 3. Pathologically confirmed rectal tubular adenocarcinoma; Differentiation into Grade 1-3, i.e., high, intermediate, and low-grade adenocarcinoma; pMMR/MSS phenotype; 4. Medium and low rectal cancer with the lower edge of the tumor located within 10cm from the anal verge; 5. Inclusion of treatment-naïve risk factors: cT4/cN2/mrMRF+/EMVI+ or lateral lymph node involvement.

• No distant metastases; 7. ECOG score 0-1; 8. Hepatitis B surface antigen (HBsAg) (-) and hepatitis B core antibody (HBcAb) (-). If HBsAg (+) or HBcAb (+), hepatitis B virus deoxyribonucleic acid (HBV-DNA) must < 1000 copies/mL or 200 IU/mL for enrollment; 9. HCV antibody (-); 10. Negative serum or urine pregnancy test for females of childbearing age; 11. Females of childbearing potential or males with potential reproductive partners should agree to use adequate contraception (such as intrauterine devices, birth control pills, or condoms) for the duration of the study and for 120 days after the end of the study; 12. No history of pelvic radiotherapy; 13. No history of surgery or chemotherapy for rectal cancer; 14. Not accompanied by systemic infections requiring antibiotic treatment; 15. Heart, lung, liver, and kidney function can tolerate surgery;

Exclusion criteria

• 1. Recurrent rectal cancer; 2. ECOG score of 2 points or above; 3. Occurrence of cardiovascular and cerebrovascular diseases within 6 months prior to the first dose: cerebrovascular accident/stroke, myocardial infarction, unstable angina, poorly controlled arrhythmias (including QTc interval ≥ 450 ms for males and 470 ms for females≥ (QTc interval is calculated by Fridericia's formula); 4. Presence of NYHA standard grade III.~IV. cardiac insufficiency or cardiac color ultrasound examination: LVEF (left ventricular ejection fraction) < 50%; 5. Presence of hypertension (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥90mmHg) that cannot be controlled by antihypertensive drugs; 6. Urine routine showed that urine protein was ≥++, and 24-hour urine protein was > 1.0g; 7. History of immunodeficiency, including human immunodeficiency virus (HIV) infection; Other acquired, congenital immunodeficiency diseases; History of organ or bone marrow transplantation; 8. Treatment with a live vaccine within 28 days prior to the first dose, except inactivated viral vaccines for seasonal influenza; 9. Previous and current presence of known active or suspected autoimmune disease (except for patients with hypothyroidism controlled by hormone replacement therapy and type I diabetes mellitus who only require control with insulin replacement therapy); 10. Have active tuberculosis; 11. Patients with previous and current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe impairment of lung function, etc., which may interfere with the detection and management of suspected drug-related pulmonary toxicity; 12. Previous treatment with other small molecule anti-angiogenic targeted drugs or antibody/drug therapy against immune checkpoints, such as PD-1 inhibitors, PD-L1, CTLA4, etc.; 13. Known history of severe allergy to PD-1 monoclonal antibody active ingredient, TKI inhibitor related components, or any investigational drug excipient; 14. Patients with organ bleeding or bleeding tendency, except for rectal primary tumor bleeding (the investigator needs to assess the bleeding risk); 15. Those who have suffered from malignant tumors in the past; 16. Received other types of anti-tumor or experimental therapy; 17. Pregnant or lactating females; 18. Patients with central nervous system diseases or abnormal mental status, which may affect the patient's participation in this study; 19. Patients with other severe, acute and chronic diseases that may increase the risk of participating in the study and study medication, and are judged by the investigator to be unsuitable for participating in the clinical study;