Overview

This is a prospective, multicenter, open-label, phase III randomized controlled clinical trial designed to evaluate the efficacy and safety of replacing the traditional chemotherapeutic drug mitomycin with the PD-1 inhibitor sintilimab in definitive chemoradiotherapy for limited-stage anal squamous cell carcinoma. The study plans to enroll 350 previously untreated patients with limited-stage anal squamous cell carcinoma and randomize them in a 1:1 ratio into two groups: the control group will receive the current standard treatment, namely intensity-modulated radiotherapy (IMRT) concurrent with capecitabine and mitomycin; the experimental group will receive an innovative "immunotherapy replacement" regimen, namely IMRT of the same technique concurrent with capecitabine and sintilimab. The study adopts a dual primary endpoint design, aiming to verify that the experimental group is non-inferior to the control group in the clinical complete response rate at 6 months after radiotherapy, and is significantly superior to the control group in the incidence of grade 3 or higher treatment-related acute toxicities.

Eligibility

Inclusion Criteria:

1. Histopathologically confirmed primary anal squamous cell carcinoma, including a subset of rectal squamous cell carcinomas. Definition for inclusion of rectal squamous cell carcinomas: According to Williams' criteria (1979) and WHO classification (2019), rectal squamous cell carcinomas included in this study must meet all of the following criteria: (1) Histopathologically confirmed as pure squamous cell carcinoma, excluding adenosquamous carcinoma; (2) Digital examination/endoscopy/MRI confirmation that the tumor mass is entirely located in the rectum (above the dentate line), with no evidence of primary origin in the anal canal or upward spread. If the inferior border of the tumor is within 5-6 cm from the anal verge, and the patient is scheduled to undergo radical radiotherapy and chemotherapy, the rectal squamous cell carcinoma can be diagnosed and screened for inclusion (When the primary epicenter cannot be determined, regardless of which side the tumor mass is biased towards, the diagnosis shall be considered for screening and inclusion as anal squamous cell carcinoma); (3) Female patients must be excluded for rectal metastasis from cervical squamous cell carcinoma (baseline gynecological examination is recommended).
2. Staged as cT2-T4N0M0 or cTanyN+M0 by imaging (AJCC 9th).
3. No prior tumor resection surgery (other than biopsy) or chemotherapy or other anti-tumor therapy.
4. Aged 18-75 years old.
5. ECOG performance status of 0-1.
6. Adequate organ function reserve: white blood cell (WBC) count ≥3 × 10\^9/L, absolute neutrophil count (ANC) ≥1.5 × 10\^9/L, hemoglobin (Hb) level \>90 g/L, platelet (PLT) count \>100 × 10\^9/L; serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels \<2.5 times the upper limit of normal (ULN); serum bilirubin level ≤1.5 × ULN; serum creatinine (Cr) level \<1.5 × ULN; international normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (APTT) ≤1.5 × ULN.
7. No known history of allergy to the study drugs.
8. No prior radiotherapy to the planned radiation site.
9. Non-pregnant and non-lactating women.
10. For HIV-positive patients: at the initiation of the study, a stable combined antiretroviral therapy (CART) regimen must be used, with an HIV viral load of \<50 copies/mL or below the limit of detection, and a CD4+ T-cell count \>300/µL. Patients will be closely monitored during the study, and CART management will follow antiviral treatment guideline recommendations.
11. Signed informed consent form.

Exclusion Criteria:

1. Perianal squamous cell carcinoma originating from the perianal skin without invasion of the anal canal or anal sphincter. (For tumors with an ill-defined primary site, if clinical judgment indicates the main tumor mass involves the anal canal or is associated with anal sphincter invasion requiring sphincter-preserving chemoradiotherapy, the patient is eligible for inclusion.)
2. Perianal Paget's disease.
3. Pregnant or lactating women.
4. Severe comorbidities or any medical/psychiatric condition deemed unsuitable for participation in this study.
5. Patients with prior antitumor immunotherapy (e.g., anti-CTLA-4, anti-PD-1, or anti-PD-L1 monoclonal antibodies, etc.), with the exception of anti-HPV vaccination.
6. History of other malignancies diagnosed within the past 3 years, except for curatively treated basal cell carcinoma of the skin and/or completely resected carcinoma in situ of the cervix, breast, or thyroid.
7. Requires chronic use of immunosuppressive medications.
8. Patients with severe autoimmune diseases, including but not limited to: symptomatic interstitial lung disease, or active infectious/non-infectious pneumonia; active inflammatory bowel disease (including Crohn's disease, ulcerative colitis); rheumatoid arthritis; scleroderma; systemic lupus erythematosus; autoimmune vasculitis; myasthenia gravis; myositis; autoimmune hepatitis; antiphospholipid syndrome; Wegener's granulomatosis; Sjögren's syndrome; Guillain-Barré syndrome; or multiple sclerosis, etc.
9. History of organ transplantation or allogeneic stem cell transplantation.
10. Patients with laboratory test values not meeting the relevant criteria within 7 days prior to enrollment.
11. Patients with significantly impaired cardiac, hepatic, pulmonary, renal, or bone marrow function.
12. Patients with severe, uncontrolled medical conditions or infections. Examples include: severe myocardial infarction, heart failure, unstable angina, or unstable arrhythmia within the past 6 months; respiratory failure and chronic obstructive pulmonary disease; active hepatitis B virus (HBV) infection (HBV-DNA ≥2000 U/mL); hepatitis C virus (HCV) infection; active tuberculosis infection, etc.
13. Concurrent use of other investigational drugs or participation in other clinical trials.
14. Patients who refuse or are unable to sign the informed consent form for participation in the trial.
15. Patients with known allergies or contraindications to the investigational anti-tumor drug or any of its excipients.
16. Patients deemed by the investigator to be unsuitable for participation in the study and unlikely to comply with the study procedures, restrictions, and requirements.