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.
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).
Staged as cT2-T4N0M0 or cTanyN+M0 by imaging (AJCC 9th).
No prior tumor resection surgery (other than biopsy) or chemotherapy or other anti-tumor therapy.
Aged 18-75 years old.
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.)
Perianal Paget's disease.
Pregnant or lactating women.
Severe comorbidities or any medical/psychiatric condition deemed unsuitable for participation in this study.
Parallel
Intensity-Modulated Radiotherapy (IMRT)
RadiationIntensity-modulated radiotherapy (IMRT) will be administered: * Primary tumor: 1.8 Gy per fraction, 28-30 fractions, total dose 50.4-54 Gy; * Metastatic lymph nodes: 1.68-1.8 Gy per fraction, 30 fractions, total dose 50.4-54 Gy; * Elective nodal regions: 1.5 Gy per fraction, 28-30 fractions, total dose 42-45 Gy; Treatment will be administered 5 days per week, concurrently with systemic chemotherapy (capecitabine ± mitomycin/sintilimab), in accordance with institutional standard practice for anal squamous cell carcinoma.
Capecitabine
DrugOral capecitabine at 825 mg/m² twice daily on days of radiotherapy, concurrent with IMRT, as part of the chemoradiotherapy backbone for both study arms.
Sintilimab
Biological/VaccineIntravenous sintilimab at 200 mg every 3 weeks, administered concurrently with capecitabine and IMRT to the experimental arm as an immunotherapy replacement for mitomycin.
Mitomycin (MMC)
DrugIntravenous mitomycin at 10 mg/m² as a single bolus dose on day 1 of radiotherapy, administered only to the control arm as part of the standard chemoradiotherapy regimen.
Clinical Complete Response (cCR) Rate
cCR is defined as the simultaneous fulfillment of the following criteria: ① Digital rectal examination (DRE): no palpable nodule or ulcer, with only a smooth scar or fibrosis remaining; ② Anoscopy: no macroscopic evidence of residual tumor, with histopathological biopsy required for confirmation if suspicious lesions are present; ③ PET/CT: no residual tumor or new metastatic disease, or no evidence of residual tumor on contrast-enhanced CT or MRI if PET/CT is unavailable.
Grade ≥3 acute TRAEs
According to the CTCAE version 5.0 criteria, non-hematologic toxicities of grade ≥3 (including cutaneous and mucosal reactions, gastrointestinal reactions, and genitourinary reactions), hematologic toxicities (including leukopenia, neutropenia, thrombocytopenia, and anemia, excluding lymphopenia), and immune-related adverse events occurring from the start of local treatment to 90 days after the completion of treatment will be evaluated. The investigator will determine whether these events are treatment-related adverse events.
AEs rate
The incidence and severity of all-grade adverse events during treatment and post-treatment will be evaluated according to CTCAE version 5.0, and investigators will determine whether they are immune-related adverse events (irAEs).
Quality of life (QoL) in cancer patients
Quality of life in cancer patients will be evaluated using the European Organisation for Treatment and Research of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30. The scoring and interpretation of the QLQ-C30 scales were performed according to the EORTC guidelines. Each item is scored from 0 to 100, with higher scores indicating better functioning on the functional scales/items and more severe symptoms on the symptom scales/items.
quality of life (QoL) in anal cancer patients
Anal cancer-specific quality of life will be evaluated using the European Organisation for Treatment and Research of Cancer (EORTC) Quality of Life Questionnaires QLQ-ANL27. The scoring and interpretation of the QLQ-ANL27 scales were performed according to the EORTC guidelines.
Anal function
Anal function will be evaluated using the Wexner incontinence score. This scoring system consists of 5 items evaluating the frequency of gas incontinence, frequency of liquid incontinence, frequency of solid incontinence, frequency of wearing pads, and lifestyle alterations, with a score ranging from 0-4 for each question. The total score is calculated, with higher scores indicating poorer anal function.
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