Anal Squamous Cell Carcinoma, Limited-stage
Conditions
Keywords
anal squamous cell carcinoma, intensity-modulated radiotherapy, immune checkpoint inhibitors, immunotherapy
Brief summary
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.
Interventions
Intensity-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.
DRUGCapecitabine
Oral capecitabine at 825 mg/m² twice daily on days of radiotherapy, concurrent with IMRT, as part of the chemoradiotherapy backbone for both study arms.
BIOLOGICALSintilimab
Intravenous sintilimab at 200 mg every 3 weeks, administered concurrently with capecitabine and IMRT to the experimental arm as an immunotherapy replacement for mitomycin.
DRUGMitomycin (MMC)
Intravenous 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.
Sponsors
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response (cCR) Rate | 6 months after radiotherapy | 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 | From the start of local treatment to 90 days after the completion of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AEs rate | 2 years after randomization | 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 | Baseline, 3 days after completion of radiotherapy, 1 month after radiotherapy, 3 months after radiotherapy, 6 months after radiotherapy, every 3 months up to 2 years after randomization | 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 | Baseline, 3 days after completion of radiotherapy, 1 month after radiotherapy, 3 months after radiotherapy, 6 months after radiotherapy, every 3 months up to 2 years after randomization | 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 | Baseline, 3 days after completion of radiotherapy, 1 month after radiotherapy, 3 months after radiotherapy, 6 months after radiotherapy, every 3 months up to 2 years after randomization | 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. |
| PFS | 2 years after randomization | Progression-free survival (PFS) is defined as the time from enrollment to the first documentation of disease recurrence or progression per RECIST 1.1 criteria, or death from any cause, whichever occurs first. For participants without any event, PFS will be censored at the last follow-up. |
| CFS | 2 years after randomization | Colostomy-free survival (CFS) is defined as the time from enrollment to the first occurrence of permanent colostomy (due to tumor residual/recurrence, severe treatment-related toxicity leading to loss of anal function, or disease progression/recurrence) or death from any cause, whichever occurs first. For participants without any event, CFS will be censored at the last follow-up. |
| LRFS | 2 years after randomization | Locoregional recurrence-free survival (LRFS) is defined as the time from enrollment to the first occurrence of locoregional disease progression (local recurrence or regional lymph node recurrence) or death from any cause, whichever occurs first. For participants without any event, LRFS will be censored at the last follow-up. Local recurrence (LR) is defined as the reappearance of tumor in the anal canal, perianal skin, rectum, or anastomotic site. Persistent disease (tumor that never achieved clinical complete response \[cCR\] after chemoradiotherapy) is considered an event for statistical analysis, but assessment of residual disease within 6 months after radiotherapy completion is not recommended. Regional lymph node recurrence is defined as the reappearance of tumor in regional lymph node drainage areas within the radiation field, including inguinal, mesorectal, presacral, internal iliac, external iliac, and obturator lymph nodes. |
| DMFS | 2 years after randomization | Distant metastasis-free survival (DMFS) is defined as the time from enrollment to the first occurrence of distant metastasis or death from any cause, whichever occurs first. For participants without any event, DMFS will be censored at the last follow-up. |
| OS | 2 years after randomization | Overall survival (OS) is defined as the time from enrollment to death from any cause. For participants without any event, OS will be censored at the last follow-up. |
| Rate of treatment interruption | 2 years after randomization | The proportion of any unplanned radiotherapy interruptions during the scheduled radiotherapy course due to treatment-related adverse events. |
Countries
China
Contacts
CONTACTYangmei Zhou, MD, PhD
CONTACTYuan Tang, MD, PhD
PRINCIPAL_INVESTIGATORJing Jin, MD, PhD
Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Outcome results
None listed