Phase III Randomized Study of Induction Chemotherapy with Modified DCF Regimen Followed by Chemoradiotherapy vs. Standard Chemoradiotherapy in Locally Advanced Anal Squamous Cell Carcinoma

The primary objective of this study is to evaluate the **efficacy** of induction chemotherapy using modified DCF (4 cycles) followed by standard chemoradiotherapy (CRT) compared to standard CRT alone in patients with locally advanced anal squamous cell carcinoma. The primary endpoint is the comparison of disease-related event-free survival at 2 years. This is clinically relevant as it aims to determine whether the addition of induction chemotherapy can improve outcomes in this patient population, potentially leading to changes in standard treatment protocols.

Secondary objectives include:

• Overall survival at 2 and 3 years.
• Respect rate of dose constraints, focusing on radiotherapy quality control.
• Assessment of acute toxicity of treatment in two arms.
• Evaluation of late toxicity of treatment in two arms up to 3 years post-treatment.
• Complete response rate at 6 months following the end of CRT.
• Pelvic recurrence rate at 2 years.
• Metastatic recurrence rate at 2 years.
• Colostomy-free survival at 2 and 3 years.
• Quality of life assessment using EORTC QLQ-C30, EORTC QLQ-ANL27, Jorge & Wexner Score, and sexual health assessment with EORTC SHQ-22.
• Disease-free survival at 3 years.

These secondary objectives provide a comprehensive evaluation of the treatment's impact on survival, recurrence, toxicity, and quality of life, offering valuable insights into the overall benefits and risks associated with the treatment regimens under investigation.

The clinical trial focuses on individuals diagnosed with **locally advanced anal squamous cell carcinoma**. The study population includes both male and female participants, aged between 18 and 75 years, with the possibility of including those over 75 if they have a favorable oncodage G8 score or have undergone an oncogeriatric assessment. Participants are required to have a measurable tumor on MRI and must be capable of receiving chemotherapy and radiotherapy. The trial does not include individuals with major comorbidities that could hinder treatment delivery, and all participants must have a WHO performance status of less than 2. The sponsor has not provided information regarding the total number of participants. The trial population selection considers the ability to undergo treatment and the absence of significant health issues that could interfere with the study's objectives.

The clinical trial is a **randomized**, **controlled**, phase III study designed to evaluate the efficacy of induction chemotherapy followed by chemoradiotherapy compared to standard chemoradiotherapy in patients with **locally advanced anal squamous cell carcinoma**. The trial aims to compare disease-related event-free survival at two years between the two treatment arms. Participants will be randomly assigned to receive either the induction chemotherapy regimen, which includes **capecitabine**, **mitomycin**, **cisplatin**, **docetaxel**, and **fluorouracil**, followed by chemoradiotherapy, or the standard chemoradiotherapy alone. The trial is expected to commence recruitment on January 31, 2024, and conclude by January 31, 2027.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven anal squamous cell carcinoma, measurable tumor on MRI, and a WHO performance status of less than 2. Participants must be aged between 18 and 75, or older if they have a favorable oncodage G8 score or oncogeriatric assessment. The trial will exclude individuals with major comorbidities that could impede treatment delivery. Following the screening, participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the primary endpoint of disease-related event-free survival and secondary endpoints, including overall survival, colostomy-free survival, and quality of life scores.

The expected duration of participant involvement is up to 29 weeks, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout its duration.

The clinical trial involves the administration of several **chemotherapy** agents, each with specific dosing regimens and routes of administration. **Capecitabine** is provided in the form of a film-coated tablet, administered orally. The maximum daily dose is 1650 mg/m², with a treatment period extending up to 6 weeks. This medication is utilized as part of the chemotherapy regimen in the trial.

**Mitomycin** is administered as a solution for injection or infusion, delivered intravenously. The maximum daily dose is 10 mg/m², with a treatment period of up to 29 days. This agent is also part of the chemotherapy protocol being evaluated in the study.

**Cisplatin** is provided as a solution for injection, administered via intravenous injection. The maximum daily dose is 40 mg/m², with a treatment period of up to 6 weeks. This medication is included in the chemotherapy regimen under investigation.

**Docetaxel** is administered as a solution for infusion, delivered intravenously. The maximum daily dose is 40 mg/m², with a treatment period of up to 6 weeks. This agent is part of the chemotherapy treatment being assessed in the trial.

**Fluorouracil** is provided as a solution for injection or infusion, administered intravenously. The maximum daily dose is 1200 mg/m², with a treatment period of up to 6 weeks. This medication is included in the chemotherapy regimen being evaluated.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The study aims to compare the efficacy of induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced anal squamous cell carcinoma.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **disease-related event-free survival (DFS)**. DFS is defined as the time from the date of randomization to the occurrence of the first event, which may include residual tumor at 6 months requiring an abdominoperineal resection (APR), progression, recurrence (local or metastatic), or death. If the patient is alive without any event, the date of the last news will be considered.

Secondary endpoints include overall survival (OS), colostomy-free survival (CFS), toxicities and grades according to the International Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, response rate evaluated by mRECIST criteria 1.1 and clinical examination, quality of life scores, pelvic recurrence rate at 2 years, and metastatic recurrence rate at 2 years. These parameters will be measured and collected at specified intervals throughout the trial to ensure comprehensive data analysis.