Phase III Randomized Trial of Neoadjuvant Chemotherapy and Pelvic Reirradiation Versus Chemotherapy Alone in Locally Recurrent Rectal Cancer

The primary objective of this phase III randomized trial is to assess the efficacy of **neoadjuvant chemotherapy** followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with locally recurrent rectal cancer (LRRC). This is clinically relevant as achieving a higher rate of R0 resections can significantly improve patient outcomes by reducing the likelihood of residual disease and potential recurrence.

Secondary objectives include:

• Comparing neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on 3-year Disease-Free Survival and 3-year Overall Survival.
• Evaluating the impact on surgical morbidity and mortality (Dindo classification) at 30 days post-surgery.
• Assessing compliance to the neoadjuvant treatment regimen.
• Determining the rate of good tumor response.
• Evaluating quality of life at two years after surgery.
• Assessing the toxicity of the neoadjuvant treatment.

The clinical trial involves participants diagnosed with **rectal cancer**, specifically those with recurrent rectal cancer after local excision. The study population includes both male and female subjects, aged 18 years and older, who have previously undergone pelvic irradiation for primary rectal cancer or primary recurrence. The trial does not provide the total number of participants, as this information was not disclosed by the sponsor. Participants were selected based on specific criteria, including adequate hematologic, hepatic, and renal function, and the absence of distant metastasis. The trial population is characterized by a willingness and ability to comply with scheduled visits and study procedures. Lifestyle considerations such as diet and physical activity are not specified in the available data. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants involved.

The clinical trial is a **randomized**, **controlled**, and **double-blind** study designed to evaluate the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus chemotherapy alone in patients with locally recurrent rectal cancer. The trial aims to assess the rate of curative surgery (R0 resection) in previously irradiated patients. The study is expected to run from July 8, 2022, to December 31, 2025, with an estimated duration of participant involvement of up to 17 months, depending on the treatment regimen assigned.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history. The inclusion criteria require participants to have a histologically proven first or second locally recurrent rectal cancer, adequate organ function, and no distant metastasis. Following the screening, eligible participants will be randomized to receive either chemotherapy alone or chemotherapy followed by pelvic reirradiation. The chemotherapy regimen includes **irinotecan hydrochloride trihydrate**, **levoleucovorin**, **fluorouracil**, **oxaliplatin**, and **capecitabine**, administered via intravenous and oral routes as appropriate.

Throughout the trial, participants will attend regular follow-up visits to monitor treatment compliance, assess tumor response, and evaluate any treatment-related toxicity using the International Common Terminology Criteria for Adverse Events (CTCAE) grading system v5.0. Secondary endpoints include 3-year disease-free and overall survival rates, surgical morbidity and mortality, and quality of life assessments using QLQ-C30 and QLQ-CR29 questionnaires at specified intervals. The end-of-study visit will occur after the completion of the treatment regimen and final assessments.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's primary endpoint is the proportion of curative surgeries achieved, while secondary endpoints focus on long-term survival, treatment compliance, and quality of life outcomes. The study is conducted under strict ethical guidelines, ensuring informed consent and adherence to regulatory standards.

The clinical trial involves the administration of several **experimental medications**. The first medication is **CAMPTO 20 mg/mL**, a solution for infusion containing **irinotecan hydrochloride trihydrate**. This pharmaceutical form is a solution to be diluted for intravenous use. The maximum daily dose is 180 mg/m², with a total maximum dose of 1080 mg/m² over a treatment period of up to 12 weeks. The administration is conducted intravenously, and participant compliance is monitored through scheduled dosing and infusion records.

Another medication used in the trial is **ELVORINE 100 mg/10 mL**, a solution for injection containing **levoleucovorin**. This solution is administered intravenously, with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m² over a 12-week period. The administration schedule is carefully monitored to ensure adherence to the dosing regimen.

The trial also includes **FLUOROURACILE ACCORD 50 mg/mL**, a solution for infusion containing **fluorouracil**. This medication is administered intravenously, with a maximum daily dose of 1200 mg/m² and a total maximum dose of 14400 mg/m² over a 12-week period. The infusion process is closely monitored to maintain participant compliance and safety.

**ELOXATINE 5 mg/mL**, a solution for infusion containing **oxaliplatin**, is another medication used in the study. It is administered intravenously, with a maximum daily dose of 85 mg/m² and a total maximum dose of 510 mg/m² over a 12-week period. The administration is conducted under strict monitoring to ensure proper dosing and participant adherence.

Lastly, the trial includes **Xeloda 150 mg film-coated tablets**, containing **capecitabine**. This medication is administered orally, with a maximum daily dose of 1600 mg/m² and a total maximum dose of 27200 mg/m² over a treatment period of up to 17 weeks. Participant compliance is monitored through pill counts and patient diaries to ensure adherence to the oral dosing schedule.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of curative surgery, specifically **R0 resection**, in patients with locally recurrent rectal cancer (LRRC) who have previously undergone pelvic irradiation. This endpoint will determine the effectiveness of neoadjuvant chemotherapy followed by pelvic reirradiation compared to chemotherapy alone.

Secondary endpoints include the 3-year disease-free survival and 3-year overall survival rates, which will provide insights into the long-term benefits of the treatment regimens. Surgical morbidity and mortality will be evaluated using the Dindo classification within the first 30 days post-surgery. Treatment compliance will be measured by the proportion of patients receiving the full allocated neoadjuvant treatment. The proportion of good tumor response will be assessed by the reduction in LRRC size by 50% after preoperative treatment, as determined by MRI and defined as good radiological responders based on existing literature.

Additionally, the trial will monitor treatment-related toxicity using the International Common Terminology Criteria for Adverse Events (CTCAE) grading system version 5.0. Quality of life will be evaluated using the QLQ-C30 and QLQ-CR29 questionnaires at multiple timepoints: before neoadjuvant treatment, before surgery, and at 6 months, one year, and two years post-surgery. These assessments will provide a comprehensive evaluation of the treatment's impact on patients' well-being and overall health outcomes.