Preoperative FOLFOX Versus Postoperative Risk-Adapted Chemotherapy in Locally Advanced Rectal Cancer: A Phase III Randomized Trial

The primary objective of this randomized phase III trial is to evaluate **disease-free survival** (DFS) in patients with locally advanced rectal cancer and low risk for local failure. DFS is defined as the time from randomization to the occurrence of any of the following events: no surgery or non-radical (R2) surgery of the primary tumor, locoregional recurrence after R0/1 resection, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause. The clinical relevance of this objective lies in its potential to improve the 3-year DFS probability from 76% in the standard arm to 85% in the investigational arm, with a hazard ratio of 0.60, thereby providing significant insights into the efficacy of preoperative FOLFOX compared to postoperative risk-adapted chemotherapy.

Secondary objectives include: - Assessment of acute and late **toxicity** according to NCI CTCAE version 5.0. - Evaluation of chemotherapy compliance (completion rate). - Analysis of surgical morbidity and complications. - Determination of pathological UICC-staging, including pCR (ypT0N0) rate. - Measurement of R0 resection rate and negative circumferential resection rate (CRM > 1mm). - Tumor regression grading according to Dworak in the experimental arm. - Rate of sphincter-sparing surgery. - Rate of W&W (watch and wait) with or without local regrowth. - Cumulative incidence of local and distant recurrences. - Overall survival. - Quality of life and functional outcome based on treatment arm and surgical procedures.

The clinical trial involves participants diagnosed with **locally advanced rectal cancer**. The study population includes both male and female subjects, aged 18 years and older, with no upper age limit specified. Participants are required to have a histologically confirmed diagnosis of rectal adenocarcinoma located 0 to 16 cm from the anal verge, as measured by rigid rectoscopy. The trial does not specify any particular gender distribution, and both genders are included independently. Participants must have adequate hematological, hepatic, renal, and metabolic function parameters, and a WHO/ECOG Performance Status of 0 or 1. The trial population was selected based on specific MRI-defined inclusion criteria and staging requirements, including high-resolution MRI of the pelvis and transrectal endoscopic ultrasound. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of preoperative FOLFOX compared to postoperative risk-adapted chemotherapy in patients with **locally advanced rectal cancer** and low risk for local failure. This is a randomized, phase III trial conducted by the German Rectal Cancer Study Group. The primary endpoint is disease-free survival, defined as the time from randomization to events such as non-radical surgery, locoregional recurrence, second primary cancer, metastatic disease, or death from any cause. The trial aims to improve the 3-year disease-free survival probability from 76% to 85% with a hazard ratio of 0.60, requiring a sample size of 550 patients.

The trial involves a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed rectal adenocarcinoma, adequate organ function, and specific MRI-defined inclusion criteria. Participants will undergo high-resolution MRI and transrectal endoscopic ultrasound for local staging, and spiral-CT of the abdomen and chest to exclude distant metastases. The trial duration is estimated to end by April 2030, with recruitment starting in October 2020. Participants will be involved for a maximum treatment period of 12 months, with conditions for early termination including non-compliance or adverse events.

Follow-up visits will assess acute and late toxicity, compliance with chemotherapy, surgical morbidity, and complications. Secondary endpoints include pathological staging, tumor regression grading, and quality of life assessments. The end-of-study visit will evaluate overall survival and cumulative incidence of recurrences. The trial employs a double-blind, controlled methodology to ensure unbiased results. Participants will receive treatments such as **calcium folinate pentahydrate**, **oxaliplatin**, **fluorouracil**, and **capecitabine**, administered intravenously or orally, depending on the specific regimen. The trial is not categorized as low intervention and is a therapeutic confirmatory phase III clinical trial.

The clinical trial involves the administration of several **experimental medications**. **Calcium Folinate Pentahydrate** is provided as a solution for injection or infusion. It is administered intravenously with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m² over a treatment period of up to 12 months. This compound serves as a detoxifying agent for antineoplastic treatment, ensuring the mitigation of toxic effects associated with chemotherapy.

**Oxaliplatin** is another experimental medication used in this trial, formulated as a solution for infusion. It is administered intravenously with a maximum daily dose of 130 mg/m² and a total maximum dose of 520 mg/m² over a 12-month period. Oxaliplatin functions as an antineoplastic agent, contributing to the treatment of cancer by interfering with the growth of cancer cells.

**Fluorouracil** is administered as a solution for injection, also via the intravenous route. The maximum daily dose is set at 1200 mg/m², with a total maximum dose of 14400 mg/m² over the course of 12 months. As an antineoplastic agent, Fluorouracil plays a critical role in inhibiting cancer cell proliferation.

**Capecitabine** is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 2000 mg/m², with a total maximum dose of 112000 mg/m² over a 12-month period. Capecitabine is an antineoplastic agent that is metabolized into 5-fluorouracil in the body, targeting cancer cells effectively.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus remains on evaluating the efficacy and safety of the experimental medications in patients with locally advanced rectal cancer.

The efficacy of the clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)**. This is defined as the time from randomization to the occurrence of one of the following events: no surgery or non-radical (R2) surgery of the primary tumor, locoregional recurrence after R0/1 resection of the primary tumor, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurs first. The trial aims to demonstrate an improvement in the 3-year DFS probability from 76% in the standard arm to 85% in the investigational arm, with a hazard ratio of 0.60. The study is powered at 90% with a two-sided significance level of 5%, requiring a total sample size of 550 patients to achieve statistical significance.

Secondary endpoints include the assessment of acute and late toxicity according to NCI CTCAE version 5.0, compliance with chemotherapy, surgical morbidity and complications, pathological UICC-staging including pCR (ypT0N0) rate, R0 resection rate, negative circumferential resection rate (CRM > 1mm), tumor regression grading according to Dworak in the experimental arm, rate of sphincter-sparing surgery, rate of W&W with or without local regrowth, cumulative incidence of local and distant recurrences, overall survival, and quality of life and functional outcome based on treatment arm and surgical procedures.