Phase III Trial of Short-Course Radiotherapy vs. Chemoradiotherapy with Capecitabine, Fluorouracil, and Oxaliplatin in Intermediate/High-Risk Rectal Cancer

The primary objective of this randomized phase III trial is to evaluate **organ preservation** in patients with MRI-defined intermediate and high-risk rectal cancer. Organ preservation is clinically significant as it aims to maintain the rectum intact without major surgery or stoma, thereby potentially improving the quality of life for patients. The trial hypothesizes an improvement in the 3-year organ preservation rate from 30% in the control arm to 40% in the investigational arm, with a hazard ratio of 0.76.

The secondary objectives of the study include:

• Disease-free survival
• Rate of clinical complete response after total neoadjuvant therapy (TNT)
• Rate of immediate total mesorectal excision (TME) after TNT
• Cumulative incidence of locoregional regrowth after clinical complete response (cCR)
• Rate of salvage surgery after locoregional regrowth
• Cumulative incidence of local recurrence after (salvage) surgery
• Postoperative complications of (salvage) surgery
• Rate of sphincter-sparing (salvage) surgery
• Pathological TNM-staging
• R0 resection rate; negative circumferential resection rate
• Tumor regression grading according to Dworak
• Neoadjuvant rectal score
• Quality of TME according to MERCURY
• Acute and late toxicity assessment according to NCI CTCAE V.5.0
• Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation
• Cumulative incidence of distant metastases
• Overall survival
• Translational/biomarker studies

The clinical trial involves a total of **14 participants** diagnosed with **intermediate and high-risk rectal cancer**. The study population includes both male and female subjects, aged 18 years and older, with no upper age limit specified. Participants were selected based on a histologically confirmed diagnosis of rectal adenocarcinoma located 0-12 cm from the anocutaneous line, as determined by rigid rectoscopy. The trial includes individuals with adequate hematological, hepatic, renal, and metabolic function parameters, and a WHO/ECOG Performance Status of 0 or 1. The selection process also considered MRI-defined high-risk conditions, such as specific tumor characteristics and evidence of extramural venous invasion. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The trial population includes a vulnerable population, as indicated by the inclusion of both male and female subjects without an upper age limit. Participants provided informed consent to partake in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of short course radiotherapy versus chemoradiotherapy, followed by consolidation chemotherapy, in patients with MRI-defined intermediate and high-risk **rectal cancer**. The trial aims to assess the primary endpoint of organ preservation, defined as survival with the rectum intact, no major surgery, and no stoma. The study hypothesizes an improvement in the 3-year organ preservation rate from 30% in the control arm to 40% in the investigational arm, with a sample size of 702 patients required to achieve statistical significance.

The trial will span approximately nine years, with an estimated recruitment start date of July 1, 2020, and an estimated end date of March 31, 2029. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of rectal adenocarcinoma, MRI-defined high-risk conditions, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response, assess toxicity, and evaluate secondary endpoints such as disease-free survival and overall survival. The end-of-study visit will conclude the participant's involvement, with data collection on long-term outcomes and quality of life.

Participant involvement is expected to last up to 18 months, with conditions for early termination including the occurrence of major surgery, stoma formation, or significant adverse events. The trial will utilize a combination of oral and intravenous administration of investigational products, including **capecitabine**, **fluorouracil**, **calcium folinate pentahydrate**, and **oxaliplatin**. The study will adhere to rigorous ethical standards, ensuring informed consent and compliance with regulatory requirements throughout the trial duration.

The clinical trial involves the administration of several **experimental medications**. The first medication is **Xeloda**, available in two dosages: 500 mg and 150 mg film-coated tablets. The active substance in Xeloda is **capecitabine**, a chemical compound. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 2000 mg/m², with a total maximum dose of 168,000 mg/m² for the 500 mg tablets and 158,200 mg/m² for the 150 mg tablets. The treatment period is up to 18 months.

Another medication used in the trial is **5-FU medac**, a solution for injection containing **fluorouracil** as the active substance. This medication is administered intravenously. The maximum daily dose is 1250 mg/m², with a total maximum dose of 11,250 mg/m². The treatment duration is also up to 18 months.

**Calciumfolinat-GRY®** is used in three different formulations: 500 mg/50 ml, 300 mg/30 ml, and 100 mg/10 ml solutions for injection. The active substance is **calcium folinate pentahydrate**, also known as leucovorin calcium pentahydrate. These solutions are administered intravenously. The maximum daily dose for each formulation is 400 mg/m², with a total maximum dose of 3600 mg/m². The treatment period is up to 18 months.

**Oxaliplatin Accord** is another medication used in the trial, provided as a concentrate for solution for infusion. The active substance is **oxaliplatin**, and it is administered intravenously. The maximum daily dose is 130 mg/m², with a total maximum dose of 780 mg/m². The treatment duration is up to 18 months.

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 treatments. All medications are chemically derived and have been authorized for use in the trial.

Efficacy in this clinical trial will be assessed primarily through the endpoint of organ preservation in patients with intermediate and high-risk rectal cancer. Organ preservation is defined as survival with the rectum intact, without major surgery or stoma. The primary endpoint will not be achieved if any of the following occur: death, major surgery other than local excision, locoregional regrowth not amenable to salvage surgery, or the presence of a stoma within six months after treatment completion. The trial hypothesizes an improvement in the 3-year organ preservation rate from 30% in the control arm to 40% in the investigational arm, with a hazard ratio of 0.76.

Secondary endpoints include disease-free survival, rate of clinical complete response after total neoadjuvant therapy (TNT), rate of immediate total mesorectal excision (TME) after TNT, cumulative incidence of locoregional regrowth after clinical complete response (cCR), rate of salvage surgery, cumulative incidence of local recurrence after surgery, postoperative complications, rate of sphincter-sparing surgery, pathological TNM-staging, R0 resection rate, tumor regression grading, neoadjuvant rectal score, quality of TME, acute and late toxicity assessment, quality of life, cumulative incidence of distant metastases, overall survival, and translational/biomarker studies.