Evaluation of Oncological Safety of Rectal Preserving Therapy with Capecitabine in Intermediate-Risk Early Rectal Cancer: A Multicenter Randomized Trial

The primary objective of this study is to determine the oncological safety of **rectal preserving therapy** for intermediate-risk early rectal cancer. This will be achieved by comparing completion surgery with adjuvant chemoradiotherapy and surveillance following local excision. The clinical relevance of this objective lies in its potential to offer a less invasive treatment option while maintaining oncological safety, which could significantly impact patient quality of life and treatment outcomes.

Secondary objectives include:

• Comparing organ preserving therapy with radical surgery in terms of treatment-related morbidity.
• Assessing unsalvageable pelvic disease at three years, defined as locoregional recurrence that cannot be treated with curative intent.
• Determining three and five-year disease-free survival and overall survival.
• Determining stoma-free survival at one, three, and five years for both patient groups.
• Evaluating the influence of organ preserving therapy on long-term morbidity.
• Investigating the impact of organ preserving therapy on health-related quality of life (HRQoL) and functional outcomes compared to radical surgery.
• Determining the cost-effectiveness of organ preserving therapy.

The clinical trial focuses on individuals diagnosed with **rectal cancer**, specifically targeting those with intermediate-risk early rectal cancer. The study population includes both male and female participants aged over 18 years, who are medically fit with a WHO performance status of 0-2, indicating they are capable of undergoing radical surgery and/or radiation. Participants must have a life expectancy of at least 12 months and no contraindications to chemotherapy, with adequate blood counts and renal function. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include individuals who have undergone endoluminal local excision of early rectal cancer without carcinoma in the resection plane, and those with specific pathological confirmations of rectal adenocarcinoma. Participants must be willing and able to comply with the study protocol, including scheduled follow-up visits and examinations. Key lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **oncological** safety of rectal preserving therapy for intermediate-risk early **rectal cancer**. This study employs a multi-centered, partially randomized, patient-preference trial design, comparing radical surgery with adjuvant chemoradiotherapy following local excision. The trial is not categorized as low intervention and is actively recruiting participants. The trial phase is identified as phase 5, with interventions being administered. The estimated recruitment start date was June 1, 2015, and the trial is expected to conclude by January 1, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as having undergone an endoluminal local excision of early rectal cancer without carcinoma in the resection plane, being medically fit, and having a life expectancy of at least 12 months. Follow-up visits are scheduled to monitor treatment-related morbidity, functional outcomes, and health-related quality of life (HRQoL) at various intervals, including 3, 6, 12, 24, and 36 months post-operatively. The primary endpoint is the three-year local recurrence rate, while secondary endpoints include short-term morbidity, unsalvageable pelvic disease at three years, stoma rate, long-term morbidity, and disease-free and overall survival at three and five-year follow-ups.

The expected length of participant involvement is up to five years, with conditions for early termination including non-compliance with the protocol, withdrawal of consent, or the occurrence of adverse events that contraindicate continued participation. The study involves the administration of **capecitabine** in the form of Xeloda 150 mg film-coated tablets, with a maximum daily dose of 400 mg/m² and a total dose not exceeding 20,800 mg/m² over a maximum treatment period of five weeks. The trial aims to provide valuable insights into the potential benefits of rectal preserving treatment in terms of oncological outcomes and cost-effectiveness.

The clinical trial involves the use of **Xeloda 150 mg film-coated tablets** as the experimental medication. The active substance in Xeloda is **capecitabine**, a chemical compound classified under the ATC code L01BC06. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The dosage is calculated based on body surface area, with a maximum daily dose of 400 mg/m² and a total maximum dose of 20800 mg/m² over the treatment period. The maximum treatment period is specified as 5 days. The medication is not a pediatric formulation and is not classified as an orphan drug. The manufacturer of Xeloda is CHEPLAPHARM ARZNEIMITTEL GMBH.

In addition to the experimental treatment, the study includes a comparison with standard-of-care therapy, which involves radical surgery and adjuvant chemoradiotherapy following local excision for early rectal cancer. The trial aims to evaluate the oncological safety of rectal preserving therapy for intermediate-risk early rectal cancer. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the three-year local recurrence rate of early rectal cancer following treatment. Secondary endpoints include short-term morbidity, which will be evaluated using the Comprehensive Classification index and the NCI CTCAE Toxicity criteria to assess treatment-related morbidity occurring during or within 30 days post-treatment. Additionally, unsalvageable pelvic disease at three years, stoma rates at one, three, and five years, and long-term morbidity such as surgical re-interventions and readmissions will be assessed at one, three, and five years.

Functional outcomes and health-related quality of life (HRQoL) will be measured using validated questionnaires, including EQ-5D, EORTC QLQ C29 & C30, and the LARS score, at admission and at 3, 6, 12, 24, and 36 months post-operatively. Health economics will be analyzed by evaluating the cost per quality-adjusted life year using the EQ-5D score, considering procedure-related costs, hospital stay costs, reintervention, morbidity-related costs, and time to return to work. Disease-free and overall survival will be monitored at three-year and five-year follow-ups.