Evaluation of Short-Course Radiotherapy Versus Total Neoadjuvant Therapy in Elderly Patients with Locally Advanced Rectal Cancer: A Randomized Clinical Trial

The primary objective of this clinical trial is to demonstrate that a neoadjuvant treatment strategy of **short-course radiotherapy (SCRT)** followed by surgery, with or without adjuvant chemotherapy, offers a superior balance between efficacy and safety compared to total neoadjuvant therapy (TNT) in older patients with **locally advanced rectal cancer**. This is clinically relevant as it aims to optimize treatment outcomes and minimize adverse effects in a population that may be more vulnerable to intensive treatment regimens.

Secondary objectives include:

• Assessing the short- and long-term efficacy of the study treatments.
• Evaluating the safety and quality of life associated with the study treatments.
• Determining the impact of the study treatments on the use of healthcare resources.

The clinical trial involves participants diagnosed with **locally advanced rectal cancer**. The study population includes both male and female subjects aged 70 years and older. Participants are required to have a histologically or cytologically confirmed adenocarcinoma of the rectum, with the distal border of the tumor located below the peritoneal reflection and within 15 cm of the anal verge. The trial targets individuals with operable stage III or high-risk stage II rectal cancer, characterized by specific features such as T4 tumors, mesorectal fascia involvement, or extramural venous invasion. Participants must demonstrate adequate bone marrow, liver, and renal function, as defined by specific laboratory criteria. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection process for the trial population is based on the inclusion criteria, which require participants to have an ECOG performance status of ≤1 if over 75 years old, or ≤2 if 75 years old or younger, and to have signed an informed consent form prior to any study-related procedures.

The clinical trial is designed to evaluate the efficacy and safety of short-course radiotherapy (SCRT) compared to total neoadjuvant therapy (TNT) in older patients with **locally advanced rectal cancer**. This is a multicentre, open-label, randomized pragmatic clinical trial. The trial will involve a comparison between two treatment strategies, with the primary objective being to determine which approach offers a better balance between efficacy and safety. The trial is expected to commence recruitment on January 15, 2024, and conclude by January 15, 2034.

Participants will be randomly assigned to receive either SCRT followed by surgery, with or without adjuvant chemotherapy, or TNT. The trial will employ a randomized, controlled design to ensure unbiased results. The primary endpoint is the Net Benefit Treatment, assessed through hierarchical outcome measures, including overall survival and progression-free survival at three years post-randomization, as well as the incidence of increased-grade peripheral sensory neuropathy and grade ≥3 toxicities during treatment.

Study visits will include an initial screening visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Follow-up visits will be scheduled to monitor treatment compliance, adverse events, and response to therapy. The end-of-study visit will assess the primary and secondary endpoints, including safety and quality of life, using standardized questionnaires. The expected duration of participant involvement will vary depending on the treatment arm, with a maximum treatment period of 14 days for certain medications like **capecitabine**.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to ethical standards, ensuring informed consent is obtained from all participants prior to any study-related procedures. The trial will utilize various medications, including **ondansetron**, **dexamethasone**, **metoclopramide**, **folinic acid**, **oxaliplatin**, and **fluorouracil**, administered via intravenous or oral routes, depending on the specific treatment regimen.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. **Ondansetron** is utilized in the form of a solution for injection/infusion. It is administered intravenously with a maximum daily dose of 8 mg. The treatment period for ondansetron is limited to one day. This medication is a chemical compound and is not formulated for pediatric use.

**Dexamethasone** is also employed as a solution for injection, administered intravenously. The maximum daily dose is 8 mg, and the treatment period is restricted to one day. Like ondansetron, dexamethasone is a chemical compound and is not intended for pediatric formulations.

**Metoclopramide** is provided as a solution for injection, administered intravenously with a maximum daily dose of 10 mg. The treatment duration is one day. This medication is a chemical compound and is not designed for pediatric use.

**Folinic Acid** is administered as a solution for injection/infusion, with an intravenous route. The maximum daily dose is 400 mg/m², and the total dose should not exceed 400 mg/m². The treatment period is one day. Folinic acid is a chemical compound and is not available in pediatric formulations.

**Capecitabine** is administered orally with a maximum daily dose of 1000 mg/m². The treatment period extends up to 14 days. This medication is a chemical compound and is not formulated for pediatric use.

**Oxaliplatin** is provided as a solution for injection, administered intravenously. The maximum daily dose is 130 mg/m², with a treatment period of one day. Oxaliplatin is a chemical compound and is not intended for pediatric formulations.

**Fluorouracil** is administered as a solution for injection, with an intravenous route. The maximum daily dose is 400 mg/m², and the treatment period is one day. This medication is a chemical compound and is not designed for pediatric use.

All medications are administered under strict compliance monitoring to ensure adherence to dosing schedules and to evaluate participant compliance throughout the trial. The trial aims to assess the efficacy and safety of these treatments in the context of neoadjuvant therapy for older patients with locally advanced rectal cancer.

Efficacy in this clinical trial will be assessed using a hierarchical set of primary endpoints, focusing on the **Net Benefit Treatment**. The primary endpoints include overall survival at 3 years post-randomization, progression-free survival at 3 years post-randomization, increased-grade peripheral sensory neuropathy at 3 years post-randomization, and grade ≥3 toxicities during treatment. These endpoints will be measured and analyzed to determine the efficacy of the treatment strategies being compared.

Secondary endpoints will further evaluate efficacy and safety, including the safety of study treatments as defined by the frequency of adverse events reported according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Additional secondary endpoints include Quality of Life assessments using the EORTC-QLQ-C30, EORTC-QLQ-C29, EORTC-QLQ-CIPN20, and EQ-5Q-5L questionnaires, compliance to treatment, pathological complete response, R0 resection, organ preservation, and the use of healthcare resources. These parameters will be collected and analyzed at specified timepoints throughout the trial to provide a comprehensive evaluation of the treatment efficacy.