Phase III Randomized Multicenter Study of D2 Resection and Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin, Fluorouracil, and Calcium Levofolinate in Advanced Gastric Adenocarcinoma

The primary objective of the GASTRICHIP trial is to compare the overall 5-year survival rates in patients with advanced **gastric adenocarcinoma** who undergo surgical treatment. The study evaluates two treatment arms: one involving curative gastrectomy with adjuvant **Hyperthermic Intraperitoneal Chemotherapy (HIPEC)** and the other involving curative gastrectomy alone. This comparison is clinically relevant as it aims to determine the efficacy of adding HIPEC to standard surgical treatment in improving long-term survival outcomes for patients with this aggressive cancer type.

Secondary objectives include:

• Comparing 3-year and 5-year recurrence-free survival.
• Studying the incidence of locoregional recurrence and comparing locoregional recurrence-free 5-year survival.
• Assessing and comparing treatment-related toxicity using the Common Terminology Criteria for Adverse Events v4.0.
• Comparing sites of recurrence.
• Identifying prognostic factors of overall 5-year survival and recurrence-free 5-year survival.
• Comparing patients' quality of life at preoperative time, M3, M6, and M12, and changes in quality of life.

The clinical trial focuses on patients diagnosed with **gastric adenocarcinoma**, specifically targeting those with advanced stages such as T3, T4, and/or with positive cytology. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have histologically confirmed resectable tumors for which a curative gastrectomy is planned. The trial involves individuals with a performance status of 1 or less and a Karnofsky Index of 70% or higher, indicating a relatively good general health status. Participants must have adequate hematological and renal function, as evidenced by specific laboratory criteria. The trial population was selected based on these inclusion criteria, and all participants provided written informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as the use of efficient contraceptive measures are required for females of childbearing potential and male subjects with partners of childbearing potential. The study does not include individuals under administrative or legal supervision and requires participants to be covered by a health system or comply with national biomedical research laws.

The clinical trial is designed to evaluate the efficacy of **Hyperthermic Intraperitoneal Chemotherapy (HIPEC)** in patients with locally advanced **gastric adenocarcinoma**. This is a randomized, multicentric, phase III study comparing overall 5-year survival rates between two groups: one undergoing curative gastrectomy with adjuvant HIPEC (Arm A) and the other undergoing curative gastrectomy alone (Arm B). The trial is expected to commence recruitment on August 1, 2024, and conclude by August 1, 2037. Participants will be randomly assigned to one of the two treatment arms, ensuring a double-blind and controlled environment to minimize bias and enhance the reliability of the results.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age (18-75 years), histologically confirmed resectable T3 or T4 gastric adenocarcinoma, and adequate organ function. Following randomization, participants will undergo the assigned surgical procedure. Follow-up visits will be scheduled to monitor treatment-related toxicity, recurrence-free survival, and overall survival. The end-of-study visit will assess the primary endpoint of overall survival and secondary endpoints, including quality of life and treatment-related morbidity and mortality.

Participant involvement is anticipated to last for the duration of the trial, with regular follow-up visits to ensure comprehensive data collection. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize **calcium levofolinate**, **fluorouracil**, and **oxaliplatin** as part of the treatment regimen, administered via intravenous or intraperitoneal routes as appropriate. The study aims to provide valuable insights into the potential benefits of HIPEC in improving survival outcomes for patients with advanced gastric adenocarcinoma.

The clinical trial involves the administration of **CALCIUM LEVOFOLINATE**, which is provided in the form of a **solution for injection**. The active substance, calcium levofolinate, is utilized as a detoxifying agent in cytostatic treatment. The medication is administered via **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily and total dose of 10 mg/m². The treatment period is limited to one day. Participant compliance is monitored through standard clinical trial procedures to ensure adherence to the dosing schedule.

**FLUOROURACIL** is another experimental medication used in this trial, presented as a **solution for infusion**. It acts as an antimetabolite and is administered intravenously. The dosage is also determined by body surface area, with a maximum daily and total dose of 400 mg/m². The treatment duration is restricted to one day. Compliance with the dosing regimen is tracked to maintain the integrity of the trial data.

The trial also includes the administration of **OXALIPLATIN**, which is provided as a **solution for infusion**. This antineoplastic agent is administered via **intraperitoneal use**. The dosage is based on body surface area, with a maximum daily and total dose of 250 mg/m². The treatment period is confined to one day. Monitoring of participant compliance is conducted to ensure accurate adherence to the prescribed dosing schedule.

In addition to the experimental medications, the trial may involve standard-of-care therapies as deemed necessary by the clinical investigators. No placebo or comparator treatment is specified in the trial protocol. The administration of all medications is conducted under strict clinical supervision to ensure participant safety and data reliability.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **overall survival** rates in patients with advanced gastric adenocarcinoma. This primary endpoint will compare the 5-year survival rates between two groups: those undergoing curative gastrectomy with adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) and those receiving curative gastrectomy alone. Secondary endpoints will include assessments of recurrence-free survival, which will be categorized into peritoneal, locoregional, and metastatic recurrences, as well as the site of recurrence. Additional secondary endpoints will evaluate treatment-related toxicity, mortality, morbidity, and quality of life.

Data collection for these endpoints will be conducted at specified intervals throughout the trial, with the final analysis occurring at the end of the study period. The trial is designed as a randomized, multicentric phase III study, ensuring a robust and comprehensive evaluation of the treatment efficacy. The study will utilize validated methods for measuring survival rates and recurrence, ensuring the reliability and accuracy of the collected data. The trial is expected to conclude by August 2037, with recruitment starting in August 2024.