Evaluation of Hyperthermic Intraperitoneal Chemotherapy with Cisplatin in Stage III Epithelial Ovarian Cancer: A Randomized Phase III Trial

The primary objective of this Phase III randomized clinical trial is to evaluate the effect of **hyperthermic intraperitoneal chemotherapy (HIPEC)** on overall survival when added to primary cytoreductive surgery in patients with FIGO stage III epithelial ovarian cancer. This study targets patients eligible for primary cytoreductive surgery resulting in no residual disease or residual disease up to 2.5 mm. The clinical relevance of this objective lies in determining whether the addition of HIPEC can improve survival outcomes in this patient population, potentially influencing future treatment protocols for advanced ovarian cancer.

Secondary objectives include:

• Comparing recurrence-free survival between both treatment arms, which is crucial for understanding the long-term efficacy of the treatment strategies.
• Comparing the time to first subsequent anticancer treatment after the first recurrent disease (TFST), providing insights into the durability of the treatment response.
• Comparing toxicity and morbidity between both treatment arms, which is essential for assessing the safety and tolerability of the treatment regimens.

The clinical trial involves a total of **38 participants** who are exclusively female, as the study focuses on patients with **FIGO stage III ovarian cancer**. The age range of the participants is 18 years and older, ensuring that all individuals are adults. Participants were selected based on their eligibility for primary cytoreductive surgery, with the condition that they have either no residual disease or residual disease up to 2.5 mm. The study population is characterized by a general good health status, as evidenced by the requirement for a WHO performance status of 0-2, indicating that participants are fit for major surgery. Additionally, participants must have adequate bone marrow, hepatic, and renal function. The trial does not include male subjects or vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified in the data provided. The selection criteria ensure that participants are capable of understanding the patient information and completing health-outcome questionnaires, which are prerequisites for randomization in the study.

The clinical trial is a **Phase III randomized** study designed to evaluate the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) on overall survival when added to primary cytoreductive surgery in patients with FIGO stage III ovarian cancer. The trial employs a **double-blind, controlled** methodology to ensure unbiased results. The estimated duration of the trial is from January 2020 to July 2025, with participants expected to be involved for a maximum treatment period of 66 weeks, depending on the specific treatment arm they are assigned to.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of FIGO stage III ovarian cancer, and adequate organ function. Following successful screening, participants will be randomized to receive either primary cytoreductive surgery with or without HIPEC. Subsequent follow-up visits will be scheduled to monitor the participants' health status, treatment response, and any adverse events. These visits will include assessments of overall survival, recurrence-free survival, and time to first subsequent anticancer treatment. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator determines it is in the participant's best interest. The primary endpoint of the study is overall survival, defined as the time from randomization to death from any cause. Secondary endpoints include recurrence-free survival and the time to first subsequent anticancer treatment. The trial will utilize standardized follow-up schemes and clinical symptom evaluations to assess disease progression or recurrence.

The clinical trial involves the administration of several **experimental medications**. **Carboplatin**, marketed as CARBOPLATINE MEDAC 10 mg/mL, is provided as a **solution for infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 6 mg and a total dose of 6 mg over a treatment period of up to 3 weeks. The active substance, carboplatin, is of chemical origin and is classified under the ATC code L01XA02.

**Paclitaxel**, under the brand name Paclitaxel Eugia 6 mg/mL, is also a **solution for infusion**. It is delivered through **intravenous infusion** with a maximum daily and total dose of 175 mg/m² over a 3-week period. The active substance, paclitaxel, is chemically derived and falls under the ATC code L01CD01.

**Bevacizumab**, marketed as Avastin 25 mg/mL, is a **concentrate for solution for infusion**. It is administered via **intravenous infusion** with a maximum daily and total dose of 15 mg/kg over a treatment period of up to 66 weeks. Bevacizumab is a protein-based substance and is not classified under a specific ATC code in this context.

**Sodium thiosulfate** is provided as a **solution for injection** and is administered through **intravenous infusion**. The maximum daily and total dose is 21 g/m², with a treatment period of 1 day. The active substance is of chemical origin and does not have an ATC classification in this trial.

**Cisplatin**, marketed as Cisplatine Accord 1 mg/mL, is a **concentrate for solution for infusion**. It is administered via **intraperitoneal use** with a maximum daily and total dose of 220 mg over a 1-day treatment period. The active substance, cisplatin, is chemically derived and classified under the ATC code L01XA01.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. All medications are administered in accordance with the specified routes and dosages to evaluate their effects in the context of the study's objectives.

Efficacy in this clinical trial will be assessed primarily through the measurement of **overall survival**. This is defined as the time from randomization to the date of death from any cause. For participants who are alive at the time of analysis, their survival time will be censored at the date of last contact, referred to as the "last known alive date." In cases where participants were randomized but had no follow-up, overall survival will be censored at the date of randomization.

Secondary endpoints include **recurrence-free survival**, which is the time between the date of randomization and the first date of documented disease progression or recurrence, as determined by the GCIG criteria, or death due to any cause, whichever occurs first. Disease recurrence or progression will be regularly evaluated via a standardized follow-up scheme and/or following clinical symptoms. Additionally, the time to first subsequent anticancer treatment after first recurrent disease (TFST) will be measured. The toxicity and morbidity will be reported until 30 days after the end of chemotherapy, using the Common Toxicity Criteria for Adverse Events (CTCAE v5.0) for all events, and the Clavien-Dindo method for surgery-related events.