Short-course HIPEC in Advanced Epithelial Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multicenter, single-arm, feasibility phase 2 trial on safety and efficacy of short-course regimen of intra-operative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the time of fast-track interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) for high tumor burden epithelial ovarian cancer (EOC).

Detailed Description
-----------------
This study was initially designed to explore the safety and efficacy of short-course HIPEC in terms of median progression-free survival (PFS) as the primary outcome. However, due to slow accrual, the design was subsequently amended to explore the primary outcome measure of PD9 (i.e.: proportion of patients with disease progression or death occurring within 9 months of IDS plus HIPEC). The hypothesis was the short-course HIPEC could decrease PD9 with low rates of morbidity and mortality. In these settings, we explore a comprehensive treatment approach involving fast-track advanced cytoreductive surgery (CRS) plus short-course HIPEC at the time of IDS following NACT for high tumor burden patients with stage III-IV ovarian cancer. Advanced CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity, and fast-track recovery strategies were also applied to improve patient outcomes. HIPEC was performed according to the closed-abdomen technique using CDDP (25 mg/L of perfusate/m2, total limit of 240mg) or CDDP plus Doxorubicin (15mg/L) for 30 minutes, with an intra-abdominal target temperature of 41-43°C. Perfusate (2L/m2, ranging from 4L to 6L) was circulated using an extracorporeal circulation device (Performer HT; RAND, Medolla, Italy) at a flow rate of 700 ml/min. Systemic chemotherapy included the standard combination of carboplatin and paclitaxel as neo-adjuvant plus adjuvant regimens.

Official Title
-----------------
Short-course Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at Interval Debulking Surgery for High Tumor Burden Ovarian Cancer

Conditions
-----------------
Ovarian Cancer

Intervention / Treatment
-----------------
* Procedure: Cytoreductive Surgery (CRS)
* Procedure: Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
* Drug: Neoadjuvant Chemotherapy (NACT)
* Drug: Adjuvant Chemotherapy
* Procedure: Fast-track recovery strategy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with no previous treatment and candidates for elective surgery with histological diagnosis of epithelial ovarian carcinoma; Clinical stage IIIB to IV, without suspicion of extra-abdominal metastasis; No other malignancies in activity; No previous treatments such as radiation, chemotherapy (except neoadjuvant chemotherapy in the study protocol) or major abdominal surgery; Absence of neuro-psychiatric disorders, history of drug allergies, and pregnancy or breast feeding; Aged between 18 and 70 years; Performance status 0-2 (ECOG, Eastern Cooperative Oncology Group) and / or greater than 70 points by the Karnofsky scale; Appropriated cardio-respiratory, hepato-renal and hematological reserves; Signing of the Consent Form. Exclusion Criteria: Evidence of extensive retroperitoneal lymph node involvement or unresectable disease (i.e., massive involvement of the small bowel, mesentery, or hepatic pedicle, and ureteral or biliary obstruction) at the time of CRS/HIPEC; Residual disease after the CRS greater than or equal to 2.5 mm (CC-2 and CC-3); Limiting obesity for CRS or HIPEC; Disease progression, apparent or confirmed uncontrolled infection, or health impairment during NACT.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIPEC<br>Neoadjuvant Chemotherapy (NACT) followed by Cytoreductive Surgery (CRS) under a Fast-track recovery strategy plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC) and thus, Adjuvant Chemotherapy | Procedure: Cytoreductive Surgery (CRS)<br>* CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity.<br>Procedure: Hyperthermic Intraperitoneal Chemotherapy (HIPEC)<br>* HIPEC was performed according to the closed-abdomen technique using CDDP (25 mg/L of perfusate/m2, total limit of 240mg) for the first 10 patients and thus, using CDDP plus Doxorubicin (15mg/L) thereafter, both for 30 minutes, with an intra-abdominal target temperature of 41-43°C. Perfusate (2L/m2, ranging from 4L to 6L) was circulated using an extracorporeal circulation device (Performer HT; RAND, Medolla, Italy) at a flow rate of 700 ml/min.<br>Drug: Neoadjuvant Chemotherapy (NACT)<br>* Systemic chemotherapy included the standard combination of carboplatin (AUC 6) and paclitaxel (175 mg/m2) administered every 21 days as neoadjuvant (2-4 cycles) plus adjuvant regimens (2-4 cycles), in the total of 6 cycles of systemic chemotherapy.<br>* Other names: Paclitaxel;Drug: Adjuvant Chemotherapy<br>* Systemic chemotherapy included the standard combination of carboplatin (AUC 6) and paclitaxel (175 mg/m2) administered every 21 days as neoadjuvant (2-4 cycles) plus adjuvant regimens (2-4 cycles), in the total of 6 cycles of systemic chemotherapy.<br>* Other names: Paclitaxel;Procedure: Fast-track recovery strategy<br>* A comprehensive fast-track program was applied to accelerate recovery, reduce morbidity, and shorten convalescence for patients enrolled in our trial.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PD9 | Proportion of patients with disease progression or death occurring within 9 months of IDS plus HIPEC | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative 30-day mortality rate | Mortality rates up to 30-day after surgery | 30 days | 
| Postoperative complication rates | Complications rates up to 30-day after surgery | 30 days | 
| Assessment of quality of life (QLQ-C30/EORTC) | Assessment of quality of life according to the QLQ-C30/EORTC scales. | Baseline (i.e., at the time of hospital admission for IDS plus HIPEC); after CRS/HIPEC (i.e., at the time of restarting the systemic chemotherapy); after protocol (i.e., at 3-6 weeks after the last syst | 
| Overall survival (OS) | We defined OS as the time from starting the NACT to death. | 24 months | 
| Progression-free Survival (PFS) | We defined PFS as the time from starting the NACT to disease progression. | 24 months | 
| Disease-free Survival (DFS) | We defined DFS for patients without no gross residual disease as the time from IDS plus HIPEC to disease progression. | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ovarian Cancer