Efficacy of HIPEC as NACT and Postoperative Chemotherapy in the Treatment of Advanced-Stage Epithelial Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
This project is a multi-center, prospective, randomized controlled clinical observation the safety and efficacy of hyperthermic intraperitoneal chemotherapy as neoadjuvant chemotherapy(NACT) and postoperative chemotherapy after interval debulking surgery (IDS) for advanced-stage epithelial ovarian cancer . PR/SD rate, percentage of optimal debulking surgery and 3-year disease-free survival is the primary end points of this project.

Detailed Description
-----------------
The current standard treatment for epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer is maximal cytoreductive surgery followed by intravenous chemotherapy with or without intraperitoneal chemotherapy (IP). Recently, the organizations of SGO and ASCO recommended that women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to novisible disease) should receive neoadjuvant chemotherapy. Hyperthermia promotes chemotherapy to penetrate deeper into the cancer tissue. Therefore, hyperthermic intraperitoneal chemotherapy (HIPEC) as neoadjuvant chemotherapy and postoperative chemotherapy after interval debulking surgery in the treatment of ovarian cancer could lead to higher response rate and better survival outcomes.

Official Title
-----------------
A Phase III Multicenter Prospective Randomized Controlled Clinical Trial of HIPEC as NACT and Postoperative Chemotherapy After Interval Debulking Surgery in the Treatment of Advanced-Stage Epithelial Ovarian Cancer

Conditions
-----------------
Fallopian Tube Cancer, Primary Peritoneal Carcinoma, Epithelial Ovarian Cancer

Intervention / Treatment
-----------------
* Procedure: Hyperthermic Intraperitoneal Chemotherapy
* Procedure: Interval debulking surgery
* Drug: neoadjuvant chemotherapy
* Drug: adjuvant chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Disease status primary epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer (Stage III and IV) Fagotti score by laparoscopic exploration >= 6 After receiving HIPEC+neoadjuvant chemotherapy (NACT) or NACT alone, the curative effects evaluated according to RICIST criteria is partial remission (PR) and stable disease (SD). Residual tumor < 1cm after completion of interval debulking surgery 18 < Age < 70 year old Expected survival > 3 months Performance status: ECOG 0-1 Adequate bone marrow function Hb ≥8 g/dl (After correction in case of iron deficient anemia) WBC ≥ 3,000/mm3, Platelet ≥ 100,000/mm3 Adequate renal function Creatinine ≤ 1.5 mg/dl, and adequate hepatic function Bilirubin ≤ 1.5 mg/dl and AST and ALT ≤ 80 IU/L Voluntary participation after getting written informed consent. Exclusion Criteria: Fagotti score by laparoscopic exploration < 6 After receiving HIPEC+neoadjuvant chemotherapy (NACT) or NACT alone, the progression of disease (PD) is evaluated by doctor. Suboptimal debulking (residual tumor > 1cm) Extensive adhesion in peritoneal cavity Previous History of other malignancies (except excision of skin cancer, thyroid cancer) Poorly controlled disease e.g. atrial fibrillation, stenocardia, cardiac insufficiency, persistent hypertension despite medicinal treatment, ejection fraction<50% Receiving other chemotherapy, radiotherapy or immunotherapy Patients who are unsuitable candidates by doctor's decision Without given written informed consent

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2 intraperitoneally in succession 2 cycles of neoadjuvant chemotherapy: paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks Interval debulking surgery Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2 intraperitoneally in succession 2 cycles of adjuvant chemotherapy: paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks | Procedure: Hyperthermic Intraperitoneal Chemotherapy<br>* HIPEC is performed as neoadjuvant chemotherapy(NACT) and postoperative chemotherapy after interval debulking surgery (IDS) for advanced-stage epithelial ovarian cancer. The first HIPEC is conducted within 24h after laparoscopic exploration or Interval debulking surgery: Paclitaxel 175 mg/m^2, 43°C, 90min. The second HIPEC is performed after 48 hours of the first HIPEC. The second HIPEC regimens are cisplatin 75 mg/m^2, 43°C, 90min.<br>* Other names: HIPEC;Procedure: Interval debulking surgery<br>* Cytoreductive surgery (CRS) is performed after neoadjuvant chemotherapy.<br>* Other names: IDS;Drug: neoadjuvant chemotherapy<br>* Systemic chemotherapy regimens after HIPEC treatment are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 2 cycles in experimental group. Systemic chemotherapy regimens after laparoscopic exploration are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 3 cycles in control group.<br>* Other names: NACT;Drug: adjuvant chemotherapy<br>* Systemic chemotherapy regimens after HIPEC treatment are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 2 cycles in experimental group. Systemic chemotherapy regimens after IDS are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 3 cycles in control group.<br>* Other names: ACT;|
| Active Comparator: Control group<br>3 cycles of neoadjuvant chemotherapy: paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks Interval debulking surgery 3 cycles of adjuvant chemotherapy: paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks | Procedure: Interval debulking surgery<br>* Cytoreductive surgery (CRS) is performed after neoadjuvant chemotherapy.<br>* Other names: IDS;Drug: neoadjuvant chemotherapy<br>* Systemic chemotherapy regimens after HIPEC treatment are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 2 cycles in experimental group. Systemic chemotherapy regimens after laparoscopic exploration are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 3 cycles in control group.<br>* Other names: NACT;Drug: adjuvant chemotherapy<br>* Systemic chemotherapy regimens after HIPEC treatment are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 2 cycles in experimental group. Systemic chemotherapy regimens after IDS are paclitaxel 175 mg/m^2 IV>3 hour+ carboplatin AUC = 5-6 IV>1 hour, every 3 weeks for 3 cycles in control group.<br>* Other names: ACT;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PR/SD rate | calculate the percent of partial remission (PR) plus stable disease (SD) of patients received HIPEC+NACT or NACT alone in both two arms | Through study completion, an average of 1 year | 
| Percentage of optimal debulking surgery | evaluate the percentage of optimal debulk (residual disease < 1cm) after interval debulking surgery between study arms | Through study completion, an average of 1 year | 
| Disease-free survival rate | assess disease free survival rate during 3 years in both study arms | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | assess overall survival rate during 3 years in both study arms | 3 years | 
| Risk factors for morbidity and mortality | determine percent of patients wtih Grade I-IV adverse events according to NCI criteria, Common Terminology Criteria for AE (CTCAE 4.0). | Through study completion, an average of 1 year | 
| Quality of life | Evaluated according to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer (EORTC QLQ-C30) | 3 years | 
| Quality of life for ovarian cancer | Evaluated according to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Ovarian Cancer Module (QLQ-OV28) | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hyperthermic Intraperitoneal Chemotherapy, Neoadjuvant Chemotherapy, Interval Debulking Surgery, Advanced-Stage Epithelial Ovarian Cancer, Postoperative Chemotherapy