Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer

Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer: A Randomized Phase II Trial

The OvIP1 study is designed to examine how drug dose and perfusion temperature affect the pharmacokinetics and pharmacodynamics of cisplatin used as (hyperthermic) intraperitoneal chemoperfusion, as an adjunct to surgery, in women with stage III epithelial ovarian cancer.

Stage III ovarian cancer (OC) remains an important cause of cancer related mortality in women. After successful initial treatment, most patients eventually develop recurrent peritoneal disease which can only arise from peritoneal minimal residual disease (pMRD) left after primary cytoreductive surgery (CRS). Intensification of locoregional therapy through intraoperative intraperitoneal chemoperfusion (IPEC) immediately following CRS may prevent or delay peritoneal recurrence. Although IPEC, usually under hyperthermic conditions, is increasingly used in OC, its efficacy and the potential benefit of hyperthermia are at present unknown.The primary aim of this study is to assess the pharmacokinetic and pharmacodynamic properties of IP cisplatin administered under normothermic or hyperthermic conditions, and at different dosing schedules. Additional endpoints include surgery related morbidity and mortality, quality of life, overall survival, disease free survival, peritoneal recurrence free survival, peritoneal cytology, and exploration of potential biomarkers.

Inclusion Criteria:

• Tumor type:

  * Biopsy proven serous epithelial ovarian carcinoma or peritoneal carcinoma

• Primary or recurrent disease

• Extent of disease:

  • Positive retroperitoneal lymph nodes and /or microscopic metastasis beyond the pelvis (FIGO stage III, Appendix (47))
  • Stage IV with unilateral pleural fluid allowed
  • Complete or nearly complete macroscopic cytoreduction at the time of surgery (CC-0 or CC-1) deemed possible based on imaging, laparoscopy, or both

• Second-line patients; platinum sensitive

• Age over 18 years

• No major cardiac or respiratory disease

• Adequate performance status (Karnofsky index > 70%)

• Adequate mental faculty, allowing to understand the proposed treatment protocol and provide informed consent

• Expected life expectancy more than 6 months

• Laboratory data:

  • Serum creatinine ≤ 1.5 mg/dl or a calculated Glomerular Filtration Rate (GFR) (CKD-EPI) ≥ 60 mL/min/1.73 m2
  • Serum total bilirubin ≤ 1.5 mg/dl, except for known Gilbert's disease
  • Platelet count > 100.000/µl
  • Hemoglobin > 9g/dl
  • Neutrophil granulocytes > 1.500/ml
  • International Normalized Ratio (INR) ≤ 2

• Absence of alcohol and/or drug abuse

• No other concurrent malignant disease

• No inclusion in other clinical trials interfering with the study protocol

• No concurrent chronic systemic immune or hormone therapy, except neoadjuvant chemotherapy

• Absence of any severe organ insufficiency

• No pregnancy or breast feeding

• Written informed consent

Exclusion Criteria:

• Severe or uncontrolled cardiac insufficiency, including recent (< 6 months) occurrence of myocardial infarction, the presence of congestive cardiac insufficiency, of symptomatic angor in spite of optimal medical care, of cardiac arrhythmia requiring medical treatment presenting insufficient rhythm control, or uncontrolled arterial hypertension
• Pregnancy or breast feeding
• Platinum resistant or refractory disease
• Active bacterial, viral or fungal infection
• Active gastro-duodenal ulcer
• Parenchymal liver disease (any stage cirrhosis)
• Uncontrolled diabetes mellitus
• Severe obstructive or restrictive respiratory insufficiency
• Psychiatric pathology capable of affecting comprehension and judgment faculty
• Tumor in the presence of obstruction
• Evidence of extra-abdominal disease (with the exception of unilateral malignant pleural effusion) or extensive liver metastasis