Ovarian Cancer, Primary Peritoneal Cancer
Conditions
Keywords
Cytoreductive surgery, (H)ipec, Ovarian cancer, Cisplatin, Peritoneal carcinomatosis, Pharmacokinetics, Pharmacodynamics
Brief summary
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.
Detailed description
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.
Interventions
PROCEDURECytoreductive surgery
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer
DRUGIPEC with Cisplatin (75mg/m²)
Intraperitoneal normotherm (37°C) administration of Cisplatin (75mg/m²) , during 90min
DRUGIPEC with Cisplatin (100mg/m²)
Intraperitoneal normotherm (37°C) administration of Cisplatin (100mg/m²), during 90min
DRUGHypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)
Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min
DRUGHIPEC with Cisplatin (100mg/m²)
Intraperitoneal hypertherm (41°C) administration of Cisplatin (100mg/m²), during 90min
Sponsors
University Hospital, Ghent
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry | 1 tumor nodule will be immediately fixed in liquid nitrogen after cytoreductive surgery and chemoperfusion. Frozen sections will be ablated through study completion | This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cancer-specific Quality of Life-C30 | 3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion | This will be investigated using the cancer-specific (C30) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires |
| Disease-specific Quality of Life-OV28 | 3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion | This will be investigated using the disease-specific (OV28) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires |
| Maximum perfusate concentration (Cmax) of cisplatin | T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion) | Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS) |
| Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin | T=0min (before chemoperfusion); T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion) | Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS) |
| Pharmacodynamics (PD) of cisplatin will be analyzed by visualizing the amount of DNA double-strand breaks (dsb) via the specific DNA-adduct immunohistochemical Liedert staining | 1 tumor nodule will be immediately fixed in 4% paraformaldehyde and immunohistochemical stainings will be done through study completion | PD of cisplatin will be studied via Pt-DNA adduct formation, using the Liedert staining which is specific for Pt-\[Guanine, Guanine\] adducts (Pt-\[GG\]) using Mab R-C18. The amount of double-strand breaks (dsb) will be analyzed then via fluorescence microscopy |
| Surgical morbidity and mortality will be measured using Dindo-Clavien classification | Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion | This will be estimated with the Dindo-Clavien classification |
| Disease free survival | 24 months after finishing the adjuvant chemotherapy | Time interval between date of surgery and disease progression or death |
| Peritoneal recurrence free survival | 24 months after finishing the adjuvant chemotherapy | Time interval between date of surgery and peritoneal recurrence or death |
| Expression analysis of selected biomarkers = Excision repair cross-complementation group 1 (ERCC1), Methylguanine methyltransferase enzyme (MGMT), Breast cancer gene 1 (BRCA1), Copper transporter 1 (CTR1) using quantitative PCR | 1 tumor nodule will be immediately fixed in liquid nitrogen. Histological coupes will be made through study completion | Gene expression of potential predictive biomarkers using qPCR |
| Stromal composition and density of tumor tissues via analyzing collagen density, fibroblast Proliferation and DNA-intrastrand adduct formation of Pt-[GG] | 1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion | Analyzing collagen density using the sirius red staining, analyzing fibroblast proliferation using alfa smooth-muscle action (α-SMA) stainings and DNA intrastrand adduct formation of Pt-\[GG\] with the Liedert staining using Mab R-C18 |
| Overall survival | 24 months after finishing the adjuvant chemotherapy | Calculated from date of surgery until death |
Countries
Belgium
Outcome results
None listed