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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
56
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer
Intraperitoneal normotherm (37°C) administration of Cisplatin (75mg/m²) , during 90min
Intraperitoneal normotherm (37°C) administration of Cisplatin (100mg/m²), during 90min
UZ Ghent
Ghent, East-Flanders, Belgium
Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry
This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS)
Time frame: 1 tumor nodule will be immediately fixed in liquid nitrogen after cytoreductive surgery and chemoperfusion. Frozen sections will be ablated through study completion
Surgical morbidity and mortality will be measured using Dindo-Clavien classification
This will be estimated with the Dindo-Clavien classification
Time frame: Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion
Cancer-specific Quality of Life-C30
This will be investigated using the cancer-specific (C30) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires
Time frame: 3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion
Disease-specific Quality of Life-OV28
This will be investigated using the disease-specific (OV28) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires
Time frame: 3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion
Maximum perfusate concentration (Cmax) of cisplatin
Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)
Time frame: T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion)
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Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min
Intraperitoneal hypertherm (41°C) administration of Cisplatin (100mg/m²), during 90min
Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin
Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)
Time frame: T=0min (before chemoperfusion); T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion)
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
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
Time frame: 1 tumor nodule will be immediately fixed in 4% paraformaldehyde and immunohistochemical stainings will be done through study completion
Overall survival
Calculated from date of surgery until death
Time frame: 24 months after finishing the adjuvant chemotherapy
Disease free survival
Time interval between date of surgery and disease progression or death
Time frame: 24 months after finishing the adjuvant chemotherapy
Peritoneal recurrence free survival
Time interval between date of surgery and peritoneal recurrence or death
Time frame: 24 months after finishing the adjuvant chemotherapy
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
Gene expression of potential predictive biomarkers using qPCR
Time frame: 1 tumor nodule will be immediately fixed in liquid nitrogen. Histological coupes will be made through study completion
Stromal composition and density of tumor tissues via analyzing collagen density, fibroblast Proliferation and DNA-intrastrand adduct formation of Pt-[GG]
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
Time frame: 1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion