Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer (OvIP1)

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.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Primary Peritoneal Cancer
• Intervention / Treatment: Procedure: Cytoreductive surgery; Drug: IPEC with Cisplatin (75mg/m²); Drug: IPEC with Cisplatin (100mg/m²); Drug: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²); Drug: HIPEC with Cisplatin (100mg/m²)

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • East-Flanders
    • Ghent, East-Flanders, Belgium, 9000
      • UZ Ghent

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low dose, normothermic; CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy	Procedure: Cytoreductive surgery; Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer; Drug: IPEC with Cisplatin (75mg/m²); Intraperitoneal normotherm (37°C) administration of Cisplatin (75mg/m²) , during 90min
Experimental: high dose, normothermic; CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy	Procedure: Cytoreductive surgery; Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer; Drug: IPEC with Cisplatin (100mg/m²); Intraperitoneal normotherm (37°C) administration of Cisplatin (100mg/m²), during 90min
Experimental: low dose, hyperthermic; CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy	Procedure: Cytoreductive surgery; Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer; Drug: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²); Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min
Experimental: high dose, hyperthermic; CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy	Procedure: Cytoreductive surgery; Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer; Drug: HIPEC with Cisplatin (100mg/m²); Intraperitoneal hypertherm (41°C) administration of Cisplatin (100mg/m²), during 90min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	1 tumor nodule will be immediately fixed in liquid nitrogen after cytoreductive surgery and chemoperfusion. Frozen sections will be ablated through study completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical morbidity and mortality will be measured using Dindo-Clavien classification	This will be estimated with the Dindo-Clavien classification	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	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	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)	T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion)
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)	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	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	24 months after finishing the adjuvant chemotherapy
Disease free survival	Time interval between date of surgery and disease progression or death	24 months after finishing the adjuvant chemotherapy
Peritoneal recurrence free survival	Time interval between date of surgery and peritoneal recurrence or death	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	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	1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Wim P Ceelen, MD, PhD, University Hospital, Ghent

Publications and helpful links

General Publications

• Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol. 2013 Apr;10(4):211-24. doi: 10.1038/nrclinonc.2013.5. Epub 2013 Feb 5.
• Foley OW, Rauh-Hain JA, del Carmen MG. Recurrent epithelial ovarian cancer: an update on treatment. Oncology (Williston Park). 2013 Apr;27(4):288-94, 298.
• Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. doi: 10.1056/NEJMoa052985.
• Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, Wadler S, Sickel J. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001 Feb 15;19(4):1001-7. doi: 10.1200/JCO.2001.19.4.1001.
• Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, Franklin EW, Clarke-Pearson DL, Malviya VK, DuBeshter B. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996 Dec 26;335(26):1950-5. doi: 10.1056/NEJM199612263352603.
• Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005340. doi: 10.1002/14651858.CD005340.pub2.
• Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E, Ioannidis JP. Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst. 2006 Nov 15;98(22):1655-63. doi: 10.1093/jnci/djj443.
• Ceelen WP, Van Nieuwenhove Y, Van Belle S, Denys H, Pattyn P. Cytoreduction and hyperthermic intraperitoneal chemoperfusion in women with heavily pretreated recurrent ovarian cancer. Ann Surg Oncol. 2012 Jul;19(7):2352-9. doi: 10.1245/s10434-009-0878-6. Epub 2009 Dec 29.
• Issels RD. Hyperthermia adds to chemotherapy. Eur J Cancer. 2008 Nov;44(17):2546-54. doi: 10.1016/j.ejca.2008.07.038. Epub 2008 Sep 11.
• Sun X, Li XF, Russell J, Xing L, Urano M, Li GC, Humm JL, Ling CC. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry. Radiother Oncol. 2008 Aug;88(2):269-76. doi: 10.1016/j.radonc.2008.05.015. Epub 2008 Jun 5.
• Bijelic L, Jonson A, Sugarbaker PH. Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer. Ann Oncol. 2007 Dec;18(12):1943-50. doi: 10.1093/annonc/mdm137. Epub 2007 May 11.
• Helm CW. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. Oncologist. 2009 Jul;14(7):683-94. doi: 10.1634/theoncologist.2008-0275. Epub 2009 Jul 16.
• de Bree E, Helm CW. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. Expert Rev Anticancer Ther. 2012 Jul;12(7):895-911. doi: 10.1586/era.12.72.
• Mulier S, Claes JP, Dierieck V, Amiel JO, Pahaut JP, Marcelis L, Bastin F, Vanderbeeken D, Finet C, Cran S, Velu T. Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence. Curr Pharm Des. 2012;18(25):3793-803. doi: 10.2174/138161212802002616.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): August 25, 2021

Study Registration Dates

• First Submitted: September 23, 2015
• First Submitted That Met QC Criteria: October 1, 2015
• First Posted (Estimated): October 2, 2015

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Cisplatin; Ovarian cancer; Pharmacodynamics; Cytoreductive surgery; (H)ipec; Peritoneal carcinomatosis
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Neoplastic Processes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Neoplasm, Residual; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: AGO/2015/002