title: HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.
abstract: This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital Bonn, Bonn, Germany; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, USA; Center for Integrated Oncology Cologne Bonn, University Hospitals Cologne and Bonn, Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Zivanovic
authors.forename: Alina
authors.initials: A
authors.lastname: Abramian
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kullmann
authors.forename: Christine
authors.initials: C
authors.lastname: Fuhrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Coch
authors.forename: Tobias
authors.initials: T
authors.lastname: Hoeller
authors.forename: Hauke
authors.initials: H
authors.lastname: Ruehs
authors.forename: Mignon Denise
authors.initials: MD
authors.lastname: Keyver-Paik
authors.forename: Christian
authors.initials: C
authors.lastname: Rudlowski
authors.forename: Stefan
authors.initials: S
authors.lastname: Weber
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kiefer
authors.forename: Martin L
authors.initials: ML
authors.lastname: Poelcher
authors.forename: Thore
authors.initials: T
authors.lastname: Thiesler
authors.forename: Babak
authors.initials: B
authors.lastname: Rostamzadeh
authors.forename: Michael
authors.initials: M
authors.lastname: Mallmann
authors.forename: Nico
authors.initials: N
authors.lastname: Schaefer
authors.forename: Maryse
authors.initials: M
authors.lastname: Permantier
authors.forename: Sandra
authors.initials: S
authors.lastname: Latten
authors.forename: Joerg
authors.initials: J
authors.lastname: Kalff
authors.forename: Juergen
authors.initials: J
authors.lastname: Thomale
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
authors.forename: Walther C
authors.initials: WC
authors.lastname: Kuhn
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures / Q000379:methods*; D018736:DNA Adducts / Q000032:analysis; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000628:therapy*; D009375:Neoplasms, Glandular and Epithelial / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D002945:Cisplatin
keywords: HIPEC; chemotherapy; cisplatin; hyperthermic intraoperative intraperitoneal chemoperfusion; ovarian cancer; phase I