title: Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer.
abstract: OBJECTIVE
  Hyperthermic intraperitoneal chemotherapy (HIPEC) may improve the outcome of patients with initially unresectable ovarian cancer who are eligible for complete cytoreductive surgery (CCRS) after neoadjuvant chemotherapy. The main objective of this multicenter phase-I study was to identify the recommended dose of cisplatin for HIPEC at CCRS after neoadjuvant carboplatin and paclitaxel (CP).
  
  
  METHODS
  Patients were treated with 6cycles of CP followed by CCRS and HIPEC using cisplatin heated for one hour at 42°C+/-1°C. Four cisplatin dose-levels were evaluated: 50, 60, 70, 80mg/m(2). Dose-limiting toxicities (DLTs) were defined as a grade≥IIIb adverse event (Dindo classification). The Continual Reassessment Method was used for this dose-finding study, with a target percentage of DLT set at 20%. Twenty-two cycles (15mg/kg/cycle) of maintenance bevacizumab therapy were planned after surgery.
  
  
  RESULTS
  Between June-2011 and September-2012, 30 patients were recruited. No DLT occurred at the first three dose-levels (4, 4 and 5 patients at 50, 60 and 70mg/m(2) respectively). At dose-level 4 (80mg/m(2), 17 patients), four DLTs occurred: renal failure (n=2), peritonitis (n=1) and hemorrhage (n=1). Eight weeks after surgery, creatinine clearance was reduced to <30mL/min in 3 patients, all treated at 80mg/m(2), and between 30 and 60mL/min in 6 patients (2, 1, 1 and 2 at the four dose-levels respectively). Twenty patients started maintenance bevacizumab, and 7 received the 22 courses initially planned.
  
  
  CONCLUSIONS
  Based on the observed DLTs and prolonged impairment of renal function, we recommend a dose of 70mg/m(2) of cisplatin for HIPEC.
authors.affiliation: Department of Surgery, Gustave Roussy, Villejuif, France. Electronic address: sebastien.gouy@gustaveroussy.fr.
authors.forename: S
authors.initials: S
authors.lastname: Gouy
authors.affiliation: Department of Surgery, Institut Claudius Regaud, Toulouse, France.
authors.forename: G
authors.initials: G
authors.lastname: Ferron
authors.affiliation: Department of Surgery, Hôpital Lyon Sud, Bénite, France.
authors.forename: O
authors.initials: O
authors.lastname: Glehen
authors.affiliation: Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Bayar
authors.affiliation: Department of Surgery and CRAN, UMR 7039, Université de Lorraine, CNRS Institut de Cancérologie de Lorraine Vandoeuvre-les-Nancy, France.
authors.forename: F
authors.initials: F
authors.lastname: Marchal
authors.affiliation: Department of Surgery, Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: C
authors.initials: C
authors.lastname: Pomel
authors.affiliation: Department of Surgery, Centre Val d'Aurelle, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Quenet
authors.affiliation: Department of Surgery, Centre Hospitalier l'Archet II, Nice, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Bereder
authors.affiliation: Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France; University Paris Sud, Villejuif, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: Department of Surgery, Gustave Roussy, Villejuif, France; University Paris Sud, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Morice
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin
keywords: Bevacizumab; Cisplatin; Cytoreductive surgery; HIPEC; Ovarian cancer; Phase 1 trial