title: Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II Trial.
abstract: OBJECTIVE
  The aims of this study were to determine the dose and schedule of i.p. cisplatin with i.p. gemcitabine in patients with persistent disease at second-look assessment, the toxicity of this regimen, and the time to treatment failure and overall survival.
  
  
  METHODS
  We performed a Phase I/II evaluation of i.p. cisplatin at 75 mg/m(2) on day 1 with planned gemcitabine at 500, 750, 1000, or 1250 mg/m(2) i.p. on days 1, 8, and 15 on a 28-day schedule for four courses. Eligible patients completed surgical cytoreduction followed by adjuvant platinum-based chemotherapy. They had second-look assessment showing microscopic or macroscopic (< or =1 cm) disease, followed by i.p. port placement.
  
  
  RESULTS
  The Phase I dose-limiting toxicity was grade 3 thrombocytopenia at day 15 on dose level 1 (n = 5). The protocol was amended, and the Phase II portion accrued to 30 patients, who were given i.p. cisplatin (75 mg/m(2)) on day 1 and gemcitabine at 500 mg/m(2) on days 1 and 8 on a 21-day schedule for four courses. Nine patients were removed from the study: one each for hypersensitivity, cellulitis, and i.p. port malfunction; two for progression of disease; and four for renal toxicity. Other toxicities included grade 3 nausea (7%) and transient grade 3 neuropathy (3%). Grade 1 or 2 neuropathy was frequently seen (80%). Five patients (17%) returned to the operating room at a median of 6 months (range, 1-20 months) after i.p. therapy for evaluation of abdominal pain; two patients had recurrence, and all had areas of fibrous tissue with encasement of the bowel. In two patients, the fibrous tissue was causing partial bowel obstruction. No other patients had symptoms prompting surgical exploration. Pharmacokinetic (PK) studies showed a median area under the curve (AUC) i.p. of 3041 h. micro M (range, 676-5702 h. micro M) and AUC in plasma of 4.0 h. micro M (range, 0.92-8.2 h. micro M) reached between 120 and 240 min; the pharmacological advantage was 759-fold (range, 217-1415-fold) for i.p. versus plasma drug levels. The mean residence time of gemcitabine with i.p. administration was 4.7 h. The median time to progression of the intent to treat population was 15.93 months (95% confidence interval, 9.13-25.9 months), with a median overall survival of 43.5 months [95% confidence interval, (34.66- infinity)]. No statistical differences were seen with respect to overall survival if patients were grouped in terms of optimal debulking or not (median not reached versus 34.8 months, respectively; P = 0.16) or whether visible disease was present or not at the start of i.p. therapy (34.8 versus 47.7 months; P = 0.47). With regard to time to treatment failure, a statistical difference favored patients with optimal versus nonoptimal primary debulking (25.2 versus 10.2 months, respectively; P = 0.03).
  
  
  CONCLUSIONS
  The median time to treatment failure and overall survival of 15.9 months and 43.5 months, respectively, are consistent with our historical data in patients receiving i.p. platinum-based regimens for consolidation. The fibrotic changes seen in explored patients suggest local toxicity of this combination. The absolute benefit of i.p. consolidation requires randomized trials to assess efficacy.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. Sabbatip@MSKCC.org
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: Mario
authors.initials: M
authors.lastname: Leitao
authors.forename: Ennapadam
authors.initials: E
authors.lastname: Venkatraman
authors.forename: Sybil
authors.initials: S
authors.lastname: Anderson
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.forename: Don
authors.initials: D
authors.lastname: Dizon
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Flaherty
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bloss
authors.forename: Dennis
authors.initials: D
authors.lastname: Chi
authors.forename: David
authors.initials: D
authors.lastname: Spriggs
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007274:Injections, Intraperitoneal; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine