title: Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.
abstract: OBJECTIVE
  This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.
  
  
  METHODS
  Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m(2)), along with day 2 i.p. cisplatin (75 mg/m(2)) and day 8 i.p. paclitaxel (60 mg/m(2)). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed.
  
  
  RESULTS
  Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥ grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration-time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C(24h) levels, the 42 cycles at ≥ 500 mg/m(2) i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m(2). Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months).
  
  
  CONCLUSIONS
  This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m(2). The favorable toxicity profile at doses <1,000 mg/m(2), which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona 85724, USA. schambers@azcc.arizona.edu
authors.forename: Setsuko K
authors.initials: SK
authors.lastname: Chambers
authors.forename: H-H Sherry
authors.initials: HH
authors.lastname: Chow
authors.forename: Mike F
authors.initials: MF
authors.lastname: Janicek
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Cragun
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Hatch
authors.forename: Haiyan
authors.initials: H
authors.lastname: Cui
authors.forename: Cynthia
authors.initials: C
authors.lastname: Laughren
authors.forename: Mary C
authors.initials: MC
authors.lastname: Clouser
authors.forename: Janice L
authors.initials: JL
authors.lastname: Cohen
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wright
authors.forename: Nisreen
authors.initials: N
authors.lastname: Abu Shahin
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007274:Injections, Intraperitoneal; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D000068437:Pemetrexed; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D017239:Paclitaxel; D002945:Cisplatin