title: Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution.
abstract: OBJECTIVE
  This article reports the pharmacokinetics (PK) of heated intra-operative intraperitoneal oxaliplatin and its tolerance profile. Oxaliplatin has demonstrated significant activity in advanced colorectal cancer, and this is the first publication concerning its intraperitoneal administration.
  
  
  METHODS
  Twenty consecutive patients with peritoneal carcinomatosis (PC) of either gastrointestinal or uniquely peritoneal origin underwent complete cytoreductive surgery followed by intra-operative intraperitoneal chemo-hyperthermia (IPCH) with increasing doses of oxaliplatin. We performed IPCH using an open procedure (skin pulled upwards), at an intraperitoneal temperature of 42-44 degrees C, with 2 l/m2 of 5% dextrose instillate in a closed circuit. The flow-rate was 2 l/min for 30 min. Patients received intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2) just before the IPCH to maximize the effect of oxaliplatin. We treated at least three patients at each of the six intraperitoneal oxaliplatin dose levels (from 260 to 460 mg/m2) before progressing to the next. We analysed intraperitoneal, plasma and tissue samples with atomic absorption spectrophotometry.
  
  
  RESULTS
  The mean duration of the entire procedure was 8.4 +/- 2.7 h. Half the oxaliplatin dose was absorbed in 30 min at all dose levels. Area under the curve (AUC) and maximal plasma concentration (Cmax) increased with dose. At the highest dose level (460 mg/m2), peritoneal oxaliplatin concentration was 25-fold that in plasma. AUCs following intraperitoneal administration were consistently inferior to historical control AUCs after intravenous oxaliplatin (130 mg/m2). Intratumoral oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 17.8-fold higher than that in non-bathed tissues. Increasing instillate volume to 2.5 l/m2 instead of 2 l/m2 dramatically decreased oxaliplatin concentration and absorption. There were no deaths, nor severe haematological, renal or neurological toxicity, but we observed two fistulas and three deep abscesses.
  
  
  CONCLUSIONS
  Heated intraperitoneal chemotherapy gives high peritoneal and tumour oxaliplatin concentrations with limited systemic absorption. We recommend an oxaliplatin dose of 460 mg/m2 in 2 l/m2 of 5% dextrose for intraperitoneal chemo-hyperthermia, at a temperature of 42-44 degrees C over 30 min. We may be able to improve these results by increasing the intraperitoneal perfusion duration or by modifying the instillate composition.
authors.affiliation: Department of Surgical Oncology, Institut Gustave Roussy Comprehensive Cancer Center, Villejuif, France. elias@igr.fr
authors.forename: D
authors.initials: D
authors.lastname: Elias
authors.forename: M
authors.initials: M
authors.lastname: Bonnay
authors.forename: J M
authors.initials: JM
authors.lastname: Puizillou
authors.forename: S
authors.initials: S
authors.lastname: Antoun
authors.forename: S
authors.initials: S
authors.lastname: Demirdjian
authors.forename: Otmany A
authors.initials: OA
authors.lastname: El
authors.forename: J P
authors.initials: JP
authors.lastname: Pignon
authors.forename: L
authors.initials: L
authors.lastname: Drouard-Troalen
authors.forename: J F
authors.initials: JF
authors.lastname: Ouellet
authors.forename: M
authors.initials: M
authors.lastname: Ducreux
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000628:therapy*; D011446:Prospective Studies; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin