title: A phase I trial of oxaliplatin for intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination from colorectal and appendiceal cancers.
abstract: BACKGROUND
  Cytoreductive surgery with intraperitoneal hyperthermic chemoperfusion (IPHC) has evolved into a promising approach for peritoneal surface malignancy. A large body of literature suggests that oxaliplatin has excellent cytotoxicity against colorectal cancer. Therefore, we undertook a phase I evaluation of IPHC with oxaliplatin for peritoneal dissemination from colorectal and appendiceal cancers to establish the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD).
  
  
  METHODS
  Cohorts of three patients underwent cytoreductive surgery followed by a 2-h IPHC with escalating doses of oxaliplatin at a target outflow temperature of 40 degrees C. The initial peritoneal oxaliplatin dose was 200 mg/M(2) with increases planned in 50 mg/M(2 )increments. Plasma and perfusate samples were collected during the IPHC and evaluated using emission spectrometry techniques. Normal tissue and tumor samples were collected before and after the IPHC for analysis. DLT was defined as a grade 3 toxicity lasting 5 days.
  
  
  RESULTS
  Fifteen patients were enrolled at two dose levels. Peritoneal fluid areas under the curve (AUCs) were above those of plasma. Additionally, intratumoral oxaliplatin was similar to that of surrounding normal tissue. Dose-limiting toxicities at 250 mg/M(2 )were observed in two of three patients enrolled in this study.
  
  
  CONCLUSIONS
  We found that IPHC with 200 mg/M(2 )of oxaliplatin is well tolerated and is the MTD for a 2-h chemoperfusion. Higher doses are not feasible with this perfusion protocol given the significant toxicities associated with 250 mg/M(2 )oxaliplatin. Based on the data from this phase I study, we propose to conduct further studies with oxaliplatin delivered at 200 mg/M(2).
authors.affiliation: Department of General Surgery, Surgical Oncology Service, Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jhstewar@wfubmc.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Stewart
authors.forename: Perry
authors.initials: P
authors.lastname: Shen
authors.forename: Greg
authors.initials: G
authors.lastname: Russell
authors.forename: Joyce
authors.initials: J
authors.lastname: Fenstermaker
authors.forename: Libby
authors.initials: L
authors.lastname: McWilliams
authors.forename: Faith M
authors.initials: FM
authors.lastname: Coldrun
authors.forename: Keith E
authors.initials: KE
authors.lastname: Levine
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Jones
authors.forename: Edward A
authors.initials: EA
authors.lastname: Levine
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001063:Appendiceal Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D010478:Chemotherapy, Cancer, Regional Perfusion; D015179:Colorectal Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D007263:Infusions, Parenteral; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin