title: Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study.
abstract: BACKGROUND
  The drugs and protocols used for hyperthermic intraperitoneal chemotherapy (HIPEC) vary among institutions. Here we show the efficacy of the 3-drug combination of mitomycin C (MMC), 5-fluorouracil (5FU), and oxaliplatin (OHP) in an in vitro simulation of HIPEC and the safety of HIPEC with these drugs during a Phase I study of patients at high risk of developing colorectal peritoneal metastasis.
  
  
  METHODS
  To simulate HIPEC, we used HCT116 and WiDr cells to assess the growth inhibitory efficacy of MMC 2 μg/mL, 5FU 200 μg/mL, and OHP 40 μg/mL as single drugs or their combination after an exposure time of 30 min at 37 or 42 °C. In addition, nine patients underwent surgical resection of tumors and HIPEC with MMC, 5FU, and an escalating dose of OHP (90/110/130 mg/m²). Dose-limiting toxicity was monitored.
  
  
  RESULTS
  In the simulation, the 3-drug combination showed marked tumor-suppressive effects compared with those from ten times higher dose of OHP 400 μg/mL, with significant augmentation under hyperthermic conditions. No dose-limiting toxicity occurred in the clinical study. Dose escalation was completed at the final level of OHP.
  
  
  CONCLUSIONS
  The MMC-5FU-OHP combination showed marked growth inhibition against colorectal cancer cells under hyperthermic conditions in vitro. In the phase I study, the recommended dose of OHP was determined as 130 mg/m² when used with MMC and 5FU; HIPEC using MMC-5FU-OHP appears to be safe and feasible for patients at high risk of colorectal peritoneal metastasis.
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan. Electronic address: tomoharu@belle.shiga-med.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sonoda
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takebayashi
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Mekata
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shiomi
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Naka
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tani
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D066298:In Vitro Techniques; D007263:Infusions, Parenteral; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009366:Neoplasm Seeding; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016685:Mitomycin; D005472:Fluorouracil
keywords: 5-FU; HIPEC; L-OHP; MMC; Peritoneal dissemination