title: A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer.
abstract: BACKGROUND
  Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP.
  
  
  METHODS
  Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined.
  
  
  RESULTS
  All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %).
  
  
  CONCLUSIONS
  The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.
authors.affiliation: University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. maggedr@upmc.edu
authors.forename: D
authors.initials: D
authors.lastname: Magge
authors.forename: A H
authors.initials: AH
authors.lastname: Zureikat
authors.forename: D L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: M P
authors.initials: MP
authors.lastname: Holtzman
authors.forename: H A
authors.initials: HA
authors.lastname: Choudry
authors.forename: J H
authors.initials: JH
authors.lastname: Beumer
authors.forename: J F
authors.initials: JF
authors.lastname: Pingpank
authors.forename: J L
authors.initials: JL
authors.lastname: Holleran
authors.forename: S
authors.initials: S
authors.lastname: Strychor
authors.forename: D E
authors.initials: DE
authors.lastname: Cunningham
authors.forename: H L
authors.initials: HL
authors.lastname: Jones
authors.forename: H J
authors.initials: HJ
authors.lastname: Zeh
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002272:Carcinoembryonic Antigen / Q000097:blood; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077150:Oxaliplatin
chemical_list: D002272:Carcinoembryonic Antigen; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil