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A Phase I Trial of Isolated Hepatic Perfusion (IHP) Using 5-FU and Oxaliplatin in Patients with Unresectable Isolated Liver Metastases from Colorectal Cancer

  • Magge, D.1
  • Zureikat, A. H.1
  • Bartlett, D. L.1
  • Holtzman, M. P.1
  • Choudry, H. A.1
  • Beumer, J. H.2, 3
  • Pingpank, J. F.1
  • Holleran, J. L.2
  • Strychor, S.2
  • Cunningham, D. E.4
  • Jones, H. L.1
  • Zeh, H. J. III1
  • 1 University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 2 University of Pittsburgh Cancer Institute, Molecular Therapeutics Drug Discovery Program, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 3 University of Pittsburgh, Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 4 University of Pittsburgh Cancer Institute, UPCI Biostatistics Facility, Pittsburgh, PA, USA , Pittsburgh (United States)
Published Article
Annals of Surgical Oncology
Springer - Society of Surgical Oncology
Publication Date
Apr 11, 2013
DOI: 10.1245/s10434-013-2960-3
Springer Nature


BackgroundIsolated 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.MethodsStandard 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.ResultsAll 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/m2, resulting in expansion of DL1 at 200 mg/m2 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 %).ConclusionsThe MTD for IHP was 200 mg/m2 5-FU with 40 mg/m2 oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

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