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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

Authors
  • 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)
Type
Published Article
Journal
Annals of Surgical Oncology
Publisher
Springer - Society of Surgical Oncology
Publication Date
Apr 11, 2013
Volume
20
Issue
7
Pages
2180–2187
Identifiers
DOI: 10.1245/s10434-013-2960-3
Source
Springer Nature
Keywords
License
Yellow

Abstract

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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