title: Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.
abstract: Liver transplantation offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who fall within established criteria. For those outside such criteria, or with high-risk pathologic features in the explant, HCC recurrence rates are higher. We conducted a multicenter phase I trial of sorafenib in liver transplantation patients with high-risk HCC. Subjects had HCC outside the Milan criteria (pre- or post-transplant), poorly differentiated tumors, or vascular invasion. We used a standard 3+3 phase I design with a planned duration of treatment of 24 weeks. Correlative studies included the number of circulating endothelial cells (CECs), plasma biomarkers, and tumor expression of p-Erk, p-Akt, and c-Met in tissue micro-arrays. We enrolled 14 patients with a median age of 63 years. Of these, 93% were men and 71% had underlying hepatitis C virus (HCV) and 21% had HBV. The maximum tolerated dose of sorafenib was 200 mg BID. Grade 3-4 toxicities seen in >10% of subjects included leukopenia (21%), elevated gamma-glutamyl transferase (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, one patient died and four recurred. The mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean soluble vascular endothelial growth factor receptor-2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression to correlate with increased risk of recurrence. Post-transplant sorafenib was found to be feasible and tolerable at 200 mg PO BID. The effect of post-transplant sorafenib on recurrence-free survival is potentially promising but needs further validation in a larger study.
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Abby B
authors.initials: AB
authors.lastname: Siegel
authors.affiliation: Norris Comprehensive Cancer Center, Los Angeles, Calif., USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: El-Khoueiry
authors.affiliation: Geffen School of Medicine, Los Angeles, Calif., USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Wash., USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Guthrie
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Goyal
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, San Francisco, Calif., USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.affiliation: Knight Cancer Institute, Portland, Oreg., USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Verna
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Lorna
authors.initials: L
authors.lastname: Dove
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Emond
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Samstein
authors.affiliation: Geffen School of Medicine, Los Angeles, Calif., USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Busuttil
authors.affiliation: Division of Pathology and Cell Biology, Columbia University, New York, N.Y., USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Remotti
authors.affiliation: Division of Pathology and Cell Biology, Columbia University, New York, N.Y., USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Coffey
authors.affiliation: Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Brown
keywords: Hepatocellular carcinoma; High risk; Liver transplant; Phase I; Sorafenib