Originally published as JCO Early Release 10.1200/JCO.2008.20.9908 on May 26 2009

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Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study

Andrew X. Zhu, Dushyant V. Sahani, Dan G. Duda, Emmanuelle di Tomaso, Marek Ancukiewicz, Onofrio A. Catalano, Vivek Sindhwani, Lawrence S. Blaszkowsky, Sam S. Yoon, Johanna Lahdenranta, Pankaj Bhargava, Jeffrey Meyerhardt, Jeffrey W. Clark, Eunice L. Kwak, Aram F. Hezel, Rebecca Miksad, Thomas A. Abrams, Peter C. Enzinger, Charles S. Fuchs, David P. Ryan, Rakesh K. Jain

From the Division of Hematology/Oncology, Department of Radiology, Department of Radiation Oncology, Division of Surgical Oncology, Massachusettes General Hospital and Harvard Medical School; Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School; and Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Corresponding author: Andrew X. Zhu, MD, PhD, Massachusetts General Hospital, 55 Fruit St, LH/POB, Room 232, Boston, MA, 02114; e-mail: azhu{at}partners.org.

Purpose To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.

Patients and Methods We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.

Results Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.

Conclusion Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

A.X.Z., D.V.S., and D.G.D. contributed equally to this work. A.X.Z. and R.K.J. are co-senior authors.

Supported in part by Pfizer (A.X.Z.) and by National Institutes of Health Grants No. P01CA80124 and R01CA115767 (R.K.J.) and M01-RR-01066, Harvard Clinical and Translational Science Center.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00361309 [ClinicalTrials.gov] .

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