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. RyanRakesh K. Jain

Research output: Contribution to journalArticlepeer-review

Abstract

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 1α, 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.

Original languageEnglish
Pages (from-to)3027-3035
Number of pages9
JournalJournal of Clinical Oncology
Volume27
Issue number18
DOIs
Publication statusPublished - Jun 20 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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