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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 1alpha, 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.
SUBMITTER: Zhu AX
PROVIDER: S-EPMC2702235 | biostudies-literature | 2009 Jun
REPOSITORIES: biostudies-literature
Zhu Andrew X AX Sahani Dushyant V DV Duda Dan G DG di Tomaso Emmanuelle E Ancukiewicz Marek M Catalano Onofrio A OA Sindhwani Vivek V Blaszkowsky Lawrence S LS Yoon Sam S SS Lahdenranta Johanna J Bhargava Pankaj P Meyerhardt Jeffrey J Clark Jeffrey W JW Kwak Eunice L EL Hezel Aram F AF Miksad Rebecca R Abrams Thomas A TA Enzinger Peter C PC Fuchs Charles S CS Ryan David P DP Jain Rakesh K RK
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20090526 18
<h4>Purpose</h4>To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.<h4>Patients and methods</h4>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). ...[more]