title: Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
abstract: OBJECTIVE
  To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology/Oncology, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. azhu@partners.org
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Dushyant V
authors.initials: DV
authors.lastname: Sahani
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Onofrio A
authors.initials: OA
authors.lastname: Catalano
authors.forename: Vivek
authors.initials: V
authors.lastname: Sindhwani
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
authors.forename: Johanna
authors.initials: J
authors.lastname: Lahdenranta
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhargava
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Meyerhardt
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Rebecca
authors.initials: R
authors.lastname: Miksad
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D015415:Biomarkers / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D054377:Chemokine CXCL12 / Q000097:blood; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D015850:Interleukin-6 / Q000097:blood; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D013234:Stem Cells / Q000166:cytology; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D054377:Chemokine CXCL12; D007211:Indoles; D015850:Interleukin-6; D011758:Pyrroles; D000077210:Sunitinib