Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
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.
Zhu
Andrew X
AX
Division of Hematology/Oncology, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. azhu@partners.org
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
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
D000970:Antineoplastic Agents; D015415:Biomarkers; D054377:Chemokine CXCL12; D007211:Indoles; D015850:Interleukin-6; D011758:Pyrroles; D000077210:Sunitinib