Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value.
OBJECTIVE
Sunitinib--a multitargeted tyrosine kinase inhibitor--can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study.


METHODS
Toxicity was evaluated every two weeks during the first cycle of therapy. Biomarker changes from baseline were tested after adjusting for multiple comparisons. Correlation between toxicities and overall survival (OS) or time-to-tumor progression (TTP) was evaluated in a Cox model using log-transformed levels or change in biomarkers, after stratifying by stage and adjusting for baseline level.


RESULTS
Myeloid and lymphoid blood cell counts decreased by 20% to 50% after sunitinib treatment (P < 0.05 for all). The extent of the early decrease in neutrophils and monocytes, and the development of nonhematologic toxicities (i.e., skin toxicities), were significantly associated with both OS and TTP (P < 0.05). Changes in circulating cells significantly associated with specific changes in plasma biomarkers (i.e., changes in platelets with changes in VEGF-C and soluble-VEGFR3; changes in neutrophils with changes in IL-8, TNF-α, and soluble-VEGFR2).


CONCLUSIONS
The adverse effects of sunitinib, particularly on the hematopoietic system, may be rapid and appear directly related to its activity in HCC. This exploratory study suggests that early hematopoietic toxicities may potentially predict outcome in advanced HCC after sunitinib treatment.
Zhu
Andrew X
AX
Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. azhu@partners.org
Duda
Dan G
DG
Ancukiewicz
Marek
M
di Tomaso
Emmanuelle
E
Clark
Jeffrey W
JW
Miksad
Rebecca
R
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 / Q000009:adverse effects* / Q000493:pharmacokinetics; D015415:Biomarkers / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002452:Cell Count; D016207:Cytokines / Q000097:blood; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000097:blood; D000077210:Sunitinib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D006454:Hemoglobins; D007211:Indoles; D011758:Pyrroles; C020622:hemoglobin B; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib