Phase II study of sorafenib in patients with advanced hepatocellular carcinoma Journal Article
| Authors: | Abou-Alfa, G. K.; Schwartz, L.; Ricci, S.; Amadori, D.; Santoro, A.; Figer, A.; de Greve, J.; Douillard, J. Y.; Lathia, C.; Schwartz, B.; Taylor, I.; Moscovici, M.; Saltz, L. B. |
| Article Title: | Phase II study of sorafenib in patients with advanced hepatocellular carcinoma |
| Abstract: | Purpose: This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients. Methods: Patients with inoperable HCC, no prior systemic treatment, and Child-Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients. Results: Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy. Conclusion: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents. © 2006 by American Society of Clinical Oncology. |
| Keywords: | immunohistochemistry; survival; mitogen activated protein kinase; adult; cancer survival; controlled study; human tissue; treatment outcome; treatment response; aged; aged, 80 and over; disease-free survival; middle aged; survival analysis; major clinical study; overall survival; genetics; clinical trial; fatigue; sorafenib; area under the curve; diarrhea; drug dose reduction; drug efficacy; liver cell carcinoma; skin toxicity; treatment duration; antineoplastic agents; benzenesulfonates; carcinoma, hepatocellular; liver neoplasms; pyridines; hand foot skin reaction; disease free survival; cancer staging; antineoplastic agent; neoplasm staging; anorexia; controlled clinical trial; multiple cycle treatment; phase 2 clinical trial; protein kinase inhibitor; nausea; stomatitis; vomiting; drug administration schedule; tumor markers, biological; pathology; tumor marker; rash; protein kinase inhibitors; rna; gene expression regulation; gene expression regulation, neoplastic; blood; drug mechanism; multicenter study; liver tumor; prediction and forecasting; predictive value of tests; extracellular signal-regulated map kinases; drug administration; alopecia; rna, neoplasm; liver biopsy; benzenesulfonic acid derivative; pyridine derivative; desquamation; tumor necrosis |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 24 |
| Issue: | 26 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2006-09-10 |
| Start Page: | 4293 |
| End Page: | 4300 |
| Language: | English |
| DOI: | 10.1200/jco.2005.01.3441 |
| PUBMED: | 16908937 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 533" - "Export Date: 4 June 2012" - "CODEN: JCOND" - "Source: Scopus" |
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