Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Memorial Sloan-Kettering Cancer Center, York, NY 10022, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2006; 24(26):4293-300. DOI: 10.1200/JCO.2005.01.3441
Source: PubMed


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.
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.
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.
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.

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Available from: Brian Schwartz, Oct 13, 2015
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    • "These results compare favorably with the sorafenib phase II study conducted by Abou-Alfa et al (17) in patients with advanced HCC; three (2.2%) of the 137 treated patients achieved PR, eight (5.8%) achieved a minor response and 46 (33.6%) achieved SD for at least 16 weeks. The TTP and OS time were 4.2 and 9.2 months, respectively. "
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    ABSTRACT: The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55-73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2-6.2) and 10.4 (95% CI, 10-11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC.
    Oncology letters 10/2014; 8(4):1783-1787. DOI:10.3892/ol.2014.2376 · 1.55 Impact Factor
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    • "Sorafenib was the first agent significantly increasing clinical outcome of advanced HCC [21] [22] [23]. A phase 2 study enrolling advanced HCC and Child-Pugh class A or B status indicated a median OS 9.2 months and a median time to progression 5.5 months [21]. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). "
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    ABSTRACT: Background: Hepatocellular carcinoma (HCC) patients require different treatment strategies according to disease extension, liver function, and patient's fitness. We evaluated HCC multidisciplinary management in clinical practice. Methods: Consecutive patients were followed and treated with tailored medical, locoregional, and surgical treatments, according to disease stage and patient's fitness (age, Cumulative Illness Rating Scale (CIRS)). Activity, efficacy, and safety were evaluated. Results: Thirty-eight patients were evaluated: median age, 74; elderly 92%; CIRS secondary 28 (74%); Child-Pugh A 20 (53%), B 11 (29%); and Barcelona Clinic Liver Cancer (BCLC) 0 2 (5%), A 9 (24%), B 10 (26%), C 13 (34%), and D 4 (11%). Overall survival (OS) was 30 months. At 9 months median follow-up, among 25 unresectable HCC, OS was 10 months; BCLC B-D unfit for sorafenib showed OS 3 months. Ten patients (40%) received sorafenib: Child-Pugh A 5 (50%) and B 5 (50%) and disease control rate 89%, progression-free survival 7 months, and OS 9 months. G3-4 toxicities: anorexia, hypertransaminaemia, hyperbilirubinemia, and hypercreatininemia. Limiting toxicity syndromes were 40%, all multiple sites. Conclusion: HCC patients require multidisciplinary clinical management to properly select tailored treatments according to disease stage, fitness, and liver function. Patients suitable for sorafenib should be carefully selected, monitored for individual safety, and prevalently characterized by limiting toxicity syndromes multiple sites.
    BioMed Research International 05/2014; 2014:806391. DOI:10.1155/2014/806391 · 3.17 Impact Factor
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    • "The tumor growth-inhibitory effects of sorafenib may be attributed to the inhibition of tumor angiogenesis (24) and molecular markers involved in angiogenesis may be candidates. Preliminary biomarker evaluations have indicated that baseline soluble VEGFR and phosphorylated extracellular signal-regulated kinase levels are indicative of the sorafenib response in RCC (25) and HCC (26), respectively. However, at present, there are no proven biomarkers for selecting patients with ABC that are likely to benefit from antiangiogenic therapy (27). "
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    ABSTRACT: A standard systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) is yet to be identified. Sorafenib has been developed for the treatment of solid tumors, including breast cancer, as an oral multikinase inhibitor with antiangiogenic and antiproliferative activity. The aim of the present study was to assess the efficacy and safety of sorafenib in patients with HER2-negative ABC by performing a meta-analysis. A literature search was applied to databases, including PubMed, EMBASE, the Cochrane Library Databases, American Society of Clinical Oncology and the European Society for Medical Oncology, with the search terms 'advanced breast cancer' and 'sorafenib' and relevant studies were selected for analysis. The data extracted from the selected studies included progression-free survival (PFS), time to progression (TTP), overall survival (OS) and overall response rate (ORR). Major adverse events (AEs) were also analyzed. A total of four randomized controlled trials containing 844 cases were identified. Combined results revealed that when compared with chemotherapy (or with anti-hormone receptor therapy) alone, sorafenib-based therapy significantly increased the PFS [hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.54-1.02] and TTP (HR, 0.74; 95% CI, 0.50-0.97), but not the OS (HR, 0.95; 95% CI, 0.75-1.15) and ORR (relative risk, 1.19; 95% CI, 1.01-1.39). In addition, the incidence of grade 3/4 AEs, including hand-foot skin syndrome, anemia, fatigue, rash and stomatitis, were significantly increased in patients that received sorafenib-based therapy. Therefore, the results from the current meta-analysis indicated that sorafenib-based therapy improved the PFS and TTP in patients with HER2-negative ABC, but not the OS and ORR. In addition, combination treatment was associated with increased toxicities and frequently required dose reductions.
    Experimental and therapeutic medicine 05/2014; 7(5):1420-1426. DOI:10.3892/etm.2014.1603 · 1.27 Impact Factor
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