Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma
Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma
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DOI：
10.1634/theoncologist.2008-0185
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发表时间：
2009-01-01
期刊：
影响因子：
5.8
通讯作者：
Pazdur, Richard
中科院分区：
文献类型：
--
作者：
Kane, Robert C.;Farrell, Ann T.;Pazdur, Richard
目的。描述美国食品和药物管理局(FDA)审查和批准索拉非尼(Nexavar(R)；拜耳制药公司(Bayer PharmPharmticals Corp.)，新泽西州蒙特维尔，以及奥尼克斯制药公司(Onyx PharmPharmticals Corp.)，加利福尼亚州埃默里维尔)用于治疗不能切除的肝细胞癌(HCC)患者的试验设计。FDA独立分析了一项国际双盲安慰剂对照试验，比较了最佳支持性护理加索拉非尼或匹配安慰剂对总存活率的影响。符合条件的患者有不能切除的、经活检证实的肝细胞癌，并且以前没有接受过系统治疗。在602名随机患者(安慰剂，303人；索拉非尼，299人)中，基线特征平衡良好，97%为Child-Pugh A评分，根据肝外转移或肝脏外静脉结构中可见的肿瘤放射学定义，总体上有70%的人肝细胞癌“进展”。潜在的肝病包括乙肝(18%)、丙型肝炎(28%)和与酒精有关的(26%)。试验在预先指定的第二次中期分析后停止，该分析显示，索拉非尼具有统计学上显著的生存优势[中位数，10.7vs7.9月；风险比，0.69(95%可信区间，(0.55，0.87)，p=0.00058]。接受索拉非尼治疗的患者的不良反应包括55%的腹泻(3级，10%)，21%的手足综合征(3级，8%)，19%的皮疹(3级，1%)，以及2.7%的心肌缺血或梗塞(安慰剂为1.3%)。在服用索拉非尼的患者中，9%的患者(安慰剂，4%)出现治疗后出现的高血压，4%的患者(安慰剂，1%)出现3级高血压；40%(安慰剂，37%)的患者出现血脂升高；35%(安慰剂，11%)出现低磷血症。索拉非尼是第一个在不能切除的肝癌的随机试验中证明对生存有好处的全身疗法，并已获得FDA的批准。肿瘤学家2009；14：95-100
Purpose. To describe the U. S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar (R); Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC).Experimental Design. The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy.Results. Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55%(grade 3, 10%), hand-foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%).Conclusions. Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication. The Oncologist 2009; 14: 95-100