Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial
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索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
DOI：
10.1016/s1470-2045(08)70285-7
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发表时间：
2009-01-01
期刊：
影响因子：
51.1
通讯作者：
Guan, Zhongzhen
中科院分区：
文献类型：
--
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
背景大多数肝细胞癌发生在亚太地区，慢性B型肝炎感染是一个重要的病因。因此，在亚太地区人群中评估新治疗选择的疗效和安全性非常重要。我们进行了一项多国111期、随机、双盲、安慰剂研究。一项旨在评估索拉非尼在亚太地区晚期乳腺癌患者中的疗效和安全性的对照试验方法在2005年9月20日至2007年1月31日期间，未接受过既往系统治疗且Child-Pugh肝功能A级的肝细胞癌患者，随机分配接受口服索拉非尼（400 mg）或安慰剂，每日两次，6周为一个周期，在每个6周周期结束时测量疗效。根据是否存在肉眼可见血管浸润或肝外扩散（或两者）、东部肿瘤协作组体力状态和地理区域对合格患者进行分层。通过交互式语音应答系统以2：1的比例集中进行随机化。没有预定义的主要终点;评估了总生存期、至疾病进展时间（TTP）、至症状进展时间（TTSP）、疾病控制率（DCR）和安全性。本试验注册于ClinicalTrials.gov，编号NCT 00492752。结果来自中国、韩国和台湾23个中心的271例患者参加了本研究。其中，226例患者被随机分配到实验组（n=150）或安慰剂组（n=76）。索拉非尼治疗患者的中位总生存期为6.5个月（95% CI 5.56-7.56），而安慰剂治疗患者的中位总生存期为4.2个月（3.75-5.46）（风险比[HR] 0.68 [95% CI 0.50-0.93]; p=0.014）。索拉非尼组的中位TTP为2.8个月（2.63-3.58），而安慰剂组为1.4个月（1.35-1.55）（HR 0.57 [0.42-0.791; p=0.0005）。在149例接受索拉非尼治疗的可评估患者中，最常报告的3/4级药物相关不良事件为手足皮肤反应（HFSR; 16例患者[10.7%]）、腹泻（9例患者[6.0%]）和疲乏（5例患者[3.4%]）。导致剂量减少的最常见不良事件是HFSR（17例患者[11.4%]）和腹泻（11例患者[7.4%]）;这些不良事件很少导致停药。解释索拉非尼对治疗亚太地区晚期肝细胞癌患者有效，耐受性良好。结合索拉非尼肝细胞癌评估随机方案（SHARP）试验的数据，索拉非尼似乎是治疗晚期肝细胞癌的合适选择。
Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase 111, randomised, double-blind, placebo. controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma.Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatorcellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752.Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% Cl 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.791; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation.Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.