Adding sorafenib to doxorubicin therapy substantially improved progression-free survival and overall survival of advanced hepatocellular carcinoma in a phase II study, according to a report in the Nov. 17 issue of JAMA.

Median time to progression, the primary end point of the trial, also was significantly longer with the combined therapy, said Dr. Ghassan K. Abou-Alfa of Memorial Sloan-Kettering Cancer Center, New York, and his associates.

The multicenter, double-blind study began when doxorubicin was “the accepted standard control group for randomized trials involving hepatocellular carcinoma [HCC],” they noted. Sorafenib has since been established as a new standard treatment for the disease and an appropriate control regimen in such trials. It is approved for treatment of unresectable HCC.

A total of 96 patients with advanced, inoperable HCC were enrolled from 25 treatment centers. They were randomly assigned to receive either intravenous doxorubicin every 3 weeks plus twice daily oral sorafenib (47 patients) or doxorubicin plus an identical-looking placebo (49 patients), until disease progression or an unacceptable drug-related toxicity occurred.

The primary outcome measure was time to HCC progression. The median interval was 6.4 months with the combined therapy, significantly longer than the 2.8 months seen in the control group, Dr. Abou-Alfa and his colleagues said (JAMA 2010;304:2154-60).

This reduction represents a 50% decrease in risk of progression for the combined therapy over doxorubicin plus placebo, they noted.

In a “competing risk” analysis, the cumulative incidence of HCC progression at 4 months was 26% with the combined treatment and 55% with doxorubicin plus placebo.

A total of 25 patients in the combined treatment group died, compared with 38 in the control group. Median overall survival was 14 months for doxorubicin plus sorafenib, compared with 6.5 months for doxorubicin plus placebo, which represents a 51% reduction in the risk of death with the combined treatment.

Median progression-free survival was 6 months with doxorubicin plus sorafenib, compared with 2.7 months with doxorubicin plus placebo, which represents a 46% reduction in the risk of progression or death with the combined treatment.

In addition, a greater proportion of patients receiving combined treatment (62%) showed shrinkage of target lesions, compared with patients receiving doxorubicin plus placebo (29%).

Adverse effects of the combined treatment “were essentially additive and similar to what would be expected for each drug used as a single agent,” Dr. Abou-Alfa and his associates said.

Treatment-related left ventricular systolic dysfunction was noted in 19% of patients given combined therapy, compared with only 2% of those given doxorubicin plus placebo. Although this adverse effect was usually asymptomatic, it warrants further careful investigation, they noted.

Now that sorafenib can be used on its own in clinical trials, a phase III trial is underway to compare sorafenib alone against doxorubicin plus sorafenib. The results will help determine whether combining the two agents is truly synergistic, they added.

This study was supported by Bayer. Dr. Abou-Alfa and some of his associates also reported receiving research support and serving as consultants for Bayer.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据11月17日发表于《美国医学会杂志》(JAMA)的一项多中心双盲II期临床研究结果，在对晚期肝细胞癌患者使用阿霉素治疗时加用索拉非尼可显著延长患者无进展生存和总体生存时间。

 

本研究共纳入来自25个医学中心的96例晚期HCC患者(已无法进行手术)。47例患者被随机分入阿霉素(每3周1次，静脉给药)加索拉非尼(每天2次，口服给药)联合治疗组， 49例患者被分入阿霉素加安慰剂(外表与索拉非尼片完全一致)组，试验一直持续到疾病进展或出现无法接受的药物毒性反应为止。研究的主要终点是中位疾病进展时间。

 

联合治疗组患者出现疾病进展的中位时间(6.4个月)显著长于对照组(2.8个月)，前者出现疾病进展的风险较后者低50%(JAMA 2010;304:2154-60)。竞争风险分析显示，在治疗第4个月时，HCC疾病进展累积发生率在联合治疗组和对照组分别为26%和55%。联合治疗组和对照组的死亡例数分别为25和38例，中位总体生存时间分别为14和6.5个月，前者死亡风险较后者降低51%。联合治疗组和对照组患者中位无进展生存时间分别为6和2.7个月，前者出现疾病进展或死亡的风险较后者降低46%。联合治疗组(62%)出现肿瘤体积缩小的患者比例也高于对照组(29%)。

 

联合治疗组和对照组患者出现的总体不良反应基本类似，但两组患者分别有19%和2%出现治疗相关性左心室收缩功能不全。尽管该不良反应通常并无临床症状，但仍需对其进行进一步调查。

 

本研究由拜耳公司赞助。部分研究者接受了来自拜耳公司的研究经费支持并担任该公司顾问。

 

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