Gish Robert G, Porta Camillo, Lazar Lucian, Ruff Paul, Feld Ronald, Croitoru Adina, Feun Lynn, Jeziorski Krzysztof, Leighton John, Gallo José, Kennealey Gerard T
California Pacific Medical Center, San Francisco, CA 94115, USA.
J Clin Oncol. 2007 Jul 20;25(21):3069-75. doi: 10.1200/JCO.2006.08.4046.
The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX).
Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) > or = 60%, Cancer of the Liver Italian Program (CLIP) score < or = 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score.
At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm.
NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.
本研究的目的是比较接受诺拉曲塞（NOL）或多柔比星（DOX）治疗的不可切除或转移性肝细胞癌（HCC）患者的总生存期（OS）。
来自北美、欧洲和南非的445例HCC患者被随机分配接受NOL或DOX治疗。符合条件的患者卡氏评分（KPS）≥60%，意大利肝癌项目（CLIP）评分≤3，且器官功能良好。主要终点是OS。次要终点包括无进展生存期（PFS）、客观缓解率和安全性。治疗组在年龄、性别、种族和潜在肝病方面均衡良好。随机分组根据KPS和CLIP评分进行分层。
在最终分析时，377例患者死亡。NOL组的中位OS为22.3周，DOX组为32.3周（P = 0.0068）。风险比为0.753，支持DOX组。NOL组的客观缓解率（完全缓解[CR]加部分缓解[PR]）为1.4%，DOX组为4.0%。NOL组的中位PFS为12周，DOX组为10周（P = 0.7091）。NOL组的中位治疗失败时间为8.4周，DOX组为9.1周（P = 0.0969）。3级和4级口腔炎、呕吐、腹泻和血小板减少症在NOL组更常见。脱发在DOX组更常见。因毒性而退出研究的患者在NOL组比DOX组更多。
NOL在这项III期试验中显示出最小的活性。在该剂量和方案下对HCC进行进一步探索是没有必要的。
