A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study
A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study
复制标题
DOI：
10.1093/annonc/mdr151
复制
发表时间：
2012-02-01
影响因子：
50.5
通讯作者：
Aglietta, M.
中科院分区：
文献类型：
--
作者：
Grignani, G.;Palmerini, E.;Aglietta, M.
目的：经过标准的多模式治疗，复发和不可切除的高级别骨肉瘤的预后是令人沮丧的，并且在过去的几十年里没有改变。最近，有丝分裂原激活的蛋白激酶在骨肉瘤标本中被激活，这表明它们是多激酶抑制剂索拉非尼的合适靶点。因此，我们探讨了索拉非尼在复发和不可切除骨肉瘤患者中的活性。实验设计：bb0 - 14岁的患者，在标准治疗后进展，有资格接受400mg索拉非尼，每日两次，直到进展或不可接受的毒性。主要终点是4个月时的无进展生存期（PFS）。次要目标是PFS，总生存期（OS），临床获益率（CBR），定义为6个月无进展和安全性。这项非随机II期研究采用Simon两阶段设计。采用Kaplan-Meier法计算95%置信区间（95% ci）的PFS和OS。所有的测试都是双面的。结果：35例患者入组。4个月时PFS为46% （95% CI 28%至63%）。中位PFS和OS分别为4个月（95% CI 2-5）和7个月（95% CI 7-8）。CBR为29% （95% CI 13% ~ 44%）。我们观察到3例（8%）部分缓解（pr）， 2例（6%）轻微缓解（= 6个月）。值得注意的是，在SD患者中观察到肿瘤密度降低和[F-18] 2-氟-2-脱氧-d -葡萄糖-正电子发射断层扫描反应。16例（46%）患者减少或短暂中断索拉非尼治疗，1例（3%）患者因毒性而永久停药。结论：索拉非尼作为二线或三线治疗在4个月的PFS方面表现出活性，具有一些前所未有的持久反应。索拉非尼是首个在骨肉瘤患者中显示活性的靶向治疗药物，值得进一步研究。
Purpose: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma.Experimental design: Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided.Results: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (= 6 months. Noteworthy, tumor density reduction and [F-18] 2-fluoro-2-deoxy-D-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity.Conclusions: Sorafenib demonstrated activity as a second-or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.