Future directions in the treatment of osteosarcoma.
Future directions in the treatment of osteosarcoma.
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DOI：
10.1097/mop.0000000000000298
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发表时间：
2016-02
影响因子：
3.6
通讯作者：
Gorlick R
中科院分区：
文献类型：
--
作者：
Bishop MW;Janeway KA;Gorlick R
骨肉瘤的总体存活率在过去30年中基本保持不变，尽管试图通过剂量强化和基于反应的修改来改善结果。这篇综述描述了当代临床试验的最新发现，骨肉瘤生物学和基因组复杂性的理解进展，以及使用靶向和免疫介导性治疗的潜在机会。最近来自国际合作试验的结果未能证明使用一种设计来改善结果的能力，在该设计中，随机问题是基于术前化疗的组织学反应而决定的。新的预后标记物可在诊断时评估，对识别骨肉瘤亚型至关重要。临床试验的重点现在已经转移到新药的系列II期研究，以评估其在复发和难治性疾病中的活性。深入的分析揭示了患者基因组的严重不稳定性和异质性，几乎普遍存在TP53异常。虽然驱动突变事件尚未明确确定，但特定路径上频繁的错位可能暗示了治疗利用的机会。基因组的复杂性可能支持免疫介导性治疗的作用。严格的临床前研究可能会产生治疗骨肉瘤的新策略，这将为下一代临床试验提供信息，并有机会确定将改善生存结果的药物。
Overall survival rates for osteosarcoma have remained essentially unchanged over the past three decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. While driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. Rigorous preclinical investigations are potentially generating novel strategies for treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.