Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series
Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series
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DOI：
10.1093/annonc/mdi317
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发表时间：
2005-10-01
影响因子：
50.5
通讯作者：
Dresemann, G
中科院分区：
文献类型：
--
作者：
Dresemann, G
背景：脑IV级恶性肿瘤，如多形性胶质母细胞瘤（GBM），预后较差。血小板衍生生长因子（PDGF）信号的自分泌和旁分泌回路以及其他信号转导途径被认为在胶质母细胞瘤转化中发挥作用，参与这些途径的分子可能成为治疗抑制剂的潜在靶点。伊马替尼是一种PDGF受体α和β的抑制剂，以及其他选定的酪氨酸激酶，用于治疗慢性髓性白血病（CML）和胃肠道间质瘤（GIST）。不幸的是，伊马替尼与许多传统化疗药物一样，作为单一疗法治疗GBM的疗效有限。在临床前研究中，化学治疗剂羟基脲被证明与伊马替尼一起具有细胞毒性作用。患者和方法：我们对30例难化疗和放疗的IV级进展性GBM患者进行了羟基脲和伊马替尼联合治疗的试验。所有30例患者在中位19周观察时间后均可评估。结果：伊马替尼和羟基脲联合治疗的有效率为20%，包括完全缓解和部分缓解。有反应或病情稳定的患者的综合临床获益率为57%。中位进展时间为10周，中位总生存期为19周。3例患者在联合治疗下继续生存，最短持续时间为106周。6个月和2年无进展生存率分别为32%和16%。结论：疗效结果，结合伊马替尼和羟基脲耐受性良好的发现，表明该组合治疗GBM有希望。
Background: Grade IV malignancies of the brain, such as glioblastoma multiforme (GBM), are associated with a dismal prognosis. Autocrine and paracrine loops of platelet-derived growth factor (PDGF) signaling, as well as other signal transduction pathways, have been postulated to play a role in glioblastoma transformation, and molecules involved in these pathways can potentially serve as targets for therapeutic inhibitory agents. Imatinib, an inhibitor of PDGF receptors alpha and beta, as well as other selected tyrosine kinases, is indicated for treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Unfortunately, imatinib, as with many conventional chemotherapeutic agents, has limited efficacy as monotherapy in GBM. In preclinical studies, the chemotherapeutic agent hydroxyurea is demonstrated to have cytotoxic effects additive with imatinib.Patients and methods: We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time.Results: Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively.Conclusion: The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.