Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.
Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.
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DOI：
10.1158/1078-0432.ccr-08-1141
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发表时间：
2009-02-15
期刊：
影响因子：
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通讯作者：
Kong HH
中科院分区：
文献类型：
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作者：
Azad NS;Aragon-Ching JB;Dahut WL;Gutierrez M;Figg WD;Jain L;Steinberg SM;Turner ML;Kohn EC;Kong HH
索拉非尼是一种血管内皮生长因子受体（VEGFR）-2和RAF激酶抑制剂，通常会导致皮肤毒性。我们回顾性分析了接受索拉非尼和贝伐单抗联合抗血管生成治疗的患者的皮肤毒性。去势抵抗性前列腺癌和转移性非小细胞肺癌患者入组II期研究，接受索拉非尼400 mg BID治疗。一项I期研究探索了索拉非尼200 - 400 mg BID联合贝伐珠单抗5 - 10 mg/kg每2周一次治疗晚期实体瘤患者的效果。确定了最大程度皮肤毒性的发生概率，作为索拉非尼累积剂量的函数。其他分析比较了毒性程度、药代动力学和患者风险因素。96例患者入组：54例患者接受索拉非尼治疗，42例患者接受贝伐珠单抗/索拉非尼治疗。在50/96例（52%）患者中观察到HFSR（手足皮肤反应）。16/54例（30%）索拉非尼患者和24/42例（57%）贝伐珠单抗/索拉非尼患者发生2 - 3级HFSR（p = 0.012），与索拉非尼累积暴露相关（p = 0.0008）。在调整HFSR风险与高血压之间的相关性（p = 0.01）后，24/42例随机接受贝伐珠单抗治疗的I期患者发生2 - 3级HFSR的风险高于索拉非尼（p = 0.013），这是HFSR的唯一毒性。HFSR与基线神经病变史、既往紫杉烷/铂类药物治疗或全身索拉非尼水平之间无相关性。索拉非尼相关HFSR与索拉非尼累积剂量增加相关。在接受贝伐珠单抗/索拉非尼联合抗VEGF治疗的患者中，HFSR增加，这一发现不能用两种药物之间的药代动力学相互作用来解释。我们的研究结果表明，HFSR的病理生理可能与VEGF抑制。
Sorafenib, a vascular endothelial growth factor receptor (VEGFR)-2 and RAF-kinase inhibitor, commonly causes skin toxicity. We retrospectively analyzed dermatologic toxicity in patients receiving combined anti-angiogenic therapy sorafenib and bevacizumab. Castration-resistant prostate cancer and metastatic non-small cell lung cancer patients were accrued to phase II studies, receiving sorafenib400mg BID. A phase I study explored sorafenib 200–400mg BID with bevacizumab 5–10mg/kg every 2 weeks in patients with advanced solid tumors. Probability of development of maximum grade of dermatologic toxicity as a function of the cumulative dose of sorafenib was determined. Additional analyses compared extent of toxicity, pharmacokinetics, and patient risk factors. Ninety-six patients were enrolled: 54 pts received sorafenib, 42 received bevacizumab/sorafenib. HFSR (hand-foot skin reaction) was observed in 50/96(52%) patients. Grade 2–3 HFSR developed in 16/54(30%) sorafenib patients and 24/42(57%) bevacizumab/sorafenib patients (p=0.012) and was associated with cumulative sorafenib exposure (p=0.0008). 24/42 phase I patients randomized to start with bevacizumab had increased risk of grade 2–3 HFSR than those starting with sorafenib (p=0.013) after adjusting for association between HFSR risk and hypertension (p=0.01), which was the only toxicity associated with HFSR. There was no association between HFSR and baseline history of neuropathy, prior taxane/platinum treatment, or systemic sorafenib levels. Sorafenib-related HFSR is associated with increasing cumulative sorafenib dose. HFSR is increased in patients treated with bevacizumab/sorafenib combination anti-VEGF therapy, and this finding is not explained by pharmacokinetic interaction between the two agents. Our results suggest that the pathophysiology of HFSR may be related to VEGF inhibition.