Ciombor Kristen K, Feng Yang, Benson Al Bowen, Su Yingjun, Horton Linda, Short Sarah P, Kauh John Sae Wook, Staley Charles, Mulcahy Mary, Powell Mark, Amiri Katayoun I, Richmond Ann, Berlin Jordan
Division of Medical Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, A445A Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43212, USA,
Invest New Drugs. 2014 Oct;32(5):1017-27. doi: 10.1007/s10637-014-0111-8. Epub 2014 Jun 4.
To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival.
This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate.
Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment.
The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.
评估硼替佐米联合阿霉素治疗晚期肝细胞癌患者的疗效和耐受性，并将蛋白酶体抑制的药效学标志物与反应和生存情况相关联。
这项II期、开放标签、多中心研究在21天周期内检测了硼替佐米（第1、4、8、11天静脉注射1.3mg/m²）和阿霉素（第1、8天静脉注射15mg/m²）的疗效。主要终点是客观缓解率。
38例接受治疗的患者中，最佳反应为1例部分缓解（2.6%）、10例（26.3%）病情稳定、17例（44.7%）病情进展；10例患者无法评估。中位无进展生存期为2.2个月。中位总生存期为6.1个月。最常见的3至4级毒性为高血压、葡萄糖不耐受、腹水、谷丙转氨酶升高、高血糖和血栓形成/栓塞。治疗开始时白细胞介素-6、白细胞介素-8、巨噬细胞炎症蛋白-1α升高且核因子κB的电泳迁移率变动分析呈阳性的患者无进展生存期较差。治疗开始时白细胞介素-8和血管内皮生长因子升高的患者总生存期较差。如果治疗后血清巨噬细胞炎症蛋白-1α/CCL3的自然对数有变化，则患者的总生存期有所改善。治疗后调节激活正常T细胞表达和分泌因子/CCL5水平显著下降。
阿霉素和硼替佐米联合用药在肝细胞癌患者中耐受性良好，但未达到主要终点。蛋白酶体抑制标志物的探索性分析表明其可能具有预后和预测作用，应在硼替佐米有效的肿瘤类型中进一步探索。
