Division of Gynaecology, Istituto Europeo di Oncologia (IEO), Milan, Italy.
Int J Gynecol Cancer. 2012 Jun;22(5):792-800. doi: 10.1097/IGC.0b013e318251051a.
Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD.
Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study.
Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease.
The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.
聚乙二醇脂质体阿霉素（PLD）是一种已被确立的复发性卵巢癌治疗方法。在其他肿瘤类型中的临床前和临床证据表明，蛋白酶体抑制剂硼替佐米与 PLD 具有协同作用。
先前接受过铂类（100%）和紫杉烷（95%）治疗的复发性卵巢癌患者（N=58）接受硼替佐米，1.3mg/m2静脉注射（第 1、4、8 和 11 天）和 PLD，30mg/m2静脉注射（第 1 天），每 3 周一次。使用实体瘤反应评估标准和妇科肿瘤学组标准评估肿瘤反应。实施了最优的 2 期设计。在研究的第 2 阶段，纳入了 10 名铂类敏感患者，在治疗前和治疗期间对其外周血进行了基因表达谱分析。
硼替佐米-PLD 周期的中位数为 3.5。38 名铂类敏感患者中，有 9 例有反应（中位持续时间为 4.8 个月）。铂类耐药组由于无反应而在第 1 阶段关闭。毒性为中度，主要包括血液学、胃肠道和粘膜炎事件。在总共 58 名患者中，有 9 名患者报告有周围神经病变（无 3 级）。转录谱分析确定了与核糖核蛋白复合物、RNA 加工和蛋白质翻译相关的基因的存在。与进展性疾病患者相比，有反应或疾病稳定的患者的基因表达变化更为明显。
硼替佐米和 PLD 的联合应用具有良好的耐受性，但抗肿瘤活性不足以支持进一步在卵巢癌中进行研究。
