上海交通大学医学院附属第一人民医院 妇科
主要从事卵巢癌的综合诊疗及临床转化研究。至今已发表SCI论文20余篇，第一或通讯作者近10篇，累计总影响因子20+包括：International Journal of Cancer，Frontiers in Oncology等杂志。
卵巢癌已经进入精准治疗时代，抗血管生成药物和PARPi为卵巢癌的主要靶向药物，抗血管生成和PARPi在一线维持治疗和复发治疗的卵巢癌患者中均显示出不错的疗效。为了能够为患者带来更大的生存获益，探索该两种药物的联合治疗方案是否可以进一步增强PARP抑制剂或抗血管生成单药疗效的临床研究也正在进行中。
（一）、抗血管药物在卵巢癌中的应用
血管生成是癌症的6大特征之一(1)，血管生成促进肿瘤相关新血管系统的产生，提供营养和氧气，排出代谢废物和二氧化碳。在卵巢癌症中，血管生成诱导腹水形成和多发转移扩散，促进肿瘤进展并导致预后不良(2)。因此血管生成已经成为癌症靶向治疗的重要焦点。
抗血管生成药物是卵巢癌治疗史上的最早的靶向药物，无特定的生物标志物，抗血管生成药物按照作用机制主要分为3大类：靶向VEGF/VEGFR通路药物，如贝伐珠单抗(3)、TKIs（tyrosine kinase inhibitors）药物，如nintedanib(4, 5)、sunitinib(6)、pazopanib(7, 8)、cediranib(9, 10)、sorafeni(11)及其他抗管药物如trebananib(12)。
贝伐珠单抗最具代表性的两个一线维持治疗的临床研究为ICON-7(13)和GOG-218(14)。在ICON7中，贝伐珠单抗7.5mg/kg维持用药12个周期，而GOG-218为贝伐珠单抗15mg/kg维持治疗16个周期。ICON7研究得出结论，贝伐珠单抗改善了卵巢癌症的PFS（贝伐组21.8个月 vs 对照组20.3个月，HR:0.81，95%CI 0.70-0.94，P=0.004）。此外，进展风险高的患者（FIGO IV期疾病或FIGO III期疾病，减瘤手术后残留疾病>1.0cm）从贝伐珠单抗维持治疗中获益最多，贝伐珠单抗组PFS为18.1个月vs 对照组14.5个月，OS分别为36.6和28.8个月。因此，贝伐珠单抗在高危进展风险患者中延长了3.6个月的中位PFS(13)。GOG-218主要关注高危进展风险患者，发现贝伐珠单抗在卵巢癌症中延长了中位PFS约4个月，进展风险降低了28%。这些临床研究的一致性表明，进展风险高的患者可能是一线贝伐珠单抗的理想获益患者(14)。
（二）、PARPi在卵巢癌中的应用
聚ADP-核糖聚合酶抑制剂（PARPi）的诞生促进卵巢癌的治疗发生重大变革，开启了卵巢癌维持治疗的新时代。PARPi的抗肿瘤活性主要通过合成致死机制发挥作用。在同源重组缺陷（HRD）的肿瘤中，PARPi对PARP的抑制会导致无法准确修复的双链DNA断裂的积累，从而导致合成致死(15, 16)。BRCA1和BRCA2通过同源重组在DNA双链断裂修复中起着至关重要的作用，高级别浆液性卵巢癌患者BRCA1/2突变的发生率为20-25%(17-20)。HRD不限于BRCA突变的肿瘤，约50%的高级别浆液性卵巢肿瘤存在HRD(17)。目前我国临床上常见的PARPi有奥拉帕利，尼拉帕利，氟唑帕利，帕米帕利。
奥拉帕利最具代表性的一线维持治疗的临床研究为SOLO1(21)，铂敏感复发性卵巢癌的维持治疗的研究为SOLO2(22)，尼拉帕利最具代表性一线维持治疗的研究为PRIMA(23)，铂敏感复发性卵巢癌维持治疗的研究为NOVA(24)，氟唑帕利的代表性研究为FZOCUS-3(25)，帕米帕利的代表性研究为BGB-290-102(26)。但是在BRCA野生型尤其HRD（-）卵巢癌患者，无论一线维持或是铂敏感复发后维持，各种PARPi的获益均相对较低。
（三）、抗血管药物联合PARPi在卵巢癌中的应用
基础研究表明血管生成抑制剂与PARPi联合应用显示出叠加作用，即1+1 > 2。缺氧诱导同源重组修复基因如BRCA1和RAD51的下调，可增强PARPi的敏感性(27, 28)。一项II期试验比较了西地尼布联合奥拉帕利与单独奥拉帕利治疗复发性铂敏感卵巢癌的疗效(29)。接受西地尼布联合奥拉帕利治疗的患者中位PFS为17.7个月，而接受奥拉帕利单药治疗的患者为9.0个月（HR:0.42，95%CI: 0.23-0.76，P=0.005）。单药奥拉帕利的ORR为47.8%，而西地尼布联合奥拉帕利为79.6%（OR:4.24，95%CI:1.53-12.22，P=0.002）。潜在机制可能是，西地尼布可增加肿瘤缺氧，并抑制血小板衍生生长因子受体下调BRCA1/2和RAD51，减少同源重组修复缺陷，增加奥拉帕利敏感性(30)。奥拉帕利/西地尼布组约70%的患者出现3/4级毒性。NSGO-AVANOVA2/ENGOT-ov24 II期试验研究了尼拉帕利联合贝伐珠单抗对铂敏感复发性卵巢癌的疗效(31)。在铂敏感复发性卵巢癌症患者中，尼拉帕利联合贝伐珠单抗的中位PFS为11.9个月，而单药尼拉帕利组患者中位PFS则为5.5个月（HR:0.35，95%CI 0.21-0.57，P<0.0001）。65%接受尼拉帕利+贝伐珠单抗治疗的患者和45%接受单药尼拉帕利治疗的患者发生3级或更严重的不良事件。上述抗血管药物联合PARPi用药方案需要进一步大样本的三期试验。III期试验PAOLA-1评估了奥拉帕利联合贝伐珠单抗作为一线维持治疗新诊断、晚期、高级别卵巢癌症的效果(32)。奥拉帕利联合贝伐珠单抗组的中位PFS为22.1个月，安慰剂联合贝伐珠珠单抗组为16.6个月（HR:0.59，95%CI 0.49-0.72，P<0.001）。利用BRCA突变与否和HRD状态进行亚组分析，包括BRCA突变在内的HRD阳性患者的中位PFS分别为37.2和17.7个月（HR:0.33，95%CI:0.25-0.45）。在BRCA野生型的HRD阴性患者中，中位PFS为28.1和16.6个月（HR:0.43，95%CI:0.28-0.66）。在贝伐珠单抗中加入奥拉帕利不会增加贝伐珠单抗的已知毒性。奥拉帕利联合贝伐珠单抗作为一线维持治疗为HRD阳性患者提供了显著的PFS获益。
抗血管生成药物联合PARPi是一种新的治疗选择，两者强强联合发挥强效作用。当前最重要的是要确定哪些患者是单药治疗或联合治疗的最佳人群；同时，这需要考虑单药或联合治疗的安全性、肿瘤生物标志物、经济、毒性、患者偏好以及临床中治疗方案选择的顺序。后续还应关注抗血管生成和PARPi治疗的固有和适应性耐药机制，为卵巢癌患者获得长期高质量生存提供保障。
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