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卵巢癌铂耐药:PFI“二分法”的局限性与可能的改进

李笑宇, 张楠, 狄文

李笑宇, 张楠, 狄文. 卵巢癌铂耐药:PFI“二分法”的局限性与可能的改进[J]. 肿瘤防治研究, 2024, 51(10): 813-819. DOI: 10.3971/j.issn.1000-8578.2024.24.0677
引用本文: 李笑宇, 张楠, 狄文. 卵巢癌铂耐药:PFI“二分法”的局限性与可能的改进[J]. 肿瘤防治研究, 2024, 51(10): 813-819. DOI: 10.3971/j.issn.1000-8578.2024.24.0677
LI Xiaoyu, ZHANG Nan, DI Wen. Platinum Resistance in Ovarian Cancer: Limitations of PFI Binary Classification and Potential Improvements[J]. Cancer Research on Prevention and Treatment, 2024, 51(10): 813-819. DOI: 10.3971/j.issn.1000-8578.2024.24.0677
Citation: LI Xiaoyu, ZHANG Nan, DI Wen. Platinum Resistance in Ovarian Cancer: Limitations of PFI Binary Classification and Potential Improvements[J]. Cancer Research on Prevention and Treatment, 2024, 51(10): 813-819. DOI: 10.3971/j.issn.1000-8578.2024.24.0677

卵巢癌铂耐药:PFI“二分法”的局限性与可能的改进

详细信息
    作者简介:

    李笑宇(2001-),女,博士在读,主要从事妇产科临床与基础研究,ORCID: 0009-0002-7987-9320

    张楠(1989-),女,博士,主治医师,主要从事妇科肿瘤的基础和临床研究,ORCID: 0000-0002-8996-6105

    狄文: 上海交通大学医学院附属仁济医院主任医师,教授,博士生导师,上海市妇科肿瘤重点实验室主任,中国医师协会妇产科医师分会会长,中华医学会妇产科学分会副主任委员,上海市医师协会妇产科医师分会会长,上海市母婴安全专家委员会主任委员,《中华妇产科杂志》副总编,《中国实用妇科与产科杂志》和《上海医学》副主编以及多家杂志编委。担任国家卫生健康委员会住院医师规范化培训规划教材《妇产科学》、国家卫生和计划生育委员会“十三五”英文版规划教材全国高等学校教材《妇产科学》等多本教材主编。  获2010年教育部科技进步二等奖、2022年中华医学科技奖二等奖、2022年上海市科学技术奖一等奖、2018年上海医学科技奖一等奖、2009年上海医学奖二等奖及2009年上海科技进步三等奖。所编教材荣获2009年上海交通大学第十二届优秀教材特等奖、2011年上海市高校优秀教材二等奖、2015年上海普通高校优秀教材奖。2008年入选上海市科委优秀学科带头人培养计划、2011年入选上海市领军人物 。

    通信作者:

    狄文(1960-),男,博士,主任医师,教授,主要从事妇产科临床与基础研究,E-mail: diwen163@163.com,ORCID: 0000-0003-4007-3856

    *并列第一作者

  • 中图分类号: R737.31

Platinum Resistance in Ovarian Cancer: Limitations of PFI Binary Classification and Potential Improvements

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  • 摘要:

    卵巢癌是一种较为常见的妇科恶性肿瘤,临床上主要通过无铂间期将复发性卵巢癌分为铂耐药性与铂敏感性,分别对应不同的治疗方式及预后。铂耐药性卵巢癌的治疗十分困难,随着研究的深入,有学者提出根据无铂间期的“二分法”存在一定局限性。因此,本文将对复发性卵巢癌的分类、铂耐药性卵巢癌的治疗困境、无铂间期“二分法”的局限性与新的分类思路作一综述,帮助临床工作者更好地了解卵巢癌分类方面的研究进展,从而制定更加有效的治疗策略。

     

    Abstract:

    Ovarian cancer is a common gynecologic malignancy. In clinical practice, recurrent ovarian cancer is mainly classified into two categories on the basis of platinum-free interval, platinum-resistant and platinum-sensitive, corresponding to different treatment modalities and prognoses. The treatment of platinum-resistant ovarian cancer is challenging. Some scholars have pointed out limitations in the binary classification of platinum-free interval. In this article, the classification of recurrent ovarian cancer, the treatment challenges of platinum-resistant ovarian cancer, the limitations of the platinum-free interval binary classification, and new classification perspectives were reviewed to help physicians enhance their understanding on the research progress in ovarian cancer classification and develop more effective treatment strategies.

     

  • 据2020年全球癌症报告显示,肝癌是中国第五大常见恶性肿瘤,我国新发病例数与死亡病例数约占全球50%,其中肝细胞癌(HCC)占我国原发性肝癌的90%[1]。由于肝癌早期诊断不足,绝大多数患者确诊时已到中晚期,超过60%的患者在晚期发生转移后被确诊,导致总体5年生存率 < 16%[2]。相比之下,肝癌早期的患者生存期有较大改善,早期治疗可以显著逆转疾病的进展并延长生存时间,使5年生存率 > 70%[3]。据统计,2020年亚洲地区中国的肝癌死亡率(17.2/10万)最高,日本的肝癌死亡率(4.8/10万)显著低于全球平均水平[4],可能得益于日本对肝癌早诊早治的重视。日本早在2002年开始由政府资助对40岁以上人群进行HBV和HCV感染筛查,并对HCV和HBV感染者进行定期肝癌筛查,故而肝癌早期诊断率在60%以上[5]。为达成“健康中国2030”规划纲要中总体癌症5年生存率提高15%的目标,我国肝癌早筛早诊工作任重道远。

    目前,肝脏超声(US)和血清甲胎蛋白(AFP)检测在肝癌的早期筛查中达到普遍应用,但效果并不满意。肝脏超声敏感度为51%~87%,特异性为80%~100%,易受观察者主观影响,且对病灶大小要求高[6]。AFP作为肝癌的特异性肿瘤标志物,在妊娠状态、生殖细胞肿瘤和良性肝病的患者中亦可升高,缺乏足够的敏感度[7]。随着液体活检技术和成像技术的发展,研究者不断钻研以寻求肝癌早期无创诊断的突破点,现就肝癌无创早期诊断的研究进展作一综述。

    AFP是临床上应用最广泛的肝癌标志物,AFP存在3种糖链异质体,其中AFP异质体(alpha fetoprotein heterogeneity, AFP-L3)主要来源于肝癌细胞,并且AFP-L3与AFP的比值(AFP-L3%)是肝癌早期诊断的高特异性标志物。相关专家共识[8]提出针对低AFP水平人群,AFP-L3可以对肝癌进行预测及早期诊断,并把AFP-L3%≥10%界定为肝癌诊断的阳性截断值。Zhou等[9]荟萃分析显示AFP-L3%对诊断早期HCC具有高特异性(92%),但敏感度低(34%),应更加重视AFP-L3%诊断早期HCC的高特异性优势,这是未来AFP-L3%临床应用发展的主要方向。该研究基于检测AFP-L3%的不同方法进行了亚组分析,结果表明微总量分析系统(μTAS)是提高检测灵敏度的最佳方法,可能为HCC的诊断提供更有利的结果。周何琪等[10]研究表明单一标志物难以获得最优的诊断效能,对AFP阴性的肝癌人群联合检测AFP-L3%与血清异常凝血酶原(PIVKA-Ⅱ)具有较理想的敏感度,有效减少肝癌的漏诊率,为肝癌的诊断提供了新策略。

    脱-γ-羧基凝血酶原(des-gamma carboxy prothrombin, DCP),又称为维生素K缺乏诱导的凝血酶原-Ⅱ(PIVKA-Ⅱ),是一种在肝癌中产生的异常蛋白质。肝细胞中的凝血酶原由氨基酸残基构成,凝血酶原前体经过维生素K依赖性γ-谷氨酰羧化酶羧化氨基酸残基合成凝血酶原。肝癌细胞缺乏羧化酶,不能羧化所有的氨基酸残基,产生DCP,在肝癌患者中DCP大多异常地升高[11]。有研究[12-13]支持DCP和AFP联合在HCC中具有更好的诊断效果,高水平的DCP在预测肿瘤大小、门静脉栓塞和血管侵犯方面比AFP更有利。基于性别、年龄、AFP-L3、AFP、DCP,研究者构建了GALAD评分,多个国家研究发现GALAD评分在慢性乙型和丙型肝炎以及肝硬化患者中具有识别早期肝癌的优异性能,并被指南推荐认可[14-16]

    磷脂酰肌醇聚糖-3(glypican-3, GPC-3)是一种细胞表面硫酸肝素蛋白多糖。相关研究在HCC细胞和组织中发现高度表达的GPC-3,通过调控Wnt信号转导通路来控制HCC细胞增殖,从而影响肿瘤的生长和转移[17]。一项荟萃分析[18]评估了GPC-3在HCC和肝硬化病例之间鉴别诊断的准确性,结果显示血清GPC-3在HCC和肝硬化中的诊断效能虽然不如AFP,但GPC-3和AFP二者联合有着比单一GPC-3或AFP更好的诊断效能,建议GPC-3与其他标志物联合检测。基于GPC-3在HCC细胞的膜表达,GPC-3可被用作治疗干预的靶标。迄今为止,开发了各种针对GPC-3的免疫治疗方案,包括使用人源化抗GPC3细胞毒抗体、免疫毒素疗法和基因疗法,因此GPC-3具有广阔的临床应用前景[19]

    α-L-岩藻糖苷酶(α-L-fucosidase, AFU)是一种溶酶体酶,自Deugnier等首次报告AFU在肝癌患者血清中升高,AFU作为早期诊断肝癌的指标被人们逐渐认识[20]。Liu等[21]首次对乙肝表面抗原和丙肝抗体阴性的肝癌患者(NBNC-HCC)的血清生物标志物进行大规模回顾性分析,评估了5种血清生物标志物(AFP、AFU、GPC-3、γ-谷氨酰转移酶同工酶Ⅱ和肝细胞生长因子)在HCC诊断中的潜力,结果显示AFP/AFU组合具有较好的诊断效能,可用于从健康对照中识别NBNC-HCC,并且从高危患者中及早识别肝炎相关HCC。

    微小核糖核酸(miRNA)是一类单链非编码小RNA,可调控特定的靶基因表达水平,参与机体新陈代谢、凋亡、肿瘤发生等过程。一项横断面研究[22]证实miRNA 21-5p和miRNA 155-5p在肝癌中表现为上调,是肝癌的致癌因子,miRNA 29c-3p则表现为下调,具有抑癌作用,表明miRNAs参与肿瘤发生发展并发挥抑癌基因或癌基因的作用。Wang等[23]发现HCC中miR-122、miR-148a和miR-1246的血清外泌体水平显着高于肝硬化和正常者,与慢性肝炎患者差异不大,因此仍需要进一步研究区分肝癌和慢性肝炎的标志物。近年大多数研究不再集中在单个miRNAs上,一些新兴组合模型成为研究的热点,包括用于HCC诊断的多种miRNAs组合或者与其他传统肿瘤标志物结合的诊断模型。吕金明等[24]分析比较了肿瘤标志物AFP、癌胚抗原(CEA)及血清miR-122水平在乙肝、肝硬化、早期肝癌患者中的变化。与AFP、CEA单独检测相比,血清miR-122联合AFP、CEA检测对早期肝癌的诊断效能明显提高,说明miR-122可作为早期肝癌的诊断指标。Zhou等建立了由7种miRNA(miR-122、miR-192、miR-21、miR-223、miR-26a、miR-27a和miR-801)组成的血清标志物组合,在早期肝癌检测上敏感度较AFP提高30%,并且利用这7种miRNA开发了国际首个miRNA肝癌检测试剂盒,目前在临床上已开展应用并被肝癌诊疗指南所认可推荐[25-26]

    循环肿瘤DNA(ctDNA)是一种源于肿瘤细胞(原发肿瘤及转移肿瘤)释放到循环中的循环无细胞DNA(cfDNA)。早在肿瘤能被影像学检测到或引起临床症状之前,肿瘤细胞就会将带有遗传物质的ctDNA释放循环中去,因此ctDNA有望成为癌症检测的生物标志物[27]。血浆中ctDNA的变化包括量变及质化,前者是指总ctDNA浓度,后者是指DNA畸变,如单核苷酸变异、拷贝数异常和甲基化变化[28]。肿瘤患者cfDNA水平和ctDNA拷贝数的增加是由循环中凋亡和坏死肿瘤细胞数量的增加所致。Yan等[29]研究发现血浆cfDNA水平不仅在HCC患者中升高,在伴有严重炎性反应的肝纤维化患者中也升高,但HCC患者血浆cfDNA水平与肝纤维化患者相比明显升高。多项研究[30-31]表明肝癌患者血清或血浆中的cfDNA浓度比慢性肝炎患者高3~4倍,是健康对照组的近20倍。甲基化在肿瘤进展中扮演着重要角色,是常见的表观遗传变化。一项荟萃分析[32]系统评估了肝癌中DNA甲基化的作用,在针对HCC患者血清和健康者血清的病例对照研究中,发现六个HCC相关基因(RASSF1A、p16、CDH1、RUNX3、GSTP1和WIF1)高甲基化与患HCC风险显著相关,推测异常甲基化DNA可能成为预测肝癌发生的标志物。Xu等[33]通过分析比较HCC组织和正常血液中的ctDNA,并构建了一个HCC特异性甲基化标志物组诊断预测模型,该模型显示出优于AFP的诊断性能,并显示ctDNA甲基化标志物与肿瘤负担、治疗反应和分期高度相关。ctDNA特异性基因改变在一定程度上也反映了肿瘤的生物学特性,在血浆DNA中检测到的热点突变几乎总是与相应肿瘤中检测到的相同突变相关。一项研究[34]通过应用高通量测序平台从ctDNA中检测HCC中的肿瘤相关突变,使用二代测序技术(NGS)研究TERT启动子、CTNNB1和TP53中的热点突变,在主要乙型肝炎病毒阳性队列中的8/41(约20%)血浆样本中检测到肿瘤相关突变,表明ctDNA中的遗传信息反映了原发肿瘤的状况,为ctDNA在肝癌诊断预测中的作用提供了相关证据支持。但循环ctDNA在血液中表达水平低,且仅占总cfDNA的一小部分(< 0.01%),使得在HCC筛查中建立ctDNA相关的早期诊断检测仍具有挑战性,克服早期肝癌中cfDNA中ctDNA含量低所带来的挑战至关重要[35]

    骨桥蛋白(osteopontin, OPN)是一种新型的血清生物标志物,是近些年来研究的热点。OPN是一种糖蛋白,由成骨细胞T细胞、巨噬细胞分泌,在多种肿瘤中高表达,参与了肿瘤细胞增殖、存活、血管生成、侵袭和转移[36]。一项纳入80例丙型肝炎病毒(HCV)相关HCC患者的研究[37]发现HCC组血清OPN水平显着高于正常组,是一种潜在的肿瘤标志物,有望在慢性HCV感染导致的肝硬化患者中监测OPN表达水平,以便在早期阶段监测HCC的发生,从而改善这些患者的预后和生存率。一项荟萃分析[38]证实OPN在诊断HCC方面的敏感度高于AFP,AFP联合OPN可经进一步提高早期HCC诊断的敏感度。张洪川等[39]研究证实肝癌组织中的骨桥蛋白阳性表达率显著高于正常组织与不典型增生组织,可见骨桥蛋白可预测肝癌的发生。

    醛酮还原酶家族1成员B10(aldo-keto reductase family 1 member B10, AKR1B10)通过催化脂肪族和芳香族醛的还原,调节细胞增殖和分化中的重要信号分子,在HCC发生发展中发挥调控作用,但早期HCC患者中AKR1B10的表达模式尚不清楚[40]。最近一项多中心研究[41]验证了AKR1B10作为检测HCC的标志物,与健康对照组相比,HCC患者血清样本中的AKR1B10水平高出18倍以上((1567.3±292.6)pg/ml vs.(85.7±10.9)pg/ml),并确定了267.9 pg/ml为血清AKR1B10的最佳诊断截止值。血清AKR1B10的曲线下面积(AUC)0.896、敏感度72.7%和特异性95.7%比AFP(AUC 0.816、敏感度65.1%和特异性88.9%)具有更好的诊断参数,在检测AFP阴性HCC方面具有优势。将AKR1B10和AFP二者联合起来用于诊断HCC,结果显示HCC诊断的敏感度和阴性预测值较单独使用AFP显著提高。AKR1B10表达也与病毒性肝炎发展为HCC风险相关,在一项针对获得持续病毒学应答(SVR)的慢性丙型肝炎(CHC)患者的研究中,AKR1B10高表达是HCC发展的独立危险因素,HCC发展的5年累积发生率在AKR1B10高表达组与AKR1B10低表达组分别为13.7%和0.5%。因此,AKR1B10不仅是一种癌症生物标志物,而且还是一种新的预测标志物,用于评估实现SVR的CHC患者发生HCC的风险[42]

    与其他大多数恶性肿瘤不同,HCC可以通过无创性检查诊断,并且可以仅根据影像学开始治疗,无需通过活检证实[43]。在当前大多数临床实践指南中,增强计算机断层扫描(CT)和磁共振成像(MRI)已取代活检作为诊断具有特征性成像特征HCC的首选方法[44]。除了使用细胞外造影剂的动态CT和MRI外,现在更新的指南还包括使用肝胆造影剂的磁共振成像作为一线诊断筛查,超声造影(CEUS)作为二线诊断筛查[45]

    肝胆造影剂由两种基于钆的造影剂(GBCA)组成,分别为钆塞酸二钠(Gd-EOB-DTPA)和钆基二甘胺,包含传统GBCA和肝胆造影剂的双重性质[45]。Gd-EOB-DTPA具有亲脂性EBO基团,可被肝脏细胞特异性吸收,具有50%的吸收率,注射后10~40分钟呈现肝胆特异性成像。正常肝细胞呈现明显强化,而癌前病变或恶性肝细胞肿瘤的功能减弱或缺失,因此在该期中呈低增强,出现早于肝癌发生的血流动力学变化,有助于肝脏局灶性病变的发现同时判断病灶良恶性,特别是在直径 < 1.0 cm的微小病灶诊断中显示出优势[46]。Gd-EOB-DTPA可提高直径≤1.0 cm肝癌的检出率,对高度异型增生结节等癌前病变也有鉴别力[47]。2022年原发性肝癌诊疗指南[26]推荐了钆塞酸二钠增强磁共振(EOB-MRI)作为肝癌诊断的影像学检查方法。

    与常规超声检查相比,超声造影(CEUS)可实现对组织的微血管灌注情况动态、实时连续的观察,能够更好地发现病变并且对病变良恶性质的判定有一定价值,具有无创、无辐射、易重复、安全性高的特点。一项前瞻性多中心研究[48]发现,对于10~20 mm HCC的诊断,CEUS显示出比CT(76.8%)和MRI(83.2%)更高的特异性,为92.9%。基于肝脏影像报告和数据管理系统(LI-RADS),相关学者建立了CEUSLI-RADS,有助于肝脏肿瘤的分级诊断,特别是能对肝硬化背景下的肝内结节动态监测其发生发展趋势[49]。一项回顾性研究显示CEUS LI-RADS对肝内结节具有出色的诊断性能,可以准确区分恶性肿瘤和良性结节,其中LR-5级对HCC诊断的敏感度、特异度分别为86%、96%,以此实现无需进行病理确认即可对HCC进行可靠的影像诊断[50]

    肠道微生物群通过肠-肝轴使肠道和肝脏建立紧密联系,肠道微生物可通过肠道菌群失调、肠道渗漏、细菌代谢产物促进慢性肝病逐渐向肝纤维化、肝硬化、肝癌进展[51]。肠道微生物群失调会导致肠道通透性增加,肠道屏障被破坏,出现肠道渗漏,最终导致微生物易位和增加肝脏对微生物群衍生产物和代谢物的暴露。肠道微生物释放的毒素,如脂多糖(LPS)可被Toll样受体4(TLR4)特异性识别并释放炎性介质(IL-1、IL-6和肿瘤坏死因子),通过免疫调控从而促进肝癌发生[52]。目前,通过二代测序技术(如16S rDNA基因测序、鸟枪法宏基因组学)或代谢组学分析技术,对健康人群和HCC患者的粪便样本进行分析,发现某些肠道微生物及其相关代谢产物可能具有诊断HCC的潜力[53]。Ponziani等[54]探索发现合并HCC的非酒精性脂肪性肝病(NAFLD)相关肝硬化患者肠道菌群中缺乏保护性细菌,肠道炎性反应加重,作为肠道炎性反应标志物的粪便盖卫蛋白升高证实了这一点,认为肠道微生物群谱和全身炎性反应显著相关,可形成促使肝癌发生的局部微环境。NAFLD是全球肝癌的第三大病因,针对这类肝癌高危人群,是否能通过肠道微生物早期识别肝癌的发生并阻止或延缓疾病的进展仍需要进一步探索。Ren等[55]研究发现,早期HCC粪便微生物多样性增加,产生LPS的细菌丰度增加, 表明HCC患者中各种有害细菌或古生菌过度生长。同时该研究首次对HCC患者的肠道微生物组进行了表征分析,从中筛选出30种最佳微生物标志物,构建了HCC诊断模型,并验证了肠道微生物作为早期HCC非侵入性标志物的潜力。肠道菌群谱受各种因素影响,不同地区、不同病因、不同营养摄入水平使得肠道微生物谱变化各有差异,这些差异限制了肠道微生物模型的广泛应用,仍需针对不同人群进行验证性实验。

    一直以来,肝癌的早期诊断是肝癌诊疗中的一大挑战,早期预测肝癌的发生给疾病的预后和结局带来明显的改善。目前肝癌早期无创诊断在生物标志物、成像技术、微生物组等方面的研究取得的成效显著,但未发现独立的肝癌筛查工具,建议使用多种生物标志物组合与成像技术、微生物组相结合,建立一个标准化、规范化的早癌筛查体系。同时现有的研究多是单中心小样本研究,受地区、人群、肿瘤异质性等各种因素所限制,研究成果尚未能在临床推广,未来仍需开展多中心大规模的前瞻性研究来获得更有力的证据。如今随着健康体检的推行,肝癌普查的模式也有所改变,传统普遍采用AFP结合B型超声的筛查方式效率低下,目前指南提出根据对人群患肝癌风险进行评估,精准化分层制定肝癌筛查与监测方案[56],对提高肝癌早期诊断率意义重大。

    Competing interests: The authors declare that they have no competing interests.
    利益冲突声明:
    所有作者均声明不存在利益冲突。
    作者贡献:
    李笑宇:资料收集、文章撰写
    张 楠:文章修改
    狄 文:指导及审阅文章
  • 表  1   近年来关于铂耐药性卵巢癌治疗的临床研究

    Table  1   Recent clinical studies on the treatment of platinum-resistant ovarian cancer

    Study Time Medication PFI Result
    McGuire WP, et al[16] 2009-2019 Olaratumab plus
    liposomal doxorubicin
    versus liposomal
    doxorubicin alone
    PFI<12 months PFS: 18.1(8.7-27.0) versus 17.3(14.1-31.9)
    OS: 72.3(52.4-86.7) versus 70.6(51.4-106.4)
    ORR: 12.9%(6.6-22.1) versus 16.4%(9.2-26.2)
    DOR: 39.1(26.1-56.1) versus 16.9(15.3-NA)
    Gaillard S, et al[17] 2015-2018 Lurbinectedin versus
    pegylated liposomal
    doxorubicin or
    topotecan
    PFI 1-6 months PFS: 3.5(2.1-3.7) versus 3.6(2.7-3.8)
    OS: 11.4(9.0-14.2) versus 10.9(9.3-12.5)
    ORR: 14.5%(10.1-19.8) versus 12.7%(8.6-17.8)
    DOR: 4.0(1.9-5.7) versus 3.7(3.6-7.2)
    McNeish IA, et al[18] 2010-2015 Saracatinib plus
    paclitaxel versus
    placebo plus
    paclitaxel
    PFI<6 months PFS: 29(22-37) versus 34(23-46)
    OS: 10.1(8.3-16.2) versus 12.3(11.0-14.4)
    ORR: 29 versus 43
    QoL: 66.9(1.89) versus 73.1(2.56)
    Liu JF, et al[19] 2011-2016 MM121 plus paclitaxel
    versus paclitaxel alone
    Platinum resistant
    or refractory
    PFS: 3.8(3.48-4.63) versus 3.7(2.56-5.52)
    OS: 13.7(8.77-NA) versus 10.1(8.77-NA)
    Pujade-Lauraine E,
    et al[20]
    2015-2019 Avelumab alone
    versus avelumab plus
    liposomal doxorubicin
    versus liposomal
    doxorubicin alone
    PFI<180 days OS: 11.8 (8.9-14.1) versus 15.7
    (12.7-18.7) versus 13.1 (11.8-15.5)
    PFS: 1.9 (1.8-1.9) versus 3.7
    (3.3-5.1) versus 3.5 (2.1-4.0)
    ORR: 3.7% (1.5-7.5) versus 13.3%
    (8.8-19.0) versus 4.2% (1.8-8.1)
    DOR: 9.2 (6.4-NA) versus 8.5
    (6.1-NA) versus 13.1 (5.5-NA)
    DCR: 33.0% (26.3-40.2) versus 57.4%
    (50.0-64.6) versus 48.9% (41.6-56.3)
    Pujade-Lauraine E,
    et al[21]
    2010-2014 Volasertib versus
    chemotherapy
    Platinum resistant
    or refractory
    DCR: 30.6% (18.0-43.2) versus 43.1% (29.5-56.7)
    PFS: 13.1 (6.6-30.1) versus 20.6 (11.6-30.7)
    OS: 60.1 (31.3-95.4) versus 68.6 (28.7-119.4)
    Pujade-Lauraine E,
    et al[14]
    2009-2015 Chemotherapy versus
    chemotherapy plus
    bevacizumab
    PFI<6 months PFS: 3.4 (2.10-3.75) versus 6.8 (5.62-7.79)
    ORR: 12.5% (7.1-17.9) versus 28.2% (20.8-35.6)
    DOR: 5.4 (3.81-9.23) versus 9.4 (6.60-11.63)
    OS: 9.4 (6.60-11.63) versus 16.6 (13.70-18.99)
    Lorusso D, et al[22] 2012-2016 Pertuzumab plus
    chemotherapy versus
    placebo plus
    chemotherapy
    Platinum resistant
    or refractory
    PFS: 4.3 (3.65-6.11) versus 2.7 (2.14-4.73)
    ORR: 14.8% (7.0-26.2) versus 8.7% (3.3-18.0)
    OS: 10.2 (6.67-15.24) versus 8.4 (6.14-11.99)
    Morre KN, et al[15] 2015-2020 Mirvetuximab
    soravtansine
    versus chemotherapy
    PFI<6 months PFS: 4.1 (3.75-4.53) versus 4.4 (2.83-5.59)
    ORR: 22 (17.2-27.9) versus 12 (6.6-19.1)
    OS: 15.6 (12.85-18.04) versus 13.9 (11.40-18.50)
    CA125 react: 51 (44.1-58.3) versus 27 (17.6-37.8)
    DOR: 5.7 (4.17-8.51) versus 7.3 (4.14-NA)
    下载: 导出CSV

    表  2   既往使用过其他治疗对复发时间及再次复发后治疗疗效的影响

    Table  2   Effect of previous use of other treatments on time to recurrence and efficacy of subsequent treatment after recurrence

    Study Previous treatment Treatment after recurrent Patient characteristic Result
    Cecere SC, et al[32] Olaparib after platinum-based chemotherapy Platinum-based chemotherapy PFI>12 months versus 6<PFI≤12 months versus PFI<6 months ORR: 22.2% versus 11.1% versus 9.5%
    Baert T, et al[33] Olaparib or no olaparib after platinum-based chemotherapy Platinum-based chemotherapy PARPi treatment before versus no PARPi treatment before DPR: 40% versus 9%
    Rose PG, et al[34] Olaparib or no olaparib after platinum-based chemotherapy Platinum-based chemotherapy PARPi treatment before versus no PARPi treatment before PFS: 8.0 versus 19.1 month (HR=4.01, 95%CI: 2.25-7.16, P<0.001)
    Frenel JS, et al[35] Olaparib or placebo after platinum-based chemotherapy Platinum- or non-platinum-based chemotherapy Placebo before versus olaparib before (All patients) TTSP: 12.1 versus 6.9 month (HR=2.17, 95%CI: 1.47-3.19)
    (Patients with platinum-based chemotherapy) TTSP: 14.3 versus 7.0 (HR=2.89, 95%CI: 1.73-4.82)
    Himoto Y, et al[36] New adjuvant chemotherapy / PDS versus NACT-IDS NACT-IDS is associated with shorter time to recurrence (P=0.017, HR=1.57)
    Ekmann-Gade AW,
    et al[37]
    New adjuvant chemotherapy / PDS versus NACT-IDS TFI: 372 days versus 497 days, P=0.042
    Luo Y, et al[38] New adjuvant chemotherapy / PDS versus NACT-IDS Number of platinum-resistant diseases: 99/283 (35%) versus 29/58 (50%, OR=2.950, P=0.001)
    Petrillo M, et al[39] New adjuvant chemotherapy / PDS versus NACT-IDS PFI: 13 versus 21; P=0.014 Proportion of platinum-resistant diseases: 35.9% versus 5.0%; P=0.006
    Note: TTSP: time to symptomatic progression.
    下载: 导出CSV
  • [1]

    Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. doi: 10.3322/caac.21834

    [2]

    Stewart C, Ralyea C, Lockwood S. Ovarian Cancer: An Integrated Review[J]. Semin Oncol Nurs, 2019, 35(2): 151-156. doi: 10.1016/j.soncn.2019.02.001

    [3]

    Wilson MK, Pujade-Lauraine E, Aoki D, et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease[J]. Ann Oncol, 2017, 28(4): 727-732. doi: 10.1093/annonc/mdw663

    [4]

    Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin[J]. J Clin Oncol, 1991, 9(3): 389-393. doi: 10.1200/JCO.1991.9.3.389

    [5]

    Friedlander M, Trimble E, Tinker A, et al. Clinical trials in recurrent ovarian cancer[J]. Int J Gynecol Cancer, 2011, 21(4): 771-775. doi: 10.1097/IGC.0b013e31821bb8aa

    [6]

    Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. Ovarian Cancer, Version 2. 2020, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2021, 19(2): 191-226.

    [7]

    Havasi A, Cainap SS, Havasi AT, et al. Ovarian Cancer-Insights into Platinum Resistance and Overcoming It[J]. Medicina (Kaunas), 2023, 59(3): 544. doi: 10.3390/medicina59030544

    [8]

    Davis A, Tinker AV, Friedlander M. "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit?[J]. Gynecol Oncol, 2014, 133(3): 624-631. doi: 10.1016/j.ygyno.2014.02.038

    [9]

    da Costa AABA, Dos Santos ES, Cotrim DP, et al. Prognostic impact of platinum sensitivity in ovarian carcinoma patients with brain metastasis[J]. BMC Cancer, 2019, 19(1): 1194. doi: 10.1186/s12885-019-6382-x

    [10]

    Baert T, Ferrero A, Sehouli J, et al. The systemic treatment of recurrent ovarian cancer revisited[J]. Ann Oncol, 2021, 32(6): 710-725. doi: 10.1016/j.annonc.2021.02.015

    [11]

    St Laurent J, Liu JF. Treatment Approaches for Platinum-Resistant Ovarian Cancer[J]. J Clin Oncol, 2024, 42(2): 127-133. doi: 10.1200/JCO.23.01771

    [12]

    Pejovic T, Fitch K, Mills G. Ovarian cancer recurrence: “is the definition of platinum resistance modified by PARP inhibitors and other intervening treatments?”[J]. Cancer Drug Resist, 2022, 5(2): 451-458. doi: 10.20517/cdr.2021.138

    [13]

    Richardson DL, Eskander RN, O'Malley DM. Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance: A Narrative Review[J]. JAMA Oncol, 2023, 9(6): 851-859.

    [14]

    Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase Ⅲ trial[J]. J Clin Oncol, 2014, 32(13): 1302-1308.

    [15]

    Moore KN, Vergote I, Oaknin A, et al. FORWARD Ⅰ: a Phase Ⅲ study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer[J]. Future Oncol, 2018, 14(17): 1669-1678. doi: 10.2217/fon-2017-0646

    [16]

    McGuire WP, Penson RT, Gore M, et al. Randomized phase Ⅱ study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer[J]. BMC Cancer, 2018, 18(1): 1292. doi: 10.1186/s12885-018-5198-4

    [17]

    Gaillard S, Oaknin A, Ray-Coquard I, et al. Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL)[J]. Gynecol Oncol, 2021, 163(2): 237-245. doi: 10.1016/j.ygyno.2021.08.032

    [18]

    McNeish IA, Ledermann JA, Webber L, et al. A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer[J]. Ann Oncol, 2014, 25(10): 1988-1995. doi: 10.1093/annonc/mdu363

    [19]

    Liu JF, Ray-Coquard I, Selle F, et al. Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer[J]. J Clin Oncol, 2016, 34(36): 4345-4353. doi: 10.1200/JCO.2016.67.1891

    [20]

    Pujade-Lauraine E, Fujiwara K, Dychter SS, et al. Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase Ⅲ study design[J]. Future Oncol, 2018, 14(21): 2103-2113. doi: 10.2217/fon-2018-0070

    [21]

    Pujade-Lauraine E, Selle F, Weber B, et al. Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase Ⅱ Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study[J]. J Clin Oncol, 2016, 34(7): 706-713. doi: 10.1200/JCO.2015.62.1474

    [22]

    Lorusso D, Hilpert F, González Martin A, et al. Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer[J]. Int J Gynecol Cancer, 2019, 29(7): 1141-1147. doi: 10.1136/ijgc-2019-000370

    [23]

    Champer M, Huang Y, Hou JY, et al. Adherence to treatment recommendations and outcomes for women with ovarian cancer at first recurrence[J]. Gynecol Oncol, 2018, 148(1): 19-27. doi: 10.1016/j.ygyno.2017.11.008

    [24]

    Lindemann K, Gao B, Mapagu C, et al. Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance[J]. Gynecol Oncol, 2018, 150(2): 239-246. doi: 10.1016/j.ygyno.2018.05.020

    [25]

    Tatsuki S, Shoji T, Abe M, et al. Efficacy and Safety of Platinum Rechallenge in Patients With Platinum-resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer: A Multicenter Retrospective Study[J]. Anticancer Res, 2022, 42(9): 4603-4610. doi: 10.21873/anticanres.15964

    [26]

    Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer[J]. N Engl J Med, 2019, 381(25): 2416-2428. doi: 10.1056/NEJMoa1911361

    [27]

    DiSilvestro P, Banerjee S, Colombo N, et al. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial[J]. J Clin Oncol, 2023, 41(3): 609-617. doi: 10.1200/JCO.22.01549

    [28]

    McMullen M, Karakasis K, Madariaga A, et al. Overcoming platinum and PARP-inhibitor resistance in ovarian cancer[J]. Cancers (Basel), 2020, 12(6): 1607. doi: 10.3390/cancers12061607

    [29]

    Park J, Kim SI, Jeong SY, et al. Second-line olaparib maintenance therapy is associated with poor response to subsequent chemotherapy in BRCA1/2-mutated epithelial ovarian cancer: A multicentre retrospective study[J]. Gynecol Oncol, 2022, 165(1): 97-104. doi: 10.1016/j.ygyno.2022.02.002

    [30]

    Liu J, Jiao X, Gao Q. Neoadjuvant chemotherapy-related platinum resistance in ovarian cancer[J]. Drug Discov Today, 2020, 25(7): 1232-1238. doi: 10.1016/j.drudis.2020.04.015

    [31]

    Lim MC, Song YJ, Seo SS, et al. Residual cancer stem cells after interval cytoreductive surgery following neoadjuvant chemotherapy could result in poor treatment outcomes for ovarian cancer[J]. Onkologie, 2010, 33(6): 324-330. doi: 10.1159/000313823

    [32]

    Cecere SC, Giannone G, Salutari V, et al. Olaparib as maintenance therapy in patients with BRCA 1-2 mutated recurrent platinum sensitive ovarian cancer: Real world data and post progression outcome[J]. Gynecol Oncol, 2020, 156(1): 38-44. doi: 10.1016/j.ygyno.2019.10.023

    [33]

    Baert T, Ataseven B, Bommert M, et al. 828P Expected observed response to platinum-based chemotherapy after poly (ADP-ribose) polymerase inhibitor treatment for relapsed ovarian cancer[J]. Ann Oncol, 2020, 31(Suppl 4): S624.

    [34]

    Rose PG, Yao M, Chambers LM, et al. PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer[J]. Anticancer Drugs, 2021, 32(10): 1086-1092. doi: 10.1097/CAD.0000000000001219

    [35]

    Frenel JS, Kim JW, Aryal N, et al. Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial[J]. Ann Oncol, 2022, 33(10): 1021-1028. doi: 10.1016/j.annonc.2022.06.011

    [36]

    Himoto Y, Cybulska P, Shitano F, et al. Does the method of primary treatment affect the pattern of first recurrence in high-grade serous ovarian cancer?[J]. Gynecol Oncol, 2019, 155(2): 192-200. doi: 10.1016/j.ygyno.2019.08.011

    [37]

    Ekmann-Gade AW, Hogdall CK, Engelholm SA, et al. Neoadjuvant Chemotherapy Reduces the Treatment-free Interval After First-line Treatment in Patients With Advanced Ovarian Cancer[J]. Anticancer Res, 2020, 40(5): 2765-2770. doi: 10.21873/anticanres.14248

    [38]

    Luo Y, Lee M, Kim HS, et al. Effect of neoadjuvant chemotherapy on platinum resistance in stage ⅢC and Ⅳ epithelial ovarian cancer[J]. Medicine (Baltimore), 2016, 95(36): e4797. doi: 10.1097/MD.0000000000004797

    [39]

    Petrillo M, Ferrandina G, Fagotti A, et al. Timing and pattern of recurrence in ovarian cancer patients with high tumor dissemination treated with primary debulking surgery versus neoadjuvant chemotherapy[J]. Ann Surg Oncol, 2013, 20(12): 3955-3960. doi: 10.1245/s10434-013-3091-6

    [40]

    Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[J]. Ann Oncol, 2019, 30(5): 672-705. doi: 10.1093/annonc/mdz062

    [41]

    Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers[J]. JAMA, 2017, 317(23): 2402-2416. doi: 10.1001/jama.2017.7112

    [42]

    Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers[J]. Nat Rev Cancer, 2004, 4(10): 814-819. doi: 10.1038/nrc1457

    [43]

    Tan DS, Rothermundt C, Thomas K, et al. “BRCAness”syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations[J]. J Clin Oncol, 2008, 26(34): 5530-5536. doi: 10.1200/JCO.2008.16.1703

    [44]

    Bu H, Chen J, Li Q, et al. BRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group[J]. J Obstet Gynaecol Res, 2019, 45(11): 2267-2274. doi: 10.1111/jog.14090

    [45]

    Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group[J]. J Clin Oncol, 2012, 30(21): 2654-2663. doi: 10.1200/JCO.2011.39.8545

    [46]

    Gu P, Pan LL, Wu SQ, et al. CA 125, PET alone, PET-CT, CT and MRI in diagnosing recurrent ovarian carcinoma: a systematic review and meta-analysis[J]. Eur J Radiol, 2009, 71(1): 164-174. doi: 10.1016/j.ejrad.2008.02.019

    [47]

    Hall M, Rustin G. Recurrent ovarian cancer: when and how to treat[J]. Curr Oncol Rep, 2011, 13(6): 459-471. doi: 10.1007/s11912-011-0199-3

    [48]

    Rustin GJ, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study[J]. Ann Oncol, 1996, 7(4): 361-364. doi: 10.1093/oxfordjournals.annonc.a010602

    [49]

    Wilder JL, Pavlik E, Straughn JM, et al. Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation[J]. Gynecol Oncol, 2003, 89(2): 233-235. doi: 10.1016/S0090-8258(03)00051-9

    [50]

    Lee CK, Simes RJ, Brown C, et al. A prognostic nomogram to predict overall survival in patients with platinum-sensitive recurrent ovarian cancer[J]. Ann Oncol, 2013, 24(4): 937-943. doi: 10.1093/annonc/mds538

    [51]

    Atallah GA, Kampan NC, Chew KT, et al. Predicting Prognosis and Platinum Resistance in Ovarian Cancer: Role of Immunohistochemistry Biomarkers[J]. Int J Mol Sci, 2023, 24(3): 1973. doi: 10.3390/ijms24031973

    [52]

    Pylväs-Eerola M, Liakka A, Puistola U, et al. Cancer Stem Cell Properties as Factors Predictive of Chemoresistance in Neoadjuvantly-treated Patients with Ovarian Cancer[J]. Anticancer Res, 2016, 36(7): 3425-3431.

    [53]

    Uno K, Yoshikawa N, Tazaki A, et al. Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy[J]. Sci Rep, 2022, 12(1): 4513. doi: 10.1038/s41598-022-08503-7

    [54]

    Patch AM, Christie EL, Etemadmoghadam D, et al. Whole-genome characterization of chemoresistant ovarian cancer[J]. Nature, 2015, 521(7553): 489-494. doi: 10.1038/nature14410

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  • 收稿日期:  2024-07-14
  • 修回日期:  2024-07-23
  • 录用日期:  2024-08-07
  • 网络出版日期:  2024-08-19
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