2025年7月《JAMA》杂志发表一篇综述《Ovarian Cancer》
重要性
卵巢癌是全球女性癌症发病和癌症死亡的第八大常见原因。2022年,全球约有 324 398 人被诊断出患有卵巢癌,206 839 人死于卵巢癌。据估计,2025年美国将有 20 890 名女性被诊断出患有卵巢癌,12 730 名患者将死于卵巢癌。
观察结果
约 90% 的卵巢癌是上皮性恶性肿瘤,其中 70% 至 80% 为高级别浆液性卵巢癌。较少见的上皮亚型包括子宫内膜样癌、透明细胞癌、低级别浆液性癌、粘液性癌和癌肉瘤。卵巢癌诊断时的中位年龄为 63 岁。危险因素包括年龄较大、乳腺癌或卵巢癌家族史、子宫内膜异位症和未生育。遗传因素与 25% 的病例相关,主要与 BRCA1/2 基因变异有关。诊断时,约 95% 的患者会出现非特异性症状,如腹痛、腹胀、尿急和尿频,约 80% 的患者已处于晚期(III-IV 期),包括盆腔外病变、腹水和腹部包块。诊断和分期评估包括盆腔超声;胸部、腹部和骨盆计算机断层扫描(CT);以及血清肿瘤标志物,如糖类抗原 125(CA-125)、糖类抗原 19-9(CA 19-9)和癌胚抗原(CEA)。早期卵巢癌(定义为局限于卵巢或输卵管[I期]或局限于盆腔[II期])的一线治疗是手术(子宫切除术、双侧输卵管卵巢切除术、大网膜切除术和淋巴结清扫术),随后进行辅助化疗(卡铂和紫杉醇)。经过治疗,早期卵巢癌的 5 年总生存率为 70% 至 95%。晚期卵巢癌可采用初次肿瘤细胞减灭术(切除腹腔内所有可见的癌症)和辅助化疗(卡铂和紫杉醇)治疗,或采用新辅助化疗,随后进行肿瘤细胞减灭术和辅助化疗。大多数晚期卵巢癌患者接受贝伐珠单抗(一种阻断血管生成的单克隆抗体)和/或聚腺苷二磷酸核糖聚合酶(PARP)抑制剂的维持治疗。经过治疗,晚期卵巢癌的 5 年总生存率为 10% 至 40% 。然而,携带 BRCA 相关基因变异的个体在接受 PARP 抑制剂治疗后,其 5 年总生存率约为 70%。尽管初始缓解率达 80%,但约 75% 的晚期患者会在 2 年内出现卵巢癌复发。
结论与相关性
美国每年约有 21 000 名女性被诊断出患有卵巢癌,其中约 80% 在诊断时已处于晚期。早期卵巢癌的一线治疗是手术和基于铂类的辅助化疗。晚期卵巢癌的治疗包括肿瘤细胞减灭术、基于铂类的化疗以及靶向维持治疗,如贝伐珠单抗和/或 PARP 抑制剂。
在美国女性中,患卵巢癌的终生风险为1/91,因卵巢癌死亡的终生风险为1/143。[1] 约80%的卵巢癌在诊断时已处于晚期。[2-4] 早期发现很困难,因为没有有效的筛查方法,且95%的患者最初症状非特异性,如腹痛、腹胀、尿急或尿频。 上皮性恶性肿瘤占卵巢癌的90%。[5] 其中70%至80%为高级别浆液性卵巢癌。[5] 早期卵巢癌包括I期(局限于卵巢或输卵管)和II期(累及子宫或其他盆腔器官)(图1)。通过手术和以铂类为基础的辅助化疗,早期卵巢癌患者的5年总生存率为70%至95%。[2,4] 晚期卵巢癌包括III期(累及盆腔和腹主动脉旁淋巴结或盆腔外腹膜)和IV期(转移至肝脏、脾脏或腹腔外),可通过肿瘤细胞减灭术、以铂类为基础的化疗以及靶向治疗(如抗血管生成药物贝伐珠单抗和/或PARP抑制剂)联合治疗。晚期卵巢癌的初始缓解率为80%,但约75%的晚期卵巢癌患者在2年内复发,5年总生存率为10%至40%。[2,4] 约50%的晚期卵巢癌患者存在遗传性(胚系)或肿瘤获得性(体细胞)BRCA1/2 或其他BRCA相关基因变异,当使用PARP抑制剂治疗时,其5年总生存率接近70%。[6] 本综述重点关注高级别浆液性卵巢癌的诊断和管理。框1提供了一些关于卵巢癌的常见问题和解答。
框1. 关于卵巢癌的常见问题
卵巢癌常见的首发体征和症状是什么?
高达95%的卵巢癌女性最初会出现非特异性症状,如腹痛、腹胀和尿急。晚期卵巢癌的体征和症状可能包括腹水、可触及的腹部包块和/或呼吸困难(由腹胀或胸腔积液引起)。
是否有有效的方法可以降低卵巢癌风险?
美国预防服务工作组(US Preventive Services Task Force)在2018年建议,不对无症状且无高风险遗传性癌症综合征的个体以及高风险个体(例如,BRCA1/2基因变异携带者)使用经阴道超声和/或糖类抗原125(CA125)进行卵巢癌筛查。有BRCA基因变异家族史或有一级亲属在任何年龄患有卵巢癌或早发性乳腺癌(年龄<40岁)的女性应进行基因检测。建议已完成生育的BRCA1携带者在35至40岁之间接受双侧输卵管-卵巢切除术,BRCA2携带者在40至45岁之间接受该手术,林奇综合征女性在45至50岁之间接受该手术。
卵巢癌患者的初始治疗和预后如何?
早期卵巢癌(I-II期)的一线治疗是手术,随后进行铂类化疗,其5年总生存率为70%至95%。晚期卵巢癌(III-IV期)采用肿瘤细胞减灭术、铂类化疗和靶向治疗(贝伐珠单抗和/或PARP抑制剂)联合治疗,其5年生存率为10%至40%。然而,通过PARP抑制剂治疗,患有晚期卵巢癌且具有BRCA相关基因变异的患者5年生存率约为70%。
方法
在PubMed数据库中检索了1995年1月1日至2025年5月3日期间发表的描述随机临床试验(RCT)、荟萃分析、系统评价和实践指南的英文文章,共识别出1733项RCT、1457项荟萃分析、1770项系统评价和295项指南。优先选择高质量的RCT和荟萃分析。最终纳入123篇文章,包括65项RCT、9项荟萃分析、5项系统评价、16项指南、6篇叙述性综述、12项前瞻性观察性研究和10项回顾性观察性研究。
流行病学与危险因素
卵巢癌是全球女性第八大常见癌症和癌症死亡原因。[7] 2022年,全球估计新增卵巢癌324,398例,死亡206,839例,发病率和死亡率分别为每10万女性年6.6例和4.2例。[7] 在美国,自2004年以来,卵巢癌的发病率和死亡率每年下降约3%,原因是口服避孕药使用的增加(预防反复排卵相关的卵巢损伤)、具有高风险基因变异(如BRCA1/2,遗传性乳腺癌和卵巢癌综合征)的女性接受预防性输卵管-卵巢切除术,以及治疗方案的改进。[1] 在全球范围内,卵巢癌发病率在英国、奥地利、荷兰和挪威等其他高收入国家有所下降,但在非洲和亚洲部分地区等一些低收入地区有所上升。[7,8]
卵巢癌主要起源于上皮(90%)。世界卫生组织2020年确认了6种主要上皮亚型:高级别浆液性 high-grade serous(70%-80%)、子宫内膜样 endometrioid(10%-20%)、透明细胞 clear cell(5%-10%)、低级别浆液性 low-grade serous(5%-10%)、粘液性 mucinous(3%-5%)和癌肉瘤 carcinosarcoma(1%-3%)。[5] 较少见的情况是,卵巢癌涉及生殖细胞肿瘤 germ cell tumors(3%-5%)和性索间质肿瘤 sex cord stromal tumors(2%-5%)。[5]
卵巢癌诊断的中位年龄为63岁,但在具有胚系BRCA基因变异的患者中要早10年。[9] 约25%的卵巢癌是遗传性的,由DNA损伤修复基因的胚系致病性变异引起:其中90%是BRCA1和BRCA2基因变异[10],10%归因于其他基因变异,包括DNA错配修复基因(林奇综合征)和参与DNA双链断裂修复系统的基因,如CHEK2、RAD51、BRIP1和PALB2。[11] 具有BRCA基因变异的患者一生中患卵巢癌的估计风险为20%至70%,具有错配修复基因变异的风险为10%至18%。[12,13]
卵巢癌的内分泌和生殖危险因素包括子宫内膜异位症(风险比,4.20;95% CI,3.59-4.91)[14]、不孕症(标准化发病率比,2.0;95% CI,1.8-4.0)和绝经后雌激素治疗(相对风险,1.31;95% CI,1.21-1.41)。[15] 可能的保护因素包括多产(每增加一次分娩的比值比,0.81;95% CI,0.75-0.85)、母乳喂养(比值比,0.72;95% CI,0.68-0.76)和口服避孕药使用(比值比,0.66;95% CI,0.52-0.83)。[15]
病理生理学与分子生物学
上皮性卵巢癌的发病机制尚不清楚,但基因表达谱分析表明,大多数高级别浆液性卵巢癌可能起源于输卵管伞端的癌前病变,并转移至卵巢和腹腔(图1)。[16] 约50%的高级别浆液性卵巢癌在DNA同源重组修复基因中存在遗传变异(25%为遗传性/胚系,25%为肿瘤获得性/体细胞),导致无法修复DNA双链断裂,称为同源重组缺陷(HRD)。BRCA1和BRCA2基因变异约占HRD病例的一半,存在于所有高级别浆液性卵巢癌的25%中。[17] 剩余的HRD病例由同源重组修复通路中的其他基因引起,包括CHEK2、RAD51、BRIP1和PALB2。
预防高风险个体
卵巢癌高风险个体包括具有胚系BRCA1/2基因变异者,以及有卵巢癌家族史(任何年龄)或早发性乳腺癌(年龄<40岁)家族史者。美国国家综合癌症网络(NCCN)指南建议,对有卵巢上皮癌一级或二级亲属(任何年龄发病)者,或根据遗传咨询其个人或家族癌症史提示为遗传性乳腺癌和卵巢癌综合征者,进行卵巢癌易感基因(ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, EPCAM, PALB2, RAD51C, RAD51D)检测。[10]
对于已知携带卵巢癌易感基因的患者,预防性双侧输卵管-卵巢切除术是最有效的预防卵巢癌的措施。[18] 一项包含3项前瞻性研究、涉及9192名具有BRCA1/2变异女性的荟萃分析报告称,双侧输卵管-卵巢切除术在4年内将卵巢癌风险降低了81%(风险比,0.19;95% CI,0.13-0.27)。[19] NCCN指南建议:BRCA1基因变异携带者在完成生育后于35至40岁、BRCA2携带者在40至45岁、携带其他致病基因变异(如林奇综合征)的女性在45至50岁接受双侧输卵管-卵巢切除术。[10] 在预防性手术前,临床医生应讨论提前绝经的潜在影响(例如,血管舒缩症状、骨质疏松症、心血管疾病、认知能力下降、对性功能的不良影响风险增加),对于无个人乳腺癌史的绝经前女性应考虑激素替代治疗。[10]
口服避孕药可降低未接受双侧输卵管-卵巢切除术的高风险年轻个体(如BRCA变异携带者)的卵巢癌风险。一项针对使用口服避孕药的BRCA1/2变异女性的荟萃分析,基于2项涉及10,981名女性的研究报告,其卵巢癌风险比为0.62(95% CI,0.52-0.74);来自8项包含10,390名女性的研究报告的比值比为0.49(95% CI,0.38-0.63)。[20] 同样,另一项包含5项观察性研究、涉及1503名具有BRCA1/2致病性变异参与者的荟萃分析报告称,口服避孕药使用与卵巢癌风险降低相关(汇总相对风险,0.50;95% CI,0.33-0.75),每增加10年使用时间与风险降低36%相关(汇总相对风险,0.64;95% CI,0.53-0.78)。[21]
普通人群
美国妇产科医师学会(American College of Obstetricians and Gynecologists)和国际妇产科联盟(International Federation of Gynecology and Obstetrics)指南建议,考虑为普通人群采用手术和激素预防方法以降低卵巢癌风险。[22,23] 对于因良性疾病(例如,因子宫肌瘤行子宫切除术或因结肠疾病行盆腔手术)接受盆腔手术的绝经后女性,可考虑行双侧输卵管-卵巢切除术。对于无生育意愿且接受盆腔手术的绝经前女性,可在保留卵巢的同时行双侧输卵管切除术(切除输卵管),以避免提前绝经及其对健康的潜在不良影响。[22,23]
一项包含24项病例对照和队列研究的荟萃分析报告称,与从未使用者相比,曾使用过口服避孕药者的卵巢癌发病率降低(比值比,0.73;95% CI,0.66-0.81)。使用口服避孕药超过10年与较低风险相关(比值比,0.43;95% CI,0.37-0.51)。[24] 归因于口服避孕药使用的终生卵巢癌风险降低估计为0.54%(需治疗数,185人使用口服避孕药5年)。[24]
筛查
美国预防服务工作组(US Preventive Services Task Force)在2018年建议,不对无症状且无高风险遗传综合征的女性进行卵巢癌筛查,该建议基于2项大型RCT(PLCO和UKCTOCS;N = 271103)。这些研究发现,在平均风险的无症状女性中,与不筛查相比,使用年度经阴道超声和/或糖类抗原125(CA125)检测未能显著降低死亡率(PLCO:相对风险,1.18;95% CI,0.82-1.71;UKCTOCS:风险比,0.91;95% CI,0.76-1.09)。[25] 同样,针对高风险个体(例如,具有BRCA基因变异者)的大型前瞻性研究也表明,使用经阴道超声和CA125进行筛查的阳性预测值较低(4.6%-10.8%),且不能降低卵巢癌死亡率。[26-29] 因此,不推荐进行卵巢癌筛查,即使对于高风险个体也是如此。
临床表现
在卵巢癌诊断前,95%的女性报告出现非特异性症状的逐渐发作,如腹痛、腹胀、尿急或尿频。[30] 一项前瞻性病例对照研究比较了有盆腔包块的女性(84例良性,44例卵巢癌)与就诊于初级保健诊所的女性(n = 1709)的症状,发现卵巢癌患者更频繁地报告腹胀(70% vs 38%;P < .001)、腹部增大(64% vs 19%;P < .001)、尿急/尿频(55% vs 32%;P = .002)、腹痛(50% vs 30%;P = .006)和盆腔痛(41% vs 26%;P = .02)。[31] 腹胀、腹部增大和尿急/尿频的组合症状在43%的卵巢癌患者中观察到,而在非卵巢癌患者中仅为8%(比值比,9.4;95% CI,5.0-17.7)。[31] 在一项针对1725名美国和加拿大卵巢癌女性的调查中,89%的早期疾病患者和97%的晚期疾病患者在诊断前报告有症状,且症状类型在不同分期之间无显著差异。[30] 持续性腹痛或腹胀、腹水、可触及的腹部或盆腔包块、体重减轻和呼吸困难(由腹胀或胸腔积液引起)可能提示晚期卵巢癌。极少数情况下(<1%的患者),卵巢癌可表现为由远处转移(骨痛、癫痫发作)或副肿瘤综合征(小脑变性、周围性多神经病)引起的腹腔外症状。[32]
诊断
诊断性检查包括询问个人和家族癌症史,以确定患者是否存在已知的与卵巢癌相关的遗传变异(如BRCA1/2),以及进行体格检查,包括盆腔和腹部评估以检查是否有可触及的包块或腹水(框2)。盆腔超声对于识别恶性附件包块具有高敏感性(70%-93%)和特异性(80%-98%)。[33,34] 腹部/盆腔计算机断层扫描(CT)对诊断的敏感性(60%-90%)和特异性(85%-94%)较低,但对检测腹膜疾病和大网膜增厚(这是分期和计划的重要发现)的敏感性为94%。[34,35] 卵巢癌的详细分期系统见补充材料中的eTable 1。[36] 与CT相比,腹部磁共振成像(MRI)在评估腹膜癌病以及肠系膜或肠浆膜受累方面更敏感(92%-94%)和特异(85%-98%)。[34,35,37] 如果在CT或MRI成像后仍不确定癌症的可切除性,可在开腹手术前行诊断性腹腔镜检查以确定可切除性。[38] 全身正电子发射断层扫描(PET)在检测腹腔外病变(如远处淋巴结[例如,纵隔、腹股沟、锁骨上]和肺转移)方面比CT(43%-55%)具有更高的敏感性(73%-75%),可能改变治疗方案,采用全身治疗而非腹部肿瘤减灭术。[39,40]
框2. 上皮性卵巢癌的诊断性检查癌症史(个人和家族)遗传性疾病:遗传性乳腺癌和卵巢癌综合征(BRCA基因变异)、林奇综合征一级或二级亲属中有乳腺癌、卵巢癌、子宫内膜癌、结肠癌或胰腺癌临床检查(包括盆腔检查)血清肿瘤标志物CA125CA19-9 和 CEA(适用于疑似[基于影像学发现]或确诊为粘液性组织学类型者)影像学检查由经验丰富的检查者进行盆腔超声检查(用于评估附件包块特征,尤其在早期疾病中)口服和静脉注射对比剂的胸部、腹部和盆腔计算机断层扫描(CT)(用于临床分期和手术计划)在特定病例中的附加工具腹部弥散加权磁共振成像(MRI)、腹腔镜检查或微创开腹术(用于评估腹膜癌病的范围和可切除性)全身18F-氟脱氧葡萄糖正电子发射断层扫描(PET)(用于评估可疑的远处淋巴结和腹腔外病灶)内窥镜检查(食管胃十二指肠镜检查和结肠镜检查):如果疑似(基于CA19-9升高、CEA升高、CA125/CEA比值≤25和/或影像学发现)或确诊为粘液性组织学类型,以排除原发性胃肠道肿瘤从诊断性空心针活检或手术标本中获取足够肿瘤样本进行病理学检查 a腹水或胸腔积液的细胞学评估(如果存在)遗传和分子检测对所有上皮性卵巢癌患者进行BRCA1/2和其他卵巢癌易感基因的胚系检测(以筛查遗传性乳腺癌和卵巢癌综合征并为治疗决策提供信息)。对于未发现胚系致病性BRCA1/2变异的患者,应进行肿瘤组织的体细胞BRCA1/2检测以指导治疗决策。对晚期高级别浆液性或子宫内膜样卵巢癌进行肿瘤同源重组缺陷(HRD)检测(为治疗决策提供信息)对子宫内膜样、透明细胞或粘液性亚型患者进行肿瘤错配修复系统检测——特别是免疫组织化学和微卫星不稳定性检测(以筛查林奇综合征)
缩写: CA125,糖类抗原125;CA19-9,糖类抗原19-9;CEA,癌胚抗原。
注: a 在推测为早期疾病时应避免术前活检,以防止恶性细胞溢出到腹腔。
血清肿瘤标志物
血清肿瘤标志物,如CA125、人附睾蛋白4(HE4)、糖类抗原19-9(CA19-9)和癌胚抗原(CEA),不能用于诊断上皮性卵巢癌,但有助于监测治疗反应和治疗后监测。糖类抗原125(CA125)是最常升高的血清肿瘤标志物[41],根据包含2374名卵巢肿瘤女性的17项研究,CA125(≥35 U/mL)在诊断时在大约50%的早期卵巢癌患者和75%至92%的晚期卵巢癌患者中升高。[42] 人附睾蛋白4(HE4)是另一种血清肿瘤标志物,可用于早期上皮性卵巢癌的检测(敏感性,65%-83%;特异性,78%-99%)。[43] CA19-9和CEA水平升高与粘液性胃肠道癌相关,可能在粘液性卵巢肿瘤患者中检测到。原发性卵巢粘液癌罕见,因此应进行上、下消化道内镜检查以评估是否为胃肠道原发肿瘤转移至卵巢。CA125/CEA比值大于25提示为原发性粘液性卵巢肿瘤而非胃肠道转移至卵巢。[2,4,41]
活检
对于推测为早期卵巢癌的患者,术前活检(例如,细针穿刺)是禁忌的,因为它可能导致肿瘤破裂和恶性细胞溢出到腹腔。通常对手术标本进行术中冰冻切片以做出卵巢癌的病理诊断。[4,44] 对于不适合初次手术的晚期疾病患者,需要术前组织分析(首选空心针活检或细针穿刺)以确认卵巢癌诊断并指导化疗选择。对于符合初次手术条件(无需术前化疗)的晚期疾病患者,术中诊断性活检即可满足要求。对于有腹水或胸腔积液的患者,腹腔穿刺术或胸腔穿刺术可提供细胞学诊断并缓解症状。[2,4]
遗传和分子检测
NCCN和美国临床肿瘤学会(ASCO)指南建议对所有上皮性卵巢癌患者进行胚系血液检测,以筛查遗传性BRCA1/2变异。[10,13,45] 胚系检测结果为阴性时,应进行手术标本评估以检测肿瘤特异性获得性(体细胞)BRCA1/2变异。胚系和体细胞检测为患者及其高危亲属的治疗和咨询提供信息(框2)。[10,13,45] 对晚期、高级别浆液性或子宫内膜样卵巢癌进行HRD检测也能指导治疗[46],HRD阳性与对铂类化疗以及DNA修复抑制剂(如PARP抑制剂)治疗的更高反应性相关。[42] NCCN指南推荐对子宫内膜样、透明细胞或粘液性亚型进行错配修复(MMR)肿瘤检测,以筛查林奇综合征。[4,13]
早期卵巢癌的治疗
推测为早期卵巢癌的一线治疗是手术切除肿瘤并进行分期,随后进行以铂类为基础的辅助化疗(图2)。大多数早期卵巢癌患者的手术包括:(1) 整块切除受累卵巢和输卵管,以避免手术期间癌细胞溢出到腹膜;(2) 切除对侧卵巢和输卵管的子宫切除术和输卵管-卵巢切除术;(3) 腹膜后(盆腔和腹主动脉旁)淋巴结清扫术;(4) 大网膜切除术;(5) 随机腹膜活检;(6) 腹腔液细胞学检查。对于某些粘液性卵巢癌患者也可能进行阑尾切除术。[4,47] 术中分期很重要,因为通过影像学检查推测为早期卵巢癌的患者中,约30%在腹膜后淋巴结、大网膜和腹膜表面活检的最终病理检查中发现隐匿性转移病灶。[4,47]
对于I期疾病且考虑未来生育的患者,可接受保留生育功能的手术,包括单侧输卵管-卵巢切除术(保留子宫和对侧无卵巢癌的卵巢/输卵管)。[2,4] 在双侧输卵管-卵巢切除术前行卵母细胞冷冻保存可能为未来的辅助生殖方法(如体外受精和子宫胚胎移植)提供可能。建议术前咨询肿瘤生育专家。一项针对211名因单侧上皮性卵巢癌(IA期,n = 126;IC期,n = 85)接受保留生育功能手术的女性进行的多机构回顾性研究发现,5年总生存率和无复发生存率因亚型而异,IA期1-2级疾病最高(100%和97.8%),IC期3级疾病较低(66.7%和66.0%)。[48]
辅助化疗在早期卵巢癌中的获益取决于分期、组织学类型和肿瘤分级,关于辅助化疗的决定应综合考虑年龄、合并症、体能状态和可能的不良事件(表;补充材料中的eTable 2)。[49-54,65,67,68] 一项包含5项RCT、涉及1277名早期卵巢癌女性的Cochrane荟萃分析发现,与不接受化疗相比,以铂类为基础的辅助化疗改善了10年总生存率(风险比,0.72;95% CI,0.57-0.92;无绝对数据)。[97] 在高危疾病患者(IA期3级、IB-IC期2-3级、II期或任何透明细胞卵巢癌)中,接受辅助化疗的患者比未接受辅助化疗的患者有更好的10年总生存率(风险比,0.52;95% CI,0.33-0.81;无绝对数据)。[97]
晚期卵巢癌的治疗
晚期上皮性卵巢癌的治疗通常包括肿瘤细胞减灭术、全身化疗和个体化维持治疗的组合(图2)。[2,4] 对于围手术期并发症风险低且影像学评估为可切除的晚期卵巢癌患者,推荐在铂类辅助化疗前行初次肿瘤细胞减灭术(子宫切除术加双侧输卵管-卵巢切除术和大网膜切除术)。[98-100] 卵巢癌累及其他器官的患者可能需要切除肿大的腹膜后盆腔和腹主动脉旁淋巴结、脾脏、肠管和膈肌。[98-101]
对于围手术期并发症风险高或在初次手术中不太可能实现完全肿瘤细胞减灭的晚期卵巢癌患者,应接受新辅助化疗,随后进行间歇性肿瘤细胞减灭术和辅助性全身化疗(表;补充材料中的eTable 2)。[55-58,102] 一项包含4项III期RCT、涉及1692名晚期卵巢癌患者的荟萃分析发现,接受间歇性肿瘤细胞减灭术的患者(n = 847)与接受初次肿瘤细胞减灭术的患者(n = 845)相比,总生存期相似(风险比,0.96;95% CI,0.86-1.08),且术后并发症发生率更低(相对风险,0.22;95% CI,0.13-0.38)。[103] 对于III期卵巢癌患者,在间歇性肿瘤细胞减灭术期间可考虑腹腔热灌注化疗(HIPEC),即在手术期间将加热的铂类化疗药物注入腹腔(补充材料中的eTable 2)。[102,104-107]
晚期卵巢癌的一线全身化疗包括卡铂联合紫杉醇,每3周一次,共6个周期(表;补充材料中的eTable 2)。[4,59-68,108,109] 接受初次肿瘤细胞减灭术的患者在术后6周内开始接受6个周期的化疗。接受间歇性肿瘤细胞减灭术的患者通常在手术前接受3至4个周期的化疗,手术后接受2至3个周期的化疗。[102] 对于无法耐受标准方案的患者,每周一次的卡铂和紫杉醇方案(提供与每3周方案相同的累积剂量)是一个合理的替代方案。[65,67,68] 两项大型III期RCT(GOG-0218和ICON7)表明,在晚期卵巢癌患者的化疗中加入贝伐珠单抗,随后进行贝伐珠单抗维持治疗长达22个周期(15个月),与单独化疗相比,平均无进展生存期(PFS)延长了2至4个月(GOG-0218:14.1个月 vs 10.3个月;中位随访17个月;ICON7:24.1个月 vs 22.4个月;中位随访28个月)(表;补充材料中的eTable 2)。[69,71] 当这两项试验在包含3401名患者的荟萃分析中合并分析时,贝伐珠单抗组与单独化疗组相比,PFS有所改善(风险比,0.72;95% CI,0.65-0.81;无绝对数据),但总生存期没有改善。[110] ICON7试验中一个预设的502名高风险患者(IV期、不可手术的III期或III期卵巢癌术后残留病灶>1 cm)亚组的探索性分析显示,贝伐珠单抗组与单独化疗组相比,平均总生存期有所改善(39.3个月 vs 34.5个月;风险比,0.78;95% CI,0.63-0.97)。[70]
根据患者对化疗的反应、组织学类型、BRCA/HRD状态以及合并症情况,晚期卵巢癌患者在初始治疗后可考虑贝伐珠单抗和/或PARP抑制剂(奥拉帕利或尼拉帕利)维持治疗(表;补充材料中的eTable 2)。[69-78,111-113] 指南推荐PARP抑制剂用于对铂类化疗有反应的高级别浆液性或子宫内膜样卵巢癌患者的维持治疗,尤其是在BRCA变异或HRD阳性肿瘤中。[2,4] PARP抑制剂为口服给药,奥拉帕利剂量为300 mg每日两次,持续2年;尼拉帕利剂量为200 mg至300 mg每日一次,持续3年。[6] 在一项包含391名BRCA变异高级别晚期卵巢癌患者的III期RCT中(补充材料中的eTable 2),与安慰剂相比,奥拉帕利提供了7年总生存获益(67.0% vs 46.5%;中位总生存期,未达到 vs 75.2个月;风险比,0.55;95% CI,0.40-0.76)。[73,74] 在另一项包含806名对铂类化疗和贝伐珠单抗有反应的晚期卵巢癌患者的III期试验中,与安慰剂加贝伐珠单抗相比,在贝伐珠单抗基础上加用奥拉帕利改善了HRD阳性肿瘤(包括BRCA变异)患者的5年总生存率(65.5% vs 48.4%;中位总生存期,75.2个月 vs 57.3个月;风险比,0.62;95% CI,0.45-0.85)。对于BRCA变异患者,5年总生存率为73.2% vs 53.8%(中位总生存期,75.2个月 vs 66.9个月;风险比,0.60;95% CI,0.39-0.93);对于无BRCA变异患者,为54.7% vs 44.2%(中位总生存期,未达到 vs 52.0个月;风险比,0.71;95% CI,0.45-1.13)(补充材料中的eTable 2)。[75,76] 其他三项研究PARP抑制剂维持治疗的试验发现,BRCA变异肿瘤患者的PFS最高,其次是HRD阳性肿瘤患者,HRD阴性肿瘤患者的PFS最低(补充材料中的eTable 2)。[77,111,112]
预后与监测
接受治疗的早期卵巢癌患者的总体5年生存率为70%至95%,而晚期疾病患者的5年生存率为10%至40%。[114] 超过80%的晚期卵巢癌患者初始获得完全缓解(治疗后影像学检查无疾病证据)。在铂类化疗后进行PARP抑制剂维持治疗,可将BRCA变异或HRD阳性晚期卵巢癌患者的5年总生存率提高到约70%。[74,76]
目前尚无基于证据的治疗后随访方案,因此监测应根据疾病分期、组织学类型、遗传变异以及对初始治疗的影像学和血清肿瘤标志物反应进行个体化。初始治疗后获得完全缓解的患者应在头2年内每2至4个月进行一次临床再评估和CA125检测(如果初始升高),第3至5年每3至6个月一次,之后每年一次。计算机断层扫描(CT)成像应根据复发风险或临床复发怀疑(例如腹痛、腹胀、体重减轻、CA125水平升高)进行个体化安排。[2,4]
卵巢癌复发
约75%的晚期卵巢癌患者和10%至30%的早期卵巢癌患者在2年内复发。[2,4] 关于追加治疗、参加临床试验或启动姑息治疗的决定应个体化(图3)。复发性疾病的治疗取决于无铂间期——即从最后一次铂类化疗给药到复发的时间——它预测对后续铂类治疗的反应。首次复发时,约80%的患者为铂敏感疾病(无铂间期≥6个月),20%为铂耐药疾病(无铂间期<6个月)。[115] 随着每次缓解和复发,无铂间期会缩短,约60%至75%的复发性疾病患者会发展为铂耐药。[115] 复发性卵巢癌患者应进行肿瘤检测,以确定叶酸受体α(FRα [FOLR1])和ERBB2(原HER2/neu)的表达,为潜在的治疗靶点提供依据。
铂敏感卵巢癌
对于铂敏感复发性卵巢癌患者,推荐采用以铂类为基础的化疗(卡铂联合聚乙二醇化脂质体多柔比星、吉西他滨或紫杉醇)联合或不联合贝伐珠单抗(表;补充材料中的eTable 2)。[83-90] 该治疗的中位PFS为8至13个月。[115] 对于铂敏感疾病,如果影像学和体能状态提示疾病可能可切除,可在化疗前考虑二次肿瘤细胞减灭术(表;补充材料中的eTable 2)。[79-82]
临床试验数据支持在未使用过PARP抑制剂、对铂类化疗有反应且携带BRCA1/2基因变异的患者中,使用PARP抑制剂(奥拉帕利、尼拉帕利或卢卡帕利)作为复发性疾病的维持治疗(表)。[91-94,116,117] 一项包含295名BRCA基因变异和铂敏感复发性卵巢癌患者的III期RCT显示,与安慰剂相比,奥拉帕利维持治疗提供了12.9个月的中位总生存获益(51.7个月 vs 38.8个月;风险比,0.74;95% CI,0.54-1.00)。[91,92] 尼拉帕利和卢卡帕利也显示出相似的结果(补充材料中的eTable 2)。[93,94,116,117]
对于复发性卵巢癌且无BRCA变异或一线治疗已接受过PARP抑制剂的患者,可考虑贝伐珠单抗维持治疗。[118] 一项包含484名首次铂敏感复发患者的III期RCT报告称,在铂类化疗基础上加用贝伐珠单抗,随后进行贝伐珠单抗维持治疗,与单独化疗相比,改善了中位PFS(12.4个月 vs 8.4个月;风险比,0.48;95% CI,0.38-0.61)(补充材料中的eTable 2)。[87,88]
铂耐药卵巢癌
铂耐药复发性卵巢癌可采用单药非铂类化疗(聚乙二醇化脂质体多柔比星、吉西他滨、每周紫杉醇或拓扑替康)治疗,其中位PFS为3至9个月。[95,115] 在一项包含361名铂耐药复发性卵巢癌患者的III期RCT中,贝伐珠单抗联合化疗与单独化疗相比,改善了PFS(6.7个月 vs 3.4个月;风险比,0.48;95% CI,0.38-0.61)(表;补充材料中的eTable 2)。[95]
对于30%至35%的铂耐药卵巢癌患者,其肿瘤表现出高FRα表达,并且已接受过1至3轮任何类型的抗癌治疗,美国食品药品监督管理局(FDA)已批准一种靶向FRα的抗体药物偶联物——索米妥昔单抗(mirvetuximab soravtansine)。[96,119] 在一项包含453名患者的III期RCT中,与常规化疗相比,米伐妥昔单抗提供了中位总生存获益(16.5个月 vs 12.7个月;风险比,0.67;95% CI,0.50-0.89)(表;补充材料中的eTable 2)。[96] 另一种最近获FDA批准的抗体药物偶联物是德曲妥珠单抗(trastuzumab deruxtecan),它靶向ERBB2,为表达ERBB2的卵巢癌患者提供了治疗选择(补充材料中的eTable 2)。[120]
姑息治疗
NCCN指南建议为所有卵巢癌患者提供支持性护理,包括对晚期或复发性疾病患者转诊进行姑息治疗评估。[4] 姑息治疗临床医生提供全面的多模式症状管理,处理疼痛、心理健康、性健康和更年期症状,并可协助过渡到临终关怀。[121] 使用姑息治疗可优化生活质量,并可能改善生存期。[121,122] 虽然并非卵巢癌特有,但与常规护理相比,针对晚期癌症的门诊姑息治疗已被证明能将1年生存率提高14%(56% vs 42%;P < .001),中位总生存期延长4.6个月(14.6个月 vs 10.0个月)。[123]
局限性
本综述有几个局限性。首先,它不是一项系统评价,纳入研究的质量未经过正式评估。其次,本综述未涵盖较少见的上皮性和非上皮性卵巢癌。第三,治疗、结果和预后估计主要来自北美和欧洲进行的试验,可能无法推广到低收入国家。
结论
在美国,每年约有21,000名女性被诊断出卵巢癌,其中约80%在诊断时为晚期卵巢癌。早期卵巢癌的一线治疗是手术和铂类辅助化疗。晚期卵巢癌的治疗包括肿瘤细胞减灭术、铂类化疗以及靶向维持治疗,如贝伐珠单抗和/或PARP抑制剂。
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