卵巢癌的系统讲解诊治课件

卵巢癌的诊治 讲 课 内 容 卵巢癌的流行病学、转移途径、症状和 体征、诊断、分期。 卵巢癌的治疗（内科治疗为主） 教 学 目 的 与 要 求 掌握： 1.卵巢癌的诊断。 2. 卵巢癌的治疗。 卵巢癌的流行病学 发病和死亡情况 ovarian cancer accounts for approximately 4% of all cancer cases in women but it is the eighth leading cause of female cancer-related death around the world. In the year 2007, an estimated 230,500 cases were diagnosed worldwide and approximately 141,000 deaths were recorded. Of these, 103,332 cases and 66,925 deaths occurred in developed countries, whilst 123,761 cases and 72,433 deaths occurred in developing countries. In the USA, a womans lifetime risk of developing ovarian cancer is approximately 1.4%. More than 80% of patients will be diagnosed over the age of 45 years with a median age at diagnosis of 63 years. Unfortunately, more than 75% of women are diagnosed at advanced stages, with a relative 5-year survival rate of 44%. 卵巢癌的发病因素 怀孕或初产年龄25岁、口服避孕药、母乳喂养，可以使 患卵巢癌的风险下降30-60%。 未产或初产年龄35岁，患卵巢癌的风险上升。 遗传因素，BRCA1（40-50%）和BRCA2（15-25%）突 变携带者与早发性卵巢癌相关。三种遗传性卵巢癌家族 ：位点特异性卵巢癌；遗传性乳腺-卵巢癌；乳腺-结肠- 子宫内膜-前列腺癌。 尚未发现环境因素与卵巢癌的发生有必然联系。 卵巢癌的病理 组织类型 上皮性卵巢癌：占2/3以上。 交界性上皮性卵巢癌 少见病理类型的卵巢癌生殖细胞瘤； 卵巢间质肿瘤；癌肉瘤（恶性混合性苗 勒氏瘤） 上皮性卵巢癌 浆液性囊腺癌:：75%-80% ； 黏液性囊腺癌： 10%； 子宫内膜样癌： 10%； 透明细胞癌：小于1% ； 移行细胞癌：小于1% 混合型上皮瘤 ： 未分化癌：小于1% ； 未分类上皮性肿瘤： epithelial ovarian cancer: suggested divides ovarian cancer into two groups. The first group, low-grade, slow-growing tumors that behave in an indolent fashion. They include borderline and low-grade micropapillary tumors. The two groups have demonstrated mutations in several oncogenes, KRAS, BRAF and ERBB2. type II ovarian cancers present as high-grade, aggressive tumors. They include serous carcinoma, malignant mixed mesodermal tumors and undifferentiated carcinomas, and display a wide range of genetic instability. These tumors are often associated with TP53 mutations. 性索 - 间质肿瘤 支持-间质细胞肿瘤 颗粒-间质细胞肿瘤 两性母细胞瘤 男性母细胞瘤 生殖细胞来源的肿瘤 无性细胞瘤 内胚窦瘤 胚胎癌 多胚瘤 绒毛膜癌 畸胎瘤 混合性生殖细胞肿瘤 转移途径 种植转移主要的转移途径 局部蔓延 淋巴转移 血行播散 The most common method of metastatic spread is the exfoliation of ovarian cancer cells into the peritoneal fluid, resulting in the seeding of the pelvic/abdominal structures and lymphatic spread, with hematogenous spread being less common. Extraperitoneal metastases were once rare, but as the survival of patients with advanced disease is improving, most of these patients will develop metastases in the liver, lung or the CNS during the later stages. 卵巢癌的临床表现 症状 Ovarian cancer is often called silent lady-killer 卵巢上皮癌：腹部包块、腹部不适、腹胀、低热、消 瘦、乏力、气短、大小便次数增多等。 恶性生殖细胞瘤：生长快，早期出现症状，肿块、腹 胀、出血、感染、发热、肿瘤扭转至急腹征。 性索间质肿瘤：部分能分泌雌激素，子宫不规则出血 、性早熟、乳腺增大、性情改变、男性化、月经少或 闭经。胃肠道症状，食欲下降、恶心等。肠梗阻。 体征 腹部和盆腔包块：上皮癌多为双侧性， 囊实性或实性，多于与周围粘连。恶性 生殖细胞肿瘤和性索间质肿瘤95%以上 为单侧性。 腹部增大和腹水，胸水偶见。 卵巢癌的诊断 诊断 症状、体征 腹水中查到癌细胞 准确率70-80%。 影像学检查 肿瘤标记物测定 CA125、AFP、HCG等 。 细针穿刺活检 剖腹探查或腹腔镜检查 有关诊断 70%发现时已是晚期 50%-70%均会复发 60%-90%为上皮性肿瘤 卵巢癌筛查的手段 CA125 影响CA125的因素： 生理情况：如月经、妊娠 疾病：子宫内膜异位、盆腔炎（结核等 ） 肿瘤：肺癌、乳癌、胰腺癌、结直肠癌 治疗手段：如大量放腹水、腹部手术、 放射性免疫治疗或检查 筛查的目标人群 50岁以后的绝经妇女 5%-10%的遗传性： 高危妇女BRCA1和BRCA2突变 携带者、乳腺癌/卵巢癌家族成 员、仅乳腺癌家族史，但是乳 腺癌发病较早 筛查的目标人群 中危妇女一个一级亲属患卵巢癌 、一个以上远房亲属患卵巢癌、或 本人患乳腺癌、接受过卵巢过度刺 激治疗而未受孕的，比正常人群患 癌率（5%）略有升高 低危妇女患病风险为1%，可以不 作为筛查的对象 卵巢癌的分期 美国癌症联合会（AJCC）卵巢癌TNM和 FIJO分期系统：原发肿瘤（T） TNM FIGO Tx 原发肿瘤不能评价 T0 无原发肿瘤证据 T1 肿瘤局限于卵巢 T1a A 肿瘤局限于一侧卵巢，包膜 完整，卵巢表面没有肿瘤，腹 水或腹腔冲洗液无恶性细胞。 美国癌症联合会（AJCC）卵巢癌TNM和 FIJO分期系统：原发肿瘤（T） TNM FIGO T1b B 肿瘤局限于双侧卵巢，包膜完 整， 卵巢表面没有肿瘤，腹水或腹腔冲 洗液无恶性细胞。 T1c C 肿瘤局限于单侧或双侧卵巢，并有 以下情况之一：包膜破裂，卵巢表 面有肿瘤，腹水或腹腔冲洗液有恶 性细胞。 美国癌症联合会（AJCC）卵巢癌TNM和 FIJO分期系统：原发肿瘤（T） TNM FIGO T2 肿瘤累及单侧或双侧卵巢，并伴盆腔 播散。 T2a A 蔓延和/或转移至子宫和/或输卵管， 腹腔冲洗液无恶性细胞。 T2b B 侵及其它盆腔组织，腹水或腹腔冲 洗液无恶性细胞。 T2c C 肿瘤盆腔播散，腹水或腹腔冲液中找 到恶性细胞 美国癌症联合会（AJCC）卵巢癌TNM和 FIJO分期系统：原发肿瘤（T） TNM FIGO T3 肿瘤累及单侧或双侧卵巢，组织学 证实腹膜表面有种植 T3a A 腹膜有镜下转移瘤 T3b B 腹膜转移结节直径2cm T3c C 腹膜转移结节直径2cm和/或区域 淋巴结转移。 任何T 腹腔外远处转移。 美国癌症联合会（AJCC）卵巢癌 TNM和FIJO分期系统： N区域淋巴结 Nx 区域淋巴结无法评估 N0 无区域淋巴结转移 N1 C 有区域淋巴结转移 美国癌症联合会（AJCC）卵巢癌 TNM和FIJO分期系统： M远处转移 Mx 远处转移无法评估 M0 无远处转移 M1 有远处转移 分期 期 T1 N0 M0 A期 T1a N0 M0 B期 T1b N0 M0 C期 T1c N0 M0 期 A期 T2a N0 M0 B期 T2b N0 M0 C期 T2c N0 M0 分期 期 T1 N0 M0 A期 T3a N0 M0 B期 T3b N0 M0 C期 T3c N0 M0 任何T N1 M0 期 任何T 任何N M1 卵巢癌的治疗 卵巢癌的手术治疗 卵巢癌的手术治疗（1） 卵巢癌手术的种类： 诊断性 ：术中取活检 明确肿瘤分期 评价治疗效果 治疗性：彻底切除肿瘤 姑息性：解除痛苦提高生活质量 卵巢癌的手术治疗（2） 全面确定分期探查手术 （适用于I、期 ） ( comprehensive staging laparotomy) 1) 腹部纵切口 2) 全面的盆腹腔探查 3) 腹腔细胞学 4) 大网膜切除 5) 全子宫双附件切除（漏斗韧带高位结 扎） 6) 盆腔及腹主动脉旁淋巴结清除（肠系 膜下动脉水平） 卵巢癌的手术治疗（3） 再分期手术（restaging laparotomy) 急诊手术后，或第一次手术仅 进行了肿物的单纯切除（未进行化 疗），而再进行的手术。 卵巢癌的手术治疗（4） 肿瘤细胞减灭术（cytoreductive surgery, debulking) 尽最大努力切除原发灶及一切转移灶， 使残余病灶2cm（微小的残余瘤与改善患 者的预后有密切关系） 对于大多数实体瘤来说，切除所有的肿 瘤手术才有意义，但是卵巢癌即使不能切 除，只要尽可能的缩减，手术就有意义。 卵巢癌的手术治疗（5） 肿瘤细胞减灭术的临床意义： 解除症状，改善生活质量 增加化疗效果：完全缓解率43% - 24% 改善预后： 缓解期31月-13月 生存期36月-16月 卵巢癌的手术治疗（6） 中间性肿瘤细胞减灭术 （interval cytoredution) 仅35%的患者能够达到满意的肿瘤细胞 减灭术，所以经过3-5个疗程化疗后，再 进行减瘤术。 缓解期18月-13月 生存期26月-20月 容易产生耐药，减瘤术应尽早完成 卵巢癌的手术治疗（7） 复发性瘤的手术 对化疗敏感和孤立可切除的病例 有一定的疗效，但是合并肠梗阻的 ，多数只能缓解症状，不能提高生 存率。 Patients with stage IA, grade I disease have an excellent survival rate of 95% at 5 years, and postsurgical therapy is not typically recommended. 卵巢癌的化学治疗 卵巢癌的化疗（1） 卵巢癌对化疗敏感，对铂类联合化 疗有70%-80%的反应率，但是大部分出 现耐药。 70年代：烷化剂 80年代：铂类 90年代：紫杉醇（1996） 国内一线化疗：PC，CAP 外国一线化疗：TP 卵巢癌的化疗（2） 复发性卵巢癌的化疗 1) 化疗敏感型：初期以铂类为基础的化疗 达到临床缓解期，停用化疗6个月以上 2) 化疗耐药型：初期化疗有反应，化疗完 成后6个月内复发 3) 顽固型：初期有反应，并发现残余病灶 4) 难治型：治疗过程中，肿瘤稳定或有进 展（本类型对二线化疗反应亦差） 卵巢癌的化疗（3 ） 常用二线化疗药物： 拓扑替康（Topotecan):托扑异构酶I抑制剂 吉西他宾（Gemcitabine):常用于周疗 多西紫杉醇（Docetaxel):可以用于周疗 脂质体阿霉素（Doxil）：作用延长，毒性 降低 口服足叶乙甙（VP16）: 单药治疗为特点 PLD挑战复发性卵巢癌标准化疗 方案 在第45届美国临床肿瘤学会（ASCO）年 会的最新临床研究（late-breaking trails）发布 会上，法国巴黎笛卡尔（de Paris Descartes）大 学埃里克布热德洛雷纳（Eric Pujade-Lauraine ）教授代表妇科肿瘤国际小组（GCIG）公布 了国际期临床研究CALYPSO研究的最 新结果。 CALYPSO研究显示卡铂-PLD方案可显著延长PFS CALYPSO研究实验组与对照组毒性反应发生率 卵巢癌的化疗（4） 腹腔化疗 优点： 肿瘤的局部浓度高 使药物广泛渗透 血中浓度低，降低 副作用 可经门脉吸收 禁忌症： 腹腔严重粘连 全腹放疗史 病变超出腹腔范围 Intraperitoneal chemotherapy has demonstrated superior results to intravenous chemotherapy GOG-172 study, which evaluated patients with stage III disease. The study reported that intraperitoneal cisplatin and intraperitoneal/intravenous paclitaxel resulted in a significant improved PFS and overall survival when compared with intravenous cisplatin and paclitaxel.Thus, intraperitoneal chemotherapy has shown that it results in a 20% reduction of recurrence and 20-25% reduction in risk of death, with survival increasing from 8 to 16 months.However, the use of intraperitoneal chemotherapy is associated with a higher rate of toxicities, with less than 50% of patients completing the recommended six cycles of chemotherapy, and treatment should be selected on an individualized basis. Maintenance Therapy（1） GOG-178 compared three cycles to 12 cycles of paclitaxel (135 mg/m2) following primary treatment. The results showed a benefit in median PFS (28 vs 21 months) favoring the 12 additional cycles of paclitaxel. The trial was closed after this interim analysis showed a benefit and long- term survival data is not available . Maintenance Therapy（2） By contrast, an Italian trial in which patients were assigned to observation versus six cycles of paclitaxel (175 mg/m2 every 3 weeks) after completing primary adjuvant therapy, found no difference in PFS or 3-year overall survival. A Korean trial compared three additional cycles of platinum and paclitaxel to observation after a complete response following first-line therapy and noted that median PFS and overall survival were similar. Maintenance Therapy（3） In addition to paclitaxel and platinum agents, other chemotherapeutic agents have been studied as consolidation therapy. Agents studied include the use of doxorubicin and topotecan; however, both failed to demonstrate a survival benefit. Maintenance Therapy（4） Additionally, the use of molecular targets have been studied, including oregovomab, a monoclonal antibody targeting the tumor antigen CA-125, and yttrium-90-labeled murine HMFG1 (90Y-muHMFG1), both of which failed to demonstrate an improvement in PFS or overall survival. Maintenance Therapy（5） The success of the intraperitoneal route in the primary setting is being extrapolated to the paradigm of consolidation therapy. A recent Phase II trial showed that consolidation therapy with intraperitoneal topotecan is a feasible option but further studies need to be performed. Second-line Chemotherapy（1 ） Until successful consolidation therapy is identified, it is estimated that over 60% of patients will experience disease recurrence after completion of primary therapy . The diagnosis of recurrence may be made based on patient symptoms, elevated CA- 125 level, or with the presence of clinical or radiographic findings of disease Second-line Chemotherapy（2 ） patient may present with an elevated CA-125 alone and the benefit of treatment at this juncture is debatable. Two parallel international trials, A Randomised Trial in Relapsed Ovarian Cancer: Early Treatment Based on CA 125 Levels Alone vs Delayed Treatment Based on Conventional Clinical Indicators (OV05) and European Organization for Research and Treatment of Cancer 55955, which completed accrual in 2005, are designed to determine the most appropriate time to initiate treatment for recurrent disease.However, until these data are available, the decision on when to begin treatment remains controversial. Second-line Chemotherapy（3 ） 6个月内复发 GP RR 31-42% ； G 10-28% 6个月后复发 铂 RR 30-64%，. TC； Liposomal doxorubicin+C 。 Liposomal doxorubicin ；topotecan RR 30% etoposide (34%), paclitaxel (20-45%) gemcitabine (13-22%) Neoadjuvant Chemotherapy all patients with advanced ovarian cancer should be assessed by an experienced gynecologic oncologist to determine the best treatment course for each patient. Molecular Targets（1） Several Phase II, as a single agent, bevacizumab has demonstrated response rates in the range of 10 -22%.When bevacizumab is combined with other cytotoxic agents, response rates of 24-78% have been reported.Phase III studies, comparing carboplatin/paclit