卵巢癌的治疗 21世纪及展望 Judith K. Wolf Professor Gynecologic Oncology

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1 卵巢癌的治疗 21世纪及展望 Judith K. Wolf Professor Gynecologic Oncology
Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX

2 卵巢癌: 2010年 一生罹患卵巢癌的风险：1/71 1 5年生存率(不同诊断年份)2
卵巢癌: 2010年 一生罹患卵巢癌的风险：1/71 1 5年生存率(不同诊断年份)2 % % % 统计学上：死亡率没有变化，但5年生存率统计学上有显著提高。 1. National Cancer Institute. SEER Surveillance, Epidemiology, and End Results Web site. Accessed April 22, 2007. 2. National Cancer Institute. SEER Surveillance, Epidemiology, and End Results Web site. Accessed April 22, 2007. 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site Accessed April 22, 2007. 2. Accessed April 22, 2007.

3 卵巢癌分期 I期 – 局限于卵巢 A. 单侧卵巢 B. 双侧卵巢 C. 细胞学阳性 II期 - 局限于盆腔 A. 扩散到子宫或输卵管
III期 – 播散至上腹部或区域淋巴结阳性 A. 显微镜下转移 B. 肉眼可见的肿瘤结节 < 2 cm C. 肉眼可见的肿瘤结节 > 2 cm IV 期 – 播散到腹腔以外, 胸水或肝实质转移

4 卵巢癌 FIGO 分期系统 分期 描述 发生率 生存率 I 局限于卵巢 20% 73% II 局限于盆腔 5% 45%
分期 描述 发生率 生存率 I 局限于卵巢 % % II 局限于盆腔 % % III 局限于腹部/淋巴结 % % IV 远处转移 % <5% Jelic S, Vasey PA. ESMO minimum clinical recommendations: ovarian cancer. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; October 18-22, 2002; Nice, France. The extent of disease in ovarian carcinoma is reflected in the FIGO staging system. The abbreviated version shown here makes several important points: The majority of patients present with advanced disease (75%), most with specifically stage III disease with seeding throughout the peritoneal cavity. Stage II disease is uncommon because most of these patients will have at least microscopic implants outside the pelvis if a proper laparotomy is done. The staging system predicts well for outcome. Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. Accessed May 2, 2007. FIGO = 国际妇产科联盟

5 卵巢癌细胞减灭术与分期 剖腹探查 活检 (分期) 目的 (减灭肿瘤细胞) 全子宫／双附件切除 腹腔冲洗/ 腹水 (分期) 评估病灶范围
满意的肿瘤切除 腹腔冲洗/ 腹水 (分期) TAH = 全子宫切除术 BSO = 双侧输卵管卵巢切除

6 一线治疗 – 标准治疗选择 最大程度地减灭肿瘤细胞 残余肿瘤最大径<1cm 铂类 + 紫杉醇类化疗 (卡铂 + 紫杉醇)
一线治疗 – 标准治疗选择 最大程度地减灭肿瘤细胞 残余肿瘤最大径<1cm Surgery is usually the first step in the care of patients. Every effort should be made to leave behind minimal residual disease. Most patients with ovarian cancer will receive chemotherapy as part of their primary treatment. Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) 铂类 + 紫杉醇类化疗 (卡铂 + 紫杉醇)

7 化疗 目前美国标准的一线化疗为：卡铂, AUC 6 到 7.5, 紫杉醇 175 mg/m2 ，每21天用药，重复6疗程
近几十年来几项研究的结果 GOG 1111 和 OV 102研究 – 紫杉醇/顺铂 vs 环鳞酰胺/顺铂 GOG 1583 和 AGO OVAR-34研究 – 卡铂替换顺铂 1. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1): Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92(9): Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17): du Bois AD, Lück HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95(17): GOG 111 and OV 10: In GOG protocol 111, patients with large volume advanced disease were randomized to either cyclophosphamide plus cisplatin, or paclitaxel plus cisplatin. This study showed superiority for the paclitaxel and cisplatin regimen compared with cyclophosphamide and cisplatin in regards to: response rate, clinical complete response rate, percentage of patients grossly disease-free at second-look laparotomy, progression-free survival, and overall survival. A confirmatory study from a European-Canadian consortium, OV 10, also randomized patients with stage IIB through IV disease to either cyclophosphamide and cisplatin or paclitaxel and cisplatin. This trial included both small volume and large volume patients. The paclitaxel and platinum combination was superior to the cyclophosphamide and platinum combination in regard to response rate, clinical complete response rate, progression-free survival, and overall survival. The numbers were similar to those seen with GOG 111. GOG 158 and AGO: Two large trials have been completed, a German trial and a U.S. GOG trial. In the German trial, 798 patients with advanced ovarian cancer were randomized to either paclitaxel and cisplatin or paclitaxel and carboplatin. The results showed the 2 regimens to be equivalent with regard to response rate, clinical complete response rate, progression-free survival, and overall survival. The large number of patients in this study made this conclusion possible. GOG protocol 158, a study that focused on patients with stage III optimal or minimal residual disease, confirmed these results. Patients were again randomized to either paclitaxel and cisplatin or paclitaxel and carboplatin. The results showed the 2 regimens to be equivalent with regard to pathologic complete response rate and progression-free survival. These 2 large trials led to the conclusion that cisplatin and carboplatin were equivalent in combination with paclitaxel, and that it would be feasible to treat these patients with the easier regimen of paclitaxel plus carboplatin. Drugs: carboplatin (Paraplatin®) cisplatin (Platinol®-AQ) cyclophosphamide (Cytoxan®, Neosar®) paclitaxel (Onxol®, Taxol®) 1. McGuire WP, et al. N Engl J Med. 1996;334(1): Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9): Ozols RF, et al. J Clin Oncol. 2003;21(17): du Bois AD, et al. J Natl Cancer Inst. 2003;95(17): GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie

8 紫杉醇在卵巢癌一线治疗中的作用 GOG 1321 14.1 26.3 16.4 30.2 10.8 25.9 ICON32 17.3
研究 入组人数 方案 中位 PFS (月) 中位 OS (月) GOG 1321 377例 III 期非满意减灭术，及IV期患者 顺铂/ 紫杉醇 (24 小时) x 6 14.1 26.3 顺铂 100 mg/m2 x 6 16.4 30.2 紫杉醇 200 mg/m2 (24 小时)* 10.8 25.9 ICON32 2074例 I－IV期患者 卡铂/ 紫杉醇 (3 小时) 17.3 36.1 卡铂 或 CAP 16.1 35.4 1. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000;18(1): 2. International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2000;360(9332): Two large randomized trials raised questions about the benefits of paclitaxel in first-line therapy of ovarian cancer. GOG protocol 132 compared high dose single agent cisplatin (100 mg/m2), high dose single agent paclitaxel (200 mg/m2/24 hours) and the combination (paclitaxel 135 mg/m2/24 hours and cisplatin 75 mg/m2), which used lower doses of each drug. Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms. More patients were able to complete all 6 cycles of prescribed therapy in the combination arm, and it had a better toxicity profile. Therefore, the authors concluded that the combination of cisplatin and paclitaxel remains the preferred initial treatment option. ICON3 showed that a control arm of single-agent carboplatin (CAP) was as effective as paclitaxel plus carboplatin. Given the favorable toxicity profile of single-agent carboplatin, the authors concluded that this is a reasonable option as first-line chemotherapy for ovarian cancer. Drugs: carboplatin (Paraplatin®) cisplatin (Platinol®-AQ) paclitaxel (Onxol®, Taxol®) *单药完全缓解/部分缓解率：紫杉醇(42%) vs 顺铂 (67%), P <.001 CAP = 环鳞酰胺, 阿霉素, 顺铂 GOG = 妇科肿瘤组 ICON = 国际卵巢癌协作组 OS = 总生存时间 PFS = 无进展生存时间 1. Muggia FM, et al. J Clin Oncol. 2000;18(1): International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):

9 卵巢癌一线治疗中紫杉醇给药方案 GOG 1581 792例 III 期满意减灭术后患者 19.4 48.8 20.7 56.7 AGO2
研究 入组患者 方案 中位 PFS (月) 中位 OS (月) GOG 1581 792例 III 期满意减灭术后患者 顺铂 75 mg/m2 紫杉醇 135 mg/m2 (24 h) 19.4 48.8 卡铂 AUC 7.5 紫杉醇 175 mg/m2 (3 h) * 20.7 56.7 * 疾病进展的相对危险度为 0.88 (95% CI) 疾病死亡的相对危险度为 0.86 (95% CI) HR =0.86 (99% CI) AGO2 798例 IIB-IV期患者 顺铂 75 mg/m2 紫杉醇 185 mg/m2 (24 h) 19.1 44.1 卡铂AUC 6 紫杉醇185 mg/m2 (3 h) 17.2 43.3 HR = 1.050 (95% CI) HR =1.045 顺铂联合化疗组毒性反应更大 1. Bookman MA, Greer BE, Ozols RF. Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95(17): Two trials have compared cisplatin paclitaxel with carboplatin paclitaxel. Both GOG 158 and an AGO trial found that the two regimens were of comparable efficacy. In both trials non-hematologic toxicities including nausea, vomiting, ototoxicity, renal toxicity, and peripheral neuropathy were less frequent in the paclitaxel carboplatin arm compared with the cisplatin paclitaxel arm. Drugs: carboplatin (Paraplatin®) cisplatin (Platinol®-AQ) paclitaxel (Onxol®, Taxol®) AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = 可信区间 GOG = 妇科肿瘤组 HR = 比值比; OS = 总生存时间 PFS = 无进展生存时间 RR = 相对危险度 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149– du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):

10 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC: 临床试验 随机化分组治疗 卡铂 AUC 5, + 多西他赛 75 mg/m2 (1 h) 每3周一次 x 6 卡铂 AUC 5, + 紫杉醇175 mg/m2 (3 h) 每3周一次 x 6 Ic-IV期卵巢癌 原发性腹膜癌 N = 1077 Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst Nov 17;96(22): The SCOTROC (Scottish Randomized Trial in Ovarian Cancer) trial compared docetaxel-carboplatin with paclitaxel-carboplatin in newly diagnosed ovarian cancer. Drugs: carboplatin (Paraplatin®) docetaxel (Taxotere®) paclitaxel (Onxol®, Taxol®) SCOTROC = 苏格兰卵巢癌随机临床研究 Q3W = 每3周一次 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):

11 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC: 研究结果 参数 多西他赛-卡铂 紫杉醇-卡铂 反应率 (标准) % 60% 反应率 (CA-125) % 77% 无进展生存时间 月 月 24个月时的总生存率 % 69% Drugs: carboplatin (Paraplatin®) docetaxel (Taxotere®) paclitaxel (Onxol®, Taxol®) DC = 多西他赛-卡铂 PC = 紫杉醇-卡铂 SCOTROC = 苏格兰卵巢癌随机临床试验 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):

12 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC: 结论 PC vs DC: PC 仍是标准方案 除了神经毒性和关节/肌酸痛，总体毒性反应方面紫杉醇组更优越 两组方案中不同紫杉类药物的神经毒性应该是可逆的 多西他塞组的骨髓毒性更严重，可能会妨碍卡铂最优剂量的使用 出于效益最大化，毒性最小化的考量，紫杉醇/卡铂 方案仍是卵巢癌治疗的标准方案 Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96(22): Drugs: carboplatin (Paraplatin®) docetaxel (Taxotere®) paclitaxel (Onxol®, Taxol®) DC = 多西他塞-卡铂 PC = 紫杉醇-卡铂 Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):

13 GOG 182-ICON5 III/IV期卵巢癌的国际研究
方案 I (对照组l) 紫杉醇 175 mg/m2 IV (3 h) d 1 卡铂 AUC 6 IV d 1 方案 II (三药 A) 紫杉醇 135 mg/m2 IV (3 h) d 1 卡铂 AUC 5 IV d 1 吉西他滨 800 mg/m2/d IV d 1, 8 方案I, II, III: 8 疗程, 间隔21天 方案 IV 和 V: 4 疗程, 间隔21天 随机化 所有患者 每一治疗组患者比例相同 主要终点事件: 无进展生存时间, 总生存时间, 反应率 方案 III (三药 B) 紫杉醇 135 mg/m2 IV (3 h) d 1 卡铂 AUC 5 IV d 1 脂质体阿霉素30 mg/m2 IV d 1 每两疗程一次 Bookman MA, et al. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clinical Oncol. 2006;24(18S):Abstract 5002. Drugs: carboplatin (Paraplatin®) doxorubicin (Adriamycin®, Doxil® Rubex®) gemcitabine hydrochloride (Gemzar®) paclitaxel (Onxol®, Taxol®) topotecan hydrochloride (Hycamtin®) 方案 IV (序贯部分 A) 卡铂 AUC 5 IV d 3 拓扑替康 mg/m2/d IV d 1-3 方案 IV (序贯部分 B) 紫杉醇 175 mg/m2 IV (3 h) d 1 卡铂 AUC 6 IV d 1 方案 V (序贯部分 A) 卡铂 AUC 6 IV d 8 吉西他滨 1000 mg/m2/d IV d 1, 8 方案 V (序贯部分 B) 紫杉醇 175 mg/m2 IV (3 h) d 1 卡铂 AUC 6 IV d 1 GOG =妇科肿瘤组; ICON = 国际卵巢癌协作组; OS = 总生存时间; PFS = 无进展生存时间; RR = 反应率 Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.

14 GOG0182-ICON5: 无进展生存时间 无进展生存的患者比例 随机化分组后的时间（月） 治疗方案
Median PFS and HR (95% CI) ( ) ( ) ( ) ( ) Bookman MA, et al. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-liposomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol. 2006;24(18S):Abstract 5002. Drugs: carboplatin (Paraplatin®) doxorubicin (Adriamycin®, Doxil® Rubex®) gemcitabine hydrochloride (Gemzar®) paclitaxel (Onxol®, Taxol®) topotecan hydrochloride (Hycamtin®) 随机化分组后的时间（月） C = 卡铂 D = 脂质体阿霉素 G = 吉西他滨 P = 紫杉醇; PFS = 无进展生存时间 T = 拓扑替康 Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.

15 GOG0182-ICON5: 总生存时间 生存的患者比例 随机化分组后的时间（月） Median OS and HR (95% CI)
( ) ( ) ( ) ( ) Bookman MA, et al. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-liposomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol. 2006;24(18S):Abstract 5002. Drugs: carboplatin (Paraplatin®) doxorubicin (Adriamycin®, Doxil® Rubex®) gemcitabine hydrochloride (Gemzar®) paclitaxel (Onxol®, Taxol®) topotecan hydrochloride (Hycamtin®) 随机化分组后的时间（月） C = 卡铂 D = 脂质体阿霉素 G = 吉西他宾 P = 紫杉醇; 0S = 总生存时间 T = 吉西他宾 Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.

16 GOG目前在研一线治疗临床试验 GOG 218 > 显微镜下残瘤的 上皮性卵巢癌、原发性腹膜癌 紫杉醇 卡铂 安慰剂 紫杉醇 卡铂
贝伐单抗 紫杉醇 卡铂 贝伐单抗 Drugs: bevacizumab injection (Avastin®) carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) 安慰剂 ×16 疗程 安慰剂 ×16 疗程 贝伐单抗 ×16 疗程 EOC = 上皮性卵巢癌 FT = 输卵管 GOG = 妇科肿瘤组 PFS = 无进展生存时间 PPC = 原发性腹膜癌 QOL = 生活质量 N = 2,000 名患者 生存以及无进展生存时间为主要终点事件 生物学和生活质量也是终点事件

17 EORTC-55971 IIIc或IV期上皮性卵巢癌 先行细胞减灭术 vs 新辅助化疗 细胞减灭术 + 3 疗程铂类为基础的化疗
化疗有反应或病灶稳定的患者行间歇性 肿瘤细胞减灭术 可以行间歇性 肿瘤细胞减灭术 Clinical Trials (PDQ®). National Cancer Institute Web site. Accessed May 11, 2007. EORTC is examining OS and PFS in patients with stage IIIC or IV ovarian cancer (allows peritoneal & fallopian tube carcinoma) treated with neoadjuvant chemotherapy followed by interval debulking surgery vs upfront cytoreductive surgery followed by chemotherapy with or without interval debulking surgery. This trial closed to accrual December We are awaiting results. Drugs: paclitaxel (Onxol®, Taxol®) 重复化疗或 二探术 重复化疗或 二探术 EORTC = 欧洲癌症治疗及研究机构 IDS = 间歇性肿瘤细胞减灭术 SLS = 二探术 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. Accessed June 12, 2007.

18 GC vs TC 诱导化疗后紫杉醇巩固化疗: 研究设计
经组织学诊断以及手术切除的IC-IV期上皮性卵巢癌，原发性腹膜癌以及输卵管癌 GC方案诱导化疗 吉西他滨 1000 mg/m2 Days 1, 8 + 卡铂 AUC 5 Day 1 x 6 疗程，每21天重复 TC方案诱导化疗 紫杉醇 175 mg/m2 Day 1 + 卡铂 AUC 6 Day 1 x 6 疗程，每21天重复 临床完全缓解 除了完全缓解以外 的其他情况 (PR, SD, PD) 除了完全缓解以外 的其他情况 (PR, SD, PD) 选择紫杉醇巩固化疗 紫杉醇 135 mg/m2 每28天重复，用12疗程 单药交替 紫杉醇 175 mg/m2 Day 1 单药交替 吉西他滨 1000 mg/m2 Days 1, 8 Gordon A, et al. ASCO Abstract 5536.

19 GC vs TC 诱导化疗后紫杉醇巩固化疗: 反应率
最佳反应率, n (%) GC诱导化疗 (n = 66) TC诱导化疗 (n = 58) P 值 完全缓解* 30 (45.5) 26 (44.8) 部分缓解 13 (19.7) 12 (20.7) 病情稳定 5 (7.6) 8 (13.8) 病灶进展 6 (9.1) 4 (6.9) 无临床数据 12 (18.2) 总反应率 (完全缓解 +部分缓解) 43 (65.2) 38 (65.5)  .999 疾病控制率 (完全缓解 +部分缓解+病灶稳定) 48 (72.7) 46 (79.3) .410 DCR, disease control rate *完全缓解 要求 CA-125水平降至正常. Gordon A, et al. ASCO Abstract 5536.

20 GC vs TC 诱导化疗后紫杉醇巩固化疗: 患者的毒性反应情况
毒性反应, n (%) GC诱导化疗 (n = 219) TC诱导化疗 (n = 220) P 值 血液学毒性 G3/4 血小板减少 88 (40.2) 55 (25.1) 30 (13.6) 10 (4.5)  .0001 G3/4 贫血 52 (23.7) 20 (9.1) 非血液学毒性  G2 神经系统病变 24 (11.0) 43 (19.5) .0165 G2 脱发 79 (36.1) 110 (50.0) .0038 血小板输注 7 (3.2) 0 (0) .0073 Gordon A, et al. ASCO Abstract 5536.

21 传统vs剂量密集型 TC化疗 (新型): 研究设计
II-IV期上皮性卵巢癌, 原发性腹膜癌或输卵管癌 根据以下因素分层 残余肿瘤最大径 ≤ 1 cm vs > 1 cm; FIGO分期 II 期 vs III期 vs IV期； 组织学类型: 透明细胞型/粘液性 vs 浆液性/其他类型 NOVEL, New Ovarian Elaborate Trial 传统TC化疗(c-TC) 紫杉醇 180 mg/m2 Day 1 + 卡铂 AUC 6.0 Day 1 每21天重复共 6-9 疗程 剂量密集型 TC方案周疗 (dd-TC) 紫杉醇80 mg/m2 Days 1, 8, 15 + 卡铂 AUC 6.0 Day 1 每21天重复共 6-9 疗程 Isonishi S, et al. ASCO Abstract 5506.

22 传统vs剂量密集型 TC化疗 (新型): 临床反应
测量 病例数, % 传统TC化疗 (n = 135) 剂量密集TC周疗 (n = 147) 客观反应率 53 56 完全缓解率 16 20 部分缓解率 38 36 未完成 31 29 疾病进展 7 3 无法评估 9 12 NOVEL, New Ovarian Elaborate Trial P = .72 Isonishi S, et al. ASCO Abstract 5506. Evaluated by WHO criteria 22

23 传统vs剂量密集型 TC化疗 (新型): 无进展生存时间 治疗 n 进展 中位PFS, 月 P 值 HR 95 %CI 传统TC 319
Isonishi S, et al. ASCO Abstract 5506. 1.0 0.9 剂量密集型TC 0.8 传统TC 0.7 0.6 无进展生存的患者比例 0.5 0.4 0.3 0.2 0.1 0.0 6 12 18 24 30 36 42 48 54 随机化入组后的时间（月） 治疗 n 进展 中位PFS, 月 P 值 HR 95 %CI 传统TC 319 200 17.2 剂量密集TC 312 160 28.0 .0015 0.714 23

24 卵巢癌：临床病程 二次肿瘤细胞减灭术 治愈 间歇性肿瘤细胞减灭术 二探术 诊断 进展 死亡 症状 化疗 #1 化疗 #2 化疗 #3+
巩固/ 维持 After diagnosis of ovarian carcinoma, the clinical course generally follows a path that includes cytoreductive surgery and multiple cycles of chemotherapy treatment if the disease progresses. To distinguish between consolidation therapy and maintenance therapy, “consolidation” implies a very short course of a different form of therapy, and “maintenance” implies a more drawn-out course of a similar type of therapy. 治愈 支持治疗 分期 初次肿瘤细胞减灭术 24

25 复发性卵巢癌 治疗目的: 延长生存时间 延缓疾病进展时间 控制疾病相关症状 将治疗相关的并发症降至最低 维持或提高生活质量 25

26 影响复发性卵巢癌治疗的因素 无治疗间期 前次化疗方案的数目 前次治疗的毒性反应 病灶的体积和部位 巩固/维持治疗的影响 对前次化疗的反应
先前生长因子的使用情况 是否需要输血 神经病变 病灶的体积和部位 腹水/胃肠道症状 一般情况 What are some of the factors that help determine future treatment recommendations when ovarian cancer recurs? The treatment-free interval is extremely important to determine optimal therapy for recurrent disease. We also consider the impact of consolidation/maintenance therapy. Many of us continue to use paclitaxel based on the consolidation or maintenance studies. We consider the number of prior regimens and the response the patient had to these prior regimens. How fast did their CA-125 decline? What kind of toxicity did the patient experience from prior therapy? Did they require growth factor support, transfusion support, and do they have residual peripheral neuropathy? The volume and site of disease is also one of the factors. A patient who has ascites and GI symptomatology is quite different than someone whose performance status is zero and really just has a tumor marker or small volume disease. 26

27 卵巢癌缓解患者的随访选择 二探手术 体格检查 CA-125 影像学 包括盆腔检查 CT 扫描 MRI? PET 扫描?
To detect recurrent ovarian cancer, we have several surveillance options: One could argue that a second-look laparotomy is actually a surveillance option. This is a controversial procedure, and is usually most appropriate as part of a clinical trial. The pendulum has swung away from routine use of second-look laparotomy, but it is still done occasionally. Physical examination, including pelvic exam, can help detect occult disease in the pelvis that’s not well imaged on a CT scan or other imaging modalities. CA-125 is not always a reliable marker for ovarian cancer. There can be false positive elevations or increases in CA-125, which is one of the reasons why it’s not reliable for ovarian cancer screening. In a patient with a history of ovarian cancer, particularly if their CA-125 was elevated at initial diagnosis, it can be a valuable marker that can aid in following disease. We recognize that some ovarian cancers have minimal or no CA-125 secretion. This appears to be particularly true for the non-serous histologies of ovarian cancer; clear cell, mucinous and endometrioid. For patients with these histologies we may be limited to detecting disease when it has crossed a threshold of symptomatic or measurable disease volume. Many questions surround the use of imaging as a surveillance option: Should we do routine imaging? Should we use this only in certain settings? What type of imaging is best? CT scan, MRI, or PET scan? Of these options, the PET/CT imaging has become somewhat more popular, but clinicians are still discovering the best way to use this. CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography 27

28 卵巢癌: 何谓复发? CA-125持续性上升 CA-125 大于 100 影像学复发 有症状提示复发 体检发现 以上联合 28

29 卵巢癌何时复发? 患者人群 研究 治疗 无进展生存 满意减灭术后的III期 GOG 114 IV 卡铂 & 紫杉醇, IP 顺铂 28 月
24 月 GOG 158 IV 紫杉醇 & 卡铂 21 月 IV 紫杉醇 & 顺铂 22 月 19 月 18 月 非满意减灭的III/IV期 GOG 111 GOG 162 IV 紫杉醇 顺铂 12 月 GOG 152 11 月 IC-IV期 SCOTROC 多西他塞 卡铂 15 月 紫杉醇 卡铂 所有 III & IV期 GOG 182 IV 紫杉醇/卡铂 x 8 16 月 This is a summary primarily of GOG studies, along with the SCOTROC trial to emphasize the median progression-free survival time. This emphasizes that the optimal patients (studies shown at the top) generally do better. The IV studies, the suboptimal studies, the broad combined studies with the SCOTROC and GOG 182 provide data to identify the median time to progression. We recognize from this data that there are differences based on each patient’s disease status at the time they were diagnosed. Drugs: carboplatin (Paraplatin®) cisplatin (Platinol®-AQ) docetaxel (Taxotere®) paclitaxel (Onxol®, Taxol®) References: GOG 114: Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19(4): GOG 172: Armstrong DK, Bundy B, Wenzel L, et al.. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New Engl J Med. 2006;354(1):34-43. GOG 158: Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17): GOG 111: McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New Engl J Med. 1996;334:1-6. GOG 162: Spriggs D, Brady M, Vacarello L, et al. A phase III randomized trial of IV cisplatin plus a 24-or 96-hour infusion of paclitaxel in epithelial ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol. 2007;25(28): GOG 152: Rose PG, Nerenstone S, Brady M, et al. Secondary surgical cytoreduction in advanced ovarian carcinoma: a Gynecologic Oncology Group study. N Engl J Med. 2004;351(24): SCOTROC: Vasey PA, Jayson GC, Gordon A, et al: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96: GOG 182: Bookman MA for the Gynecologic Cancer InterGroup (GCIG). GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol. 2006;24(18S):5002. Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel 29

30 卵巢癌治疗有效药物 FDA 批准 非FDA 批准, 纲要列表 非FDA 批准, 非纲要列表 六甲密胺 卡铂 顺铂 吉西他宾/ 紫杉醇
脂质体阿霉素 托泊替康 非FDA 批准, 纲要列表 苯丁酸氮芥 环鳞酰胺 多西他塞 阿霉素 表柔比星 依托泊苷 5-FU/LV 吉西他滨 异环鳞酰胺 伊立替康 马法兰 甲氨蝶呤 塞替帕 长春瑞滨 非FDA 批准, 非纲要列表 芳香化酶 贝伐单抗 培美曲塞 三苯氧胺 Drugs: 5-FU/LV, or 5-fluorouracil/leucovorin (Adrucil®/Wellcovorin®) altretamine (Hexalen®) bevacizumab injection (Avastin®) carboplatin (Paraplatin®) chlorambucil (Leukeran®) cisplatin (Platinol®-AQ) cyclophosphamide (Cytoxan®, Neosar®) docetaxel (Taxotere®) doxorubicin (Adriamycin®, Doxil® Rubex®) epirubicin injection (Ellence®) etoposide oral and injection (Etopophos®, Toposar®, VePesid®) gemcitabine hydrochloride (Gemzar®) ifosfamide (Ifex®) ironotecan (Camptosar®) melphalan (Alkeran®) methotrexate (Rheumatrex®, Trexall®) paclitaxel (Onxol®, Taxol®) pemetrexed (Alimta®) tamoxifen (Nolvadex®) thiotepa (Thioplex®) topotecan hydrochloride (Hycamtin®) vinorelbine tartrate (Navelbine®) 30

31 无铂间期对于反应率的影响 0-6 17% 10% 7-12 27% 29% 13-18 33% 63% 19-24 94% >24
对二线铂类化疗的反应率（%） 无铂间期 (月) Markman Gore Blackledge 0-6 17% 10% 7-12 27% 29% 13-18 33% 63% 19-24 94% >24 59% 57% 非铂类治疗 15% 20% 30% This data looks back in time at data presented by Markman and Gore, comparing the time patients were off of therapy with the expected response to platinum retreatment. Because these are older studies, these patients probably received single-agent carboplatin. They had nearly a 60 percent response rate if they had been off of therapy for more than two years. This response rate is significantly higher than you would expect compared with other agents. References: Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3): Gore ME, Fryatt I, Wiltshaw E, et. al. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol. 1990;36: Blackledge G, Lawton F, Redman C, et al. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials. Br J Cancer. 1989;59: Markman M, et al. J Clin Oncol. 1991;9(3): Gore ME, et al. Gynecol Oncol. 1990;36: Blackledge G, et al. Br J Cancer. 1989;59: 31

32 卵巢癌初次复发 敏感病例定义 0 3 6 12 18 24 月 化疗难治 化疗耐药 化疗敏感 “非常敏感” 初 次 治 疗
初 次 治 疗 月 化疗难治 化疗耐药 化疗敏感 The 6-months timeframe as a definition for platinum-sensitive vs platinum-resistant ovarian cancer patients is primarily for clinical trial purposes. Sensitivity and resistance to platinum is better viewed as a continuum. The definitions shown here for sensitivity were developed based on measurable ovarian cancer at first relapse and did not take into account CA-125 levels. “非常敏感” 定义为可测量病灶的复发, 而非生化 (CA-125)复发 32

33 ICON 4 概要 随机化分组 传统的铂类为主化疗 复发或原发卵巢癌 需要化疗的腹膜癌 先前经过铂类为主的化疗 紫杉醇联合铂类化疗 先前化疗
卡铂 (31%) 紫杉醇/铂类 (40%) 其他 (30%) 75%的患者无治疗间期 > 12 个月 Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) Reference: Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361: ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval Parmar MK, et al. Lancet. 2003;361: 33

34 ICON 4 反应率 (差异为12%; 95% CI -0.1% - 24%; p=0.06)
Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) Reference: Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361: CR = 完全缓解; ICON =国际卵巢癌协作组; Pac = 紫杉醇; Plat = 铂类; PR = 部分缓解; Parmar MK, et al. Lancet. 2003;361: 34

35 卵巢癌: ICON 4 无进展生存时间 Hazard ratio = 0.76
1.0 0.9 Hazard ratio = 0.76 (95% CI ; p < 0.001) 0.8 0.7 1年时的绝对差异 = 10% (40% to 50%; 95% CI 4% to 15%) 0.6 无进展生存的患者比例 0.5 0.4 0.3 0.2 Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) Reference: Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361: Pac-Plat Plat 0.1 0.0 1 2 3 4 从随机化入组开始计算的时间（年） 有风险的患者 紫杉醇-铂类 铂类 ICON = 卵巢癌国际协作组; Pac = 紫杉醇; Plat = 铂类 Parmar MK, et al. Lancet. 2003;361: 35

36 ICON 4: 总生存时间 Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023)
1.0 0.9 2年时的绝对差异 = 7% (50% to 57%; 95% CI 1% to 12%) 0.8 0.7 生存患者的比例 0.6 0.5 0.4 0.3 0.2 Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) Reference: Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361: Pac-Plat Plat 0.1 0.0 1 2 3 4 从随机化入组开始计算的时间（年） 有风险的患者 紫杉醇-铂类 铂类 ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Parmar MK, et al. Lancet. 2003;361: 36

37 吉西他滨/卡铂 vs 卡铂: 研究设计 铂类治疗后大于6个月复发 分层 吉西他滨 1,000 mg/m2 days 1 + 8 Plus
复发性卵巢癌 铂类治疗后大于6个月复发 分层 无进展间期 (6-12,>12个月) 一线化疗 (铂类 ± 紫杉醇) 可测量 vs 可评估 主要终点事件 = PFS 吉西他滨 1,000 mg/m2 days Plus 卡铂 AUC 4 day 1 随 机 化 分组 每21天重复 × 6 疗程 卡铂 AUC 5 day 1 Drugs: carboplatin (Paraplatin®) gemcitabine hydrochloride (Gemzar®) Reference: Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol ; 24: 每21天重复 × 6 疗程 Carbo = 卡铂 Gem = 吉西他滨 PFI = 无进展间期 PFS = 无进展生存时间 Pfisterer J, et al. J Clin Oncol. 2006; 24: 37

38 AGO OVAR 2.5 主要终点事件: 无进展生存时间
3 6 9 12 15 18 21 24 27 30 33 36 39 0.0 0.2 0.4 0.6 0.8 1.0 无进展生存时间 (月) 无进展的患者比例 Log-rank 检验P值 = 未调整 HR = 0.72 (0.57 to 0.90) 调整后的 HR* = 0.71 (0.57 to 0.89) 吉西他滨: 中位 = 8.6 个月 进展: 12.4% 吉西他滨组 (N=178) Drugs: carboplatin (Paraplatin®) gemcitabine hydrochloride (Gemzar®) Reference: Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol ; 24: 卡铂组 (N=178) 卡铂: 中位 = 5.8 个月 进展: 12.9% * 根据无进展生存间期、肿瘤大小调整 AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = 吉西他宾; Cb = 卡铂 Pfisterer J, et al. J Clin Oncol. 2006;24: 38

39 AGO OVAR 2.5 有效性结果: 总生存时间 中位 = 18.0 个月 死亡: 18.5%
1.0 0.9 中位 = 18.0 个月 死亡: 18.5% 吉西他滨组 (N=178) 0.8 卡铂组 (N=178) 0.7 生存的患者比例 0.6 Log-rank p-value = 未调整 HR = 0.96 (0.75 to 1.23) 经调整* HR = 0.92 (0.72 to 1.16) 0.5 0.4 中位 = 17.3 mo 死亡: 22.5% 0.3 Drugs: carboplatin (Paraplatin®) gemcitabine hydrochloride (Gemzar®) Reference: Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol ; 24: 0.2 0.1 0.0 6 12 18 24 30 36 42 48 54 60 月 * 根据无进展生存间期、肿瘤大小、患者一般状态调整 AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = 吉西他滨; Cb = 卡铂 Pfisterer J, et al. J Clin Oncol. 2006;24: 39

40 病例入组已完成 (目标入组 864名患者) 无进展生存时间为主要终点事件
GCIG CALYPSO 临床试验 病例入组已完成 (目标入组 864名患者) 无进展生存时间为主要终点事件 脂质体阿霉素 30 mg/m2 卡铂 AUC = 5 q 28 days x 6 随 机 分 组 卵巢癌铂类 敏感病例分层 : < 0.5 cm > cm 紫杉醇 175 mg/m2 卡铂 AUC = 5 q 21 days x 6 Trial is ongoing: For more details: Drugs: carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) pegylated liposomal doxorubicin (Doxil®) GCIG = Gynecologic Cancer Intergroup PFS = 无进展生存时间 PLD = 脂质体阿霉素 40

41 Farletuzumab (MORAb-003)在铂类敏感上皮性卵巢癌中的研究: 设计原理
FRA 在大多数的上皮性卵巢癌中过表达; 在大多数正常组织中不表达 MORAb-003与FRA的结合阻碍了Lyn激酶诱导的磷酸化过程; 介导了FRA表达的肿瘤细胞杀伤作用; 在肿瘤细胞异种移植物模型中表现出抑制肿瘤生长的作用 MORAb-003单药的 I 期研究证明：该药物没有显著副反应，提示对于铂类耐药的上皮性卵巢癌有效。 EOC, epithelial ovarian cancer; FRA, folate receptor alpha.

42 MORAb-003 在铂类敏感卵巢癌中应用: II期临床研究设计
铂类敏感的上皮性卵巢癌 6-18 个月缓解后初次复发 伴有CA125 评估的病灶 (入组58例; 符合研究条件54例) 无症状的复发患者 有症状的复发病例 先采用 卡铂/紫杉类 方案化疗 + Farletuzumab 共 6 疗程 (n = 26) 采用单药 Farletuzumab 直至疾病进展 (n = 28) EOC, epithelial ovarian cancer 单药 ORR 联合用药 ORR 对有反应者Farletuzumab 维持 比较第一次和第二次缓解时间的长短 Armstrong DK, et al. ASCO Abstract 5500.

43 MORAb II期研究: 治疗组 所有组 MORAb-003: 100 mg/m2 周疗 试验期 ：前6 名受试者 接受37.5 mg/m2 和 后6名受试者 接受62.5 mg/m2 联合治疗组每 21天用药 x 6 疗程 卡铂: AUC 5-6 紫杉类 紫杉醇 175 mg/m2 经 3 小时 或 多西他塞 75 mg/m2 Armstrong DK, et al. ASCO Abstract 5500.

44 初次和再次缓解的时间比较: n = 6 2 10.8 19.1+ 3 10.1 15.8+ 4 9.5 9.6+ 5 8.2 复发 6
受试者 初次缓解, 月 再次缓解, 月 状态 1 8.3 19.5+ 仍在缓解状态 2 10.8 19.1+ 3 10.1 15.8+ 4 9.5 9.6+ 5 8.2 复发 6 6.5 7.8+ Data as of May 5, 2008. Armstrong DK, et al. ASCO Abstract 5500.

45 根据RECIST判定 MORAb-003-002 的临床反应率 (联合化疗)
最佳反应率 完全缓解: 7.4% 部分缓解: 62.9% 疾病稳定: 25.9% 疾病进展: 3.7% 根据截止2007年12月3日提交的所有扫描结果 (~ 30%) 根据每家医疗机构对疗效的独立判定 MORAb-003 耐受性良好; 在联合化疗组未见毒性增加 总有效率: 70.3% 患者获益: 96.3% Armstrong DK, et al. ASCO Abstract 5500.

46 二次肿瘤细胞减灭术 有争议 定义不一致 二次细胞减灭术的收益似乎仅限于那些对于术后化疗有效的患者: 无进展间期>12月 孤立复发病灶
肾脏 切除的肝脏 膈肌 下腔静脉 肿块 肾静脉 二次肿瘤细胞减灭术 有争议 定义不一致 二次细胞减灭术的收益似乎仅限于那些对于术后化疗有效的患者: 无进展间期>12月 孤立复发病灶 病灶 完全切除 PFI = 无进展间期 46

47 卵巢癌二次肿瘤细胞减灭术: 术后生存 作者 Janicke Segna Zang Gadducci Eisenkop Munkarah
卵巢癌二次肿瘤细胞减灭术: 术后生存 作者 Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay 总数/范围 年代 1992 1993 2000 2001 2002 患者 30 100 60 114 25 148 46 553 中位生存时间 月 16 16.6 13 21 16.8 26 13-26 进展间期 月 <12 <17.5 <24 中位生存时间 月 8 8.8 15 25 42 12 6 6-42 进展间期 月 >12 >17.5 >36 >24 12-24 中位生存时间 月 (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 This slides summarizes retrospective reviews of secondary cytoreduction of ovarian cancer published between 1992 and The 1st median Survival column shows the overall median survival after surgery. The 2nd median survival column is the median survival of patients who had surgery for an ovarian cancer recurrence primarily with < 12 mos disease-free interval. The 3rd median survival column is the median survival of patients who had surgery for an ovarian cancer recurrence with >12 mos disease-free interval. These data suggest that survival may be improved if surgery is performed for "late" ovarian cancer recurrences, ie >12 mos disease-free interval. References: Janicke F, Holscher M, Kuhn W, et al. Radical surgical procedure improves survival time in patients with recurrent ovarian cancer. Cancer. 1992;70(8): Segna RA, Dottino PR, Mandeli JP, et al. Secondary cytoreduction for ovarian cancer following cisplatin therapy. J Clin Oncol. 1993;11(3): Zang RY, Zhang ZY, Li ZT, et al. Effect of cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer. J Surg Oncol. 2000;75(1):24-30. Gadducci A, Iacconi P, Cosio S, et al. Complete salvage surgical cytoreduction improves further survival of patients with late recurrent ovarian cancer. Gynecol Oncol. 2000;79(3): Eisenkop SM, Friedman RL, Spirtos, NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Cancer. 2000;88(1): Munkarah A, Levenback C, Wolf JK, et al. Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer. Gynecol Oncol May;81(2): Scarabelli C, Gallo A, Carbone A. Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma. Gynecol Oncol. 2001;83(3): Tay EH, Grant PT, Gebski V, et al. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Obstet Gynecol. 2002;99(6): TTP = 进展间期 47

48 GOG 213-研究负责人Robert Coleman
复发性卵巢癌或腹膜癌 无治疗间期 >6月 手术 是 随机入组 非手术 适合手术? 否 Drugs: bevacizumab injection (Avastin®) carboplatin (Paraplatin®) paclitaxel (Onxol®, Taxol®) Reference: Gynecologic Oncology Group, National Cancer Institute. Carboplatin and Paclitaxel With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) March 16, Available from: Identifier: NCT 卡铂 + 紫杉醇 卡铂+紫杉醇 + 贝伐单抗 + 贝伐单抗维持治疗 GOG = 妇科肿瘤组 TFI =无治疗间期 48

49 无铂间期对反应率的影响 0-6 17% 10% 7-12 27% 29% 13-18 33% 63% 19-24 94% >24
对二线铂类化疗的反应率（%） 无铂间期 (月) Markman Gore Blackledge 0-6 17% 10% 7-12 27% 29% 13-18 33% 63% 19-24 94% >24 59% 57% 非铂类治疗 15% 20% 30% This data looks back in time at data presented by Markman and Gore, comparing the time patients were off of therapy with the expected response to platinum retreatment. Because these are older studies, these patients probably received single-agent carboplatin. They had nearly a 60 percent response rate if they had been off of therapy for more than two years. This response rate is significantly higher than you would expect compared with other agents. References: Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3): Gore ME, Fryatt I, Wiltshaw E, et. al. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol. 1990;36: Blackledge G, Lawton F, Redman C, et al. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials. Br J Cancer. 1989;59: Markman M, et al. J Clin Oncol. 1991;9(3): Gore ME, et al. Gynecol Oncol. 1990;36: Blackledge G, et al. Br J Cancer. 1989;59: 49

50 GOG 近期对铂类耐药卵巢癌 的II期研究 研究 药物 有效率/评价 126-B 顺铂 & 环孢霉素A 3/23 (13%) 无活性
研究 药物 有效率/评价 126-B 顺铂 & 环孢霉素A /23 (13%) 无活性 126-C 六甲密胺 /30 (10%) 无活性 126-D 吡唑啉吖啶 /24 (8.4%) 无活性 126-E PSC833 + 紫杉醇 /16 (6%) 无活性 126-G CI /25 (4%) 无活性 126-H 吉西他滨 (24 h) 1/25 (4%) 无活性 126-I 9-氨基-喜树碱 /58 (14%)中度活性 126-J 多西他塞 13/58 (22%) 活性 (紫杉醇化疗后) The GOG has evaluated a variety of chemotherapeutic agents in patients with platinum-refractory ovarian cancer. In the more recent studies, patients were paclitaxel-refractory as well. Agents with 20% or greater response rate are considered active and are highlighted. Those with a response rate of 13% or less are considered inactive. Those with response rates from 14-19% are considered moderately active. Drug: docetaxel (Taxotere®) Reference: Bookman MA. Developmental chemotherapy in advanced ovarian cancer: incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182). Semin Oncol. 2002;29(1 Suppl 1):20-31. CDDP = 顺铂 GOG = 妇科肿瘤组 Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. 50

51 GOG 近期对铂类耐药卵巢癌 的II期研究 研究 药物 有效率/评价 126-K 奥沙立铂 1/25 (4%) 无活性
研究 药物 有效率/评价 126-K 奥沙立铂 1/25 (4%) 无活性 126-L 吉西他滨/顺铂 /57 (16%) 中度活性 126-M Ixabepilone 7/50 (14%) 中度活性 126-N 紫杉醇周疗 /48 (21%) 活性 (紫杉醇化疗后) 126-O Triapine-顺铂 不可行 126-P 紫杉醇 & Celecoxib 提前终止 126-Q 培美曲塞 10/48 (21%) 活性 126-R Abraxane 正在患者入组阶段 The GOG has evaluated a variety of chemotherapeutic agents in patients with platinum-refractory ovarian cancer. In the more recent studies, patients were paclitaxel-refractory as well. Agents with 20% or greater response rate are considered active and are highlighted. Those with a response rate of 13% or less are considered inactive. Those with response rates from 14-19% are considered moderately active. Drugs: paclitaxel (Onxol®, Taxol®) pemetrexed (Alimta®) Reference: Bookman MA. Developmental chemotherapy in advanced ovarian cancer: incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182). Semin Oncol. 2002;29(1 Suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. 51

52 铂类耐药的上皮性卵巢癌中培美曲塞的应用:GOG II期研究计划
复发或耐药的上皮性卵巢癌、原发性腹膜癌，经 其他优先治疗方案治疗而失败的患者 培美曲塞 900 mg/m2 静滴，每21天一疗程；先前接受过放疗的患者，培美曲塞初次使用时按照1级剂量较小用量开始， 直至疾病进展或出现毒副作用阻碍进一步治疗 Day -7 叶酸, Vitamin B12 Day -6 叶酸 Day -5 停用 NSAID, 叶酸 Days -4,-3 叶酸 Day -2 停用 NSAID, 叶酸 Day -1 地塞米松, 叶酸 Day 1 化疗, 地塞米松, Day 2 地塞米松, 叶酸 Miller DS, et al. ASCO Abstract 5524.

53 GOG评价培美曲塞的II期研究: 临床反应
分类 病例数 患者, % 反应 完全缓解 1 2.1 部分缓解 9 18.8 疾病稳定 17 35.4* 病灶增加 18 37.5 无法评估 3 6.3 总计 48 100 Miller DS, et al. ASCO Abstract 5524. *1 名患者仍在治疗中.

54 复发性卵巢癌三苯氧胺治疗 Cochrane综述
13 个研究 (11个非随机, 1 个非随机的II期研究以及 1个随机的临床研究) 568名妇女中的59 名 (10.4%) 接受三苯氧胺治疗后获得了客观反应 (RR) RR 从 0%到56%各不相同 疾病稳定的时间,从来自8个研究356名患者中的109名(30.6%)来看 ，从4周到更久不等 缺乏足够的数据来评估 RR持续时间, 生存时间,或三苯 氧胺在生活质量方面的作用 尚无来自随机对照研究的可信资料 Drug: tamoxifen (Nolvadex®) Reference: Williams CJ, Simera I. Tamoxifen for relapse of ovarian cancer. Cochrane Database of Systematic Reviews 2000;(2): CD Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD RR =反应率 54

55 GOG = Gynecologic Oncology Group
GOG 160: Trastuzumab GOG 170 人白介素-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay (170F) Mifepristone (170K) Active Drug: bevacizumab injection (Avastin®) 无足够活性 下结论尚早 有活性 GOG正在进行的 II期研究 GOG = Gynecologic Oncology Group 55 55

56 卵巢癌试验性治疗中抗血管生成药物 药物 靶点 配体结合: 贝伐单抗 VEGF-A
药物 靶点 配体结合: 贝伐单抗 VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 和 -2 受体结合: Volociximab 51 integrin IMC-1121B VEGFR-2 受体酪氨酸激酶抑制剂: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  非受体激酶抑制剂: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src 激酶 Drugs: bevacizumab injection (Avastin®) dasatinib (Sprycel®) sorafenib (Nexavar®) sunitinib (Sutent®) temsirolimus (ToriselTM) VEGF-Trap, or aflibercept EGFR = 表皮因子生长受体; Mab = 单克隆抗体; mTOR = mammalian target of rapamycin; PDGF-R = 血小板源性生长因子受体; PKC-b = 蛋白激酶 C-beta; VEGF = 血管内皮生长因子 56

57 上皮性卵巢癌治疗中以VEGF为靶点治疗的原理
人类肿瘤 VEGF 在上皮性卵巢癌中的过表达与以下相关 腹水形成 恶性进展 预后不良 临床前期实体瘤模型 抗VEGF的治疗: 延缓肿瘤进展 控制恶性胸腹水 与细胞毒性药物有协同作用 Because tumors require new blood vessel development in order to grow and metastasize, tumor vasculature provides a useful target for anticancer therapy. VEGF has been shown to be overexpressed in many types of human tumors, and its overexpression is frequently associated with malignant progression. VEGF is one of the most potent inducers of vascular permeability known—50,000-fold more potent than histamine. In preclinical models, therapies that inhibit the activity of the VEGF pathway have been shown to slow tumor progression. Combining therapies that inhibit the VEGF pathway with chemotherapy or radiation therapy has been shown to be synergistic in preclinical models. References: Han ES, Monk BJ. Bevacizumab in the treatment of ovarian cancer. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol. 2007;25(20): Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. J Clin Oncol. 2007;25(20): VEGF = 血管内皮生长因子 57

58 以VEGF为靶点的药物 通路 内皮细胞 抗-VEGF 抗体 可溶性 VEGFRs VEGF 抗-VEGFR 抗体 VEGFR-1
(贝伐单抗) VEGF 可溶性 VEGFRs (VEGF-TRAP) P P 抗-VEGFR 抗体 Numerous agents that target the VEGF pathway are in clinical development, including agents targeting the VEGF ligand and agents targeting the VEGF receptors (VEGFRs). Agents that inhibit the VEGF ligand from binding and activating its receptors include antibodies that specifically inhibit VEGF and soluble VEGFRs, which bind to other ligands that interact with VEGFR-1 and VEGFR­2. Treatment approaches that target VEGFRs are similar to those that target other growth factor receptors, such as EGFR. These include antibodies that prevent receptor activation; small-molecule inhibitors; and novel targeting agents such as ribozymes. Agents targeting the VEGF ligand inhibit VEGF activity with all its receptors and inhibit activities of the ligand on all cell types. Antibodies affect the activity of specific ligands, while soluble receptors affect the activity of multiple ligands. Agents targeting the VEGF receptor inhibit the activity of multiple VEGF family members acting through the same receptor. Small-molecule inhibitors affect multiple receptors, including those in different families (eg, FGFR, PDGFR). Highly specific antibodies and ribozymes inhibit VEGF signaling through a single targeted receptor. Drug: bevacizumab injection (Avastin®) Reference: Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005;105(4): VEGFR-1 VEGFR-2 内皮细胞 小分子抑制剂 VEGF = 血管内皮生长因子 VEGFR = VEGF受体 Podar K, et al. Blood. 2005;105(4): 58

59 贝伐单抗 – 毒性 蛋白尿 (通常 G1 – G2) 皮肤粘膜出血 动脉血栓 胃肠道穿孔 – 伤口愈合 常见 – G1 鼻出血
不常见 (3% - 5%) 危险因素: 年龄 > 65, 先前动脉血栓病史 静脉血栓的风险并不增加 胃肠道穿孔 – 伤口愈合 穿孔不常见 (占实体瘤患者人群的2% - 4% ) 伤口裂开的比例 1% In the AVF2107 study, there was a 1% incidence of arterial thromboembolic events (including myocardial infarction, transient ischemia attack, cerebrovascular accident/stroke and angina/unstable angina) in the IFL + placebo arm versus 3% in the IFL + Bevacizumab arm. A pooled analysis of the rate of arterial TE events from 5 randomized studies showed that treatment with bevacizumab increased the risk of these events two- to three-fold (up to 5%). Furthermore, certain baseline characteristics, specifically age  65 years and prior arterial TE event, conferred additional risk. Drug: bevacizumab injection (Avastin®) Reference: Han ES, Monk BJ. Bevacizumab in the treatment of ovarian cancer. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer J Clin Oncol. 2007;25(20): G1, G2 = 免疫球蛋白 GI = 胃肠道 TE = 血栓栓塞 Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. J Clin Oncol. 2007;25(20): 59

60 贝伐单抗在卵巢癌中的II期研究 Cannistra 2007 Burger 2007 Garcia 2008 患者人数 44 62 70
先前用过的 化疗方案数 2= 52% 3= 48% 1= 34% 2 = 66% Median = 2 Range 1-3 有效率 16% (PRs) 18% (PRs) 3% (CRs) 24% (PRs) 胃肠道穿孔 11% 0% 6% 动脉血栓栓塞 7% 4% 死亡 Drug: bevacizumab injection (Avastin®) References: Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33): Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33): Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 2008;26(1):76-82. Cannistra SA, et al. J Clin Oncol. 2007;25(33): Burger RA, et al. J Clin Oncol. 2007;25(33): Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = 完全反应 GI = 胃肠道 PR = 部分反应 60

61 贝伐单抗用于卵巢癌治疗的 胃肠道穿孔情况 研究 胃肠道穿孔 Burger (GOG 170D) 0/62 (0)
Garcia (ASCO 2005) 2/29 (6.9) Cannistra (ASCO 2006) 5/44 (11.4) Wright (ASCO 2006) 4/62 (6.5) Friberg (ASCO 2006) 2/13 (15.4) Monk (Gyn Oncol 2006) 1/32 (3.1) Wright (Cancer 2006) 2/23 (8.7) Bidus (Gyn Oncol 2006) 0/3 (0) Penson (ASCO 2006) 0/30 共计 16/298 (5.4%) Drug: bevacizumab injection (Avastin®) Reference: Han E, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3-6. Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = 胃肠道 61

62 NCI已注册的II期临床试验: 抗VEGF + 细胞毒性药物
方案 药物 分类 研究主要负责人 状态 MDA AVE-0005 – 多西他塞 受体 Coleman 进行中 NCT * 贝伐 (+卡铂和紫杉醇**) MAb Penson TEACO* 贝伐 + 奥沙立铂/多西他塞 Herzog MCC c 贝伐 + 多西他塞 Wenham ALSSOPR0501 贝伐 + 蛋白质结合型紫杉醇 Schwartzberg NCT 贝伐 + 拓泊替康 McGonigle NCT 贝伐 + 卡铂/吉西他滨 Copeland AVF3953 贝伐 + IV 紫杉醇/IP  贝伐单抗 McMeekin NCT 贝伐 + 奥沙立铂/吉西他滨 Horowitz Cytotoxic regimens are common in recurrent disease. There are problems with interpreting data since historical comparisons may not be valid. Ongoing clinical trials, like the OCEANS trial, will help answer questions related to potential additional benefit vs risk of anti-VEGF therapy. Drugs: bevacizumab injection (Avastin®) carboplatin (Paraplatin®) docetaxel (Taxotere®) gemcitabine hydrochloride (Gemzar®) oxaliplatin (Eloxatin®) paclitaxel (Onxol®, Taxol®) paclitaxel protein-bound (AbraxaneTM) topotecan hydrochloride (Hycamtin®) * 一线 **卡铂和紫杉醇 Bev = 贝伐单抗; Carbo = 卡铂 Gem = 吉西他滨; IP = 腹腔内 Mab = 单克隆抗体; Ox = 奥沙立铂; VEGF = 血管内皮生长因子 62

63 NCI 已注册的 II期临床研究: VEGF + EGFR 抑制剂
方案 药物 分类 研究主要负责人 状态 NCI Bev +Erlotinib MAb Friberg 进行中 NCT Alberts NCT Bev +/- Erlotinib 巩固治疗 Campos Two straight phase II and one randomized trial for consolidation therapy are active. No preliminary data yet suggests additional benefit of anti-EGFR drugs. Drugs: bevacizumab injection (Avastin®) erlotinib (Tarceva®) Bev = 贝伐单抗 EGFR = 表皮生长因子受体 Mab = 单克隆抗体 VEGF = 血管内皮生长因子 63

64 NCI 已注册的 II期临床实验: 其他抗血管生成药物
方案 药物 靶点 研究负责人 Status GOG 170-J Enzastaurin (TKI) PKC -b Usha 暂停 NCT 化疗 +/- [Enzastaurin  Enzastaurin] (未列出) 进行中 GOG 170-E Imatinib (TKI) PDGF-R Schilder 完成 NCT Kohn NCT Volociximab (MAb) 51 Integrin 多人 NCT AMG 386 (Peptibody) Angiopoietins Six additional phase II trials of other agents target tumor angiogenesis but in a manner independent of VEGF. Drugs: imatinib (Gleevec®) CT = chemotherapy; GOG = gynecologic oncology group; EGFR = 表皮生长因子受体; Mab = 单克隆抗体; PDGF-R = 血小板源性生长因子受体; PKC-b = 蛋白激酶 C-beta; TKI = 酪氨酸激酶抑制剂 64

65 贝伐单抗+拓泊替康在铂类耐药卵巢癌中的应用: 研究设计
单组, 2个研究单位 II期临床实验 出现RECIST标准定义的疾病进展 铂类耐药卵巢癌; 铂类治疗后< 6个月复发; 先前接受的化疗方案最多不超过 2种 (N = 40) 贝伐单抗 10 mg/kg Days 1, 15 + 拓泊替康 4 mg/m2 Days 1, 8, 15 28天为一个疗程 发生超出先前定义的 毒副标准的毒性反应 继续治疗，直至发生以下情况之一 因毒性反应需推迟拓泊替康治疗> 2周，或推迟贝伐单抗治疗> 2月 因拓泊替康引起的毒性反应，需要减量超过 2 次 McGonigle KF, et al. ASCO Abstract 5551.

66 铂类耐药卵巢癌患者的总生存率 (N = 30) 1.0 贝伐单抗+ 拓泊替康 .75 .50 生存的患者百分比 (%) .25 0.0 2
2 4 6 8 10 12 14 16 18 20 时间 (月) McGonigle KF, et al. ASCO Abstract 5551.

67 先前接受不同化疗方案的患者经贝伐单抗+拓泊替康治疗的无进展生存时间
先前经一种方案化疗的患者(n = 16) 1.0 先前经两种方案化疗的患者(n = 14) P = .040 by log rank test .75 未出现疾病进展的患者 (%) .50 .25 0.0 2 4 6 8 10 12 14 16 18 20 时间 (月) McGonigle KF, et al. ASCO Abstract 5551.

68 先前接受不同化疗方案的患者经贝伐单抗+拓泊替康治疗的最佳反应率
先前化疗的方案个数 最佳反应 (N =24) 部分缓解或 疾病稳定 疾病进展 总计 先前接受一种方案化疗 5 9 14 先前接受两种方案化疗 8 2 10 13 11 24 McGonigle KF, et al. ASCO Abstract 5551.

69 先前接受不同化疗方案的患者经贝伐单抗+拓泊替康治疗的总生存率
1.0 .75 生存患者 (%) .50 先前经一种方案化疗的患者 (n = 16) .25 先前经两种方案化疗的患者(n = 14) P = .043 by log-rank test 0.0 2 4 6 8 10 12 14 16 18 20 时间 (月) McGonigle KF, et al. ASCO Abstract 5551.

70 卵巢癌初次复发 敏感病例定义 0 3 6 12 18 24 月 化疗难治 化疗耐药 化疗敏感 “非常敏感” 初 次 治 疗
月 初 次 治 疗 化疗难治 化疗耐药 化疗敏感 The 6-months timeframe as a definition for platinum-sensitive vs platinum-resistant ovarian cancer patients is primarily for clinical trial purposes. Sensitivity and resistance to platinum is better viewed as a continuum. The definitions shown here for sensitivity were developed based on measurable ovarian cancer at first relapse and did not take into account CA-125 levels. “非常敏感” 定义为可测量病灶的复发,而非生化（CA 125） 复发 70

71 铂类耐药复发病例 对铂类耐药病例有效的药物 单药治疗方案 每一种化疗方案：治疗直至疾病进展, 出现无法接受的毒副反应, 或临床完全缓解
以姑息治疗为目的，序贯用药 71 71

72 Thank you!