卵巢癌化疗新进展课件.ppt
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1、卵巢癌化疗新进展The state of the art in chemotherapy for ovarian cancers,女性生殖道肿瘤:全世界统计1,Ferlay et al.GLOBOCAN 2000 IARC,WHO 2001(),Women,发病率32%Breast12%Lung&bronchus11%Colon&rectum6%Uterine corpus4%Ovary 4%Non-Hodgkin lymphoma 3%Melanomaof skin3%Thyroid2%Pancreas2%Urinary bladder20%All Other Sites,死亡率25%Lun
2、g&bronchus15%Breast11%Colon&rectum6%Pancreas5%Ovary4%Non-Hodgkinlymphoma4%Leukemia3%Uterine corpus2%Brain/ONS2%Multiple myeloma23%All other sites,Cancer Facts&Figures,ACSO,2003,美国卵巢癌流行病学特征,上海市居民卵巢癌、宫颈癌、宫体癌发病率(1974-2000,SCDC),内容简介,早期卵巢癌化疗中晚期卵巢癌化疗新辅助化疗/中间手术复发性卵巢癌化疗维持巩固治疗Ca125升高处理,卵巢癌的治疗,未治患者主要目的是治愈手术分
3、期和细胞减灭术,继而紫杉醇/铂类联合化疗复发患者主要目的是减轻症状和提高生活质量化疗可以延长生存时间最终结果长期存活:25-30%5-年 生存率从 30%(1970s)提高至 50%,Ries LAG et al.SEER Cancer Statistics Review,1975-2001,National Cancer Institute.Bethesda,MD,;2001/,2004.,卵巢癌可认为是一种慢性疾病,早期卵巢癌:FIGO I and II,全面的分期剖腹探查术经腹全子宫/双侧卵巢输卵管切除(TAH/BSO)大网膜切除淋巴结切除术(dissection)腹膜和膈膜活检(bio
4、psies)细胞学检查高危 vs 低危早期卵巢癌,Staging classifications and clinical practice guidelines of gynaecologic cancers.,早期卵巢癌,Medical Oncology:A comprehensive review.textbook,低危,高危,(510%复发率),(3040%复发率),Stage IA or IB,Stage IC,Grade 1(or 2),Grade 3Clear cell cancer,高危早期卵巢癌,Young SGO 2003 2.Young RC.Semin Oncol 27
5、(3):8-10.,2000 3.ICON-1,EORTC-ACTION:J Natnl Can Inst.Vol.95,No.2,January 15,20034.Mannel et al.GOG-175 protocol,GOG1571,2,辅助化疗的随机临床试验:3 vs 6 疗程紫杉醇+卡铂,结果6个疗程进展危险性降低了33%生存率无改善,Action&Icon3,随机临床试验无立即化疗 vs 立即化疗,结果立即化疗 生存率提高8%vs复发时化疗(82%vs 74%),FIGO Stage III and IV定义,III盆腔外腹膜种植和/或外阳性腹膜后或腹股沟淋巴结A病灶大致局限于真
6、骨盆;淋巴结阴性;镜下腹腔种植B腹腔种植灶 2 cm;淋巴结阴性C腹腔种植灶 2 cm 和/或阳性腹膜后淋巴结或腹股沟IV远处转移,Medical Oncology:A comprehensive review.textbook,准确全面分期依据手术探查和 病理组织学、细胞学检查根据腹腔内转移灶的大小对III期再分为IIIa、IIIb、IIIc腹膜后淋巴结转移影响分期肝表面和肝实质转移分属III期和IV期,Stage I:局限于卵巢 Stage II:局限于盆腔 Stage III:局限于腹腔 Stage IV:远处转移,晚期卵巢癌:关键临床实验1,GOG 1111 and OV-102Cis
7、platin+paclitaxel vs cisplatin+cyclophosphamideImproved survival and progression-free survival withcisplatin+paclitaxel GOG 1323Cisplatin vs paclitaxel vs cisplatin+paclitaxelNo statistaical difference in overall survivalICON-34Carboplatin+paclitaxel vs carboplatin or CAP(cyclophosphamide+doxorubici
8、n+cisplatin)No statistical difference in survivalGOG 1585;AGO-OVAR6Carboplatin+paclitaxel preferred combination overcisplatin+paclitaxel,1.McGuire WP et al.N Engl J Med 1996,334:1-84.ICON Group.Lancet 2002,360:505-5152.Piccart M et al.Int J Gyn Cancer 2003,13(suppl 2),144-1485.Ozols RF et al.J Clin
9、Oncol 2003;21:3194-32003.Muggia F et al.J Clin Oncol 2000,18:106-1156.du Bois et al.J Natl Cancer Inst.2003 Sep 3;95(17):1320-9,晚期卵巢癌:关键临床实验2,ICON-5-GOG182(2006)Carboplatin+paclitaxel vs Gemcitabin triplet vs Doxil Triplet vs Topotecan duble+TP vs Gemcitabin dublet+TP(cyclophosphamide+doxorubicin+ci
10、splatin)No statistical difference in survivalGOG 172(2006)cisplatin+paclitaxel iv/ip preferred combination overcisplatin+paclitaxel ivJGOG(2009)Carboplatin(d1)+paclitaxel 80mg weekly perferred Carboplatin+paclitaxel,Armstrong D,et al.N Engl J Med 2006;354:34-43.Isonishi S,et al.the Lancet 2009;374:1
11、331-38,TP方案成为晚期卵巢癌一线化疗的“标准”,1996,2000,GOG111(N=410)-期,环磷酰胺750mg/m2顺铂75mg/m2,泰素35mg/m2(24h)顺铂75mg/m2,VS,ORR:73%60%p=0.01,CR:51%31%p=0.01,PFS:18mo 13mo p=0.001,OS:38mo 24mo p=0.001,毒性:泰素/顺铂组有较多的血液学毒性和神经毒性,但毒性可控,OV10(N=688)-期,环磷酰胺750mg/m2顺铂75mg/m2,泰素175mg/m2(3h)顺铂75mg/m2,ORR:77%66%p=0.01,CR:50%36%p=0.0
12、1,PFS:16.6mo 12mo p=0.0005,OS:35mo 25mo p=0.0016,毒性:泰素/顺铂组有较多的血液学毒性和神经毒性,但毒性可控,VS,J Natl Cancer Inst 2000;92:699708,McGuire,et al.N Engl J Med 1996 334:1-6,GOG158:Ovarian(optimal III),Cisplatin 75 mg/m2Paclitaxel 135 mg/m2(24 h),Carboplatin AUC 7.5Paclitaxel 175 mg/m2(3 h),Epithelial Ovarian Cancer
13、Optimal Stage III No prior therapy Elective Second-Look Non-Inferiority Design,Open:03-Apr-95Closed:26-Jan-98Accrual:792 pts(evaluable),I,II,Ozols,et al.Proc J Clin Oncol 21:3194,2003,GOG158:Ovarian(optimal III),CDDP-Paclitaxel(24-h)(n=400)median 48.8 m,Carbo-Paclitaxel(3-h)(n=392)median 56.7 m,Adju
14、sted Cox analysisHR 0.86(95%CI 0.71 1.04),Ozols,et al.Proc J Clin Oncol 21:3194,2003,56.7 vs 48.8 m=7.9 m,晚期卵巢癌的化疗,总之:手术和化疗后约 75%患者临床完全缓解(CCR),但复发率 50%长期生存率 20 25%,提高疗效的可能对策,引入更有效的方案紫杉醇/卡铂+新药腹腔化疗增加剂量强度新的细胞毒性药物分子靶向治疗对复发癌更有效的治疗发明有效的维持治疗,Ozols,Seminars in Oncology,vol 29;Suppl 1(Feb)2002:32-42.,提高初治卵巢癌
15、化疗疗效:三药联合化疗,标准治疗PC+X,GOG0182-ICON5,比较五种方案治疗晚期卵巢上皮癌或原发性腹膜癌的III期随机临床试验,Michael A Bookman,MDFox Chase Cancer CenterPhiladelphia,PA,Proc ASCO 2005:Abstract 5002,GOG0182-ICON5,GOG0182-ICON5:无进展生存,Median PFS and HR(95%CI)16.1 1.00016.4 0.990(0.884-1.107)16.4 0.998(0.891-1.117)15.3 1.094(0.979-1.224)15.4 1
16、.052(0.940-1.176),GOG0182-ICON5:总生存,Median OS and HR(95%CI)40.0 1.00040.4 0.978(0.838-1.141)42.8 0.972(0.832-1.136)39.1 1.068(0.918-1.244)40.2 1.035(0.888-1.206),GOG0182-ICON5:结论,加入第三种细胞毒性药物增加了血液学毒性,但是这种毒性是可控制的在所有评价的方案中,加入第三种细胞毒药物不能改善患者预后(包括无进展生存和总生存),Proc ASCO 2005:Abstract 5002,IV IP,提高初治卵巢癌化疗疗效:改
17、变用途径,GOG172,Cisplatin 75 mg/m2Paclitaxel 135 mg/m2(24 h),Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2(24 h)IV d1Paclitaxel 60 mg/m2 IP d8,上皮性卵巢癌 III期 满意减灭术 术前无治疗 选择性二探,Open:23-Mar-98Closed:29-Jan-01Accrual:415 例(可评价),I,II,Armstrong,et al.NEJM 354:34-43,2006,GOG172:Ovarian(optimal III)IP vs.IV,CDDP(
18、IV)Paclitaxel(IV)(n=210),CDDP(IP)Paclitaxel(IP+IV)(n=206),Armstrong,et al.NEJM 354:34-43,2006,GOG 172,结论:静脉内紫杉醇联合腹腔内顺铂和紫杉醇可改善理想减灭术后 III期卵巢癌患者的生存率,3周疗周疗,提高初治卵巢癌化疗疗效:增加用药频率,PC紫杉醇周疗 vs 标准PT3周疗(JGOG,2009),每周疗:Paclitaxel 80mg d1,8,15 Carboplatin AUC 6 d13周疗:Paclitaxel 180mg d1 Carboplatin AUC 6 d1,Isonis
19、hi S,et al.the Lancet 2009;374:1331-38,晚期卵巢癌化疗,卡铂和紫杉醇:卡铂(AUC=56)紫杉醇(175mg/m2)滴注 3小时,每3周重复,共68个疗程(catrgory 1)顺铂和紫杉醇:紫杉醇(135mg/m2)iv d1,DDP 100mg/m2 ip d2,紫杉醇(60mg/m2)ip d8,每3周重复,共68个疗程(catrgory 1)卡铂和多西紫杉醇:卡铂(AUC=56)多西紫杉醇(60-75mg/m2)滴注 1小时,每3周重复,共68个疗程(catrgory 1)如对泰素过敏,可改用其他替代药物(如:泰素帝,topotecan,健择,或脂
20、质体阿霉素)。不能耐受静脉化疗者,可选用口服化疗药,如:VP-16。,举例:Case 1,53岁,女性表现为腹胀无腹腔外肿瘤生长证据肿瘤中等度大实施活检后患者被转至妇科肿瘤医师,举例:Case 1,对此患者实施了满意的细胞减灭术.残留肿瘤最大直径:1cm.1枚腹主动脉旁淋巴结累及病理:中分化浆液性乳头状癌转至寻求化疗,举例:Case 1,我们的患者选择腹腔化疗2个周期化疗后她的CA125水平自122降至10患者无症状,继续接受了4个周期的化疗盆腔检查、CT扫描、CA125结果均正常,新辅助化疗与中间性细胞减灭术,Neoadjuvant ChemotherapyInterval Cytoredu
21、ction,中间性细胞减灭术(12th IGCS曼谷,2008),随机非劣性实验:718例IIIc-IV期卵巢癌初次细胞减灭术化疗6程Vs化疗3程细胞减灭术化疗3程总生存率:29 m vs 30 mPFS:12 m vs 12 m,Vergote et al.12th biennial meeting of IGCS,Bangkok,Thailand,2008,肠系膜根部转移肝实质多发转移,上皮性卵巢癌:Epithelial Ovarian Cancer(EOC)100例患者的典型“结局”,Early stage(I-II),Advanced stage(III-IV),Clinical pa
22、rtial response(cPR),Stable disease(SD),Progression,Relapse/Progression,Clinical complete response(cCR),25,75,8,40,35,Pathologic partialResponse(pPR),Pathologic completeResponse(pCR),16,24,Relapse,2nd3rd line therapy,8,73,FIGO annual report on treatments of gynecological cancers Editor:Pecorelli S.In
23、tern J Gynecol&Obstet,Nov 2003 supplement,复发性卵巢癌目前的治疗,Current Management of Recurrent Ovarian Cancer,0.00,0.25,0.50,0.75,1.00,0,12,24,36,48,60,72,84,Time(Months),Probability PFS,AGO OVAR-3:du Bois A et al.J Natl Cancer Inst 2003;95:132030,约 25%患者于一线TC(paclitaxel+Carb.)治疗后6-12个月复发,约 50%患者于一线TC治疗后12个月
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