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1、恶性黑色素瘤恶性黑色素瘤1概述l好发于白色人种，我国的发病率并不高l59，580的新发病例，7770死于该病 (2005)l发病率上升: 男性上升最快,女性仅次于肺癌l发病中位年龄: 45-55岁2发病因素发病因素l紫外线照射l先前存在的黑色素病变（如结构不良痣）l遗传因素l外伤l内分泌l化学致癌物质l免疫缺陷3临床表现临床表现l雀斑型雀斑型占占10-15%多见于60-70岁，女性较多好发于头、颈、手背等暴露部位为4型中恶性程度最低的一种较大的、平的棕黄色或棕色病灶l表浅蔓延型表浅蔓延型最多见，约占最多见，约占70%好发于50岁左右, 无性别差异女性多发于肢体，男性多发于躯干其恶性程度介于雀斑
2、型和结节型之间略隆起的色素性损害，边界不规则，色素不均匀，呈混杂颜色4临床表现临床表现l结节型结节型占占12%左右左右平均发病年龄50岁左右，男女比例为2:1好发于背部，垂直生长为其唯一生长方式4型中最恶性的一型灰色带有桃红色彩的结节，当病灶继续生长时其颜色变成蓝黑色，并较早发生溃疡和淋巴结转移l肢端色斑样黑色素瘤肢端色斑样黑色素瘤主要发生于手掌、脚底及甲下有辐射生长期和垂直生长期两个过程辐射生长期的病灶镶嵌棕黄、棕褐或黑色，并不高出皮面辐射生长期持续1年左右，如不及时处理，病灶呈结节状隆起，提示进入垂直生长期，淋巴结转移率增加，预后差5镜下肿瘤浸润深度镜下肿瘤浸润深度6ClarklI:肿瘤局
3、限于表皮的基底膜内肿瘤局限于表皮的基底膜内(原位黑色素瘤原位黑色素瘤)lII:肿瘤已穿透基底膜肿瘤已穿透基底膜,但仅浸润至真皮乳头层但仅浸润至真皮乳头层lIII:肿瘤沿真皮乳头层和网状层积聚肿瘤沿真皮乳头层和网状层积聚lIV:肿瘤已浸润真皮网状层肿瘤已浸润真皮网状层lV:肿瘤浸润至皮下组织肿瘤浸润至皮下组织(带有主观性带有主观性,如真皮乳头层和网状层无明确界如真皮乳头层和网状层无明确界限限,III/IV缺乏衡量标准缺乏衡量标准)7Breslowl目镜测微器直接测量肿瘤厚度目镜测微器直接测量肿瘤厚度l估计预后估计预后 0.75 mm 0.761.5 mm 1.514.00 mm 4.00 mml
4、亦有其他分档亦有其他分档8AJCCStagingAmerican Joint Committee on Cancer9TNM分期分期l该领域主要的进展该领域主要的进展AJCC的新的分期系统前哨淋巴结活检的应用lI期至期至III期的局限性恶黑分期中主要的进展有期的局限性恶黑分期中主要的进展有Breslow肿瘤厚度和有否溃疡应用于T分期Clark分期仅应用于肿瘤厚度1.0mm的分期受累的淋巴结数目和是否临床可扪及应用于N分期卫星灶或肿瘤与淋巴结中途转移病灶包括于N分期10111213生存曲线生存曲线Balch CM, et al. J Clin Oncol 2001; 19:363514预后因素预
5、后因素l原发病灶肿瘤厚度溃疡浸润水平l淋巴侵犯淋巴结转移数目l远处转移远处转移血LDH水平15淋巴结阳性数目Balch CM, et al. J Clin Oncol 2001; 19:362216转移部位转移部位Balch CM, et al. J Clin Oncol 2001; 19:362217辅助治疗辅助治疗l化疗化疗无益处l生物治疗和化疗联合生物治疗和化疗联合等待 SWOG 0008 (HD-IFN-CVD)l免疫治疗免疫治疗18辅助免疫治疗辅助免疫治疗l高剂量高剂量IFN-l低低剂量量IFN-lIL-2lTretinoinlGM-CSFl l肿肿瘤疫苗瘤疫苗瘤疫苗瘤疫苗19辅助免
6、疫治疗辅助免疫治疗l高剂量高剂量IFN-l低低剂量量IFN-lIL-2lTretinoinlGM-CSFl肿瘤疫苗瘤疫苗20Patients with Stage B/ Melanoma (N = 280)Observation(n = 137)High-doseIFN-(n = 143)ECOG1684Kirkwood JM, et al. J Clin Oncol 1996; 14:71Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks21疗效疗效IFN-ObservationPvalue(one-sided)5-
7、yRFS(%)37260.00235-yOS(%)46370.0237RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 1996; 14:7122毒性毒性l治疗延迟治疗延迟/中断中断:50%l/度毒性度毒性:76%l危及生命毒性危及生命毒性:9%l2例患者因肝功能衰竭死亡例患者因肝功能衰竭死亡Kirkwood JM, et al. J Clin Oncol 1996; 14:7123ECOG1690Observation(n=212)Low-doseIFN-(n=215)High-dos
8、eIFN-(n=215)Patients with Stage B/ Melanoma (N = 642)Regimen (Low-dose IFN-):3 MU/d SC TIW 2 yearsKirkwood JM, et al. J Clin Oncol 2000; 18:244424疗效疗效ObservationLDIFN-HDIFN-Pvalue5-yRFS(%)354044*0.0545-yOS(%)555352NSRFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2000;
9、 18:244425毒性毒性Kirkwood JM, et al. J Clin Oncol 2000; 18:244426Patients with Stage B/ Melanoma (N = 880)GMKvaccine(n = 440)High-doseIFN-(n = 440)ECOG1694Kirkwood JM, et al. J Clin Oncol 2001; 19:2370Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks27疗效疗效IFN-GMKvaccinePvalue5-yRFS(%)6249
10、0.00275-yOS(%)78730.0147RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2001; 19:237028EORTC18952Observation(n=279)Intermediate-doseIFN-(n=553)High-doseIFN-(n=556)Patients with Stage B/ Melanoma (N = 1388)Regimen (IFN-):10 MU/m2 IV 5 days/week 4 weeks10 MU/d SC TIW 1 y
11、ears or 5 MU/d SC TIW 2 yearsEggermont, AM, et al. Lancet 2005; 366:118929疗效疗效ObservationIMIFN-HDIFN-Pvalue4.5-yDMFI(%)4047*43#*0.05#0.484.5-yOS(%)485348NSDMFI: distant metastasis free intervalOS: Overall survivalEggermont, AM, et al. Lancet 2005; 366:118930毒性毒性Eggermont, AM, et al. Lancet 2005; 366
12、:118931比较比较ECOG1684ECOG1690ECOG1694EORTC18952RFSresultpositive borderline positive borderlineOSresultpositivenegativepositivenegativeStageB(T4N0)11%25%23%26%RFS: Relapse-free survivalOS: Overall survival32辅助免疫治疗辅助免疫治疗l高剂量高剂量IFN-l低低剂量量IFN-lIL-2lTretinoinlGM-CSFl肿瘤疫苗瘤疫苗33Patients with Node-positive Me
13、lanoma (N = 444)Observation(n = 219)Low-doseIFN-(n = 225)WHO16Cascinelli N, et al. Lancet 2001; 358:866Regimen:3 MU/m2 SC TIW 3 yearsCascinelli N, et al. Lancet 1994; 343:91334疗效疗效IFN-ObservationPvalue5-yRFS(%)27.528.40.505-yOS(%)35370.71RFS: Relapse-free survivalOS: Overall survivalCascinelli N, et
14、 al. Lancet 1994; 343:913Cascinelli N, et al. Lancet 2001; 358:86635Patients with Stage B/ Melanoma (N = 674)Observation(n = 336)Low-doseIFN-(n = 338)UKCCRHancock BW, et al. J Clin Oncol 2004; 22:53Regimen:3 MU/m2 SC TIW 2 years36疗效疗效IFN-ObservationPvalue5-yRFS(%)33300.35-yOS(%)46420.6RFS: Relapse-f
15、ree survivalOS: Overall survivalHancock BW, et al. J Clin Oncol 2004; 22:5337辅助免疫治疗辅助免疫治疗lHigh-doseIFN-lLow-doseIFN-lIL-2lTretinoinlGM-CSFlTumorvaccine38Patients with T3/4N0M0 Melanoma (N = 223)Observation(n = 110)Low-doseIFN-+IL-2(n = 113)德国一项研究德国一项研究Hauschild A, et al. J Clin Oncol 2003; 21:288339
16、方案方案(IFN-+IL-2)lIFN-3MU/m2SCdays1-5week1IL-29MU/m2SCdays1-4week2IFN-3MU/m2SCTIWweeks3-6Repeatedfor8cyclesHauschild A, et al. J Clin Oncol 2003; 21:288340疗效疗效IFN-+IL-2ObservationPvalue5-yRFS(%)70.169.90.935-yOS(%)7774.50.93RFS: Relapse-free survivalOS: Overall survivalHauschild A, et al. J Clin Oncol
17、 2003; 21:288341辅助免疫治疗辅助免疫治疗l高剂量高剂量IFN-l低低剂量量IFN-lIL-2lTretinoinlGM-CSFl肿瘤疫苗瘤疫苗42Patients with Stage AB Melanoma (N = 407)Low-doseIFN-+Placebo(n = 201)Low-doseIFN-+Isotretinoin(n = 206)德国研究德国研究Richtig E, et al. J Clin Oncol 2005; 23:865543方案方案(IFN-+Isotrenoin)lIFN-3MU/m2SCTIW2yearsIsotrenitoin20mg/3
18、0mgQD2years(20mgforpts73kg,30mgforpts73kg)Richtig E, et al. J Clin Oncol 2005; 23:865544疗效疗效IFN-+IsotrenoinIFN-+PlaceboPvalue5-yRFS(%)55670.255-yOS(%)76810.8RFS: Relapse-free survivalOS: Overall survivalRichtig E, et al. J Clin Oncol 2005; 23:865545辅助免疫治疗辅助免疫治疗l高剂量高剂量IFN-l低低剂量量IFN-lIL-2lTretinoinlGM
19、-CSFl肿瘤疫苗瘤疫苗46GM-CSF肿瘤疫苗瘤疫苗l促树突细胞的增殖促树突细胞的增殖,成熟和迁移成熟和迁移l诱导诱导T细胞介导的细胞介导的免疫应答免疫应答l等待等待ECOG4697(GM-CSFvs观察观察)l无生存益处无生存益处l购买不到购买不到l等待与其他药物联合等待与其他药物联合的研究的研究47转移后的治疗转移后的治疗48单药有效细胞毒药物单药有效细胞毒药物AgentNo.ofevaluablepatientsORR(%)Decarbazine(DTIC)193620Temozolomide5621Carmustine(BCNU)12218Lomustine(CCNU)27013Fo
20、temustine15324Cisplatin18823Carboplatin4316Vinblastine6213Vindesine27314Paclitaxel6518Docetaxel261549常用方案常用方案l单药单药DacarbazineTemozolomidel联合化疗联合化疗CDB(DDP+DTIC+BCNU)CDBT(DDP+DTIC+BCNU+TAM)CVD(DDP+VLB+DTIC)50TAM?51Patients with Advanced Melanoma (N = 184)DDP+DTIC+BCNU(n = 92)DDP+DTIC+BCNU+TAM(n = 92)N
21、CIStudyCreagan ET, et al. J Clin Oncol 1999; 17:188452方案方案lCDB:DDP+DTIC+BCNUDDP25mg/m2days1-3DTIC220mg/m2days1-3BCNU150mg/m2day1everyotherdaylDDP+DTIC+BCNU+TAMTAM20mgQDRepeatedevery3wksCreagan ET, et al. J Clin Oncol 1999; 17:188453疗效疗效CDBCDBTPvalueORR(%)37320.52TTP(mos)3.43.10.429OS(mos)6.86.90.545
22、ORR: overall response rateTTP: time to progressionOS : overall survivalCreagan ET, et al. J Clin Oncol 1999; 17:188454单药单药vs联合化疗联合化疗55Patients with Advanced Melanoma (N = 240)DTIC(n = 121)DDP+DTIC+BCNU+TAM(n = 119)研究设计研究设计Chapman PB, et al. J Clin Oncol 1999; 17:274556方案方案lDTICaloneDTIC1000mg/m2day1
23、lCDBT:DDP+DTIC+BCNU+TAMDDP25mg/m2days1-3DTIC220mg/m2days1-3BCNU150mg/m2day1everyothercycleTAM20mgQDRepeatedevery3wksChapman PB, et al. J Clin Oncol 1999; 17:274557疗效疗效DTICCDBTPvalueORR(%)10.218.50.09OS(mos)6.47.70.51ORR: overall response rateOS : overall responseChapman PB, et al. J Clin Oncol 1999;
24、 17:274558毒性毒性(/度度)Chapman PB, et al. J Clin Oncol 1999; 17:274559DTICvsTemozolomide60Patients with Advanced Melanoma (N = 305)DTIC250mg/m2days1-5Q3wks(n = 149)Temozolomide200mg/m2days1-5Q4wks(n = 156)研究设计研究设计Middleton MR, et al. J Clin Oncol 2000; 18:15861疗效疗效DTICTemozolomidePvalueORR(%)12.113.5NSP
25、FS(mos)1.51.90.012OS(mos)6.47.70.2ORR: overall response ratePFS: progression free survivalOS : overall responseMiddleton MR, et al. J Clin Oncol 2000; 18:15862毒性和生活质量毒性和生活质量DTICTemozolomidePvalueGrade/(%)3638NSCNSmetastases-less-QOL-better-QOL: quality of lifeMiddleton MR, et al. J Clin Oncol 2000;
26、18:158Kiebert GM, et al. Cancer Invest 2003; 21:82163化疗化疗vs化疗联合生物治疗化疗联合生物治疗64Patients with Advanced Melanoma (N = 282)Temozolomide(n = 139)Temozolomide+IFN-(n = 143)DeCOGStudyKaufmann R, et al. J Clin Oncol 2005; 23:900165方案方案lTemozolomide单药单药200mg/m2days1-5Q4wkslTemozolomide+IFN-Temozolomide:200mg/
27、m2days1-5Q4wksIFN-:5MU/m2TIWKaufmann R, et al. J Clin Oncol 2005; 23:900166疗效疗效TemozolomideTemozolomide+IFN-PvalueORR(%)13.424.10.036PFS(mos)2.43.30.11OS(mos)8.49.70.16ORR: overall response ratePFS: progression-free survivalOS : overall responseKaufmann R, et al. J Clin Oncol 2005; 23:900167毒性毒性(/度度
28、)TemozolomideTemozolomide+IFN-PvalueLeucopenia4.3%20.5%0.0001Thrombocytopenia4.3%22.7%0.0001fever0.9%2.5%0.0001OthersComparableNSKaufmann R, et al. J Clin Oncol 2005; 23:900168联合联合IFN+IL-2?69Patients with Advanced Melanoma (N = 183)CVD(n = 92)CVD+IFN-+IL-2(n = 91)MDACCStudyEton O, et al. J Clin Onco
29、l 2002; 20:204570方案方案lCVDDDP20mg/m2d1-4,22-25VLB2mg/m2d1-4,22-25DTIC800mg/m2d1,22Repeatedevery6wkslCVD+IFN-+IL-2DDP20mg/m2d1-4,22-25VLB1.5mg/m2d1-4,22-25DTIC800mg/m2d1,22IFN-5MU/m2d5-9,17-21,26-30IL-29MU/m2d5-8,17-20,26-29Repeatedevery6wks71疗效疗效CVDCVD+IFN-+IL-2PvalueORR(%)25480.001TTP(mos)2.44.90.00
30、8OS(mos)9.211.90.06ORR: overall response rateTTP: time to progressionOS : overall responseEton O, et al. J Clin Oncol 2002; 20:204572血液学毒性血液学毒性Eton O, et al. J Clin Oncol 2002; 20:204573非血液学毒性非血液学毒性Eton O, et al. J Clin Oncol 2002; 20:204574Patients with Advanced Melanoma (N = 405)CVD(n = 201)CVD+IF
31、N-+IL-2(n = 204)ECOG3695Atkins MB, et al. ASCO 2003; 22:2847a75方案方案lCVDDDP20mg/m2d1-4VLB1.2mg/m2d1-4DTIC800mg/m2d1Repeatedevery3wkslCVD+IFN-+IL-2DDP20mg/m2d1-4VLB1.2mg/m2d1-4DTIC800mg/m2d1IFN-5MU/m2d1-5,8,10,12IL-29MU/m2CIV96hoursRepeatedevery3wksAtkins MB, et al. ASCO 2003; 22:2847a76疗效疗效CVDCVD+IFN
32、-+IL-2PvalueORR(%)11.916.6NSPFS(mos)3.15.00.1OS(mos)9.18.40.696ORR: overall response ratePFS: progression-free survivalOS : overall responseAtkins MB, et al. ASCO 2003; 22:2847a77Patients with Advanced Melanoma (N = 144)CVD(n = 72)CVD+IFN-+IL-2(n = 72)意大利研究意大利研究Bajetta E, et al. Ann Oncol 2006; 17:5
33、7178方案方案lCVDDDP30mg/m2d1-3VDS2.5mg/m2d1DTIC250mg/m2d1-3Repeatedevery3wkslCVD+IFN-+IL-2DDP30mg/m2d1-3VDS2.5mg/m2d1DTIC250mg/m2d1-3IFN-5MU/m2d1-5IL-29MUd1-5,8-15Repeatedevery3wksBajetta E, et al. Ann Oncol 2006; 17:57179疗效疗效CVDCVD+IFN-+IL-2PvalueORR(%)2133-TTP(mos)88NSOS(mos)1211NSORR: overall respons
34、e rateTTP: time to progressionOS : overall responseBajetta E, et al. Ann Oncol 2006; 17:57180毒性毒性(/度度)Bajetta E, et al. Ann Oncol 2006; 17:57181解救化疗解救化疗82Paclitaxel+CBPl31例转移性恶性黑色素瘤例转移性恶性黑色素瘤l94%先前先前DTIC/TMZ治疗失败治疗失败l方案方案:Paclitaxel100mg/m2days1,8,15CBPAUC2days1,8,15每每4周重复周重复Rao RD, et al. Cancer 200
35、6; 106:37583疗效疗效ResultsORR26%SD19%PFS3mosOS7.8mosORR: overall response rateSD: stable diseasePFS: progression-free survivalOS : overall responseRao RD, et al. Cancer 2006; 106:37584靶向治疗靶向治疗85SorafeniblRaf激酶小分子抑制剂激酶小分子抑制剂l80%的恶性黑色素瘤存在的恶性黑色素瘤存在B-raf突变突变l单药治疗结果令人失望单药治疗结果令人失望l剂量剂量:400mgBIDpo86联合药物治疗联合药物治疗ORR(%)SD(%)PFS(mos)OS(mos)Sorafenib+Paclitaxel+CBP3459-Sorafenib+DTIC13533.79.3Sorafenib+TMZ30426-AmaravadiRK , et al. ASCO 2006; 24:8900aLoriganP, et al. ASCO 2006; 24:8012aFlahertyKT, et al. ASCO 2004; 22:7507a87THANKS!88
