恶性黑色素瘤.

恶性黑色素瘤概述好发于白色人种，我国的发病率并不高59，580的新发病例，7770死于该病(2005)发病率上升:男性上升最快,女性仅次于肺癌发病中位年龄:45-55岁发病因素紫外线照射先前存在的黑色素病变（如结构不良痣）遗传因素外伤内分泌化学致癌物质免疫缺陷临床表现雀斑型占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表浅蔓延型最多见，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，呈混杂颜色临床表现结节型占12%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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，预后差镜下肿瘤浸润深度ClarkI:肿瘤局限于表皮的基底膜内(原位黑色素瘤)II:肿瘤已穿透基底膜,但仅浸润至真皮乳头层III:肿瘤沿真皮乳头层和网状层积聚IV:肿瘤已浸润真皮网状层V:肿瘤浸润至皮下组织(带有主观性,如真皮乳头层和网状层无明确界限,III/IV缺乏衡量标准)Breslow目镜测微器直接测量肿瘤厚度估计预后≤0.75mm0.76~1.5mm1.51~4.00mm＞4.00mm亦有其他分档AJCCStagingAmericanJointCommitteeonCancerTNM分期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I期至III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分期生存曲线BalchCM,etal.JClinOncol2001;19:3635预后因素原发病灶–肿瘤厚度–溃疡–浸润水平淋巴侵犯–淋巴结转移数目远处转移–血LDH水平淋巴结阳性数目BalchCM,etal.JClinOncol2001;19:3622转移部位BalchCM,etal.JClinOncol2001;19:3622辅助治疗化疗–无益处生物治疗和化疗联合–等待SWOG0008(HD-IFN-α±CVD)免疫治疗辅助免疫治疗高剂量IFN-α低剂量IFN-αIL-2TretinoinGM-CSF肿瘤疫苗辅助免疫治疗高剂量IFN-α低剂量IFN-αIL-2TretinoinGM-CSF肿瘤疫苗PatientswithStageⅡB/ⅢMelanoma(N=280)Observation(n=137)High-doseIFN-α(n=143)ECOG1684KirkwoodJM,etal.JClinOncol1996;14:71Regimen:20MU/m2IV5days/week×4weeks10MU/m2SCTIW×48weeks疗效IFN-αObservationPvalue(one-sided)5-yRFS(%)37260.00235-yOS(%)46370.0237RFS:Relapse-freesurvivalOS:OverallsurvivalKirkwoodJM,etal.JClinOncol1996;14:71毒性治疗延迟/中断:50%Ⅲ/Ⅳ度毒性:76%危及生命毒性:9%2例患者因肝功能衰竭死亡KirkwoodJM,etal.JClinOncol1996;14:71ECOG1690Observation(n=212)Low-doseIFN-α(n=215)High-doseIFN-α(n=215)PatientswithStageⅡB/ⅢMelanoma(N=642)Regimen(Low-doseIFN-α):3MU/dSCTIW×2yearsKirkwoodJM,etal.JClinOncol2000;18:2444疗效ObservationLDIFN-αHDIFN-αPvalue5-yRFS(%)354044**0.0545-yOS(%)555352NSRFS:Relapse-freesurvivalOS:OverallsurvivalKirkwoodJM,etal.JClinOncol2000;18:2444毒性KirkwoodJM,etal.JClinOncol2000;18:2444PatientswithStageⅡB/ⅢMelanoma(N=880)GMKvaccine(n=440)High-doseIFN-α(n=440)ECOG1694KirkwoodJM,etal.JClinOncol2001;19:2370Regimen:20MU/m2IV5days/week×4weeks10MU/m2SCTIW×48weeks疗效IFN-αGMKvaccinePvalue5-yRFS(%)62490.00275-yOS(%)78730.0147RFS:Relapse-freesurvivalOS:OverallsurvivalKirkwoodJM,etal.JClinOncol2001;19:2370EORTC18952Observation(n=279)Intermediate-doseIFN-α(n=553)High-doseIFN-α(n=556)PatientswithStageⅡB/ⅢMelanoma(N=1388)Regimen(IFN-α):10MU/m2IV5days/week×4weeks10MU/dSCTIW×1yearsor5MU/dSCTIW×2yearsEggermont,AM,etal.Lancet2005;366:1189疗效ObservationIMIFN-αHDIFN-αPvalue4.5-yDMFI(%)4047*43#*0.05#0.484.5-yOS(%)485348NSDMFI:distantmetastasisfreeintervalOS:OverallsurvivalEggermont,AM,etal.Lancet2005;366:1189毒性Eggermont,AM,etal.Lancet2005;366:1189比较ECOG1684ECOG1690ECOG1694EORTC18952RFSresultpositiveborderlinepositiveborderlineOSresultpositivenegativepositivenegativeStageⅡB(T4N0)11%25%23%26%RFS:Relapse-freesurvivalOS:Overallsurvival辅助免疫治疗高剂量IFN-α低剂量IFN-αIL-2TretinoinGM-CSF肿瘤疫苗PatientswithNode-positiveMelanoma(N=444)Observation(n=219)Low-doseIFN-α(n=225)WHO16CascinelliN,etal.Lancet2001;358:866Regimen:3MU/m2SCTIW×3yearsCascinelliN,etal.Lancet1994;343:913疗效IFN-αObservationPvalue5-yRFS(%)27.528.40.505-yOS(%)35370.71RFS:Relapse-freesurvivalOS:OverallsurvivalCascinelliN,etal.Lancet1994;343:913CascinelliN,etal.Lancet2001;358:866PatientswithStageⅡB/ⅢMelanoma(N=674)Observation(n=336)Low-doseIFN-α(n=338)UKCCRHancockBW,etal.JClinOncol2004;22:53Regimen:3MU/m2SCTIW×2years疗效IFN-αObservationPvalue5-yRFS(%)33300.35-yOS(%)46420.6RFS:Relapse-freesurvivalOS:OverallsurvivalHancockBW,etal.JClinOncol2004;22:53辅助免疫治疗High-doseIFN-αLow-doseIFN-αIL-2TretinoinGM-CSFTumorvaccinePatientswithT3/4N0M0Melanoma(N=223)Observation(n=110)Low-doseIFN-α+IL-2(n=113)德国一项研究HauschildA,etal.JClinOncol2003;21:2883方案(IFN-α+IL-2)IFN-α3MU/m2SCdays1-5week1IL-29MU/m2SCdays1-4week2IFN-α3MU/m2SCTIWweeks3-6Repeatedfor8cyclesHauschildA,etal.JClinOncol2003;21:2883疗效IFN-α+IL-2ObservationPvalue5-yRFS(%)70.169.90.935-yOS(%)7774.50.93RFS:Relapse-freesurvivalOS:OverallsurvivalHauschildA,etal.JClinOncol2003;21:2883辅助免疫治疗高剂量IFN-α低剂量IFN-αIL-2TretinoinGM-CSF肿瘤疫苗PatientswithStageⅡAⅡBMelanoma(N=407)Low-doseIFN-α+Placebo(n=201)Low-doseIFN-α+Isotretinoin(n=206)德国研究RichtigE,etal.JClinOncol2005;23:8655方案(IFN-α+Isotrenoin)IFN-α3MU/m2SCTIW×2yearsIsotrenitoin20mg/30mgQD×2years(20mgforpts≤73kg,30mgforpts73kg)RichtigE,etal.JClinOncol2005;23:8655疗效IFN-α+IsotrenoinIFN-α+PlaceboPvalue5-yRFS(%)55670.255-yOS(%)76810.8RFS:Relapse-freesurvivalOS:OverallsurvivalRichtigE,etal.JClinOncol2005;23:8655辅助免疫治疗高剂量IFN-α低剂量IFN-αIL-2TretinoinGM-CSF肿瘤疫苗GM-CSF肿瘤疫苗促树突细胞的增殖,成熟和迁移诱导T细胞介导的免疫应答等待ECOG4697(GM-CSFvs观察)无生存益处购买不到等待与其他药物联合的研究转移后的治疗单药有效细胞毒药物AgentNo.ofevaluablepatientsORR(%)Decarbazine(DTIC)193620Temozolomide5621Carmustine(BCNU)12218Lomustine(CCNU)27013Fotemustine15324Cisplatin18823Carboplatin4316Vinblastine6213Vindesine27314Paclitaxel6518Docetaxel2615常用方案单药–Dacarbazine–