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 0.75 mm 0.761.5 mm 1.514.00 mm 4.00 mm亦有其他分档,AJCC Staging,American Joint Committee on Cancer,TNM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,Balch CM, et al. J Clin Oncol 2001; 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,Balch CM, et al. J Clin Oncol 2001; 19:3622,转移部位,Balch CM, et al. J Clin Oncol 2001; 19:3622,辅助治疗,化疗无益处生物治疗和化疗联合等待 SWOG 0008 (HD-IFN-CVD)免疫治疗,辅助免疫治疗,高剂量 IFN-低剂量 IFN-IL-2TretinoinGM-CSF肿瘤疫苗,辅助免疫治疗,高剂量 IFN-低剂量 IFN-IL-2TretinoinGM-CSF肿瘤疫苗,Patients with Stage B/ Melanoma (N = 280),Observation(n = 137),High-dose IFN-(n = 143),ECOG 1684,Kirkwood JM, et al. J Clin Oncol 1996; 14:71,Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks,疗效,RFS: Relapse-free survivalOS: Overall survival,Kirkwood JM, et al. J Clin Oncol 1996; 14:71,毒性,治疗延迟/中断: 50%/度毒性: 76%危及生命毒性: 9%2 例患者因肝功能衰竭死亡,Kirkwood JM, et al. J Clin Oncol 1996; 14:71,ECOG 1690,Observation(n=212),Low-dose IFN-(n=215),High-dose IFN-(n=215),Patients with Stage B/ Melanoma (N = 642),Regimen (Low-dose IFN-):3 MU/d SC TIW 2 years,Kirkwood JM, et al. J Clin Oncol 2000; 18:2444,疗效,RFS: Relapse-free survivalOS: Overall survival,Kirkwood JM, et al. J Clin Oncol 2000; 18:2444,毒性,Kirkwood JM, et al. J Clin Oncol 2000; 18:2444,Patients with Stage B/ Melanoma (N = 880),GMK vaccine(n = 440),High-dose IFN-(n = 440),ECOG 1694,Kirkwood JM, et al. J Clin Oncol 2001; 19:2370,Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks,疗效,RFS: Relapse-free survivalOS: Overall survival,Kirkwood JM, et al. J Clin Oncol 2001; 19:2370,EORTC 18952,Observation(n=279),Intermediate-dose IFN-(n=553),High-dose IFN-(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 years or 5 MU/d SC TIW 2 years,Eggermont, AM, et al. Lancet 2005; 366:1189,疗效,DMFI: distant metastasis free intervalOS: Overall survival,Eggermont, AM, et al. Lancet 2005; 366:1189,毒性,Eggermont, AM, et al. Lancet 2005; 366:1189,比较,RFS: Relapse-free survivalOS: Overall survival,辅助免疫治疗,高剂量 IFN-低剂量 IFN-IL-2TretinoinGM-CSF肿瘤疫苗,Patients with Node-positive Melanoma (N = 444),Observation(n = 219),Low-dose IFN-(n = 225),WHO 16,Cascinelli N, et al. Lancet 2001; 358:866,Regimen:3 MU/m2 SC TIW 3 years,Cascinelli N, et al. Lancet 1994; 343:913,疗效,RFS: Relapse-free survivalOS: Overall survival,Cascinelli N, et al. Lancet 1994; 343:913,Cascinelli N, et al. Lancet 2001; 358:866,Patients with Stage B/ Melanoma (N = 674),Observation(n = 336),Low-dose IFN-(n = 338),UKCCR,Hancock BW, et al. J Clin Oncol 2004; 22:53,Regimen:3 MU/m2 SC TIW 2 years,疗效,RFS: Relapse-free survivalOS: Overall survival,Hancock BW, et al. J Clin Oncol 2004; 22:53,辅助免疫治疗,High-dose IFN-Low-dose IFN-IL-2TretinoinGM-CSFTumor vaccine,Patients with T3/4N0M0 Melanoma (N = 223),Observation(n = 110),Low-dose IFN-+ IL-2(n = 113),德国一项研究,Hauschild A, et al. J Clin Oncol 2003; 21:2883,方案 (IFN-+ IL-2),IFN-3 MU/m2 SC days 1-5 week 1 IL-2 9 MU/m2 SC days 1-4 week 2 IFN-3 MU/m2 SC TIW weeks 3-6 Repeated for 8 cycles,Hauschild A, et al. J Clin Oncol 2003; 21:2883,疗效,RFS: Relapse-free survivalOS: Overall survival,Hauschild A, et al. J Clin Oncol 2003; 21:2883,辅助免疫治疗,高剂量 IFN-低剂量 IFN-IL-2TretinoinGM-CSF肿瘤疫苗,Patients with Stage AB Melanoma (N = 407),Low-dose IFN-+ Placebo(n = 201),Low-dose IFN-+ Isotretinoin(n = 206),德国研究,Richtig E, et al. J Clin Oncol 2005; 23:8655,方案 (IFN-+ Isotrenoin),IFN-3 MU/m2 SC TIW 2 years Isotrenitoin 20mg/30mg QD 2 years (20mg for pts 73kg, 30mg for pts 73kg),Richtig E, et al. J Clin Oncol 2005; 23:8655,疗效,RFS: Relapse-free survivalOS: Overall survival,Richtig E, et al. J Clin Oncol 2005; 23:8655,辅助免疫治疗,高剂量 IFN-低剂量 IFN-IL-2TretinoinGM-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 ECOG 4697 (GM-CSF vs 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,常用方案,单药DacarbazineTemozolomide联合化疗CDB (DDP + DTIC + BCNU)CDBT (DDP + DTIC + BCNU + TAM)CVD (DDP + VLB + DTIC),TAM?,Patients with Advanced Melanoma (N = 184),DDP + DTIC + BCNU(n = 92),DDP + DTIC + BCNU + TAM(n = 92),NCI Study,Creagan ET, et al. J Clin Oncol 1999; 17:1884,方案,CDB: DDP + DTIC + BCNUDDP 25mg/m2 days 1-3DTIC 220mg/m2 days 1-3BCNU 150mg/m2 day 1 every other dayDDP + DTIC + BCNU + TAMTAM 20mg QD Repeated every 3 wks,Creagan ET, et al. J Clin Oncol 1999; 17:1884,疗效,ORR: overall response rateTTP: time to progressionOS : overall survival,Creagan ET, et al. J Clin Oncol 1999; 17:1884,单药 vs 联合化疗,Patients with Advanced Melanoma (N = 240),DTIC(n = 121),DDP + DTIC + BCNU + TAM(n = 119),研究设计,Chapman PB, et al. J Clin Oncol 1999; 17:2745,方案,DTIC aloneDTIC 1000mg/m2 day 1CDBT: DDP + DTIC + BCNU + TAMDDP 25mg/m2 days 1-3DTIC 220mg/m2 days 1-3BCNU 150mg/m2 day 1 every other cycleTAM 20mg QD Repeated every 3 wks,Chapman PB, et al. J Clin Oncol 1999; 17:2745,疗效,ORR: overall response rateOS : overall response,Chapman PB, et al. J Clin Oncol 1999; 17:2745,毒性 (/度),Chapman PB, et al. J Clin Oncol 1999; 17:2745,DTIC vs Temozolomide,Patients with Advanced Melanoma (N = 305),DTIC250mg/m2 days 1-5 Q3wks(n = 149),Temozolomide200mg/m2 days 1-5 Q4wks(n = 156),研究设计,Middleton MR, et al. J Clin Oncol 2000; 18:158,疗效,ORR: overall response ratePFS: progression free survivalOS : overall response,Middleton MR, et al. J Clin Oncol 2000; 18:158,毒性和生活质量,QOL: quality of life,Middleton MR, et al. J Clin Oncol 2000; 18:158,Kiebert GM, et al. Cancer Invest 2003; 21:821,化疗 vs 化疗联合生物治疗,Patients with Advanced Melanoma (N = 282),Temozolomide(n = 139),Temozolomide + IFN-(n = 143),DeCOG Study,Kaufmann R, et al. J Clin Oncol 2005; 23:9001,方案,Temozolomide 单药200mg/m2 days 1-5 Q4wksTemozolomide + IFN-Temozolomide: 200mg/m2 days 1-5 Q4wksIFN-: 5MU/m2 TIW,Kaufmann R, et al. J Clin Oncol 2005; 23:9001,疗效,ORR: overall response ratePFS: progression-free survivalOS : overall response,Kaufmann R, et al. J Clin Oncol 2005; 23:9001,毒性 (/度),Kaufmann R, et al. J Clin Oncol 2005; 23:9001,联合 IFN + IL-2?,Patients with Advanced Melanoma (N = 183),CVD(n = 92),CVD + IFN-+ IL-2(n = 91),MDACC Study,Eton O, et al. J Clin Oncol 2002; 20:2045,方案,CVDDDP 20mg/m2 d1-4, 22-25VLB 2mg/m2 d1-4, 22-25DTIC 800mg/m2 d1, 22 Repeated every 6wks,CVD + IFN-+ IL-2DDP 20mg/m2 d1-4, 22-25VLB 1.5mg/m2 d1-4, 22-25DTIC 800mg/m2 d1, 22IFN-5MU/m2 d5-9, 17-21, 26-30IL-2 9MU/m2 d5-8, 17-20, 26-29 Repeated every 6wks,疗效,ORR: overall response rateTTP: time to progressionOS : overall response,Eton O, et al. J Clin Oncol 2002; 20:2045,血液学毒性,Eton O, et al. J Clin Oncol 2002; 20:2045,非血液学毒性,Eton O, et al. J Clin Oncol 2002; 20:2045,Patients with Advanced Melanoma (N = 405),CVD(n = 201),CVD + IFN-+ IL-2(n = 204),ECOG 3695,Atkins MB, et al. ASCO 2003; 22:2847a,方案,CVDDDP 20mg/m2 d1-4VLB 1.2mg/m2 d1-4DTIC 800mg/m2 d1 Repeated every 3wks,CVD + IFN-+ IL-2DDP 20mg/m2 d1-4VLB 1.2mg/m2 d1-4DTIC 800mg/m2 d1IFN-5MU/m2 d1-5, 8, 10, 12IL-2 9MU/m2 CIV 96 hours Repeated every 3wks,Atkins MB, et al. ASCO 2003; 22:2847a,疗效,ORR: overall response ratePFS: progression-free survivalOS : overall response,Atkins MB, et al. ASCO 2003; 22:2847a,Patients with Advanced Melanoma (N = 144),CVD(n = 72),CVD + IFN-+ IL-2(n = 72),意大利研究,Bajetta E, et al. Ann Oncol 2006; 17:571,方案,CVDDDP 30mg/m2 d1-3VDS 2.