恶性黑色素瘤PPT参考课件.ppt

1、恶性黑色素瘤,1,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,2,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,3,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

2、性损害，边界不规则，色素不均匀，呈混杂颜色,4,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,5,镜下肿瘤浸润深度,6,Clark,I: 肿瘤局限于表皮的基底膜内 (原位黑色素瘤) II: 肿

3、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),7,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,8,AJCC Staging,American Joint Committee on Cancer,9,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 Bresl

4、ow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,10,11,12,13,生存曲线,Balch CM, et al. J Clin Oncol 2001; 19:3635,14,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,15,淋巴结阳性数目,Balch CM, et al. J Clin Oncol 2001; 19:3622,16,转移部位,Balch CM, et al. J Clin Oncol 2001; 1

5、9:3622,17,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,18,辅助免疫治疗,高剂量 IFN- 低剂量 IFN- IL-2 Tretinoin GM-CSF 肿瘤疫苗,19,辅助免疫治疗,高剂量 IFN- 低剂量 IFN- IL-2 Tretinoin GM-CSF 肿瘤疫苗,20,Patients with Stage B/ Melanoma (N = 280),Observation (n = 137),High-dose IFN- (n = 143),ECOG 1684,Kirkwood JM, et al. J Cli

6、n Oncol 1996; 14:71,Regimen: 20 MU/m2 IV 5 days/week 4 weeks 10 MU/m2 SC TIW 48 weeks,21,疗效,RFS: Relapse-free survival OS: Overall survival,Kirkwood JM, et al. J Clin Oncol 1996; 14:71,22,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; 14:71,23,ECOG 1690,Obs

7、ervation (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; 18:2444,24,疗效,RFS: Relapse-free survival OS: Overall survival,Kirkwood JM, et al. J Clin Oncol 2000; 18:2444,2

8、5,毒性,Kirkwood JM, et al. J Clin Oncol 2000; 18:2444,26,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 weeks 10 MU/m2 SC TIW 48 weeks,27,疗效,RFS: Relapse-free survival

9、OS: Overall survival,Kirkwood JM, et al. J Clin Oncol 2001; 19:2370,28,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 weeks 10 MU/d SC TIW 1 years or 5 MU/d SC TIW 2 years,Egge

10、rmont, AM, et al. Lancet 2005; 366:1189,29,疗效,DMFI: distant metastasis free interval OS: Overall survival,Eggermont, AM, et al. Lancet 2005; 366:1189,30,毒性,Eggermont, AM, et al. Lancet 2005; 366:1189,31,比较,RFS: Relapse-free survival OS: Overall survival,32,辅助免疫治疗,高剂量 IFN- 低剂量 IFN- IL-2 Tretinoin GM-

11、CSF 肿瘤疫苗,33,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; 343:913,34,疗效,RFS: Relapse-free survival OS: Overall survival,Cascinelli N, et a

12、l. Lancet 1994; 343:913,Cascinelli N, et al. Lancet 2001; 358:866,35,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,36,疗效,RFS: Relapse-free survival OS: Overall survival,Hancock

13、 BW, et al. J Clin Oncol 2004; 22:53,37,辅助免疫治疗,High-dose IFN- Low-dose IFN- IL-2 Tretinoin GM-CSF Tumor vaccine,38,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; 21:2883,39,方案 (IFN-+ IL-2),IFN-3 MU/m2 SC day

14、s 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; 21:2883,40,疗效,RFS: Relapse-free survival OS: Overall survival,Hauschild A, et al. J Clin Oncol 2003; 21:2883,41,辅助免疫治疗,高剂量 IFN- 低剂量 IFN- IL-2 Tretinoin GM-CSF 肿瘤疫苗,4

15、2,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; 23:8655,43,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,

16、 et al. J Clin Oncol 2005; 23:8655,44,疗效,RFS: Relapse-free survival OS: Overall survival,Richtig E, et al. J Clin Oncol 2005; 23:8655,45,辅助免疫治疗,高剂量 IFN- 低剂量 IFN- IL-2 Tretinoin GM-CSF 肿瘤疫苗,46,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,47,转移后的治疗,48,

17、单药有效细胞毒药物,49,常用方案,单药 Dacarbazine Temozolomide 联合化疗 CDB (DDP + DTIC + BCNU) CDBT (DDP + DTIC + BCNU + TAM) CVD (DDP + VLB + DTIC),50,TAM?,51,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; 17:1884,52

18、,方案,CDB: DDP + DTIC + BCNU DDP 25mg/m2 days 1-3 DTIC 220mg/m2 days 1-3 BCNU 150mg/m2 day 1 every other day DDP + DTIC + BCNU + TAM TAM 20mg QD Repeated every 3 wks,Creagan ET, et al. J Clin Oncol 1999; 17:1884,53,疗效,ORR: overall response rate TTP: time to progression OS : overall survival,Creagan ET

19、, et al. J Clin Oncol 1999; 17:1884,54,单药 vs 联合化疗,55,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; 17:2745,56,方案,DTIC alone DTIC 1000mg/m2 day 1 CDBT: DDP + DTIC + BCNU + TAM DDP 25mg/m2 days 1-3 DTIC 220mg/m2 da

20、ys 1-3 BCNU 150mg/m2 day 1 every other cycle TAM 20mg QD Repeated every 3 wks,Chapman PB, et al. J Clin Oncol 1999; 17:2745,57,疗效,ORR: overall response rate OS : overall response,Chapman PB, et al. J Clin Oncol 1999; 17:2745,58,毒性 (/度),Chapman PB, et al. J Clin Oncol 1999; 17:2745,59,DTIC vs Temozol

21、omide,60,Patients with Advanced Melanoma (N = 305),DTIC 250mg/m2 days 1-5 Q3wks (n = 149),Temozolomide 200mg/m2 days 1-5 Q4wks (n = 156),研究设计,Middleton MR, et al. J Clin Oncol 2000; 18:158,61,疗效,ORR: overall response rate PFS: progression free survival OS : overall response,Middleton MR, et al. J Cl

22、in Oncol 2000; 18:158,62,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; 21:821,63,化疗 vs 化疗联合生物治疗,64,Patients with Advanced Melanoma (N = 282),Temozolomide (n = 139),Temozolomide + IFN- (n = 143),DeCOG Study,Kaufmann R, et al. J Clin

23、 Oncol 2005; 23:9001,65,方案,Temozolomide 单药 200mg/m2 days 1-5 Q4wks Temozolomide + IFN- Temozolomide: 200mg/m2 days 1-5 Q4wks IFN-: 5MU/m2 TIW,Kaufmann R, et al. J Clin Oncol 2005; 23:9001,66,疗效,ORR: overall response rate PFS: progression-free survival OS : overall response,Kaufmann R, et al. J Clin

24、Oncol 2005; 23:9001,67,毒性 (/度),Kaufmann R, et al. J Clin Oncol 2005; 23:9001,68,联合 IFN + IL-2?,69,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; 20:2045,70,方案,CVD DDP 20mg/m2 d1-4, 22-25 VLB 2mg/m2 d1-4, 22-25 DTIC 800mg

25、/m2 d1, 22 Repeated every 6wks,CVD + IFN-+ IL-2 DDP 20mg/m2 d1-4, 22-25 VLB 1.5mg/m2 d1-4, 22-25 DTIC 800mg/m2 d1, 22 IFN-5MU/m2 d5-9, 17-21, 26-30 IL-2 9MU/m2 d5-8, 17-20, 26-29 Repeated every 6wks,71,疗效,ORR: overall response rate TTP: time to progression OS : overall response,Eton O, et al. J Clin

26、 Oncol 2002; 20:2045,72,血液学毒性,Eton O, et al. J Clin Oncol 2002; 20:2045,73,非血液学毒性,Eton O, et al. J Clin Oncol 2002; 20:2045,74,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,75,方案,CVD DDP 20mg/m2 d1-4 VLB 1.2mg/m2 d1

27、-4 DTIC 800mg/m2 d1 Repeated every 3wks,CVD + IFN-+ IL-2 DDP 20mg/m2 d1-4 VLB 1.2mg/m2 d1-4 DTIC 800mg/m2 d1 IFN-5MU/m2 d1-5, 8, 10, 12 IL-2 9MU/m2 CIV 96 hours Repeated every 3wks,Atkins MB, et al. ASCO 2003; 22:2847a,76,疗效,ORR: overall response rate PFS: progression-free survival OS : overall response,Atkins MB, et al. ASCO 2003; 22:2847a,77,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; 17:571,78,方案,CVD DDP 30mg/m2 d1-3 VDS 2.5