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1、恶性黑色素瘤恶性黑色素瘤概述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型
2、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，预后差镜下肿瘤浸润深度镜下肿瘤浸润深度ClarklI: 肿瘤局限
3、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)Breslowl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
4、.00 mml亦有其他分档亦有其他分档AJCC StagingAmerican Joint Committee on CancerTNM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分期生存曲线生存曲线Balch CM, et al. J Clin Oncol 2001; 19:3635预后因素预后因素l
5、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水平淋巴结阳性数目Balch CM, et al. J Clin Oncol 2001; 19:3622转移部位转移部位Balch CM, et al. J Clin Oncol 2001; 19:3622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辅助免疫治疗辅助免疫治疗l高剂
6、量高剂量 IFN-l低低剂量量 IFN-lIL-2lTretinoinlGM-CSFl肿瘤疫苗瘤疫苗Patients with Stage B/ Melanoma (N = 280)Observation(n = 137)High-dose IFN-(n = 143)ECOG 1684Kirkwood JM, et al. J Clin Oncol 1996; 14:71Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks疗效疗效RFS: Relapse-free survivalOS: Overall survival
7、Kirkwood JM, et al. J Clin Oncol 1996; 14:71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; 14:71ECOG 1690Observation(n=212)Low-dose IFN-(n=215)High-dose IFN-(n=215)Patients with Stage B/ Melanoma (N = 642)Regimen (Low-dose IFN-):3
8、 MU/d SC TIW 2 yearsKirkwood JM, et al. J Clin Oncol 2000; 18:2444疗效疗效RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2000; 18:2444毒性毒性Kirkwood JM, et al. J Clin Oncol 2000; 18:2444Patients with Stage B/ Melanoma (N = 880)GMK vaccine(n = 440)High-dose IFN-(n = 440)ECOG
9、 1694Kirkwood JM, et al. J Clin Oncol 2001; 19:2370Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks疗效疗效RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2001; 19:2370EORTC 18952Observation(n=279)Intermediate-dose IFN-(n=553)High-dose IFN-(n=556)Patients wi
10、th 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 yearsEggermont, AM, et al. Lancet 2005; 366:1189疗效疗效DMFI: distant metastasis free intervalOS: Overall survivalEggermont, AM, et al. Lancet 2005; 366:1189毒性毒性Eggermont, AM, et al. La
11、ncet 2005; 366:1189比较比较RFS: Relapse-free survivalOS: Overall survival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Patients with Node-positive Melanoma (N = 444)Observation(n = 219)Low-dose IFN-(n = 225)WHO 16Cascinelli N, et al. Lancet 2001; 358:866Regimen:3 MU/m2 SC TIW 3 yearsC
12、ascinelli N, et al. Lancet 1994; 343:913疗效疗效RFS: Relapse-free survivalOS: Overall survivalCascinelli N, et al. Lancet 1994; 343:913Cascinelli N, et al. Lancet 2001; 358:866Patients with Stage B/ Melanoma (N = 674)Observation(n = 336)Low-dose IFN-(n = 338)UKCCRHancock BW, et al. J Clin Oncol 2004; 22
13、:53Regimen:3 MU/m2 SC TIW 2 years疗效疗效RFS: Relapse-free survivalOS: Overall survivalHancock BW, et al. J Clin Oncol 2004; 22:53辅助免疫治疗辅助免疫治疗lHigh-dose IFN-lLow-dose IFN-lIL-2lTretinoinlGM-CSFlTumor vaccinePatients with T3/4N0M0 Melanoma (N = 223)Observation(n = 110)Low-dose IFN-+ IL-2(n = 113)德国一项研究德国
14、一项研究Hauschild A, et al. J Clin Oncol 2003; 21:2883方案方案 (IFN-+ IL-2)lIFN-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 cyclesHauschild A, et al. J Clin Oncol 2003; 21:2883疗效疗效RFS: Relapse-free survivalOS: Overall survivalHauschild A, et al. J C
15、lin Oncol 2003; 21:2883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Patients with Stage AB Melanoma (N = 407)Low-dose IFN-+ Placebo(n = 201)Low-dose IFN-+ Isotretinoin(n = 206)德国研究德国研究Richtig E, et al. J Clin Oncol 2005; 23:8655方案方案 (IFN-+ Isotrenoin)lIFN-3 MU/m2 SC TIW 2 years I
16、sotrenitoin 20mg/30mg QD 2 years (20mg for pts 73kg, 30mg for pts 73kg) Richtig E, et al. J Clin Oncol 2005; 23:8655疗效疗效RFS: Relapse-free survivalOS: Overall survivalRichtig E, et al. J Clin Oncol 2005; 23:8655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 GM-CSF 肿瘤疫苗瘤疫苗 l促树突细胞的增殖
17、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 ECOG 4697 (GM-CSF vs 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 的研究的研究转移后的治疗转移后的治疗单药有效细胞毒药物单药有效细胞毒药物常用方案常用方案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)TAM?Patients with Advanced
18、Melanoma (N = 184)DDP + DTIC + BCNU(n = 92)DDP + DTIC + BCNU + TAM(n = 92)NCI StudyCreagan ET, et al. J Clin Oncol 1999; 17:1884方案方案lCDB: DDP + DTIC + BCNUDDP 25mg/m2 days 1-3DTIC 220mg/m2 days 1-3BCNU 150mg/m2 day 1 every other daylDDP + DTIC + BCNU + TAMTAM 20mg QD Repeated every 3 wksCreagan ET,
19、et al. J Clin Oncol 1999; 17:1884疗效疗效ORR: overall response rateTTP: time to progressionOS : overall survivalCreagan ET, et al. J Clin Oncol 1999; 17:1884单药单药 vs 联合化疗联合化疗Patients 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;
20、 17:2745方案方案lDTIC aloneDTIC 1000mg/m2 day 1lCDBT: 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 wksChapman PB, et al. J Clin Oncol 1999; 17:2745疗效疗效ORR: overall response rateOS : overall responseChapman PB, et al. J
21、 Clin Oncol 1999; 17:2745毒性毒性 (/度度)Chapman PB, et al. J Clin Oncol 1999; 17:2745DTIC vs TemozolomidePatients with Advanced Melanoma (N = 305)DTIC250mg/m2 days 1-5 Q3wks(n = 149)Temozolomide200mg/m2 days 1-5 Q4wks(n = 156)研究设计研究设计Middleton MR, et al. J Clin Oncol 2000; 18:158疗效疗效ORR: overall response
22、 ratePFS: progression free survivalOS : overall responseMiddleton MR, et al. J Clin Oncol 2000; 18:158毒性和生活质量毒性和生活质量QOL: quality of lifeMiddleton MR, et al. J Clin Oncol 2000; 18:158Kiebert GM, et al. Cancer Invest 2003; 21:821化疗化疗 vs 化疗联合生物治疗化疗联合生物治疗Patients with Advanced Melanoma (N = 282)Temozolo
23、mide(n = 139)Temozolomide + IFN-(n = 143)DeCOG StudyKaufmann R, et al. J Clin Oncol 2005; 23:9001方案方案lTemozolomide 单药单药200mg/m2 days 1-5 Q4wkslTemozolomide + IFN-Temozolomide: 200mg/m2 days 1-5 Q4wksIFN-: 5MU/m2 TIWKaufmann R, et al. J Clin Oncol 2005; 23:9001疗效疗效ORR: overall response ratePFS: progr
24、ession-free survivalOS : overall responseKaufmann R, et al. J Clin Oncol 2005; 23:9001毒性毒性 (/度度)Kaufmann R, et al. J Clin Oncol 2005; 23:9001联合联合 IFN + IL-2?Patients with Advanced Melanoma (N = 183)CVD(n = 92)CVD + IFN-+ IL-2(n = 91)MDACC StudyEton O, et al. J Clin Oncol 2002; 20:2045方案方案lCVDDDP 20m
25、g/m2 d1-4, 22-25VLB 2mg/m2 d1-4, 22-25DTIC 800mg/m2 d1, 22 Repeated every 6wkslCVD + 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疗效疗效ORR: overall response rateTTP: time to progressionOS :
26、overall responseEton O, et al. J Clin Oncol 2002; 20:2045血液学毒性血液学毒性Eton O, et al. J Clin Oncol 2002; 20:2045非血液学毒性非血液学毒性Eton O, et al. J Clin Oncol 2002; 20:2045Patients with Advanced Melanoma (N = 405)CVD(n = 201)CVD + IFN-+ IL-2(n = 204)ECOG 3695Atkins MB, et al. ASCO 2003; 22:2847a方案方案lCVDDDP 20m
27、g/m2 d1-4VLB 1.2mg/m2 d1-4DTIC 800mg/m2 d1 Repeated every 3wkslCVD + 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 3wksAtkins MB, et al. ASCO 2003; 22:2847a疗效疗效ORR: overall response ratePFS: progression-free survivalOS :
28、overall responseAtkins MB, et al. ASCO 2003; 22:2847aPatients 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; 17:571方案方案lCVDDDP 30mg/m2 d1-3VDS 2.5mg/m2 d1DTIC 250mg/m2 d1-3 Repeated every 3wkslCVD + IFN-+ IL-2DDP 30mg/m2 d1-3VDS 2.5mg/m
29、2 d1DTIC 250mg/m2 d1-3IFN-5MU/m2 d1-5IL-2 9MU d1-5, 8-15 Repeated every 3wksBajetta E, et al. Ann Oncol 2006; 17:571疗效疗效ORR: overall response rateTTP: time to progressionOS : overall responseBajetta E, et al. Ann Oncol 2006; 17:571毒性毒性 (/度度)Bajetta E, et al. Ann Oncol 2006; 17:571解救化疗解救化疗Paclitaxel
30、+ 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:Paclitaxel 100mg/m2 days 1, 8, 15CBP AUC 2 days 1, 8, 15 每每4 周重复周重复 Rao RD, et al. Cancer 2006; 106:375疗效疗效ORR: overall response rateSD: stable diseasePFS: progression-free survivalOS : overall responseRao RD, et al. Cancer 2006; 106:375靶向
31、治疗靶向治疗SorafeniblRaf 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: 400mg BID po联合药物治疗联合药物治疗Amaravadi RK , et al. ASCO 2006; 24:8900aLorigan P, et al. ASCO 2006; 24:8012aFlaherty KT, et al. ASCO 2004; 22:7507aTHANKS!此课件下载可自行编辑修改，供参考！此课件下载可自行编辑修改，供参考！部分内容来源于网络，如有侵权请与我联系删除！部分内容来源于网络，如有侵权请与我联系删除！
