1、惡性黑色素瘤定義和診療概述好發于白色人種，我國的發病率并不高發病率全球最高的地方： Queensland ，Australia， 40/10萬59，580的新發病例，7770死于該病 (2005)發病率上升(年增長率3-5%)發病中位年齡: 45-55歲發病因素紫外線照射先前存在的黑色素病變（如結構不良痣）遺傳因素外傷內分泌化學致癌物質免疫缺陷臨床表現雀斑型 占10-15%多見于60-70歲，女性較多好發于頭、頸、手背等暴露部位為4型中惡性程度最低的一種較大的、平的棕黃色或棕色病灶表淺蔓延型 最多見，約占70%好發于50歲左右, 無性別差異女性多發于肢體，男性多發于軀干其惡性程度介于雀斑型和結

2、節型之間略隆起的色素性損害，邊界不規則，色素不均勻，呈混雜顏色臨床表現結節型 占12%左右平均發病年齡50歲左右，男女比例為2:1好發于背部，垂直生長為其唯一生長方式4型中最惡性的一型灰色帶有桃紅色彩的結節，當病灶繼續生長時其顏色變成藍黑色，并較早發生潰瘍和淋巴結轉移肢端色斑樣黑色素瘤 主要發生于手掌、腳底及甲下有輻射生長期和垂直生長期兩個過程輻射生長期的病灶鑲嵌棕黃、棕褐或黑色，并不高出皮面輻射生長期持續1年左右，如不及時處理，病灶呈結節狀隆起，提示進入垂直生長期，淋巴結轉移率增加，預后差早期發現1、不對稱性 Asymmetry ：將黑痣一分為二，兩邊不對稱2、邊緣 Border： 邊緣不整

3、齊，鋸齒狀改變3、顏色 Color： 雜色、粉紅、藍灰4、直徑 Diameter： 5mm5、進展 Evolution：鏡下腫瘤浸潤深度ClarkI: 腫瘤局限于表皮的基底膜內 (原位黑色素瘤)II: 腫瘤已穿透基底膜, 但僅浸潤至真皮乳頭層III: 腫瘤沿真皮乳頭層和網狀層積聚IV: 腫瘤已浸潤真皮網狀層V: 腫瘤浸潤至皮下組織(帶有主觀性, 如真皮乳頭層和網狀層無明確界限, III/IV缺乏衡量標準)Breslow目鏡測微器直接測量腫瘤厚度估計預后 0.75 mm 0.761.5 mm 1.514.00 mm 4.00 mm亦有其他分檔AJCC StagingAmerican Joint

4、Committee on CancerTNM分期該領域主要的進展AJCC的新的分期系統前哨淋巴結活檢的應用I期至III期的局限性惡黑分期中主要的進展有Breslow腫瘤厚度和有否潰瘍應用于T分期Clark分期僅應用于腫瘤厚度的分期受累的淋巴結數目和是否臨床可捫及應用于N分期衛星灶或腫瘤與淋巴結中途轉移病灶包括于N分期預后因素原發病灶腫瘤厚度潰瘍浸潤水平淋巴侵犯淋巴結轉移數目遠處轉移血LDH水平不同分期Balch CM, et al. J Clin Oncol 2001; 19:3635淋巴結陽性數目Balch CM, et al. J Clin Oncol 2001; 19:3622轉移部位B

5、alch CM, et al. J Clin Oncol 2001; 19:3622臨床治療原則盡早手術切除病變組織（根治性手術+淋巴結清掃術 ）配合化療、生物、物理、放療及中醫藥等綜合治療模式 根治性手術外科手術切除病變仍是治療惡性黑色素瘤的主要方法，一旦確診，應盡快手術切除根據浸潤深度決定手術切除范圍（應廣泛切除）切除深度一般要包括全層皮膚、肌筋膜切除原發性腫瘤的同時，應作局部淋巴結切除術手術治療效果與腫瘤的組織學類型、病灶深度及有無淋巴結轉移等有直接關系輔助治療化療無益處生物治療和化療聯合等待 SWOG 0008 (HD-IFN-CVD)免疫治療輔助免疫治療惡性黑色素細胞大多具有特異性抗

6、原，在患者血清中可查到自身腫瘤抗體存在有報道稱部分惡黑可有自發消退現象，提示本病與免疫有關免疫療法可通過增強機體免疫反應，達到殺滅殘余腫瘤細胞、控制腫瘤生長、防止腫瘤復發輔助免疫治療高劑量 IFN-低劑量 IFN-IL-2TretinoinGM-CSF腫瘤疫苗輔助免疫治療高劑量 IFN-低劑量 IFN-IL-2TretinoinGM-CSF腫瘤疫苗Patients with Stage B/ Melanoma (N = 280)Observation(n = 137)High-dose IFN-(n = 143)ECOG 1684Kirkwood JM, et al. J Clin Oncol

7、 1996; 14:71Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeksSURVIVALIFN-ObservationP value (one-sided)5-y RFS (%)37260.00235-y OS (%)46370.0237RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 1996; 14:71TOXICITY治療延遲/中斷: 50%/度毒性: 76%危及生命毒性: 9%2 例患者因肝功能衰竭死亡

8、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 MU/d SC TIW 2 yearsKirkwood JM, et al. J Clin Oncol 2000; 18:2444SURVIVALObservationLD IFN-HD IFN-P value5-y RFS (%)35404

9、4*0.0545-y OS (%)555352NSRFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2000; 18:2444TOXICITYKirkwood 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 1694Kirkwood JM, et al. J Clin Oncol 200

10、1; 19:2370Regimen:20 MU/m2 IV 5 days/week 4 weeks10 MU/m2 SC TIW 48 weeks療效IFN-GMK vaccineP value5-y RFS (%)62490.00275-y OS (%)78730.0147RFS: Relapse-free survivalOS: Overall survivalKirkwood JM, et al. J Clin Oncol 2001; 19:2370EORTC 18952Observation(n=279)Intermediate-dose IFN-(n=553)High-dose IF

11、N-(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 yearsEggermont, AM, et al. Lancet 2005; 366:1189SURVIVALObservationIM IFN-HD IFN-P value4.5-y DMFI (%)4047*43#*0.05#0.484.5-y OS (%)485348NSDMFI: distant metasta

12、sis free intervalOS: Overall survivalEggermont, AM, et al. Lancet 2005; 366:1189TOXICITYEggermont, AM, et al. Lancet 2005; 366:1189比 較ECOG 1684ECOG 1690ECOG 1694EORTC 18952RFS resultpositiveborderlinepositiveborderlineOS resultpositivenegativepositivenegativeStage B (T4N0)11%25%23%26%RFS: Relapse-fr

13、ee survivalOS : Overall survival輔助免疫治療高劑量 IFN-低劑量 IFN-IL-2TretinoinGM-CSF腫瘤疫苗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 yearsCascinelli N, et al. Lancet 1994; 343:913SURVIVALIFN-Obser

14、vationP value5-y RFS (%)27.528.40.505-y OS (%)35370.71RFS: 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 Onco

15、l 2004; 22:53Regimen:3 MU/m2 SC TIW 2 yearsSURVIVALIFN-ObservationP value5-y RFS (%)33300.35-y OS (%)46420.6RFS: Relapse-free survivalOS: Overall survivalHancock BW, et al. J Clin Oncol 2004; 22:53輔助免疫治療High-dose IFN-Low-dose IFN-IL-2TretinoinGM-CSFTumor vaccinePatients with T3/4N0M0 Melanoma (N = 2

16、23)Observation(n = 110)Low-dose IFN-+ IL-2(n = 113)GERMANYHauschild A, et al. J Clin Oncol 2003; 21:2883Regimen: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)SURVIVALIFN-+ IL-2ObservationP value5-y RFS (%)70.169.90.935-y OS (%)7

17、774.50.93RFS: Relapse-free survivalOS: Overall survivalHauschild A, et al. J Clin Oncol 2003; 21:2883輔助免疫治療高劑量 IFN-低劑量 IFN-IL-2TretinoinGM-CSF腫瘤疫苗Patients with Stage AB Melanoma (N = 407)Low-dose IFN-+ Placebo(n = 201)Low-dose IFN-+ Isotretinoin(n = 206)GERMANYRichtig E, et al. J Clin Oncol 2005; 23

18、:8655Regimen:IFN-3 MU/m2 SC TIW 2 years; Isotrenitoin 20mg/30mg QD 2 years; (20mg for pts 73kg, 30mg for pts 73kg)SURVIVALIFN-+ IsotrenoinIFN-+ PlaceboP value5-y RFS (%)55670.255-y OS (%)76810.8RFS: Relapse-free survivalOS: Overall survivalRichtig E, et al. J Clin Oncol 2005; 23:8655輔助免疫治療高劑量 IFN-低劑

19、量 IFN-IL-2TretinoinGM-CSF腫瘤疫苗 GM-CSF 腫瘤疫苗 促樹突細胞的增殖, 成熟和遷移誘導T細胞介導的 免疫應答等待 ECOG 4697 (GM-CSF vs 觀察)無生存益處購買不到等待與其他藥物聯合 的研究轉移后的治療單藥有效細胞毒藥物AgentNo. of evaluable patientsORR (%)Decarbazine (DTIC) 1936 20Temozolomide 56 21Carmustine (BCNU) 122 18Lomustine (CCNU) 270 13Fotemustine 153 24Cisplatin 188 23Carb

20、oplatin 43 16Vinblastine 62 13Vindesine 273 14Paclitaxel 65 18Docetaxel 26 15常用方案單藥DacarbazineTemozolomide聯合化療CDB (DDP + DTIC + BCNU)CDBT (DDP + DTIC + BCNU + TAM)CVD (DDP + VLB + DTIC)DTIC客觀有效率15-20(CR5%)，但是不能延長總生存期毒副反應：食欲下降、嚴重的惡心/嘔吐、骨髓抑制、流感樣癥狀新近III期臨床試驗中DTIC單藥的ORR（1998-2006年，使用嚴格的評效系統）Falkson et a

21、l 1998N (例)12.2Middleton et al 20001499.4Avril MF et al 20041176.8Bedikian Ay et al 20063567.5TMZ替莫唑胺與DTIC一樣，最后代謝為MTIC而發揮其抗腫瘤活性，但與DTIC相比，該藥口服容易吸收，毒副作用小，病人對該藥的耐受性比較好該藥能夠通過血腦屏障，可以用于黑色素瘤的腦轉移，有報告TMZ聯合全顱放療明顯優于單純放療 替莫唑胺在晚期黑色素瘤的單藥化療的有效率為15-20%，與DTIC以及福莫司汀成為黑色素瘤化療的主要有效藥物毒副作用小，一般情況稍差以及老年晚期惡黑患者，建議可以口服替莫唑胺單藥化療

22、 DTIC vs TemozolomidePatients with Advanced Melanoma (N = 305)DTIC250mg/m2 days 1-5 Q3wks(n = 149)Temozolomide200mg/m2 days 1-5 Q4wks(n = 156)SCHEDULEMiddleton MR, et al. J Clin Oncol 2000; 18:158RESULTSDTICTemozolomideP valueORR (%)12.113.5NSPFS (mos)1.51.90.012OS (mos)6.47.70.2ORR: overall respons

23、e ratePFS: progression free survivalOS : overall responseMiddleton MR, et al. J Clin Oncol 2000; 18:158TOXICITY & QOLDTICTemozolomideP valueGrade / (%)3638NSCNS metastases-less-QOL-better-QOL: quality of lifeMiddleton MR, et al. J Clin Oncol 2000; 18:158Kiebert GM, et al. Cancer Invest 2003; 21:821C

24、hemotherapy+TAM?Patients with Advanced Melanoma (N = 184)DDP + DTIC + BCNU(n = 92)DDP + DTIC + BCNU + TAM(n = 92)NCI StudyCreagan ET, et al. J Clin Oncol 1999; 17:1884REGIMENCDB: DDP + DTIC + BCNUDDP 25mg/m2 days 1-3DTIC 220mg/m2 days 1-3BCNU 150mg/m2 day 1 every other dayDDP + DTIC + BCNU + TAMTAM

25、20mg QD Repeated every 3 wksCreagan ET, et al. J Clin Oncol 1999; 17:1884RESULTSCDBCDBTP valueORR (%)37320.52TTP (mos)3.43.10.429OS (mos)6.86.90.545ORR: overall response rateTTP: time to progressionOS : overall survivalCreagan ET, et al. J Clin Oncol 1999; 17:1884單藥 vs 聯合化療Patients with Advanced Mel

26、anoma (N = 240)DTIC(n = 121)DDP + DTIC + BCNU + TAM(n = 119)Chapman PB, et al. J Clin Oncol 1999; 17:2745REGIMENDTIC 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 wksChapman PB, et al.

27、 J Clin Oncol 1999; 17:2745RESULTSDTICCDBTP valueORR (%)10.218.50.09OS (mos)6.47.70.51ORR: overall response rateOS : overall responseChapman PB, et al. J Clin Oncol 1999; 17:2745TOXICITY(/度)Chapman PB, et al. J Clin Oncol 1999; 17:2745化療 vs 化療聯合生物治療Patients with Advanced Melanoma (N = 282)Temozolomi

28、de(n = 139)Temozolomide + IFN-(n = 143)DeCOG StudyKaufmann R, et al. J Clin Oncol 2005; 23:9001REGIMENTemozolomide alone200mg/m2 days 1-5 Q4wksTemozolomide + IFN-Temozolomide: 200mg/m2 days 1-5 Q4wksIFN-: 5MU/m2 TIWKaufmann R, et al. J Clin Oncol 2005; 23:9001RESULTSTemozolomideTemozolomide + IFN-P

29、valueORR (%)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; 23:9001TOXICITY (/度)TemozolomideTemozolomide + IFN-P valueLeucopenia4.3%20.5%0.0001Thrombocytopenia4.3%22.7%0.0001fever0.9%

30、2.5%0.0001OthersComparableNSKaufmann R, et al. J Clin Oncol 2005; 23:9001聯合 IFN + IL-2Patients with Advanced Melanoma (N = 183)CVD(n = 92)CVD + IFN-+ IL-2(n = 91)MDACC StudyEton O, et al. J Clin Oncol 2002; 20:2045REGIMENCVDDDP 20mg/m2 d1-4, 22-25VLB 2mg/m2 d1-4, 22-25DTIC 800mg/m2 d1, 22 Repeated e

31、very 6wksCVD + IFN-+ IL-2DDP 20mg/m2 d1-4, 22-252 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 6wksRESULTSCVDCVD + IFN-+ IL-2P valueORR (%)25480.001TTP (mos)2.44.90.008OS (mos)9.211.90.06ORR: overall response rateTTP: time to progressionOS

32、 : overall responseEton O, et al. J Clin Oncol 2002; 20:2045血液學毒性Eton O, et al. J Clin Oncol 2002; 20:2045非血液學毒性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; 22:2847aREGIMENCVDDDP 20mg/m2 d1-42 d1-4DTIC 800mg/m2 d1 Repeated every 3wksCVD + IFN-+ IL-2DDP 20mg/m2 d1-42 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; 22:2847aRESULTSCVDC