肺癌脑转移综合治疗临床试验及总结.ppt

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level,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,肺癌脑转移综合治疗临床试验及总结,优选肺癌脑转移综合治疗临床试验及总结,概述,2040%,出现脑转移,肺癌,1864%,、乳癌,221%,、黑色素瘤,316%,、肾癌,7%,、结肠癌,211%,等,多种因素导致脑转移发病率,1.,诊断技术提高,2.,系统化疗后生存率提高,概述,肺癌发病率,肺癌脑转移,脑转移是肺癌常见的转移部位，也是患者致死的主要原因之一。,概述,肺癌脑转移,-,出现在肺癌原发灶发现之前,-,肺癌原发灶同时发现,-,发现之后,近来报道，约,81%,的肺癌脑转移发生在肺癌诊断后，其中位数为,17,个月,概述,非小细胞肺癌脑转移的发生率约,20-40%,，高到低：腺癌,大细胞未分化癌,鳞癌,肺小细胞未分化癌首次就诊，脑转移发生率,10%,，诊疗过程中为,40-50%,，存活,2,年以上的患者脑转移达,80%,。,概况,脑转移自然病程,1-2,个月；单纯化疗为,2.5-3,个月,全脑照射,4-6,月,脑转移是原发瘤治疗失败的常见原因。,脑转移途径和部位,最常见途径,-,动脉循环的血源性转移。,脑内灰白质交界以下区域血管管径变细，狭窄的血管内血流变慢，易形成瘤栓，该处是发生脑转移瘤的最常见部位。,脑转移瘤的分布与其重量（及血流量）有关，约,80%,的脑转移位于大脑半球，,15%,在小脑，,5%,在脑干。,脑转移途径和部位,脑转移可单发也可多发,单发脑转移：单个病灶、其他部位无转移,肺癌脑转移则以多发常见,CT,：单发多见约,53%,，多发,47%,MRI,：单发脑转移仅占,2533%,而多发为,6675%,，,建议增强扫描,临床表现,2/3,有神经症状,先于肺癌出现,同时出现,肺癌后出现,原发瘤患者有新的神经症状，高度怀疑,临床表现,无特异性,渐进或急性发病,四大症状,：,头疼,（,50%,）、,局灶性肌无力,（,20%-40%,）、,认知障碍,（,1/3,）、,癫痫,（,10%,首发，,40%,）,其次：步态、言语、视力障碍等,诊断,肿瘤病史及单发或多发脑部病灶,手段,-,强化,MRI,。优于强化,CT,及平扫,MRI,增强,MRI,平扫,MRI,CT 20%,强化,MRI,后仍有疑问,-,活检是唯一可靠手段,诊断,影像表现：灰白质交界处病变，边界不规则，肿瘤较小伴大片水肿,MRI:T1,像显示低于正常脑组织信号,T2,加权像显示水肿，表现高信号,小于,5mm,病变，位于颞叶或在皮质和皮层下区域或与较大病灶相邻,诊断,鉴别诊断,原发脑肿瘤（良或恶性）,脑脓肿,脑梗塞或脑出血,增强,MRI,鉴别,T1W,T2W,edema,tumor,FLAIR,C+T1W,M,M,?,T1W,C+T1W,治疗,手术治疗,立体定向放疗,全脑放射治疗,化学治疗,同步放化疗的应用,手术治疗,考虑病人,PS,、病理分类、转移瘤的位置与数量,最适当的治疗手段仍有争议,单纯全脑照射和手术加全脑照射,比较,手术治疗,原发瘤,-,影响术后生存的重要因素,70%-,全身恶化而非中枢系统,术前检查,-CT,，,ECT,，,Marker,。,如丘脑、基底节、脑干等,Flickinger等(94年):剂量17.,WBRT with or without surgery:randomized trials,CNS,central nervous system;MS,median survival;NR,not reported,（2）单发脑m,或m灶较小,少于2-3个。,Kondziolka等及Pirzkall等认为SRS的剂量应达15或16Gy后，联合全脑放射,1ys60-80%,C 病变严重水肿，伴颅高压。,CR3（7%）PR10，NS15，PD7，CR+PR（30%）,NA:not applicable;NR:not reported;+:p70,等不符,I,，,III,条件,RPA III,级：,KPS,70,手术治疗合并,WBRT,杀灭,手术部位残存癌细胞,其它微小转移灶,延长生命,作者 病历数,单纯放疗,(,周数,),手术合并放疗,(,周数,),Patchell et al,48 15 40,Vecht et al,65 26 43,Mintz et al,84 27 24,表一 单发脑转移的单纯放疗与放疗,+,手术的随机研究（中位生存期）,表二单发脑转移的单纯放疗与放疗,+,手术的非随机研究（中位生存期）,作者 病例数 单纯放疗,(,周数,),手术,+,放疗,(,周数,),Famell et al 81 36 45,Sause et al 80 29 67,Smalley et al 121,（完全切除）,36 68,Smalley et al 28,(,不完全切除,),13 57,手术治疗,单发脑转移灶的单纯全脑照射和手术加全脑照射的随机分组研究，对生存率、中枢神经系统的控制率、肿瘤进展的类型及生存质量的比较，结果显示后者明显优于前者。,手术治疗,一组回顾性研究结果,:,术后观察组与术后放疗组比较,:,两者的复发率分别为,:85%,与,21%.,中位生存期分别为,11.5,与,21,月,.,JCO 19:2074-2083,2001,auther,varial,WBRT,WBRT+Surg,P-value,Patchell,etal,n,23,25,MS,wk,15,40,0.01,Length of functional independence,wk,8,38,0.005,CNS death rate,%,50,29,0.26,Local recurrence at initial site,%,52,20,5mm,。,B,急性出血，边界不清。,C,病变严重水肿，伴颅高压。,D,有囊性变,E,原发未控的多发脑转移,立体定向治疗,总疗效,:,局部控制率,73-98%,Flickinger,等,(94,年,):,剂量,17.5Gy,局控率,85%,Shiau,等,:,剂量,18Gy,1,年局控,77-90%,立体定向治疗,尸检多发脑转移发生率高,单一病灶,应视为有多发微小灶,放射外科,+,全脑照射,:,局控率,多发脑转移灶潜在复发,合并,WBRT,的理由,JCO 19:2074-2083,2001,Not evaluate,原发瘤患者有新的神经症状，高度怀疑,单个转移瘤,Complete response,（3）拒绝手术或手术难度大,文献报道肺癌脑转移联合化疗的中位生存时间与全脑放射相仿,全脑照射+外照射补量或SRS补量,Length of functional independence,wk,Patients/metastasses,n,目的:缓解神经症状和体征,延长生存期,原发灶已得到控制，颅内为单发转移灶，全身状态尚好及年轻患者（KPS70）。,Vm26:脂溶性,可通过BBB,非小细胞肺癌脑转移的发生率约20-40%，高到低：腺癌 大细胞未分化癌鳞癌,多药化疗有效率:NSCLC 16-50%,立体定向治疗,立体定向放疗和全脑照射的联合应用仍在进一步研究中,Kondziolka,等及,Pirzkall,等认为,SRS,的剂量应达,15,或,16Gy,后，联合全脑放射,1ys60-80%,立体定向治疗,70,例单发脑转移，,WBRT,，,SRS,，,WBRT+SRS,，,3,组结果：,SRS and WBRT+SRS,比,WBRT,生存期长。,WBRT+SRS,比,WBRTnew m,时间间隔延长,INT J Cancer,，,2000,，,90,（,1,）,author,Local control%,Median survival,%receiving WBRT,Patients/metastasses,n,SRS,Surg,SRS,Surg,SRS,Surg,SRS,Surg,Schoggl,95,83,12,9,100,100,67/67,66/66,bindal,61,92,7.5,16.4,71,66,31/NR,62/NR,O,Neil,100,42,56%(1 y),62%(1 y),96,82,23/23,74/74,Patchell,1990,80,10,100,25/25,Patchell,1998,90,12,49/49,Noordijk,NR,10,100,32/32,Tabl.Comparison of survival and local control using Surg versus SRS in select trials(1),author,Local control%,Median survival,%receiving WBRT,Patients/metastasses,n,SRS,Surg,SRS,Surg,SRS,Surg,SRS,Surg,Mintz,NR,6,100,41/41,Joseph,94,7,83,120/180,Kondziolka,92,11,100,13/NR,Alexander,89,9.4,100,248/421,Flickinger,85,11,56,116/116,Andrews,82(1y),6.5,100,75/NR,Tabl.Comparison of survival and local control using Surg versus SRS in select trials(2),varial,WBRT,WBRT+SRS,P value,MS,mo,6.5,5.7,0.13,MS single metastasis,mo,4.9,6.5,0.04,MS RPA class I,mo,9.6,11.6,0.0001,MS squamous or NSCLC history,mo,3.9,5.9,0.01,Stable KPS at 6 mo,%,27,43,0.03,rate of neurologic death,%,31,28,NS,Local control of treated lesions at 1 y,%,71,82,0.01,Grade 3 acute toxicity,%,0,2,NS,Grade 4 acute toxicity,%,0,1,NS,Grade 3 late toxicity,%,2,3,NS,Grade 4 late toxicity,%,1,3,NS,Table.Results of the RTOG 95-08 randomized trial of WBRT or without SRS in patient with 1 to 3 brain metastases,author,n,Median survival,mo,Local control,%,WBRT,yes,No,yes,No,yes,No,Chidel,2000,58,78,6.4,10.5,+,80,52(2y),+,Sneed,2002,301,268,8.6,8.2,NR,NR,Sneed,1999,43,62,11.1,11.3,79,71(1y),Pirzkall,78,158,5.5,92,Chitapanarux,0,41,NA,10,NA,76,NA:not applicable;NR:not reported;+:p0.05,Table.SRS with or without WBRT,author,Intracranial control%,Elsewhere brain recurrence%,Required salvage therapy%,Required WBRT for salvage%,WBRT,yes,No,yes,No,yes,No,no,Chidel,2000,60(2y),34+(2y),26,52+,NR,NR,NR,Sneed,2002,NR,NR,NR,NR,7,37,24,Sneed,1999,63,42+,28,50+,19,40+,26,Pirzkall,NR,NR,NR,NR,NR,NR,NR,Chitapanarux,NA,33(1y),NA,NR,NA,51,29,Table.SRS with or without WBRT,NA:not applicable;NR:not reported;+:p0.05,立体定向治疗,存在问题,:,颅外转移灶及原发灶控制,治疗野外新灶出现,治疗费用高,立体定向治疗,结论,SRS is a useful tool in treatment of BM,For a single BM,RTOG95-08 trial demonstrates an improvement in median survival with SRS+WBRT.,SRS+WBRT improvement in KPS,local control and decreased use of stroids in select pts 13 BM.,The appropriate SRS dose following WBRT is 20Gy2cm,18Gy 23cm,and15Gy in tumors more than 3cm in size.,全脑照射,是脑转移的主要治疗手段,目的,:,缓解神经症状和体征,延长生存期,有效率,:70-90%,全脑照射,RTOG,的随机研究,:,40Gy/4w,40Gy/3w,30Gy/3w,及,30Gy/2w,比较,:,治疗结果,疗效维持时间,及病情进展时间相仿,全脑照射,方法,全脑照射：摆位、面罩固定、射野、,侧卧垂照与水平照射差异,整体挡铅,全脑照射,建议,不增加脑损伤前提，提高剂量,40GY,，,1516,次,单发灶或病变集中，局部加量，提高局部控制率,parameter,WBRT,(n=41),WBRT+TMZ,(n=41),Complete response,2(5),2(5),Partial response,11(27),11(27),Stable disease,12(29),17(41),Progressive disease,6(15),5(12),Not evaluate,10(24),6(15),Table.Radiologic response of brain metastase at 30 day,parameter,WBRT,(n=41),WBRT+TMZ,(n=41),Complete response,0(0),1(2),Partial response,2(5),6(15),Stable disease,4(10),10(24),Progressive disease,9(22),3(7),Not evaluate,26(63),21(51),Table.Radiologic response of brain metastase at 90 day,全脑照射,全脑照射,+,手术,全脑照射,+r,（,x,）刀,全脑照射,+,外照射补量或,SRS,补量,auther,variable,WBRT,WBRT and surgery,P value,Patchell et al,n,23,25,MS,wk,15,40,0.01,Length of functional independence,wk,8,38,0.005,CNS death rate,%,50,29,0.26,Local recurrence at initial site,%,52,20,0.02,Vecht,et al,n,31,32,MS,wk,26,43,0.04,Length of functional independence,wk,15,33,0.06,CNS death rate,%,33,35,Local recurrence at initial site,%,NR,NR,Table.WBRT with or without surgery:randomized trials,auther,variable,WBRT,WBRT and surgery,P value,Mintz et al,n,43,41,MS,wk,27,24,0.24,Length of functional independence,wk,9,8,0.98,CNS death rate,%,63,46,0.30,Local recurrence at initial site,%,NR,NR,0.02,CNS,central nervous system;MS,median survival;NR,not reported,Table.WBRT with or without surgery:randomized trials,复发脑转移的治疗,单发脑转移术后复发,4050%,，包括原部位和其它部位复发，考虑再手术，,SRS,等。,WBRT,后复发，根据时间，部位，范围等，考虑适形，,SRS,，外照射等。,SRS,后复发，有作者建议，再次,r-,刀，结果好。,（,Osaka City Med J,，,1999,，,45,（,1,）,降颅压,激素,利尿剂,甘露醇,甘露醇,+,激素,-,注意电解质平衡,颅高压者,补液速度慢及少补液,肺癌脑转移则以多发常见,化疗+放疗降低NSCLC脑外转移率,而脑内转移率无明显影响,Local control of treated lesions at 1 y,%,The appropriate SRS dose following WBRT is 20Gy,血浆,药物浓度,40%,少数学者将其应用于肺癌脑转移的治疗。,研究较少,病例少,单药化疗,Postmus,的,II,期临床研究表明，单药,Vm26,治疗后，颅内病灶的有效率为,33%,Schutte,分析了,22,例脑转移病例，单药,Topotecan,平均,化疗周期数,4,周期，颅内病灶有效率为,50%,。,联合化疗,多药化疗有效率,:NSCLC 16-50%,SCLC 30-85%,常用方案,:,Vm26+DDP,IFO+DDP,CTX+DDP+,阿霉素,联合化疗,近来,MVP,（,MMC+DDP+,长春花减酰胺）方案有效率,30%60%,。,Paclitaxel+DDP 27%44%,健择,+DDP 28%54%,联合化疗,PDD+VP16,BM from NSCLE,（,43Pts,）,P 100mg/m,2,（,d1,），,E 100mg/m,2,（,d1,，,3,，,5,）,CR3,（,7%,）,PR10,，,NS15,，,PD7,，,CR+PR,（,30%,）,MS 7months and 1year s 25%,（,Cancer,，,Vol 85,，,april 1,，,1999,）,联合化疗,联合化疗的有效率较单药提高了近,20%,文献报道肺癌脑转移联合化疗的中位生存时间与全脑放射相仿,骨髓抑制等并发症也相应加大，需要很好的支持治疗,同步放化疗,研究较少,有效率,56-80%,中位生存,WBRT,，,CT,Furuse,等,33,例,NSCLC,脑转移治疗,VDS+DDP+MMC,联合化疗,2,周期,给药第,2,天,全脑照射,DT40Gy/20f/4w,有效率,76%,中位生存,9.4,月,同步放化疗,根据：,药代动力学显示脑转移瘤的病灶区,BBB,部分,/,全部破坏,秦教授研究,-,放疗增加,BBB,通透性,化疗药物增敏,协同作用,同步放化疗,Postmus,等一组,EORTC,三期临床研究,(Sclc,脑转移,),单药,Vm26,化疗与,Vm26+WBRT,Vm26:120mg/m,2,1,3,5,天给药,;,合并放疗组,DT30Gy/10f/2w,两组有效率,:21%,57%;,中位生存,3.2,月及,3.5,月,失败原因,:,颅外病变,单药,Vm26,不够,副作用,:,骨髓抑制,同步放化疗,每周给药一次，发挥,Vm-26,的放射增敏作用，探讨国人在同期放化疗中对化疗药物的耐受性，观察其毒性及临床可行性。,同步放化疗,疗后一个月行增强,MRI,或增强,CT,扫描。,50mg/m,2,组,CR 1,例，,PR 8,例，,SD 3,例。,75mg/m,2,剂量组,CR 2,例，,PR1,例，,SD 1,例无一例病变进展。,所有病例于,2-3,月后再行检查，脑转移病变均有缩小。,同步放化疗,肺癌脑转移采用全脑照射合并,Vm-26,的综合治疗是可行的,主要毒付反应为骨髓抑制,Vm-26,最大耐受剂量为,75mg/m,2,，推荐,II,期临床用药为,50mg/m,2,中华放射肿瘤杂志（,2003,年第,4,期）。,展望,放疗,:,如何进行剂量分割及加速分割,放射增敏剂,神经外科和,SRS,适合者少,联合放和,/,或化疗,综合治疗,:,有效化疗药物,放射增敏剂,与全脑照射,