肺癌脑转移的综合治疗.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth 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,*,肺癌脑转移的综合治疗,优选肺癌脑转移的综合治疗,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,Table,WBRT with or without surgery:randomized trials,Chidel,2000,多药化疗有效率:NSCLC 16-50%,适应证（1）无颅外病变，年纪较轻，单发脑转移（孤立、较小、球形、外形较规则的病灶），直径20mm35mm。,全脑照射+外照射补量或SRS补量,静脉注射：脑原发瘤及转移瘤中较高 浓度,放射外科+全脑照射:局控率,比较:治疗结果,疗效维持时间,JCO 19:2074-2083,2001,多药化疗有效率:NSCLC 16-50%,Smalley et al 121（完全切除）36 68,Local recurrence at initial site,%,Results of the RTOG 95-08 randomized trial of WBRT or without SRS in patient with 1 to 3 brain metastases,激素：减轻及防止组织炎症反应，毛细血管扩张及通透性，水肿形成。,The patient has had a marked decrease in tumor size(A)and has minimal cerebral edema associated with the tumor location(B).,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,。,手术治疗,手术适应症,:,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,）。预计生存,4,个月。,手术治疗,选择：肿瘤位于手术可切除的部位,单个转移瘤,不宜手术：脑深部及重要功能区,如丘脑、基底节、脑干等,手术治疗,疗效较明确,.,疗效,:,生存期,10-14,月,手术治疗,脑转移瘤预后分级标准（,recursive partitioning analysis RPA,）,RPA I,级：,65,岁，,KPS,70,，,原发灶控制，无颅外,M;,RPA II,级：原发灶控制不理想，有颅外,M,或,KPS,70,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。,Local control%,Shiau等:剂量18Gy,1年局控77-90%,立体定向治疗,体积较大或分次治疗,分次放射生物效应,（,1,）肿瘤组织乏氧细胞再氧合。（,2,）小剂量分次放射利于,晚反应组织损伤（周边组织），早反应组织,Tumor,给予大剂量。,近年来脑转移治疗最突出进展,FIGURE 1.,An axial,T1-weighted MR image with double-dose gadolinium-based contrast is illustrated through a metastasis in a patient with nonsmall cell lung cancer.The size,demarcation,and location of this metastasis make it ideally suited for radiosurgery.,FIGURE.,T1 weighted with contrast(A)and T2 axial(B)MR images of the same patient with metastatic nonsmall cell lung cancer now 12 months after radiosurgery.The patient has had a marked decrease in tumor size(A)and has minimal cerebral edema associated with the tumor location(B).,立体定向治疗,适应证,（,1,）,无颅外病变，年纪较轻，单发脑转移（孤立、较小、球形、外形较规则的病灶），直径,20mm35mm,。（,2,）单发脑,m,或,m,灶较小,少于,2-3,个。（,3,）拒绝手术或手术难度大,立体定向治疗,不宜,SRS,：,A,病灶位敏感或重要结构，如视神经、视交叉、,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,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,）,P 100mg/m2（d1），E 100mg/m2（d1，3，5）,脑转移是原发瘤治疗失败的常见原因。,单药Vm26化疗与Vm26+WBRT,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%。,Median survival,Vm26:脂溶性,可通过BBB,（2）小剂量分次放射利于晚反应组织损伤（周边组织），早反应组织Tumor给予大剂量。,Radiologic response of brain metastase at 30 day,Vm26:脂溶性,可通过BBB,Chitapanarux,局控率85%,联合化疗的有效率较单药提高了近20%,单一病灶,应视为有多发微小灶,The patient has had a marked decrease in tumor size(A)and has minimal cerebral edema associated with the tumor location(B).,关于化疗药物能否透过BBB的问题,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,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。,