心脑血管药理食管癌放疗增敏研究translationvgrtchchina

心脑血管药理食管癌放疗增敏研究translationvgrtchchina高危宫颈癌患者盆腔放疗结合同期化疗与盆腔及腹主动脉旁淋巴引流区放疗的比较M.Morrisetal,NEJM,340:1137-1143,1999.高危宫颈癌患者盆腔放疗结合同期化疗与盆腔及腹主动脉旁淋巴引流区放疗的比较M.Morrisetal,NEJM,340:1137-1143,1999.

放疗

放疗+化疗 (n=193)(n=195)5年总生存率 58% 73(p=0.004)局部复发率

35% 19%(p<0.001)远处复发转移

33% 14%(p<0.001)放疗:45Gy+腔内治疗

(totaldose≥85Gy)化疗:cddp(75mg/m2,d1),5Fu(1g/m2/d,d1-4),x3放化疗综合治疗空间协同作用

(e.g.乳腺癌)独立的细胞杀伤作用

(e.g.霍奇金淋巴瘤)相互作用

(e.g.头颈,宫颈,非小细胞肺癌)“稀释”毒性

(e.g.霍奇金淋巴瘤)绝经前高危乳腺癌患者术后放疗和辅助化疗

DanishBreastCancerCooperativeGroup82bTrialM.Overgaardetal.,N.Engl.J.Med.,337:949-955,1997放化疗综合治疗空间协同作用(e.g.乳腺癌)独立的细胞杀伤作用(e.g.霍奇金淋巴瘤)相互作用(e.g.头颈,宫颈,非小细胞肺癌)“稀释”毒性(e.g.霍奇金淋巴瘤)

放疗

化疗

化疗+放疗

(EF,40Gy)(MOPP/ABVD) (IF,

≤40Gy)10年总生存

80-90% 80-90% ≈90%并发症

(RR)-白血病

11.0 70.0 ?-淋巴瘤

21.0 22.0 ?-实体肿瘤

2.8 1.1 ?-心脏

2.2-3.1 ≈1.0 ?I期和II期

霍奇金淋巴瘤(病理类型好和较好)放化疗综合治疗空间协同作用(e.g.乳腺癌)独立的细胞杀伤作用(e.g.霍奇金淋巴瘤)相互作用(e.g.头颈,宫颈,非小细胞肺癌)“稀释”毒性(e.g.霍奇金淋巴瘤)头颈鳞癌：对照-无化疗

Pignonetal.,Lancet355:949-955,2000头颈鳞癌：对照-无化疗Pignonetal.,Lancet355:949-955,2000放化疗综合治疗DoseEffectRTRT+CHAdditivityDoseEffectRTDoseEffectRTRT+CHSupra-additivity在SA-NH肿瘤中单次放疗合并氟脲嘧啶(800mg/kg)的剂量修饰因素RADIATIONDOSE(Gy)GROWTHDELAY±SE(days)6810121416182022241920212223242526272829AbsoluteGrowthDelayDMF=1.57NormalizedGrowthDelayDMF=1.2RTaloneDose(Gy)S.F.1.0E-031.0E-021.0E-011.0E+0005101520RTRT+CH放化疗综合治疗1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CH1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CH1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CHRedrawnfromSteel增强无相互作用抑制放化疗综合治疗在人类鳞癌细胞株(SQD9)中dFdC对放射的增强作用10-410-310-210-110002468101214RxalonedFdC(5µM)for3hpriortoRxSurvivingFractionAbsorbeddose(Gy)DMF=1.3DMF=1.3DMF=1.3

(Gy-1) (Gy-2)Rx 0.30 0.02Rx+dFdC 0.38 0.04放化疗合理的综合应用调整DNA/染色体的修复调节肿瘤细胞增殖增加肿瘤细胞丢失加强放疗导致的核苷类似物诱导的凋亡作用增加肿瘤细胞再充氧放化疗综合治疗：细胞水平/分子水平相互作用DNA损伤染色体细胞凋亡诱导修复异常周期5-FuMTXHUdFdCF-ara-A-??---/+?-/+---?++++?+++???--?抗代谢药DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleVinca-alcaloidesEtoposideCamptothecineTaxanes????-+??-?--+++-/++?+-/++植物衍生药放化疗综合治疗：细胞水平/分子水平相互作用DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleAdriamycinMitomycin-CBleomycinActinomycin-D-???-/+?-+?-/+--/+?+?+????-抗生素类药放化疗综合治疗：细胞水平/分子水平相互作用DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleCis-platinumBCNUCyclophosphamide+???++??---?????烷化剂放化疗综合治疗：细胞水平/分子水平相互作用放化疗综合治疗细胞水平

/分子水平相互作用或组织水平相互作用?在SA-NH肿瘤中通过分割放疗和氟脲嘧啶注射对再增殖延缓进行调节5791113150510152025Timeafterfirstfraction(day)controlFludarabine(400mg/kg)q.d.x44.5Gyq.d.x4Fludarabine3hpriortoRTMeantumordiameter±se(mm)TumorradiosensitizationNormaltissueradio-toxicityEFFICACYDMF=2.0DMF=1.2TherapeuticRatio=DMFTDMFNT治疗增益比的概念 Acuteeffect LateeffectAntimetabolites 5-Fu ++(GI,skin) MTX ++(GI) HU ++(GI) dFdC ++(GI) ±(lung) F-ara-A ++(GI) ±(SNC)Alkylatingagents cis-platinum ++(GI) +(kidney) BCNU ++(GI) +(lung) cyclophosphamide ++(GI,skin) +(lung, bladder,SNC)Antimetabolites adriamycine ++(GI,skin) +(heart,lung) mitomycin-C ++(GI,BM) +(lung) bleomycin ++(skin,GI) +(skin,lung) actinomycine-D ++(GI,BM,skin) +(lung)Plantderivatives Vinca-alcaloides -(GI,BM) ? Etoposide ? ? Taxanes +(GI) ?放化疗综合治疗：正常组织毒副作用高危宫颈癌患者盆腔放疗结合同期化疗与盆腔及腹主动脉旁淋巴引流区放疗的比较M.Morrisetal,NEJM,340:1137-1143,1999.

放疗

放疗+化疗 (n=193)(n=195)Earlytoxicity(G3-5) 10(5%) 88(45%)Earlytoxicity*(G3-5) 4(2%) 20(10%)Latetoxicity(G3-5) 22(11%) 24(12%)*

nonhematologiconlyRT:45Gy+brachytherapy(totaldose≥85Gy)Chemo:cddp(75mg/m2,d1),5Fu(1g/m2/d,d1-4),x3

高危宫颈癌患者盆腔放疗结合同期化疗与盆腔及腹主动脉旁淋巴引流区放疗的比较M.Morrisetal,NEJM,340:1137-1143,1999.EnhancementfactorEffectontumorcontrolEffectonnormaltissuetoxicity543212345EarlyLateLocalrelapse局部晚期头颈鳞癌采用放化疗交替治疗M.Merlanoetal,NEJM,327:1115-1121,1992.EnhancementfactorEffectontumorcontrolEffectonnormaltissuetoxicityEarlyLat