心脑血管药理食管癌放疗增敏物理课件

心脑血管药理食管癌放疗增敏物理心脑血管药理食管癌放疗增敏物理心脑血管药理食管癌放疗增敏物理1Radiotherapy Modalities FractionationFractionation Normal,hyper,hypo,and simultaneous boostNormal,hyper,hypo,and simultaneous boost ConformalityConformality CRT,IMRT,CTV-to-PTV margin,dose CRT,IMRT,CTV-to-PTV margin,dose distributiondistribution High LET radiationHigh LET radiation 10(10(n),100 KeV/&x-ray),10(n),100 KeV/m mm(p,m(p,)Sensitizers or biological modifiersSensitizers or biological modifiers OO2 2,chemo,gene drug,chemo,gene drugRadiotherapy ModalitiesFractioClassic Radiobiology FrameworkThe biological basis for fractionation&The biological basis for fractionation&total treatment timetotal treatment time Radiosensitivity of cell survivalRadiosensitivity of cell survival Cell cycle kinetics(proliferation)Cell cycle kinetics(proliferation)DNA damage/repair(incomplete repair)DNA damage/repair(incomplete repair)The biological basis for conformalityThe biological basis for conformality Dose/volume effectDose/volume effect Molecular targetingMolecular targetingClassic Radiobiology FrameworkRadiocurability of 8-mm A431 tumor xenografts in nude mice.Radiation dose-response curves were generated for local tumor control at 120 days after treatment with radiation alone(open circle),a single dose of C225 plus radiation(open triangle),or three doses of C225 plus radiation(filled square).Error bars are 95%confidence intervals on the TCD50.Radiocurability of 8-mm A431 t心脑血管药理食管癌放疗增敏物理课件心脑血管药理食管癌放疗增敏物理课件Tumor or early reaction normal cell=10Late reaction normal cell=3Tumor or early reaction normalCell Survival During RTCell survival fraction(log)after one and n times dose Cell survival fraction(log)after one and n times dose deliverydeliveryExample:Tumor(=10)If 0.62=TCP(35x2Gy)=0%not curable If 0.4,then SF TCP=100%always curableCell Survival During RTCell suBiologically Effective Dose(BED)The relationship between log cell killing and BED is The relationship between log cell killing and BED is always linear.always linear.For a given dose per fraction,the BED is larger for late reacting tissue than tumor or early reacting tissueBiologically Effective Dose(BTo remain BED=constant:To remain BED=constant:Without considering cell proliferation and damage/repair,small fraction dose with large number of fractions seems always good for normal tissues,meanwhile it remains similar effect for tumor.Without considering cell proliRapid Repopulation of Tumor During RTRapid Repopulation of Tumor DuTumor Cell Proliferation During RTTumor cell survival with consideration of tumor cell Tumor cell survival with consideration of tumor cell proliferation during the RTproliferation during the RTExample:tlag=21 days,tpot=3 days and =0.3,=10After the first 21 days of treatment,the dose loss for one extra day is equals to 0.77 GyIt implies that in the conventional RT(60 Gy=30 x2Gy week days),the equivalent dose is only 44 Gy Tumor Cell Proliferation DurinBiologically Effective Dose for Tumor with consideration Biologically Effective Dose for Tumor with consideration of tumor cell proliferation during the RTof tumor cell proliferation during the RTBiologically Effective Dose fIncomplete Repair of Normal Tissue During RTIncomplete Repair of Normal TiIncomplete Repair of Normal Tissue During RTExample:trep=4 hrs,DT=6 hrs,=0.3,=3It implies that in the hyper-fractionation RT(60 Gy=30 x2Gy,two fractions per days),the equivalent dose will be 66.5 Gy Incomplete Repair of Normal TiBiologically Effective Dose for a normal tissue Biologically Effective Dose for a normal tissue with consideration of incomplete repairwith consideration of incomplete repairBiologically Effective Dose fBiological Equivalence:Two dose fractionation regimens,Two dose fractionation regimens,(n(n1 1,d,d1 1)and and(n(n2 2,d,d2 2)are are biologically equivalent with respect to tumor control or biologically equivalent with respect to tumor control or normal tissue complication if and only ifnormal tissue complication if and only ifBiological Equivalence:Normalized Total Dose(NTD):convert dose to NTD Normalized Total Dose(NTD):convert dose to NTD before applying conventional RT dose response for before applying conventional RT dose response for treatment evaluationtreatment evaluationNormalized Total Dose(NTD):H&N:3DCRT vs.9 Beam IMRT(Dose-Volume Criteria)CordTumorNodesParotidsBrainstem3DCRTIMRTH&N:3DCRT vs.9 Beam IMRT(DLung:3DCRT vs.5 Beam IMRTHeartEsophagusLungSpinal CordLung:3DCRT vs.5 Beam IMRTHeaA specified dose-volume constraint can lead to an infinite number of dose responsesAn infinite number of dose-volume histograms lead to the same responseLimitations of Dose-Volume-Based Treatment Planning EvaluationConstraint:V(d 50 Gy)25%A specified dose-volume consDose Volume RelationshipA human normal organ can be described as a structure of functional subunits(FSU)-the maximum volume that can be repopulated by one clonogenic cellnephrons in the kidney renal tubule cellsnephrons in the kidney renal tubule cellslung alveolilung alveoliintestine intestinal cryptsintestine intestinal cryptsliver lobulesliver lobulesDose Volume RelationshipA humaDose Volume Relationship#cells per FSU,#of FSUs and radiosensitivity of the cells#cells per FSU,#of FSUs and radiosensitivity of the cells Tissue architecture(parallel and serial arrangement of FSUs)Tissue architecture(parallel and serial arrangement of FSUs)FSUDose Volume Relationship#cellDose-Volume EffectFor a normal organ,For a normal organ,Dose Response Volume/Dose Factor.Dose Response Volume/Dose Factor.This relationship is extremely important for the This relationship is extremely important for the justification of the dose escalation.justification of the dose escalation.Dose-Volume EffectFor a normalDose-Volume Effect(Power Law Relationship)Expected dose Expected dose D De e(convert to NTD)to a partial volume(convert to NTD)to a partial volume V Vp p,which gives the equivalent normal tissue dose response which gives the equivalent normal tissue dose response as the dose as the dose D(2Gy per fraction)D(2Gy per fraction)to whole volume to whole volume V V,has,has the relation,the relation,Dose-Volume Effect(Power LawDose-Volume EffectVp/VDe/D-lung(a=1 1.2)-liver(a=3.12)-rectum(a=8.33)-spinal cord(a=20)Large volume effectSmall volume effectDose-Volume EffectVp/VDe/D心脑血管药理食管癌放疗增敏物理课件Dose Volume Histogram(DVH)V1V3V2V4D4=100%D3=80%D2=50%D1=20%D2D4D1D3V4V3V2V1VDoseVolumeDose Volume Histogram(DVH)V1VDose-Volume Reduction:Effective VolumeDVH Reduction:DVH Reduction:D2D4D1D3V4V3V2V1VVeffDose-Volume Reduction:EffectiDose-Volume Reduction:Effective Dose or Equivalent Uniform Dose(EUD)DVH Reduction:DVH Reduction:D2D4D1D3V4V3V2V1VDeffVeffDose-Volume Reduction:EffectiEffective Dose or Equivalent Uniform Dose(EUD)Properties of EUD:Properties of EUD:Effective Dose or Equivalent UNTCP NTCP for a normal organ,V,irradiated with NTCP for a normal organ,V,irradiated with heterogeneity dose,heterogeneity dose,NTCP NTCP for a normal organ,Normal Tissue Dose Response or NTCPGyNTCP-Lung(Pneumonitis G3)-Rectum(Severe proctitis G3)TD50TD5Normal Tissue Dose Response orCalculate NTCPFind out the TDFind out the TD5 5(V),TD(V),TD5050(V)and TD(V)and TD5050(V/3)(V/3)m=2.944/lnTDm=2.944/lnTD5050(V)/TD(V)/TD5 5(V);(V);1/a=0.910241/a=0.91024*lnTDlnTD5050(V/3)/TD(V/3)/TD5050(V);(V);Calculate DVH(VCalculate DVH(Vi i,d,di i)and EUD for a normal)and EUD for a normal organ,V,in the 3D planning.organ,V,in the 3D planning.NTCP(VNTCP(V ,EUD),EUD)Calculate NTCPFind out the TD5Example Example(lung):V=VExample(lung):V=V1 1+V+V2 2 with V with V1 1/V=0.2 and/V=0.2 and d d1 1=70 Gy and d=70 Gy and d2 2=3.5 Gy.=3.5 Gy.TDTD5 5(V)=17.5 Gy;TD(V)=17.5 Gy;TD5050(V)=24.5 Gy;TD(V)=24.5 Gy;TD5050(V/3)=65 Gy.(V/3)=65 Gy.ExampleExample(lung):V=V1 ExampleExampleTumor Control Probability(TCP)N Ns s=N=N0 0 exp(-exp(-D-D-n Dn D2 2)N N0 0 is the initial number of clonogenic cells;is the initial number of clonogenic cells;N Ns s is the number of expected surviving cells(mean)after is the number of expected surviving cells(mean)after irradiation of a total dose,D=n dirradiation of a total dose,D=n d Probability of k survival cells after irradiation follows the Probability of k survival cells after irradiation follows the Poisson distribution Poisson distribution P Pk k(D)=N(D)=Ns sk k exp(-N exp(-Ns s)/k!)/k!Tumor Control model k=0(all tumor cells were killed.)Tumor Control model k=0(all tumor cells were killed.)TCP(N TCP(N0 0,D)=P,D)=P0 0(D)=exp(-Ns)(D)=exp(-Ns)Tumor Control Probability(TCPTumor Control Probability(TCP)The TCP model holds if clonogenic cells in The TCP model holds if clonogenic cells in tumor havetumor haveUniform radiation sensitivity Uniform radiation sensitivity Uniform density Uniform density Uniform dose distributionUniform dose distributionTumor Control Probability(TCPTCP for Treatment PlanningIn the clinical situation:Heterogeneous population of radiation Heterogeneous population of radiation sensitive(oxic)and resistant(hypoxic)tumor sensitive(oxic)and resistant(hypoxic)tumor cellscellsNon-uniform density of clonogenic cells in Non-uniform density of clonogenic cells in tumortumorNon-uniform dose distribution in tumorNon-uniform dose distribution in tumorTCP for Treatment PlanningIn tTCP for Treatment PlanningTCP(TCP(,V,d)=exp(-N,V,d)=exp(-Ns s),),N Ns s=V V (r)exp-(r)exp-(r)D(r)-(r)D(r)-(r)/n D(r)(r)/n D(r)2 2 d dr r V-the initial tumor volume V-the initial tumor volume r-spatial vector r-spatial vector (.)-the initial cell density with N(.)-the initial cell density with N0 0=V V (r)(r)d dr.r.TCP(TCP(,V,d)can be directly calculated if we,V,d)can be directly calculated if we know know (r),(r),(r),(r),(r)and D(r)in tumor V.(r)and D(r)in tumor V.TCP for Treatment PlanningTCP(TCP for Heterogeneous Radiosensitivity of Tumor CellsTCP for Heterogeneous Radiosensitivity of Tumor Cells A tumor with uniform cell density is irradiated by the A tumor with uniform cell density is irradiated by the uniform dose d,but different radiosensitivityuniform dose d,but different radiosensitivity Assuming that the total number of cells,NAssuming that the total number of cells,N0 0=N=N1 1+N+N2 2,where Nwhere N1 1=10=108 8 oxic cells with oxic cells with 1 1=0.4;and N=0.4;and N2 2=10=103 3 hypoxic cells with hypoxic cells with 2 2=0.133(i.e.OER=3),=0.133(i.e.OER=3),thenthenTCP=exp(-NTCP=exp(-Ns s),N),Ns s=N=N1 1 exp(-exp(-1 1D)+ND)+N2 2 exp(-exp(-2 2D)D)therefore,TCP(N,D)=TCP(Ntherefore,TCP(N,D)=TCP(N1 1,D)x TCP(N,D)x TCP(N2 2,D),D)TCP for Heterogeneous RadiosenTCP is dominated by radio-resistant tumor cells!TCP is dominated by radio-resistant tumor cells!TCP for N1TCP for N2TCP for N1+N2TCP is dominated by radio-resiTCP for Nonuniform Tumor Cell DensityRelation between the dose,D,and cells density,Relation between the dose,D,and cells density,which remains the TCP to be constant which remains the TCP to be constant 0 0 exp(-exp(-D D0 0)=)=exp(-exp(-D)=D-DD)=D-D0 0=(1/(1/)ln)ln/0 0.Dose is relatively insensitive to the cells density.Dose is relatively insensitive to the cells density.TCP for Nonuniform Tumor Cell Effect of Tumor Cells Density(=0.4;D=0.4;D0 0=60 Gy).=60 Gy)./0 Density%Dose%0D0=60 GyEffect of Tumor Cells DensityTCP for Heterogeneous Dose Distribution Tumor volume V=Tumor volume V=N N0 0;Considering V=V;Considering V=V1 1+V+V2 2,and V,and V1 1 was was irradiated with dose Dirradiated with dose D1 1 and V and V2 2 with dose D with dose D2 2:TCP=exp(-NTCP=exp(-Ns s),),N Ns s=V V1 1 exp(-exp(-D D1 1)+)+V V2 2 exp(-exp(-D D2 2)=V V1 1/V)N/V)N0 0 exp(-exp(-D D1 1)+)+V V2 2/V)N/V)N0 0 exp(-exp(-D D2 2)=ln(TCP)=ln(TCP)=V V1 1/V)lnTCP(V,D/V)lnTCP(V,D1 1)+(V)+(V2 2/V)lnTCP(V,D/V)lnTCP(V,D2 2)Therefore,Therefore,TCP for Heterogeneous Dose Dis85%of tumor volume has full dose,and the other 15%has dose 85%of tumor volume has full dose,and the other 15%has dose deficiency of 0%,10%,15%or 20%respectivelydeficiency of 0%,10%,15%or 20%respectivelyTCPGy dose deficiency in 15%of volume-0%-10%-15%-20%85%of tumor volume has full doCalculate TCP for 3D Treatment Planning Evaluation Tumor volume has Tumor volume has DVH=(VDVH=(V1 1,D,D1 1),(V),(V2 2,D,D2 2),),In the practice,TCP(V,Di)is determined from clinical dose response fittingCalculate TCP for 3D TreatmentTCP for Adenocarcinoma of ProstateGyTCPTCD50g g50 50 TCP for Adenocarcinoma of ProsCalculate TCP for 3D Treatment Planning Evaluation Example(Prostate cancer):Example(Prostate cancer):V=VV=V1 1+V+V2 2;V;V1 1/V=85%,V/V=85%,V2 2/V=15%;V/V=15%;V1 1 with dose with dose D D1 1=80 Gy and V=80 Gy and V2 2 with dose D with dose D2 2=72 Gy.=72 Gy.(TCP(V,80 Gy)=78%and TCP(V,72 Gy)=55%)(TCP(V,80 Gy)=78%and TCP(V,72 Gy)=55%)Then,Then,Calculate TCP for 3D Treatment谢谢观赏谢谢观赏谢谢观赏51