Accelerated partial breast irradiation using external beam radiotherapy—A feasibility study based on dosimetric analysis

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Original

research

article

Accelerated

partial

breast

irradiation

using

external

beam

radiotherapy—A

feasibility

study

based

on

dosimetric

analysis

Surega

Anbumani

a,∗

_{, Siddanna}

_R.

_Palled

b

_,

_Girish

_S.

_Prabhakar

a

_,

_N.

_Arunai

_Nambiraj

c

_,

Anchineyan

Pichandi

a

a_{HCG-Bangalore}_Institute_of_Oncology,_Bangalore,_India b_Kidwai_Memorial_Institute_of_Oncology,_Bangalore,_India c_VIT_University,_Vellore,_India

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received3January2012 Receivedinrevisedform 28February2012 Accepted26April2012 Keywords: APBI Doseconformity Dosehomogeneity MulticatheterISBT

a

b

s

t

r

a

c

t

Aim:ToinvestigatethefeasibilityofusingExternalBeamradiotherapyforacceleratedpartial breastirradiationbyacomparativetumourandnormaltissuedosevolumeanalysiswith thatofhighdoserateinterstitialbrachytherapy.

Background:AcceleratedPartialBreastIrradiation(APBI)ismoreclinicallyappealingbecause ofthereducedtreatmentcoursedurationandtheirradiatedarea.Brachytherapy applica-tionismoredependentontheclinician’sexpertisewhenitispractisedfreehandwithout imageguidanceandatemplate.Ithappenstobeaninvasiveprocedurewiththeuseoflocal anaesthesiawhichaddspatientdiscomfortapartfromitscostcomparedtoExternalBeam Radiotherapy.ButAPBIwithbrachytherapyismorecommonlypractisedprocedure com-paredtoEBRTowingtoitspreviousreults.Henceinthisresearchstudy,weintendtoexplore theuseofEBRTwiththeradiobiologicalcorrectionsforAPBIintheplaceofbrachytherapy. ItisdoneasadosimetriccomparisonofBrachytherapytreatmentplanswiththatofEBRT plans.

Materialsandmethods:Thecomputedtomographyimagesof15patientsundergoingISBT planningweresimulatedwithconformalphotonfields.Variousdosevolumeparametersof eachstructurewereobtainedfromtheDVHgeneratedinthebrachytherapyandthe sim-ulatedexternalbeamplanningwhichcancorrelatewellwiththelatetoxicity.Theplan qualityindicessuchasconformityindexandhomogeneityindexforthetargetvolumewere computedfromthedosimetricfactors.ThestatisticalpvaluesforCI,HIandnormaltissue dosimetricparameterswerecalculatedandtheconfidencelevelsachievablewereanalysed. Thedoseprescribedinbrachytherapywas3400cGyintenfractions.Theequivalent prescrip-tiondosefortheexternalbeamradiotherapyplanningwas3000cGyinfivefractionsapplied withradiobiologicalcorrection.

∗ _{Corresponding}_author_at:_{HCG-Bangalore}_Institute_of_Oncology,_44-45/2,_II_Cross_RRMR_Extension,_Off_Lalbagh_Double_Road,_Bangalore

560027,Karnataka,India.Tel.:+918140206535;fax:+918123478031. E-mailaddress:[email protected](S.Anbumani).

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Alltheﬁfteenpatientswerewithcompletelungdataandsixwerewithleftsidedtumours havingcompletecardiacdata.Thelungdosimetrydataandthecardiacdosimetrydataof thepatientswerestudied.LowerpercentagesoflungandcardiacV20andV5volumeswere

obtainedwithconformalplanning.Theconformityofradiationdosetothetumourvolume wasakintotheinterstitialbrachytherapyplanning.Moreovertheexternalbeamplanning resultedinmorehomogenousdosedistribution.Forthesampledpopulation,thestatistical analysisshowedaconﬁdencelevelof95%forusingEBRTasanalternatetomulticatheter ISBT.

Conclusion:TheEBRTplanningforAcceleratedPartialBreastIrradiationwasfoundtobe technicallyfeasibleintheinstitutionwheretheinterstitialbrachytherapyhappenstobe theonlyavailabletechniqueasevidentfromthedosevolumeparametersandthestatistical analysis.

1. Background

Accelerated Partial Breast Irradiation (APBI) decreases the durationofentireradiotherapy course.1 _The_reduced

treat-mentvolumemakesAPBImoreappealingtobothclinicians and patients. Theuses of brachytherapy either as HDR or LDRinterstitialimplantshaveshownpromisingresultswhich are obvious from the published research works.2,3 _But _the

interstitialimplanttechniquecanbemorecomplexand oper-atordependent.Theimplantapplicationisusuallydonewith imageguidance(Ultrasound/mammographyimages)usinga templatewhichplaysamajorroleinensuringuniformand accurateimplants.Feweroncologistspreferdoingafreehand applicationwithoutatemplateguidancewhichneedsmore expertise.

Radiobiological models based comparisonof APBI tech-niqueswas done byBovi Jet al.4 _Partial _Breast_Irradiation

techniquesforearlystagebreastcarcinomawereevaluated byAgataetal.5_A_dosimetric_analysis_was_detailed_by_Cozzi

etal.asaclinicalexperienceof3Dconformalpartialbreast irradiation.6_Maia_et_al._and_Vicini_et_al._studied_the_accelerated

partialbreast irradiation using photon ﬁelds.7,8 _Dosimetric

studyofdifferentacceleratedpartialbreastirradiation tech-niques,suchas3DCRT,IMRTandMammositeapplication,was evaluatedbyKhanAJetal.9PatelRRetal.dosimetrically com-paredthe3DCRTAPBIwiththatofmulticatheterinterstitial implantbrachytherapyforproneandsupinepositioninhelical tomotherapy.10

2. Aim

In this study,we explored the feasibilityof using external beamradiotherapyusingthreedimensionalconformal pho-tonbeamsfor APBI asan alternate practiceto afreehand interstitial brachytherapy with dosimetrical and statisti-cal analysis. The comparison was done with interstitial brachytherapy,sinceit isthe onlyavailableAPBItechnique practicedattheinstitution.

3. Materials

and

methods

3.1. Patientselection

Fifteen patients undergoing the APBI with interstitial brachytherapytechniquewereenrolledandapprovedforthe feasibility study.11 _The_patients _underwent _partial

mastec-tomy and negativesentinel lymph node biopsy or axillary dissectionforT1/T2invasiveductcarcinomaasapartofbreast conservationsurgerybetweenJuly2009andOctober2011(see Table1).Pre-treatment computedtomography imageswere takenasguidancetoassessthedistanceofthetumourbed from the known landmarks or from the skin surface. The distancesweremarkedonthepatientbody.Flexibleplastic implanttubeswereinsertedintothetumourcavityasafree handapplication.

3.2. Treatmentplanning

Aftertheinsertionofinterstitialtubes,thepatientsunderwent aCTsimulationforthetreatmentplanning.TheCTimages were sent to the PLATO treatment planning system (Ver-sion14.2.6.NucletronBV,theNetherlands).TheClinicalTarget

Table1–Patientselection.

Pt.no Age (yrs) Rxsite Lesion size (cm) No.of negative nodes Surgical margin 1 61 LBreast 3.0 20 −ve 2 70 RBreast 2.5 25 −ve 3 63 RBreast 1.9 20 −ve 4 65 RBreast 2.8 21 −ve 5 68 LBreast 3.0 23 −ve 6 71 LBreast 2.1 22 −ve 7 69 RBreast 2.7 25 −ve 8 70 RBreast 1.8 20 −ve 9 63 LBreast 1.6 23 −ve 10 61 LBreast 2.5 20 −ve 11 55 RBreast 3.0 22 −ve 12 58 RBreast 2.5 21 −ve 13 60 RBreast 2.7 24 −ve 14 62 RBreast 2.2 23 −ve 15 64 LBreast 1.2 22 −ve

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Table2–Externalbeamplanparameters.

Pt.no Rxsite No.of

beams

Energy Coplanarbeams Non

coplanar beams Wedge Weightings 1 LBreast 7 6MV 240,10,70,290 20–250 30–320 300–30 – 28:7:7:30:9:9:9 2 RBreast 5 6MV 55,345,270,231,196 – 15,45,45,15,45 40:04:04:40:12 3 RBreast 4 6MV 345,40,115,165 – – 28:24:24:24 4 RBreast 5 6MV 40,0,280,230 270–320 20–250 266–35 300–30 30,30 20:20:20:20:20 5 LBreast 7 6MV 225,275,0,60 45,30,30,45 28:7:7:30:9:9:9 6 LBreast 5 6MV 320,357,141,160,54 – 45,45,45 18:29:20:20:12 7 RBreast 6 6MV 60,4,28,0,227 280–110 227–110 45,45,30,30 29:10:10:33:10 8 RBreast 6 6MV 43,223,4,255 301–90 255–63 45,45 30:30:10:10:10:10 9 LBreast 5 6MV 319,353,106,162,55 15,45,45,15 15 32:12:12:33:12 10 LBreast 7 6MV 238,8,60,280 20–245 30–320 298–25 – 27:8:8:29:9:9:9 11 RBreast 5 6MV 50,340,270,230,195 – 45,45,45,45,45,45 35:5:5:30:15 12 RBreast 4 6MV 340,35,115,160 – – 20:20:20:20 13 RBreast 5 6MV 53,345,270,235,190 – 15,45,45,45 15 35:10:10:30:15 14 RBreast 6 6MV 40,220,5,255 301–90 255–63 45,45 30:30:10:10:10: 15 LBreast 5 6MV 320,355,140,155,53 – 45,45,45,45 20:20:30:15:15

Volumewasdelineatedasthelumpectomycavitywitha2cm margin,modiﬁedto5mmdeepanteriortoskinsurfaceand alsoalongthepectoralmuscle.11_Critical_organs_such_as

ipsi-laterallungandheartforleftsidedtumourwerealsomarked. Thecontoursweredelineatedbythesameradiation oncolo-gist.Thecatheterswerereconstructedfromskinentrytothe skinexitinthe axialCT images.Dwell positions(step size 2.5mm)inthecatheterswereactivatedinsuchawayasto fallwithintheCTVmarked.Dosepointswere computedat 3mmintervalsontheCTVdelineated.Adoseof340cGywas prescribedtothetargetdosepoints.Thenthevolumebased dose optimisationwas done (Fig. 1).The dosevolume his-togramsweregeneratedforthetargetvolumesandthecritical structures.

Fig.1–Multicatheterinterstitialbrachytherapydose distribution-axialview.

Withtheimplantedtubesinsitu,anexternalbeam ther-apycoursewasplannedinthesameCTimages.Themultiple beam arrangement was used with a combination of both coplanarandnoncoplanarbeams.12–14_The_plan_data_was

tab-ulatedindetail(Table2).Anoptimaldosedistributionwitha bettercoverageandhomogeneitywasachievedusingtypical doseweightingswithvariouswedgecombination(Fig.2).An analysisconductedonBEDofdifferentfractionationschemes basedonavailablepre-clinicalandclinicalindicationsshowed thatthetumourcontrolinbreastcarcinomacanbeeffective withabiologicalequivalentdoseof75Gy.37_According_to_the

LQmodelformula,adoseof30Gygiveninﬁvefractionsof6Gy overtendayswasfoundtoberadiobiologicallyequivalentin tumourcontrol(75Gy)tothatof50Gy/25fractionsoverﬁve

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Fig.3–Multicatheterinterstitialbrachytherapy-cumulative dosevolumehistogram.

weeks.38_Hence,_the_dose_prescribed_was_600cGY_×_ﬁve

frac-tionscalculatedusinglinearquadraticcellsurvivalmodel.15,16

Theﬁvefractionsweresimulatedasanalternateday sched-uleoverten days.Dosevolumehistogramswere generated forallthestructures(bothtargetvolumeandnormaltissues). SincethesameCTdatasetswereusedforsimulatingtheEBRT plans,eachpatientservedastheirowninternalcontrolwith respecttoanatomy.

3.3. Targetvolumedosimetry

From the Dose Volume Histogram generated from the brachytherapyplans(Fig.3),thedosimetricparameterssuch as V100, V150 and V100 forthe clinical target volume were

obtained.Thenthedoseconformityindex(CI)andthedose

homogeneityindex(HI)fortheCTVwerecalculatedfromEqs. (1)and(2)(Table3).17 DHI=V100−V150 V100 (1) CI= V100 V100−V₁₀₀ (2)

From the EBRTconformal plandose volumehistograms (Fig.4),theplanningtarget volume(PTV),referencevolume (Vref),D2 andD98 were extracted.Thedoseconformity and

homogeneityindexwerecalculatedfromtheDosimetric val-uesfromEqs.(3)and(4)18_and_tabulated_(Table_3).

HI= D2

D98

(3)

CI=PTV

Vref (4)

3.4. Normaltissuedosimetry

ThedosimetricparameterssuchasDmean,Dmax,D5andV20

wereobtainedfromthelungDVHgeneratedinbrachy plan-ning and external beam planning (Table 3). Thevalues of D20andD30fromtheheartDVHwerealsoobtainedin

addi-tiontoDmean,Dmax,D5andV20(Table4).Theseparameters

were takenintoaccountsincetheycorrelatewithlatelung toxicity inpatients receiving radiotherapy.19–24,34–36 _Cardiac

toxicitycanbeassessedwiththeavailablecardiacdosimetry data.20,25–27,34,36

3.5. Statisticalanalysis

Asummationandameancalculationweredoneforthe out-lineddosimetricdata.Thepairedtwotailedstudent’st-tests wereperformedusingStatistica5.0(StatsoftInc)softwareto assessthesigniﬁcanceofdifferencebetweenthetwogroups. Thepvaluesfortargetdoseconformity,dosehomogeneityand

Table3–CTVdosimetry.

Pt.no Interstitialbrachytherapyplanning Externalbeampalnning

V100(cc) V150(cc) V100(cc) Vref(cc) C.I. H.I. D2(cGy) D98(cGy) PTV(cc) C.I. H.I.

1 27.4 13.2 5.8 33.2 0.8253 0.5182 30.94 28.22 25.5 0.768 1.096 2 115.02 21.82 36.48 151.5 0.7592 0.8102 30.66 28.84 129.2 0.853 1.063 3 145.61 93.59 389 149.5 0.9739 0.3572 32.70 29.52 134.5 0.900 1.107 4 27.51 24.61 0.09 27.6 0.9967 0.1054 33.20 28.64 22.08 0.800 1.159 5 22.70 8.45 8.10 30.8 0.7370 0.6277 31.78 28.14 26.55 0.862 1.129 6 64.91 33.91 2.59 67.5 0.9616 0.4775 32.32 29.84 64.24 0.9665 1.083 7 61.67 43.05 7.53 69.2 0.8911 0.3019 31.60 29.52 64.91 0.938 1.070 8 34.68 28.15 0.15 34.83 0.9956 0.1882 31.40 27.79 28.8 0.827 1.129 9 31.00 19.33 3.80 34.8 0.8908 0.3764 33.30 28.84 29.07 0.8355 1.154 10 30.16 27.14 0.28 35.6 1.009 0.1001 33.16 27.46 34.8 0.978 1.20 11 40.12 30.49 5.64 44.16 1.163 0.2400 32.12 28.48 43.89 0.994 1.128 12 32.13 30.12 6.14 35.75 1.236 0.0625 30.44 29.31 39.71 1.11 1.038 13 28.6 10.12 4.1 30.14 1.167 0.6462 32.60 30.10 32.55 1.08 1.083 14 28.61 20.16 0.5 29.16 1.0178 0.2953 33.15 29.10 30.62 1.05 1.139 15 55.65 40.05 6.00 60.17 1.1208 0.2803 31.48 27.64 59.51 0.989 1.138 Mean 0.9870 0.3591 Mean 0.9301 1.114

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Fig.4–3DconformalEBRTplanning-cumulativedosevolumehistogram.

normaltissuedosimetricparameters, suchasDmean,Dmax, D5,V20,D20,D30 forthenormaltissueswerecomputedand

analysed(Table4).

4. Results

TheEBRTplansresultedinamorehomogenousdose distri-bution.Itisevidentfrom thehomogeneity index(p=7.255) (Table3andPlot1).Theexternalbeamplanningresultedin aconformaldosedistributionwhichwascomparabletothat ofbrachytherapyplanning(p=0.056)correspondingtoa con-ﬁdenceintervalof95%.(Table3andPlot2).

Theincidentalradiation dose tothelung and theheart usingEBRTplanningwassimilartothatofISBT.Aconﬁdence levelof95%wasobtainedwithallthecomputeddosimetric factors(Dmean,Dmax,D5,V20,D20,V5,V10 andD30)analysed,

whichsupportedthenullhypothesis.Hencethenormaltissue dosimetryintermsofconformalexternalbeamplanningwith photonbeamswascomparablewithbrachyplanning(Table4).

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 3DCRT ISBT

Plot1–Dosehomogeneityindex.

Table4–Normaltissuedosimetry.

Dosimetricparameters ExternalbeamAPBI ISBTAPBI p-Value

Mean Range Mean Range

Lungn=15 DmeanGy 5.1 3.2–12.2 4.0 2.0–6.14 0.047 DmaxGy 36.3 8.0–48.0 34.56 7.2–46.1 0.122 V30(%) 0.5% 0–1% 0.4% 0.0–0.65% 0.107 V20(%) 1.09% 0–3% 1.1% 0–2% 0.924 V10(%) 10% 0–15% 8.5% 0–14.1% 0.141 D5Gy 12.1 6.0–16 10.94 6.0–15.6 0.050 Heartn=6 DmeanGy 3.2 2.7–5.1 2.8 1.7–4.8 0.089 DmaxGy 15.6 11.1–28.4 14.3 10.6–26.7 0.094 V20(%) 0.15% 0–0.5% 0.11% 0.0–0.4% 0.047 V10(%) 2.8% 0–8.2% 2.5% 0–8.0% 0.153 V5(%) 20.8% 11.5–31.6% 19.5% 9.6–30.1% 0.608 D20Gy 7.9 6.0–15.5 7.49 5.89–14.9 0.142 D30Gy 7.27 6.8–10.4 7.0 6.0–9.9 0.218

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0 0.2 0.4 0.6 0.8 1 1.2 1.4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ISBT 3DCRT

Plot2–Doseconformityindex.

5. Discussion

From this feasibility study, it was inferred that the simu-latedEBRTplansgavelowdosesofradiationtothecritical organs,suchasthelung andheart,whichwascomparable withthebrachyplanning.EBRTplanningwithconformal pho-tonﬁeldsresultedinaverylowpercentageofvolumereceiving adoseof20Gyhavingaconﬁdencelevelof95%fromthe sam-pledpopulation,whichcorrelateswiththelowerincidenceof lungtoxicity.26,28,29,31–35_There_was_no_prominent_difference_in

heartmaximumandminimumdoseinbothtreatment plan-ningtechniques.

Thedoseconformityindex(CI)andthedosehomogeneity index(HI)arethequalityindicatorsofthebesttreatmentplan. Conformityindexmeasuresthedegreeofconformityofthe radiationdoseprescribedtotheclinicaltargetvolume.Ideally, CIshouldbeunityorthenearestvaluetounityincaseofa bet-tertreatmentplan.Moreconformaldosedistributioncanbe achievedwiththeuseofmultiplephotonbeamswhichgives ananalogousdosedistribution asbrachytherapytreatment plans(Table3andPlot2).

Homogeneityindex(HI)measurestheradiationdose uni-formityintheclinicaltargetvolume.TheHIvaluescalculated fromtheEBRTplansshowedthevaluesnearingtoone(Table3 andPlot1),whichisidealforahomogenousdosedistribution. Brachytherapy dose distributions are more heterogeneous aroundthe catheterinnaturewhichresultsinapoor cos-meticeffectinthepatients.Hence,itisofmajorconcernin thebrachytherapy,particularlywhenafreehandapplication happenstobetheonlyavailableoptionintheinstitution.

TheuseofEBRTinAPBIresultedinmorehomogenousdose distributionwithoutcompromisingthedoseconformity.The criticalorgandoseswerealsominimalwhichwassimilarto thedosedistributionachievedwithbrachytherapyinterstitial implants.Itwasclearlymanifestedbystatisticallyless signif-icantpvaluesandoptimalconﬁdencelevel(t0.975ort=0.05)

attainedwiththedosevolumeparameters.

Thedoseescalationofabout600cGyperfractionwith con-formalexternalbeamradiotherapypavesthewayforabetter tumourcontrol.Hence,itcanbetreatmentofchoicewhena noninvasiveprocedureispreferred.Thesetupuncertainties inthe externalbeamradiotherapy procedurecan be effec-tivelyovercomebydailytreatmentveriﬁcationmethods(Port

ﬁlms,EPID),immobilisationdevicesandwithanaddedtarget volumemargins.

6. Conclusions

Thisisasmall subset treatmentplanningfeasibilitystudy comprisingofﬁfteenpatientcasessimulatedwithEBRTplans. Thedosedistributionplannedwascomparedwiththehigh doseratebrachytherapyplanning.Itgivessatisfyingresultsof doseconformityanddosehomogeneitytothetumourvolume withacceptablesparingofnormaltissuesbasedonthe statis-ticalanalysis.Hence,theAPBIcanbeeffectivelyplannedusing the three dimensional conformal external beam radiation therapy.Patientdiscomfortduringbrachytherapyprocedures involvingsedationandapoorcosmeticeffectafterirradiation canbeavoided.ConformalEBRTcourseismorecosteffective whencomparedtobrachytherapy.Hence,itcanbesuggested as an alternative treatment modality where brachytherapy proceduresareperformedfreehandwhichistediousinnature. EnduringresearchwillfocusontheevaluationofTumour Con-trolProbabilityandNormalTissueComplicationProbabilityin EBRTandbrachytherapyplans.

Conﬂict

of

interest

Nonedeclared.

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e

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e

s

1. SandersME,ScrogginsT,AmpilFL.LiBD:APBIinearly-stage breastcancer.JClinOncol2007;25(8):996–1002.

2. ArthurDW,KooD,ZwickerRD,etal.Partialbreast brachytherapyafterlumpectomy:Low-dose-rateand high-dose-rateexperience.IntJRadiatOncolBiolPhys 2003;56(3):681–9.

3. BaglanKL,MartinezAA,FrazierRC,etal.Theuseof high-doseratebrachytherapyaloneafterlumpectomyin patientswithearly-stagebreastcancertreatedwith breast-conservingsurgery.IntJRadiatOncolBiolPhys 2001;50(4):1003–11.

4. BoviJ,QiXS,WhiteJ,LiXA.ComparisonofthreeAPBI techniques:treatmenteffectivenessbaseduponbiological models.RadiotherOncol2007;84(3):226–32.

5. KacprowskaA,JassemJ.Partialbreastirradiationinearly breastcancer.RepPractOncolRadiother2011;16(6):213–20. 6. CozziL,FogliataA,NicoliniG,RancatiT,BernierJ.Clinical

experienceonbreastirradiationwitha3Dconformal techniqueusingthreephotonﬁelds.Overviewand dosimetricanalysis.ActaOncol2004;43:558–66. 7. MaiaD,ElodieT,CharlotteP,etal.3D-conformalAPBI

treatmentplanning:thevalueofsurgicalclipsinthe delineationofthelumpectomycavity.RadiatOncol2009;4:70. 8. ViciniFA,KestinL,ChenP,BenitezP,GoldsteinNS,Martinez A.Limited-ﬁeldradiationtherapyinthemanagementofearly stagebreastcancer.JNatlCancerInst2003;95(1205–1210):18. 9. KhanAJ,KirkMC,MehtaPS,etal.Adosimetriccomparison

ofthree-dimensionalconformal,intensity-modulated radiationtherapyandMammositepartial-breastirradiation. Brachytherapy2006;5:183–8.

10. PatelRR,BeckerSJ,DasRK,MackieTR.Adosimetric comparisonofacceleratedpartialbraestirradiation techniques:multicatheterinterstitialbrachytherapy,three

(7)

dimensionalconformalradiotherapy,andsupineversus pronehelicaltomotherapy.IntJRadiatOncolBiolPhys 2007;68(3):935–42.

11. CsabaPolgár,ErikVanLimbergen,RichardPötteretal., VratislavStrnad:Patientselectionforaccelerated partial-breastirradiation(APBI)afterbreast-conserving urgery:RecommendationsoftheGroupeEuropéende Curiethérapie-EuropeanSocietyforTherapeuticRadiology andOncology(GEC-ESTRO)breastcancerworkinggroup basedonclinicalevidence;2009.

12. FormentiSC.Externalbeampartialbreastirradiation.Semin RadiatOncol2005;15:92–9.

13. NicoliniG,FogliataA,CozziL.Criticalappraisalofa non-coplanartechniqueforradiotherapyofbreast minimisinglunginvolvement.RadiotherapyOncol 2005;76(3):319.

14. YasharC,WhiteG,RiceR,PawlickiT.EvaluationofthreeAPBI techniquesunderNSABPB-39guidelines.JApplClinMedPhys 2010;11(1):274–80.Winter.

15. JoinerMC,vanderKogelAJ.Thelinearquadraticapproachto fractionationandcalculationofisoeffectrelationships.In: SteelGG,editor.Basicclinicalradiobiology.3rded.London: Arnold;1997.p.106–22.

16. vanderKogelAJ.Radiationresponseandtoleranceofnormal tissues.In:SteelG,editor.Basicclinicalradiobiology.2nded. London:Arnold;1997.p.30–9.

17. WuA,UlinK,SternikES.Adosehomogeneityindexfor evaluatingIr192Interstitialimplants.MedPhys1988;15:104–7. 18. SharmaDS,GuptaT,JalaliR,MasterZ,PhurailatpamRD,

SarinR.Highprecisionradiotherapyforcraniospinal irradiation,evaluationof3DconformalradiotherapyIMRT andhelicaltomotherapy.BJR2009;82:1000–9.

19. ChenPY,ViciniFA,BenitezP,etal.Long-termcosmetic resultsandtoxicityafteracceleratedpartial-breast irradiation:amethodofradiationdeliverybyinterstitial brachytherapyforthetreatmentofearly-stagebreast carcinoma.Cancer2006;106(5):991–9.

20. Stewart1AJ,O’FarrellDA,CormackRA,etal.Dosevolume histogramanalysisofnormalstructuresassociatedwithAPBI deliveredbyhighdoseratebrachytherapyandcomparison withwholebreastexternalbeamradiotherapyﬁelds.Radiat Oncol2008;3:39.

21. EvansES,ProsnitzRG,YuX,etal.Impactofpatientspeciﬁc factors,irradiatedleftventricularvolumeandtreatment set-uperrorsonthedevelopmentofmyocardialperfusion defectsafterradiationtherapyforleft-sidedbreastcancer.Int JRadiatOncolBiolPhys2006;66(4):1125–34.

22. YorkeED,JacksonA,RosenzweigKE,etal.Dose-volume factorscontributingtotheincidenceofradiation

pneumonitisinnon-small-celllungcancerpatientstreated withthreedimensionalconformalradiationtherapy.IntJ RadiatOncolBiolPhys2002;54(2):329–39.

23. GrahamMV,PurdyJA,EmamiB,etal.Clinicaldose-volume histogramanalysisforpneumonitisafter3Dtreatmentfor nonsmallcelllungcancer.IntJRadiatOncolBiolPhys 1999;45(2):323–9.

24. HernandoML,MarksLB,BentelGC,etal.Radiationinduced pulmonarytoxicity:adose–volumehistogramanalysisin201 patientswithlungcancer.IntJRadiatOncolBiolPhys

2001;51(3):650–9.

25. MarksLB,KocakZ,ZhouS,etal.Theassociationbetweenthe meanheartdose,meanlungdose,tumorlocationandRT associatedheartandlungtoxicity.IntJRadiatOncolBiolPhys 2005;63(2):S42.

26. McGaleP,DarbySC.Lowdosesofionisingradiationand circulatorydiseases:asystematicreviewofthepublished epidemiologicalevidence.RadiatRes2005;163(3):

247–57.

27. PrestonDL,ShimizuY,PierceDA,SuyamaA,MabuchiK. Studiesofmortalityofatomicbombsurvivors.Report13: solidcancerandnoncancerdiseasemortality:1950–1997. RadiatRes2003;160(4):381–407.

28. CarrZA,LandCE,KleinermanRA,etal.Coronaryheart diseaseafterradiotherapyforpepticulcerdisease.IntJRadiat OncolBiolPhys2005;61(3):842–50.

29. GarzaR,AlbuquerqueK,SethiA.Lungandcardiactissue dosesinleftbreastcancerpatientstreatedwith

single-sourcebreastbrachytherapycomparedtoexternal beamtangentﬁelds.Brachytherapy2006;5:235–8.

31. EarlyBreastCancerTrialists’CollaborativeGroup.Favourable andunfavourableeffectsonlong-termsurvivalof

radiotherapyforearlybreastcancer.Lancet2000;355: 1757–70.

32. CuzickH,StewartL,RutqvistJ,etal.Cause-speciﬁcmortality inlong-termsurvivorsofbreastcancerwhoparticipatedin trialsofradiotherapy.JClinOncol1994;12:447–53.

33. HallEJ,WuuCS.Radiation-inducedsecondcancers:the impactof3D-CRTandIMRT.IntJRadiatOncolBiolPhys 2003;56(1):83–8.

34. WazerDE,KaufmanS,CuttinoL,DiPetrilloT,ArthurDW. Acceleratedpartialbreastirradiation-ananalysisofvariables associatedwithlatetoxicityandlong-termcosmetic outcomeafterhigh-dose-rateinterstitialbrachytherapy.IntJ RadiatOncolBiolPhys2006;64(2):489–95.

35. ViciniFA,ChenP,WallaceM,etal.Interimcosmeticresults andtoxicityusing3dconformalexternalbeamradiotherapy todeliverAPBIinpatientswithearly-stagebreastcancer treatedwithbreast-conservingtherapy.IntJRadiatOncolBiol Phys2007;69(4):1124–30.

36. SlampaP,RzickovaJ,OndrovaB,TichaH,dolezelovaH.Sole conformalperiooperativeinterstitialbrachytherapyofearly stagebreastcarcinomausinghighdoserateafterloading: longer-termresultsandtoxicity.RepPractOncolRadiother 2008;13(2):63–8.

37. RosensteinBS,LymberoisSC,FormetiSC.Biologic

comparisonofpartialbreastirradiationprotocols.IntJRatiat OncolBiolPhys2004;60:1393–404.

38. FisherB,AndersonS,BryantJ,etal.Twentyyearfollowupof arandomizedtrialcomparingtotalmastectomy,

lumpectomy,andlumpectomyplusirradiationforthe treatmentofinvasivebreastcancer.NEnglJMed2002;347(16): 1233–41.