In the evolution of radiation oncology technology, im- proved planning and treatment delivery advanced from two-dimensional radiotherapy (2DRT) to three-dimensional conformal radiotherapy (3DCRT) two decades ago. In the last decade, intensity-modulated radiation therapy (IMRT) emerged in addition to daily image guidance and four- dimensional (4D) image-based motion management (1). Chemoradiotherapy, which was actually established mainly with a 2DRT trial-RTOG 9410, is the current standard of care in patients with inoperable stage IIIA or IIIB non-small cell lung cancer (NSCLC) when compared to sequential proto- cols (2-7). Currently, aggressive chemoradiotherapy is the standard, and is well accepted in highly selected septuage- narians with inoperable stage IIIB NSCLC (8). Convention- al doses (60-63 Gy) of 3DCRT were well-thought-out not enough to succeed for desired local control to avoid dismal survival. There has been a significant challenge in safely escalating the radiation dose over 60 Gy, while preserving the critical organ at risk (OAR) structures (9-12). In the last decade, IMRT has been the leading improvement, and has been considered as the key solution for safe dose escalation and delivery. Other accompanying challenges are the fight with unpredictable movement of the tumor during the respi- ratory phases, the need to increase the accuracy of treatment delivery during each fraction, and the necessity to clarify the heterogeneity correction in treatment planning systems. The newest technology has been improved upon in recent years by 4D image-based motion capturing and the management of treatment planning, the evolution of calculation algorithms in treatment planning systems that are capable of better es- timating the dose delivery to tumors and normal structures, and image-guided radiotherapy. All of these improvements increased the daily setup accuracy. There is a requirement for radiotherapy is evident in NSCLC, with than 60% of these patients requiring radiotherapy during treatment, and more than 40% of patients who receive radiotherapy receive it dur- ing the initial treatment (13, 14). Therefore, due to the grow- ing struggle with lung cancer, the current debate, based on inclusion of all modern technology, is whether IMRT has an advantage over 3DCRT in the outcomes of local control, sur- Chemoradiotherapy is the current standard of care in patients with advanced inoperable stage IIIA or IIIB non-small cell lung cancer (NSCLC). Three-dimensional radiotherapy (3DCRT) has been a trusted method for a long time and has well-known drawbacks, most of which could be improved by Intensity Modulated Radiotherapy (IMRT). IMRT is not currently the standard treatment of locally ad- vanced NSCLC, but almost all patients could benefit to a degree in organ at risk sparing, dose coverage conformality, or dose escala- tion. The most critical step for a radiation oncology department is to strictly evaluate its own technical and physical capabilities to determine the ability of IMRT to deliver an optimal treatment plan. This includes calculating the internal tumor motion (ideally 4DCT or equivalent techniques), treatment planning software with an up-to- date heterogeneity correction algorithm, and daily image guidance. It is crucial to optimise and individualise the therapeutic ratio for each patient during the decision of 3DCRT versus IMRT. The current liter- ature rationalises the increasing use of IMRT, including 4D imaging plus PET/CT, and encourages the applicable knowledge-based and individualised dose escalation using advanced daily image-guided radiotherapy. Key Words: 3-D conformal radiotherapy, intensity modulated radio- therapy, lung cancer Copyright 2014 © Trakya University Faculty of Medicine Balkan Med J 2014;31:286-94 Intensity-Modulated Radiotherapy versus 3-Dimensional Conformal Radiotherapy Strategies for Locally Advanced Non-Small-Cell Lung Cancer 1 Department of Radiation Oncology, Koç University Faculty of Medicine, İstanbul, Turkey 2 Department of Radiation Oncology, University of Texas M.D.Anderson Cancer Center, Texas, USA 3 Department of Radiation Oncology, Başkent University Adana Faculty of Medicine, Adana, Turkey Uğur Selek 1,2 , Yasemin Bölükbaşı 2 , James W. Welsh 2 , Erkan Topkan 3 Invited Review | 286 Address for Correspondence: Dr. Uğur Selek, Department of Radiation Oncology, Koç University Faculty of Medicine, İstanbul, Turkey Phone: +90 444 3 777 e-mail: [email protected] Received: 18.06.2014 Accepted: 13.09.2014 Available Online Date: 13.09.2014 • DOI: 10.5152/balkanmedj.2014.14529 Available at www.balkanmedicaljournal.org Cite this article as: Selek U, BölükbaşıY, Welsh JW, Topkan E. Intensity-modulated radiotherapy versus 3-dimensional conformal radiotherapy strategies for locally advanced non-small- cell lung cancer. Balkan Med J 2014;31:286-94.
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In the evolution of radiation oncology technology, im-proved planning and treatment delivery advanced fromtwo-dimensionalradiotherapy(2DRT)tothree-dimensionalconformal radiotherapy (3DCRT) two decades ago. In thelast decade, intensity-modulated radiation therapy (IMRT)emerged in addition to daily image guidance and four-dimensional (4D) image-based motion management (1).Chemoradiotherapy,whichwasactuallyestablishedmainlywitha2DRTtrial-RTOG9410,isthecurrentstandardofcareinpatientswithinoperablestageIIIAorIIIBnon-smallcelllungcancer (NSCLC)whencompared to sequentialproto-cols (2-7). Currently, aggressive chemoradiotherapy is thestandard,and iswellaccepted inhighlyselectedseptuage-narianswithinoperablestageIIIBNSCLC(8).Convention-al doses (60-63Gy) of 3DCRTwerewell-thought-out notenoughtosucceedfordesiredlocalcontroltoavoiddismalsurvival. There has been a significant challenge in safelyescalating the radiationdoseover60Gy,whilepreservingthecriticalorganatrisk(OAR)structures(9-12).Inthelastdecade, IMRThas been the leading improvement, andhas
beenconsideredasthekeysolutionforsafedoseescalationanddelivery.Other accompanying challenges are the fightwithunpredictablemovementofthetumorduringtherespi-ratoryphases,theneedtoincreasetheaccuracyoftreatmentdeliveryduringeachfraction,andthenecessitytoclarifytheheterogeneitycorrectionintreatmentplanningsystems.Thenewesttechnologyhasbeenimproveduponinrecentyearsby4Dimage-basedmotioncapturingandthemanagementoftreatmentplanning, theevolutionofcalculationalgorithmsintreatmentplanningsystemsthatarecapableofbetteres-timatingthedosedeliverytotumorsandnormalstructures,and image-guided radiotherapy.Allof these improvementsincreasedthedailysetupaccuracy.Thereisarequirementforradiotherapyisevident inNSCLC,withthan60%of thesepatients requiring radiotherapyduring treatment, andmorethan40%ofpatientswhoreceiveradiotherapyreceiveitdur-ingtheinitialtreatment(13,14).Therefore,duetothegrow-ingstrugglewith lungcancer, thecurrentdebate,basedoninclusionofallmoderntechnology,iswhetherIMRThasanadvantageover3DCRTintheoutcomesoflocalcontrol,sur-
Chemoradiotherapy is thecurrentstandardofcare inpatientswithadvanced inoperable stage IIIAor IIIBnon-small cell lung cancer(NSCLC). Three-dimensional radiotherapy (3DCRT) has been atrustedmethodforalongtimeandhaswell-knowndrawbacks,mostofwhichcouldbe improvedby IntensityModulatedRadiotherapy(IMRT).IMRTisnotcurrentlythestandardtreatmentoflocallyad-vancedNSCLC,butalmostallpatientscouldbenefittoadegreeinorgan at risk sparing, dose coverage conformality, or dose escala-tion.Themost critical step for a radiationoncologydepartment isto strictly evaluate its own technical and physical capabilities todeterminetheabilityofIMRTtodeliveranoptimaltreatmentplan.
Thisincludescalculatingtheinternaltumormotion(ideally4DCTorequivalent techniques), treatmentplanningsoftwarewithanup-to-dateheterogeneitycorrectionalgorithm,anddailyimageguidance.Itiscrucialtooptimiseandindividualisethetherapeuticratioforeachpatientduringthedecisionof3DCRTversusIMRT.Thecurrentliter-aturerationalisestheincreasinguseofIMRT,including4DimagingplusPET/CT,andencourages theapplicableknowledge-basedandindividualised dose escalation using advanced daily image-guidedradiotherapy.Key Words:3-Dconformalradiotherapy,intensitymodulatedradio-therapy,lungcancer
Copyright 2014 © Trakya University Faculty of MedicineBalkan Med J 2014;31:286-94
Intensity-ModulatedRadiotherapyversus3-DimensionalConformalRadiotherapyStrategiesforLocallyAdvancedNon-Small-CellLungCancer
1DepartmentofRadiationOncology,KoçUniversityFacultyofMedicine,İstanbul,Turkey2DepartmentofRadiationOncology,UniversityofTexasM.D.AndersonCancerCenter,Texas,USA3DepartmentofRadiationOncology,BaşkentUniversityAdanaFacultyofMedicine,Adana,Turkey
UğurSelek1,2,YaseminBölükbaşı2,JamesW.Welsh2,ErkanTopkan3
Invited Review |286
AddressforCorrespondence:Dr.UğurSelek,DepartmentofRadiationOncology,KoçUniversityFacultyofMedicine,İstanbul,TurkeyPhone:+904443777e-mail:[email protected]: 18.06.2014 Accepted: 13.09.2014 Available Online Date: 13.09.2014 • DOI: 10.5152/balkanmedj.2014.14529Available at www.balkanmedicaljournal.org
Citethisarticleas:SelekU,BölükbaşıY,WelshJW,TopkanE.Intensity-modulatedradiotherapyversus3-dimensionalconformalradiotherapystrategiesforlocallyadvancednon-small-celllungcancer.BalkanMedJ2014;31:286-94.
vival,andacuteandlatesideeffects(esophagitisandpneu-monitis).IMRTisatechnologicalimprovementinthedeliv-eryofradiotherapy,whichprovidesthepotentialtoincreasethetargetcoveragewhiledecreasingthedosestotheorganatrisktowellbelowcomplicationthresholds(15).However,itunfortunatelyincreasesthecostoftreatment.The understanding of the tolerance of normal tissues, es-
peciallylungtissue,whichisadoselimitingorgan,has im-provedinlastdecade(16).Ascliniciansrespectdose-volumeconstraintstoreducetheacuteandlatesideeffectsofradio-therapy,thereisanongoingeffortinthequantitativeanalysisofradiotherapyeffectsonnormaltissueforupdateddosevol-umeconstraints,aswellasgeneratingatlasesfordecreasinginter-observervariability(17-19).Residuallungfunctionaftertreatment is amajorqualityof life issue in lungcancerpa-tients,astherearepretreatmentcompromisesbasedonpre-ex-istingcomorbiditiesandtheprimarytumor(20).Chemoradio-therapyinlocallyadvancedNSCLCalsosignificantlyaffectslungfunctionifthecriticaldosethresholdsarenotrespectedandtheresultsfordecreasedlungfunctionparametersdeter-minedbyobjectivepulmonaryfunctiontests(PFTs)(21-23).Therefore,lungfunctionpreservationasadoselimitingfactorwasoneofthemajorreasonsforinvestigatinglungIMRT,inorder tospareasmuchparenchymal tissueaspossiblefromhigherdoses.Thequestion ofwhetherweneed IMRTor not is strictly
tiedtoquestionsofwhetherweneeddoseescalation,whetherweneedtodecreasetoxicityrelatedwithchemoradiotherapy,whetherwehavetoolstomanagetumormotion,whetherwehave adequate treatment planning software algorithms, orwhetherornotwehaveimageguidancecapabilities.
SIGNIFICANCE OF DOSE ESCALATION IN LOCALLY ADVANCED NSCLC
Thedismal survival rate followinga local recurrence inpatients who completed their lung cancer radiotherapy isunfortunate(2).Machtayetal.(9,10)reportedon11RTOGtrialsincluding1356locallyadvancedNSCLCpatientsanddocumentedlocoregionalfailureratesof46%and52%,andoverallsurvival(OS)ratesof38%and15%attwoandfiveyears,respectively.LocoregionalcontrolwasrecognisedtobeoperativeinlongtermsurvivalofNSCLCpatients(10).Inorder to improve the local regionalcontrol rates,manycenters initiateddoseescalation trials in stage IIINSCLCpatients to observe the feasibility and safety constraintsof concurrent chemoradiotherapywithhigher doses.Mostconcludedthat74Gywasatolerabledoseinthewell-con-trolled setups of 3DCRT (24-26). From a study including
106NSCLCpatientsat theUniversityofMichigan,Kongetal.(27)reasonedthateach1Gyincrementimprovedthefive-yearlocalcontrolrateby1.25%asdecreasingthedeathriskby3%.Thissuggestedthathigherradiationdoseswereassociatedwithbetteroutcomes.Increasingthedoseofra-diationwas reported to compensate the negative effect oflargetumorvolumeinmedicallyinoperablenode-negativeearlystageNSCLCpatientstreatedwithradiotherapyalone(28). Zhao et al. (28) compared a biologically equivalentdose(BED)of≤79.2Gy(physicaldoseof66Gyin2-Gydailyfractions)versus>79.2Gy,andreportedthatagrosstumorvolume (GTV)of>51.8cm3 (~4cm)caused short-ermedianOS ratesof18.2months incomparison to23.9monthswithaGTVof≤51.8cm3,despitenosurvivaldif-ferencebasedontumorvolumeremainedforwhoreceivedaBEDof>79.2Gy.Moreover,patientswithaGTV>51.8cm3hadachanceoflongermedianOSrates(30.4months)iftheyreceivedaBEDof>79.2GyincontrasttooneswhoreceivedaBEDof≤79.2Gy(18.2months).Wangetal.(12)emphasised in their retrospective reviewof theUniversityofMichiganchemoradiotherapydata, that therewasa3%reductionintheriskofdeathwith1Gyofdoseescalationintherangeof60-66Gy.MemorialSloanKetteringCancerCenterdatapublishedbyRenganetal.(11)reportedahigh-ersurvivalrateforpatientsreceiving≥64Gythanforonesreceiving<60Gy.RadiotherapydoseescalationalongwithconcurrentchemotherapyinpatientswithstageIIINSCLCwasalsoindicatedintheRTOGdatabasebyMachtayetal.(9, 10) to show increased local control andOS ratesby a1-GyincreaseinBED.Thiswasassociatedwithanapproxi-materelativeimprovementof4%insurvivalandarelativeimprovement of 3% in locoregional control.RTOG94-10compared 3-arms, including induction versus concurrentchemoradiationtherapyatastandarddoseof60-63Gyandat hyperfractionated 69.6 Gy delivered as twice-daily 1.2Gy/fraction,and revealed thatdoseescalationwithhyper-fractionation of the 69.6Gy arm hadworse survival thanthe60Gyarm(3).Yuanetal.(29)reportedaprospectivelyrandomiseddoseescalationtrialinpatientswithinoperablestageIIINSCLCwhowereenrolledon3DCRTof1.8to2Gyand68to74Gyforinvolved-fieldirradiation(IFI)cov-eringtheprimarytumourandinvolvedlymphnodes,or60to64Gycoveringtheprimarytumourandinvolvedlymphnodes,andelectivenodalirradiation(ENI).Yuanetal.(29)documentedabetteroutcomeandlocalcontrol,aswellaslowerradiationpneumonitisrates,inthedoseescalated(68-74Gy)IFIarmthanthe60GyENIarm.AlmostalldoseescalationtrialsinadvancedNSCLCwere
performedusingthe2Dor3DCRTtechniquewithout4Dim-age-basedmotioncapability.Therewasalwaysaquestionre-
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gardingwhetherIMRTandtumormotionmanagementwouldbemore sustainable using dose escalation.Themost recentRTOG0617trialinpatientswithstageIIINSCLCcomparing60Gy to 74Gy 3DCRT concurrentwith chemotherapy+/-cetuximabinfourarmsofa2x2designclosedaccrualinthehigh-dosearmbasedonaplannedinterimanalysiswithhigherdosecrossingafutilityboundary.However,aspecificcausecouldnotbedeterminedandthereportedtoxicitywasnotinagreementwiththelowersurvivalratesinthehighdosearm(30).Asitdoesnotseemrationaltoputasidealltheaccumu-lateddatafromthetrials(9-12)andconcludethatdoseescala-tionisnotbeneficial,onecaneasilyclaimthat74Gycouldbetootoxicwhendeliveredbythelimitedradiationtechniquesin the trialwithout tumormotionmanagement of 4D treat-mentplanning, imageguidance,andintensity-modulatedra-diotherapy(31).
EVOLUTION IN IMRT
AlthoughRTOG9410pavedthewayforstandardisationofchemoradiotherapywithbetterlocoregionalcontrolandhigh-erOSratesthansequentialchemotherapyfollowedbyradio-therapyregimens,addingconcurrentchemotherapyincreasedthe rate of grade 3 or higher toxicity (50% versus 30%) incomparisonwith a sequential approach (3, 5, 7).As an ad-vancementover2DRT,3D-CRThasbeenreportedtodecreasetoxicityinadditiontoallowingadoseescalationfrom60Gyto74Gyinconcurrentchemoradiotherapy(24-26).IMRTisconsideredaninnovationthatcansuccessfullyreducenormaltissuetoxicityinlocallyadvancedNSCLCpatients(32-40).It has also become obvious that IMRTneeds to be con-
sideredforhighdoseradiationtoavoidoverdosetonormaltissues,which triggereddosimetricandclinicalstudies.AsMarnitzetal.(41)atChariteCampusUniversityHospitalinBerlinreportedanaverageofa16%possibledoseescalationadvantagewithIMRTincomparisonto3DCRT.Grillsetal.(32)reportedadosimetricbenefitcomparisonperformedinWilliamBeaumontHospitalforIMRTversus3DCRT,espe-ciallyinnode-positivepatientsandinthosewithadherencetotheesophagus.TheyreportedIMRTwascapableofdeliv-ering25-30%greaterradiotherapydosesthan3D-CRTunderthesameOARconstraints.Schwarzetal.(37)atTheNeth-erlandsCancer Institute also called attention to a possibleadvantageofIMRTover3DCRT.Theysawanaveragedoseincreaseashighas35%withanevidentbenefitforlargeandconcavetumors(37).Chapetetal.(38)inLyondocumentedsignificantheartsparingwithIMRT.Christianetal.(39)attheInstituteofRoyalMarsdenreportedthatIMRTreducedthedosetothelungsandimprovetheconformityoftheplan
indosimetriccomparison to3DCRT.Researchers fromtheMDAndersonCancerCenternotedthatIMRTdosimetrical-lyhadthepotentialtodecreaselungandesophagealtoxic-ity, inaddition to sparing theheart fromhigherdoses (34,35).Liuetal.(34)comparedIMRTplanswiththe3D-CRTplansforwhichV20andmeanlungdosewerereducedforallcases,withmedian reductionsof8%and2Gy, respec-tively.Murshedetal. (35)alsonoted thatIMRTdecreasedtheV10andV20,whichcorrespondedtoareductionof>2Gyinthemeantotallungdoseanda10%probablereduc-tionintheriskofradiationpneumonitis.Theyalsoreporteddecreasedvolumesoftheheartandesophagusirradiatedto>40-50Gy. IMRTdosimetricallysoundmoresuitable than3DCRTinadvanced-stagediseasewithlargeandcomplicat-edgrosstumorvolumes,aswellasinadherencetocriticalstructures(34,35).AlthoughthereisnorandomisedtrialcomparingIMRTand
3DCRT,therearetworeliablereportsfromtheMDAndersonCancerCenter that retrospectively compared a single studycenter that treated patients in yearswith a substantial over-lapofpatients:290patients(222,3DCRTversus68,IMRT)between2000-2005byYometal.(15)and409patients(318,3DCRTversus91,IMRT)between1999-2006byLiaoetal(42).Thecommonemphasisinbothmanuscriptswasthere-duction incritical thresholddosesofOARandclinical sideeffectsdirectlyrelatedwiththequalityoflife.Yometal.(15)notedthegoodcorrelationofthepercentageoftotallungvol-ume reduction inpatients receivingdosesof at least 20Gyradiation(V20;38%witharangeof8-78%in3DCRTversus 35%witharangeof20-48%inIMRT,p<0.001),andthere-ductionin≥grade3treatment-relatedpneumonitis(TRP;32%at 12months in 3DCRTversus 8%at 12months in IMRT,p=0.002)infavorofIMRT.Liaoetal.(42)alsoindicatedthesignificant reduction in ≥ grade 3TRP rates by IMRT (ap-proximatenumbersderivedfromfigures,~25%at12monthsin 3DCRT versus ~10% at 12 months in IMRT, p=0.017).Liaoetal.(42)alsodocumentedtheoveralloutcomeoftwocohortsof3DCRTwithconventionalCTversus IMRTwith4DCTplanninginfavorofIMRTwithasignificant(mediansurvival,10.2monthsin3DCRTversus16.8monthsinIMRT,p=0.039)OSratedifference,whichcouldnotbedirectlyat-tributedtoIMRT.Overall,allreportscomparing3DCRTandIMRTrevealed
thatIMRThasthespiritstosparenormaltissuesfromhigherdosesofradiotherapyinordertodecreasethenotablesideef-fect rates,which is in agreementwith the potential of doseescalationfor localcontrolgoals.Therefore, it isnot fair toaskwhichtreatmenttechniqueisbetter.BasedontheabilityofIMRTtodeliverhigherdoseswithconcaveorsharpdosefall-offsoncriticalstructureswiththepotentialfororganpreserva-
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tion,commonsensewouldindicatethatalllocallyadvancedNSCLC patients would be treated with IMRT. The properquestionmightbewhichpatientsdefinitelyneedIMRT,asidefromthepatientswhocouldbesatisfactorilytreatedwithbothtechniques.Bezjaketal.(43)publishedtheCanadianGuide-linesonlungIMRTandindicatedaspecificgroupofpatientswhocouldbenefitthemostfromIMRT:tumorsincloseprox-imitytoanOAR(e.g.thespinalcord),alargevolumeofOARinjeopardybasedontumor/targetvolume(e.g.bilateralnodalvolume), and an additional dose escalation requirement toavoidincreasedtoxicityinnormaltissue.
UTILISATION OF MOTION AWARENESS AND MANAGEMENT
Targetmotionincorrelationwith therespiratorycycle isamajorchallengefortheidealdeliveryofradiotherapy.Theconventionalapproachistobothplananddeliverradiothera-pyduringanormalbreathingpatternwithoutanyrespiratorymanagement, but using a larger estimated volumewith anadditionalmargintocompensatetheunknownmotionduringtreatment.Thelungtumormotionandmethodstocopewith
ithavelongbeenstudiedinordertoconsiderthischangeinlungcancer treatmentplanning(44-46).TheAmericanAs-sociationofPhysicistsinMedicine(AAPM)TaskGroup76guidelinessummarisedtheadequatemethodstoaccountforthis obscuremotion by differentmethods:motion encom-passing (slowCTscanning;combinationof inhaleandex-halebreath-holdCT;and4Dimensional-CT/respiration-cor-relatedCT);respiratorygating(internalfiducialmarkersorexternalmarkerstosignalrespiration);breathhold(self-ordevice-controlled with or without respiratorymonitoring);abdominalcompressionforshallowbreathing;andrealtimetracking(47).Themostacceptedanduserfriendlymethodseems to be 4D-CT during normal breathing,which givesanaverageinternaltargetvolume(ITV)modeltocoverandcompensate respiration-related tumor motion (46, 48-50).TheITVapproachprovidesindividualisationinprescriptionby designing patient- andmotion-specificmargins that in-corporatetheextentoftumormotion.Sincethemotioncouldbemanagedwith4DCTandITV
utilisation, dose calculationwas another concern in IMRTdue to the fact that thatmotion informationandchange indensitybasedonmovementwerenotincludedinthecalcula-tioninaconventionalsetting.Additionally,breathing-related
FIG. 1. IMRT with a definitive dose of 60 Gy to the PTV in 30 fractions using a 4D-CT-based ITV approach for a NSCLC patient with T4N3M0 disease.
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intra-fractionorganmotionwasanissue.However,theplansafter4DCTsimulationaregenerallyreconstructedonanav-erage intensityprojectiondatasetanddosecalculationsareperformedwithtreatmentplanningsoftwareincludingmod-erndosealgorithmsbasedonheterogeneitycorrection,suchasMonteCarlo,collapsed-cone,convolution/superposition,anisotropicanalyticalalgorithm,andAcuros®XB(51-55).Additionally,Bortfeld et al. (56) showed that the effect oforganmotionduringIMRTdoesnotcausesystematicerrorsindosedeliveryanditaveragesthedosedistributionwithoutmotionoverthepathofthetumormotion,andthisisactuallynotdifferentfromconventionalbeams.Thevitalcomponent
in planning is 4D-CT simulation,which should be used ifavailable. If it isnotavailable,otheralternativeoptions toproduce an average image of the tumor at all respiratoryphases,suchasspiralCTorslowCTscanning,needtobeconsidered. Based on the complex extent of dose shapingandconformityrequirementinIMRTthan3DCRT,itoughttobeexpressedthatmotionawarenessand4Dplanningsup-porttoidentifythemarginsoftherunawaytargetaremorecriticalforIMRTthanforconventional3D-CRT.Therefore,the planned IMRTdoseswithmotion awareness includinga 4DCTdataset and current heterogeneity correction algo-rithmsdefinitelyrepresentthedosesdelivered.
FIG. 2. IMRT with a definitive dose of 70 Gy to the PTV in 35 fractions using a 4D-CT-based ITV approach for a NSCLC patient with T2N2M0 disease.
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FIG. 3. a, b. IMRT-based simultaneous integrated boost to 70 Gy (2 Gy/fraction/day) to integrated gross tumor volume while keeping the conventional PTV dose of 63 Gy in 35 fractions using a 4D-CT based ITV approach for a NSCLC patient with T3N2M0 disease; axial and sagittal images (a). IMRT-based simultaneous integrated boost to 70 Gy (2 Gy/fraction/day) to integrated gross tumor volume while keeping the conventional PTV dose of 63 Gy in 35 fractions using a 4D-CT based ITV approach for a NSCLC patient with T3N2M0 disease; coronal image (b).
a b
IRRADIATION OF LARGE VOLUMES TO LOW DOSES WITH IMRT
Asiswellknown,theintegraldoseisnotexpectedtode-creasewithIMRT,andthetotaldoseisdepositedtothetotalvolumeoftreatedarea,butmainlyinthelungparenchyma,whilereducingOARdosesintheesophagusandspinalcord.Therefore,thelowerdosesspreadaroundaslungV5orV10increaseincomparisonto3DCRT.Intreatmentplanevalu-ation, these low dose parameters are not considered aloneas criticalwhile there are universally set values to ensureamongallotherlungcriteria.Jinetal.(57)studiedMDAn-dersonCancerCenterdatafrom576inoperableNSCLCpa-tients to determine dose-volume thresholds for the risk oftreatment-relatedpneumonitisafterdefinitive radiotherapy.Theincidenceofgrade3ormoretreatment-relatedpneumo-nitiswasfoundtobeonly2%ifthefollowingdose-volumeparameters couldbe achieved:V5≤60%,V10≤42%,V20≤25%,V25≤20%,V35≤15%,andV50≤10%.Wangetal.(58)notedacollinearitybetweenV5andV20forpredictingtheriskofpneumonia,but theycouldnotdefineaspecificDVHparameterforV5.Shietal.(59)atPekingUniversitysharedtheiranalysisassociatedwithsevereacuteradiationpneumonitisinNSCLCpatientstreatedwithconcurrentche-motherapyandIMRT.TheyreportedthatkeepingV10below50%(pneumoniarisk:V10≤50%;5.7%versusV10>50%;29.2%) was a useful indicator for avoiding pneumonitis.Since the significance is not yet knownhowhazardous ofirradiatinglargevolumestolowdoses,basedonthesparsedataofV5andV10dosesregardingpneumonitis,manycen-terstrytokeepV5<60-65%andV10<45%inchemoradio-therapyprotocols(V5<55%andV10<40%inneoadjuvantsettingtosurgery),inadditiontoachievingdoseconstraintsofmeanlungdoseandV20.ThenumberofIMRTtreatment
fields is recommended to be limited to 5-7 to reduce lunglowdoseexposure(60).
CONCLUSION
3DCRThasbeenatrustedmethodforalongtimeandhaswell-knowndrawbacks,mostofwhichcouldbeimprovedbyIMRT.OnecannotclaimthatIMRTisthecurrentstandardinNSCLCtreatment,butalmostallpatientscouldbenefit toadegreeinOARsparing,dosecoverageconformality,ordoseescalation. The current literature and our own institutionalexperiencejustifyincreasingtheuseofIMRT,including4DimagingplusPETCT,andencourageustoproceedwiththeapplicableknowledgeandindividualiseddoseescalationus-ingadvanceddailyimageguidedradiotherapy(1,15,19,42).Therefore,offclinicalprotocol,werecommenddelivering60-70Gy(Figures1-4)totheplanningtargetvolume(PTV)in2Gy/fraction/day,or60-63GytothePTVin1.8-2Gy/frac-tion/dayplusanindividualisedsimultaneousintegratedboostdose escalation to the iGTV to 70Gy in 2-2.2Gy/fraction/daywithconcurrentchemotherapyinpatientswithinoperablestageIIINSCLC(1).Ifthepatientischemoradiotherapyin-eligiblewithapoorperformancestatusandisdisposedforra-diotherapyaloneorforpalliation,theprescriptionmightalsobeindividualisedtodeliver37.5-45Gy(Figure5)toaPTVin2.5-3Gy/fraction/dayplusanindividualisedsimultaneousintegratedboostdoseescalationtotheiGTVto45-52.5Gyin3-3.5Gy/fraction/day.Themostcriticalstepinaradiationoncologydepartment,
basedon“Primumnonnocere”,istostrictlyevaluateitstech-nicalandphysicalcapabilitiestodefinetheIMRTabilityfordelivering an optimal treatment plan including calculationof internal tumormotion (ideally 4DCTor equivalent tech-niques), treatmentplanningsoftwarewithanup-to-datehet-
FIG. 4. IMRT-based simultaneous integrated boost to 66 Gy (2.2 Gy/fraction/day) to an integrated gross tumor volume, while keeping the conventional PTV dose of 60 Gy (2 Gy/fraction/day) in 30 fractions using a 4D-CT-based ITV approach for an NSCLC patient with T3N3M0 disease.
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erogeneitycorrectionalgorithm,anddailyimageguidance.Itiscrucialtooptimiseandindividualisetherapeuticratioofra-diotherapyinourlungcancerpatientswithapplicablecutting-edgetechnologies.
Peer-review:Externallypeer-reviewed.
Author contributions: Concept-U.S.,Y.B.,J.W.W.,E.T.;Design-U.S.,Y.B.,J.W.W.,E.T.;Supervision-U.S.,E.T.;Resource-U.S.,Y.B.,J.W.W.,E.T.;Materials -U.S.,Y.B., J.W.W., E.T.;DataCollection&/or Processing-U.S.,Y.B.,J.W.W.,E.T.;Analysis&/orInterpretation-U.S.,Y.B.,E.T.;Lit-eratureSearch-U.S.,Y.B.,E.T.;Writing-U.S.,Y.B.,E.T.;CriticalReviews-U.S.,E.T.
Conflict of Interest:Noconflictofinterestwasdeclaredbytheauthors.
Financial Disclosure: Theauthorsdeclaredthatthisstudyhasreceivednofinancialsupport.
REFERENCES
1. SelekU,ChangJY.Evolutionofmodern-eraradiotherapystrategiesforunresectableadvancednon-small-cell lungcancer.Lung Cancer Man-agement2013;2:213-25.[CrossRef]
2. AuperinA,LePechouxC,RollandE,CurranWJ,FuruseK,FournelP,etal.Meta-analysisofconcomitantversussequentialradiochemotherapy
FIG. 5. IMRT-based simultaneous integrated boost to 52.5 Gy (3.5 Gy/fraction/day) to an integrated gross tumor volume, while keeping the conventional PTV dose of 37.5 Gy (2.5 Gy/fraction/day) in 15 fractions using a 4D-CT-based ITV approach for an NSCLC patient treated with radiotherapy alone to provide two benefits as follows: a safer plan with lung constraints being met, and also a higher dose to the iGTV.
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