Results of combined radiotherapy and hormonal treatment of prostate cancer patients with initial PSA value >40ng/ml

Available

online

at

www.sciencedirect.com

j o ur na l ho me p ag e :h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / r p o r

Original

article

Results

of

combined

radiotherapy

and

hormonal

treatment

of

prostate

cancer

patients

with

initial

PSA

value

>40

ng/ml

Kube ˇs

Jiri

_,

_Cvek

_Jakub

_,

_Vondráˇcek

_Vladimir

_,

_Dvoˇrák

_Jan

_,

_Argalacsová

_Sona

_,

Navrátil

Matej

_,

_Buˇril

_Jan

a_{InstituteofRadiationOncology,FacultyHospitalNaBulovceand1}st_{FacultyofMedicine,CharlesUniversity,Budínova2,Prague8,} 18000,CzechRepublic

b_{OncologicalClinic,FacultyHospitalOstrava,17.listopadu1790,Ostrava-Poruba70852,CzechRepublic}

a

r

t

i

c

l

e

i

n

f

o

Received28November2011 Receivedinrevisedform 14December2011 Accepted15January2012 Keywords: Prostatecancer PSA Highrisk Radiotherapy

a

b

s

t

r

a

c

t

Aim:ToevaluatetheoutcomeofprostatecancerpatientswithinitialPSAvalue>40ng/ml. Background:TheoutcomeofprostatecancerpatientswithveryhighinitialPSAvalueisnot knownandpatientsarefrequentlytreatedwithpalliativeintent.Weanalyzedtheoutcome ofradicalcombinedhormonaltreatmentandradiotherapyinprostatecancerpatientswith initialPSAvalue>40ng/ml.

Methods:BetweenJanuary2003andDecember2007wetreated, withcurativeintent,56

patientswithnon-metastaticprostatecancerandinitialPSAvalue>40ng/ml.The treat-mentconsistedoftwomonthsofneoadjuvanthormonaltreatment(LHRHanalog),radical radiotherapy(68–78Gy,conformaltechnique)andanoptionaltwo-yearadjuvanthormonal treatment.

Results:Themediantimeoffollowupwas61months.5-Yearoverallsurvivalwas90%.5-Year biochemicaldiseasefreesurvivalwas62%.Tstage,Gleasonscore,PSAvalue,and radiother-apydosedidnotsignificantlyinfluencetheoutcome.Lategenitourinalandgastrointestinal toxicitywasacceptable.

Conclusion:Radicaltreatmentincombinationwithhormonaltreatmentandradiotherapy

canberecommendedforthissubgroupofprostatecancerpatientswithgoodperformance statusandlifeexpectancy.

©2012GreaterPolandCancerCentre,Poland.PublishedbyElsevierUrban&PartnerSp. z.o.o.Allrightsreserved.

Background

Theprostatespecificantigen(PSA)isthemainfactorin defin-ing the extent and prognosis of disease in patients with

∗ _{Correspondingauthorat:InstituteofRadiationOncology,FacultyHospitalNaBulovceand1}st_{FacultyofMedicine,CharlesUniversity,}

Budínova2,Prague8,18000,CzechRepublic.Tel.:+420777661574;fax:+420283840873. E-mailaddress:jiri.kubes@fnb.cz(J.Kubeˇs).

prostatecancer.Theriskoflocallyadvanceddisease,1_lymph nodemetastasisanddistantbonemetastasis2_increasewith risingPSAvalue.Thepredictionvalueofnomogramsfor dis-easeextentpredictiondecreaseswithincreasingPSAvalue.3 HighinitialPSAvaluecanoccurintheabsenceofmetastatic

1507-1367/$–seefrontmatter©2012GreaterPolandCancerCentre,Poland.PublishedbyElsevierUrban&PartnerSp.z.o.o.Allrightsreserved.

diseaseinduced,forexample,byinflammationoftheprostate, butvaluesareusuallynotveryhigh.4_{Amoreaccurate} diagno-sisis,insuchcases,difficultandpotentiallyusefulmethods maybenatrium-fluoridPETscanningforthedetectionofbone metastasis5,6_{oraPETscanwith}11_C-cholin.7,8_These examina-tionsarenotstandardtoday,however.

PatientswithanextremelyhighPSAvalueareoftentreated withpalliativeintent.Themainriskofthisapproachisthe progressionof localized disease and side-effects accompa-nyingpermanenthormonalblockade.Onthe otherhand,a radical approachwith radical radiotherapy carriesthe risk of overtreatment, early progression outside the treatment volume,and side-effectsofradical radiotherapy. The addi-tionofradiotherapytothepermanent hormonaltreatment increasedoverall survivalofpatientswithlocallyadvanced prostate cancer9 _{and the addition of hormonal therapy to} radiotherapyincreasedoverallsurvivalofhighriskprostate patients.10,11 _{Thequestionremains,iftheradicaltreatment} approachisalsosuitableforpatientswithextremelyhigh ini-tialPSAvalue.

Aim

Theaimofthisworkistoevaluatetreatmentresultsinagroup ofprostatecancerpatientswithinitialPSAvalue>40ng/ml.

Materials

and

methods

BetweenJanuary2003and December2007wetreated, with curativeintent,56patientswithnon-metastaticprostate can-cerandaninitialPSAvalue>40ng/ml.Staginginvestigations included PSA, biopsy,CT or MRI scan of pelvis, and bone scan.Themaincharacteristicsofthepatientgroupare out-lined in Table 1. The treatment consisted of neoadjuvant hormonaltreatment(2months,LHRHanalog),radiotherapy andoptionaladjuvanthormonaltreatment(antiandrogen2 years).Themaincharacteristicsofthetreatmentareoutlined inTable2.Thetreatmentwasperformedonlinear acceler-atorswithanominalphotonbeamenergyof6MeV,usinga conformal3Dtechnique.Clinicaltargetvolumefortheinitial phaseoftreatmentincludedthepelvicregionwithboosttothe prostate/seminalvesiclesduringthesecondphaseorprostate

Table1–Patientcharacteristics.

Age(years) Median68(52–81)

Tstage T1 7(12.5%) T2 28(50%) T3a 9(16%) T3b 7(12.5%) T4 4(7%) Tx 1(2%) N0 56(100%) Gleasonscore2–6 25(45%) Gleasonscore7 15(27%) Gleasonscore8–10 14(25%) Gleasonscorex 2(3%) PSA(ng/ml) Median68ng/ml(42–276)

Table2–Proportionoftreatmentmodalities.

Neoadjuvanthormonal treatment Yes55(98%),No1(2%) Adjuvanthormonal treatment Yes37(66%),No19(34%)

Radiotherapy—volume Pelvis48(86%),prostate8(14%)

Radiotherapy—dose(Gy) Median74Gy(68–78Gy)

gland/seminalvesiclesonly,dependentonthedecisionofthe

physician.Thedosewas44–50Gy/22–25fractionsforthepelvic

regionand24–28Gy/12–14fractionsfortheprostate±seminal

vesicles. The totaldose was 68–78Gy/7–8 weeks.The dose

wasnormalizedtothemaximuminPTVand thedosewas

prescribedtothereferenceisodose(usually93%).Acuteand

latetoxicitywasevaluatedaccordingtotheRTOGscale.The

follow-upinvestigationswereperformedat3–6months

inter-valswithPSAexamination,physicalexamination,andcontrol

CT/MRIofpelvis,andbonescaninthecaseofPSAelevation.

PSArelapsewasassessedaccordingtothePhoenixcriteria.

Statistics

Overall survival(OS) and biochemical disease freesurvival

(bDFS)werecalculatedusingtheKaplan–Meiermethod.

Uni-variateanalysisofpredictivefactorswasundertakenusingthe

Mantel-Coxtest.Thelog-ranktestprovidedastatistical

com-parisonoftwogroups.Ap-value<0.05wasconsideredtobe

significant.

Results

The median follow up time during the evaluation period

(March 2011) was61 months. 52 patients were alive,three

patientsdiedduetotumorprogression,andonediedwithout

tumor.5-Yearoverallsurvivalwas90%and5-yearbiochemical

diseasefreesurvival(bDFS)was62%.Kaplan–Meiersurvival

curves foroverall andbiochemical-diseasefreesurvivalare

shown inFig.1.WealsoanalyzedtheinfluenceofTstage,

Gleasonscore,PSAlevel(withmediancut-off),radiotherapy target volume (prostate only versus whole pelvis), radio-therapy dose (with 74Gy cut-off), and adjuvant hormonal treatmenttothebiochemicalrelapse-freesurvival.Noneof thesefactorssignificantlyinfluencedbDFS.Therewasastrong trendforbetterresultsinthe groupwithPSAvaluesbelow themedian(67.5ng/ml,p=0.075).20(37.5%)treatmentfailures wereobservedduringthetimeofevaluation.PSArelapsealone was detectedin 10 (17.8%) patients, eight (14.3%) patients hadPSArelapsefollowedbybonedissemination,one(1.8%) patienthadPSArelapse,localrelapse,andbonedissemination andone(1.8%)patienthadPSArelapseandparaaortallymph node dissemination.Acuteandlatetoxicitywereevaluated accordingtotheRTOGscale.Therapyoftherectalbleeding withArgon-laserwasconsideredasgradeIIItoxicity.Thedata foracuteandlategastrointestinal(GI)andgenitourinal(GU) toxicitycanbefoundinTable3.Notoxicity≥2forotherorgans wasobserved.

Table3–AcuteandlateGIandGUtoxicity. RTOGscale Gr.0 Gr.1 Gr.2 Gr.3 Gr.4 AcuteGI 30% 29% 41% 0% 0% AcuteGU 16% 53.4% 27% 1.8% 1.8% LateGI 41.1% 19.6% 33.9% 5.4%a _0% LateGU 87.5% 1.8% 10.7% 0% 0%

a _{Argon-lasercoagulationwasconsideredasgr.3laterectaltoxicity.}

Fig.1–Overallsurvival(a)andbiochemical-diseasefree survival(bDFS)(b).

Discussion

AninitialPSA valuehigher than 40ng/mlis considered as a very poor prognostic factor and physicians often offer

less radical or only palliative treatment for this subgroup of patients. Thevalue ofthe PSA which excludespatients from radical treatment is not known. Some studies used PSA>150ng/mlasanexclusioncriterion.Themainproblem inthetreatmentofthissubgroupofprostatecancerpatients istheriskoflocalovertreatmentwithpossiblelateeffectsof radiotherapyintheradicalapproach.Ontheotherhand,there isahighriskofprogressionoflocalizeddiseasein combina-tion withside-effectsofthewhole-lifehormonaltreatment inthepalliativeapproach. Treatmentshouldbesufficiently effectiveinthediseasecontrolwithanacceptablefrequency ofsideeffects.Themainquestionishowmanypatientsare withouttumorprogressionuponthecompletionoftreatment andifthetreatmenttoxicityisacceptable.

A possible solution is a better selection of patients for radicaltreatment.Someproportionofpatientshad dissem-inated disease at the time of diagnosis, but a significant proportionofpatientswithhighinitialPSAhadtumor lim-ited to the prostate, without extra prostatic extension or seminal vesicle invasion.12 _{Current methods often cannot} discriminatedisseminated disease.Bonescanswith99_Tcis a standard examination in prostate cancer patients with PSA>20ng/ml. The probability of bone metastasis in this groupishigherthan 20%andtheriskincreaseswithrising values.13 Natrium fluoridePETmay offerhighersensitivity but reportsaboutthismethodarecontroversial.Markersof bone metabolism, like bone formation markers(bone spe-cific alkaline phosphatase, propeptides of type I collagen), boneresorptionmarkers(bonesialoprotein),and osteoclas-togenesis markers (osteoprotegerin) are other possibilities for improving the detection of bone metastasis.14–16 Dis-tinctsuggestionsfordiagnosingskeletallesionsforpatients with extremely high PSA levels donot exist. Secondmost probable locations of dissemination are pelvic or paraaor-tal lymph nodes. Thestandard investigation is a CT scan. Magnetic resonance imaging does not have a better sen-sitivity than a CT for detecting lymph node metastasis.17 Metastasestootherorgansareextremelyrareanditisnot nec-essarytodealwiththem.Cholin-PETisapromisingmethod withsensitivityof55–100%andspecificityof77–86%forthe detectionofprimarytumors.7,18–20_{Sensitivityandspecificity} of18F-fluorocholinforthedetectionoflymph-node metas-tasis in men with intermediate or high risk tumors were 45% and 96%,respectively.21 _{Others investigatedthe value} of this examination in the detection of bone metastasis and specifiedvaluesofsensitivityat79% andspecificityat 97%.22

Our strategy of radical treatment includes neoadjuvant hormonaltreatment,radicalradiotherapy(withdose escala-tioninsignificantproportionofmen),andoptionallyadjuvant hormonaltherapy.

Theeffectivenessofneoadjuvanthormonaltreatmentwas demonstrated in a number of clinical studies. This treat-menthasalowincidenceofside-effectsandisindicatedfor patientswithintermediateandhighriskprostatecancer.23,24 Weusedashorttermhormonaltreatment,althoughtodaya longerneoadjuvanttreatmentisrecommended.25_PSAdecline afterneoadjuvanttreatmentmaybeusedasanother prog-nosticfactorforthedecisionbetweenradicalandpalliative treatment.26

Radiotherapyisthekeyfactorindeterminingthesuccess ofradicaltreatmentandtheseverityofsideeffectsin com-parisonwiththepalliativeapproach.Theeffectofradiation dependsondose,targetvolumes,andradiotherapytechnique. Thetreatmentofthepelviclymphaticregionhassome advan-tagesincomparisonwithprostateonlyradiotherapyinhigh riskprostatecancerpatients.RTOG9413trialsdemonstrated a 13% improvement ofprogression freesurvival for pelvic RT versus prostate only RT.27–29 _{Our data showed a much} betterdisease freesurvivalfortheprostate only radiother-apy group. The limited volume was indicated only for T1 orT2stage,Gleasonscore<7and PSAbelowmedianvalue and,therefore,thenumberofthesepatientswassmall(14%). Inspite ofthis,wehypothesized that this wasa selection biasandthatwholepelvisradiotherapywasindicatedinthis extremelyhighriskgroup,especiallyhigherTstageor Glea-sonscore. Dose-response characteristics ofprostatecancer arewelldocumented.30,31 _{Effectsofhigherdosagewerenot} demonstrated inourgroup. Thereissometrend forbetter resultswithhigherdoses.Wehypothesizedthatthismight beduetotheshorttimeoffollowup.Thenextissueisthe frequencyoflateeffectsoftheradiotherapy.Weuseda3D con-formaltechnique.IMRT techniquesignificantlyreducesthe numberofsideeffects,aswasdemonstrated,32_andmaybe usedforadditionaldoseescalation.33,34_{Themajorityoflate} effectswereinourrectalbleedinggroup.5.4%ofourpatients neededtreatmentwithlasercoagulationandnoneofthem requiredsurgery.Wedidnotobserve urogenitallateeffects worsethangrade2.Ourconclusionfromtoxicitydataisthat benefitsofaddingradiotherapyaremuchhigherthan disad-vantages.Thefrequency oflate siteeffects was similar as inpublishedreportsforthe3DCRT.35_Moreover,we hypoth-esize, that by using IMRT and optimization of treatment position the frequencyof side effects may be significantly diminished.36,37

Adjuvant hormonaltherapy isa standard option inthe high risk prostate cancer group and improves overall sur-vivalofhighriskgroupby16%.38_{However,long-termadjuvant} treatmenthasmanysideeffects,includingcardiovascular dis-ordersandahigherincidenceofdiabetes,39,40_{althoughrecent} reportsdisputetheriskofcardiovasculareffects.41_Wedidnot observedstatisticallysignificantdifferencebetweenadjuvant treatmentandnoadjuvanttreatment.WeindicateAHB espe-ciallyinpatientswithhighGleasonscore(8–10)orstageT3b orhigher.AHBisoptionalforotherpatients.Interestingly,we didnotobserveanydifferencesinbDFSbetweenhigherand lowerGleasonscoregroupsorhigherandlowerTstage.We hypothesizethatneoadjuvanthormonaltreatmentin com-binationwithradicalradiotherapymaybesufficientinhigh riskpatientswithalowGleasonscoreandlowTstage.This assumptionneedsfurtherevaluation.

Treatmentfailure,inthemajorityofpatients,consistedof PSAfailurefollowedbybonemetastasis.Onlyonerelapsein the radiotherapytreatmentvolumewasobserved.Verylow frequency oflocalproblems isanother benefitofthe radi-calapproach.Therewasastatisticallyinsignificanttrendfor betterresultsforthesubgroupwithinitialPSAvaluebelow medianvalueof68ng/ml,ascanbeexpected.5-YearbDFSfor thissubgroupis76%andforpatientswithhigherinitialvalues itis48%.Icanbeconcludedthat,specifically,patientswithPSA valuesof40–70ng/mlshouldbetreatedwitharadicalintent. Dataabouttreatmentoutcomeofpatientswithveryhigh initialPSAvaluesarenotavailable.Recently,Canadianauthors publishedbDFSandOSat5years39%and78%,respectively, in64patientswithinitialPSA>40ng/ml.Ourresultsare bet-ter, possibly due to higher doses and intensive hormonal treatment.42

Conclusion

RadicaltreatmentofpatientswithinitialPSAvalues>40ng/ml hasanexcellent5-yearbiochemicaldiseasefreesurvivalwith alowriskofsideeffectsfromthetreatment.Progressionof diseaseisusuallyoutsidetheradiotherapytreatmentvolume withlocalproblemseliminated.Wecanrecommendthe rad-icaltreatmentapproachforthissubgroupofprostatecancer patientswithagoodperformancestatusandlifeexpectancy.

Conflict

of

interest

r

e

f

e

r

e

n

c

e

s

1. CaireAA,SunL,LackBD,etal.Predicting

non-organ-confinedprostatecancerinmendiagnosedafter 2000.ProstateCancerProstaticDis2010;13:248–51.

2. PartinAW,KattanMW,SubongEN,etal.Combinationof prostate-specificantigen,clinicalstage,andGleasonscoreto predictpathologicalstageoflocalizedprostatecancer.A multi-institutionalupdate.JAMA1997;277:1445–51.

3. GallinaA,JeldresC,ChunFK,etal.Predictionofpathological stageisinaccurateinmenwithPSAvaluesabove20ng/mL. EurUrol2007;52:1374–80.

4. AnimJT,KehindeEO,PrasadA,etal.Relationshipbetween serumprostatespecificantigenandthepatternof

inflammationinbothbenignandmalignantprostaticdisease inMiddleEasternmenInternational.UrolNephrol

2006;38:27–32.

5. SchirrmeisterH,GuhlmannA,ElsnerK,etal.Sensitivityin detectingosseouslesionsdependsonanatomiclocalization: planarbonescintigraphyversus18FPET.JNuclMed

1999;40:1623–9.

6. Even-SapirE,MetserU,MishaniE,etal.Thedetectionof bonemetastasesinpatientswithhighriskprostatecancer: 99mTcMDPplanarbonescintigraphy,singleandmultifield ofviewSPECT,18F-fluoridePETand18F-fluoridePET/CT.J NuclMed2006;47:287–97.

7. EschmannSM,PfannenbergAC,RiegerA,etal.Comparison of11C-cholinePET/CTandwholebody-MRIforstagingof prostatecancer.Nuklearmedizin2007;46:161–8.

8. ScattoniV,PicchioM,SuardiN,etal.Detectionof

lymph-nodemetastaseswithintegrated[11C]cholinePET/CT inpatientswithPSAfailureafterradicalretropubic

prostatectomy:resultsconfirmedbyopen

pelvic-retroperitoneallymphadenectomy.EurRadiol 2007;52:423–9.

9. WidmarkA,KleppO,SolbergA,etal.Endocrinetreatment, withorwithoutradiotherapy,inlocallyadvancedprostate cancer(SPCG-7/SFUO-3):anopenrandomisedphaseIIItrial. Lancet2009;373:301–8.

10. BollaM,ColletteL,BlankL,etal.Long-termresultswith immediateandrogensuppressionandexternalirradiationin patientswithlocallyadvancedprostatecancer(anEORTC study):aphaseIIIrandomisedtrial.Lancet2002;360: 103–6.

11. BollaM,vanTienhovenG,deReijkeTM,etal.Concomitant andadjuvantandrogendeprivation(ADT)withexternal beamirradiation(RT)forlocallyadvancedprostatecancer:6 monthsversus3yearsADT:resultsoftherandomizedEORTC PhaseIIItrial22,961.JClinOncol2007;25:5014.

12. GallinaA,JeldresC,ChunF,etal.Predictionofpathological stageisinaccurateinmenwithPSAvaluesabove20ng/mL. EurUrol2007;52:1374–80.

13. GleaveME,CouplandD,DrachenbergD,etal.Abilityofserum prostate-specificantigenlevelstopredictnormalbonescans inpatientswithnewlydiagnosedprostatecancer.Urology 1996;47:708–12.

14. JungK,LeinM,StephanC,etal.Comparisonof10serum boneturnovermarkersinprostatecarcinomapatientswith bonemetastaticspread:diagnosticandprognostic implications.IntJCancer2004;111:783–91.

15. KamiyaN,SuzukiH,YanoM,etal.Implicationsofserum boneturnovermarkersinprostatecancerpatientswithbone metastasis.Urology2010;75:1446–51.

16. KataokaA,YuasaT,KageyamaS,etal.Diagnosisofbone metastasisinmenwithprostatecancerbymeasurementof serumICTPincombinationwithalkaliphosphataseand prostate-specificantigen.ClinOncol2006;18(August(6)):480–4. 17. HovelsAM,HeesakkersRA,AdangEM,etal.Thediagnostic

accuracyofCTandMRIinthestagingofpelviclymphnodes inpatientswithprostatecancer:ameta-analysis.ClinRadiol 2008;63:387–95.

18. TestaC,SchiavinaR,LodiR,etal.Prostatecancer:sextant localizationwithMRimaging,MRspectroscopy,and 11C-cholinePET-CT.Radiology2007;244:797–806. 19. YamaguchiT,LeeJ,UemuraH,etal.Prostatecancer:a

comparativestudyof11C-cholinePETandMRimaging combinedwithprotonMRspectroscopy.EurJNuclMedMol Imaging2005;32:742–8.

20. BaumanG,BelhocineT,KovacsM,WardA,BeheshtiM, RachinskyI.(18)F-fluorocholineforprostatecancerimaging: asystematicreviewoftheliterature.ProstateCancerProstatic Dis2011,doi:10.1038/pcan.2011.35.August16[Epubaheadof print].

21. BeheshtiM,ImamovicL,BroingerG,etal.18FcholinePET/CT inthepreoperativestagingofprostatecancerinpatients withintermediateorhighriskofextracapsulardisease:a prospectivestudyof130patients.Radiology2010;254:925–33. 22. BeheshtiM,ValiR,WaldenbergerP,etal.TheuseofF-18

cholinePETintheassessmentofbonemetastasesinprostate cancer:correlationwithmorphologicalchangesonCT.Mol ImagingBiol2009;11:446–54.

23. Roach3rdM,BaeK,SpeightJ,etal.Short-termneoadjuvant androgendeprivationtherapyandexternal-beam

radiotherapyforlocallyadvancedprostatecancer:long-term resultsofrtog8610.JClinOncol2008;26:585–91.

24. D’AmicoAV,ChenMH,RenshawAA,LoffredoM,KantoffPW. Androgensuppressionandradiationvsradiationalonefor prostatecancer:arandomizedtrial.JAMA2008;299:289–95.

25. DenhamJW,SteiglerA,LambDS,etal.Short-termandrogen deprivationandradiotherapyforlocallyadvancedprostate cancer:resultsfromtheTrans-TasmanRadiationOncology Group96.01randomisedcontrolledtrial.LancetOncol 2005;6:841–50.

26. AlexanderA,CrookJ,JonesS,etal.Isbiochemicalresponse moreimportantthandurationofneoadjuvanthormone therapybeforeradiotherapyforclinicallylocalizedprostate cancer?Ananalysisofthe3-versus8-monthrandomized trial.IntJRadiatOncolBiolPhys2010;76:23–30.

27. RoachIIIM,DeSilvioM,ValicentiR,etal.Whole-pelvis, “mini-pelvis,”orprostate-onlyexternalbeamradiotherapy afterneoadjuvantandconcurrenthormonaltherapyin patientstreatedintheRadiationTherapyOncologyGroup 9413trial.IntJRadiatOncolBiolPhys2006;3:647–53. 28. LawtonCA,DeSilvioM,RoachIIIM,etal.Anupdateofthe

phaseIIItrialcomparingwholepelvictoprostateonly radiotherapyandneoadjuvanttoadjuvanttotalandrogen suppression:updatedanalysisofRTOG94-13,withemphasis onunexpectedhormone/radiationinteractions.IntJRadiat OncolBiolPhys2007;69:646–55.

29. DirixP,HaustermansK,JuniusS,WithersR,OyenR,Van PoppelH.Theroleofwholepelvicradiotherapyinlocally advancedprostatecancer.RadiotherOncol2006;79:1–14. 30. CheungR,TuckerS,LeeA,etal.Dose–response

characteristicsoflow-andintermediateriskprostatecancer treatedwithexternalbeamradiotherapy.IntJRadiatOncolBiol Phys2005;61:993–1002.

31. PollackA,ZagarsG,StarkschallG.ProstateCancerradiation doseresponse:resultsoftheM.D.AndersonphaseIII randomizedtrial.IntJRadiatOncolBiolPhys2002;53:1097–105. 32. SharmaNK,LiT,ChenDY,PollackA,HorwitzEM,

BuyyounouskiMK.Intensity-modulatedradiotherapy reducesgastrointestinaltoxicityinpatientstreatedwith androgendeprivationtherapyforprostatecancer.IntJRadiat OncolBiolPhys2010,doi:10.1016/j.ijrobp.2010.02.040. November2[Epubaheadofprint].

33. DolezelM,OdrazkaK,VaculikovaM,etal.Doseescalationin prostateradiotherapyupto82Gyusingsimultaneous integratedboost:directcomparisonofacuteandlatetoxicity with3D-CRT74GyandIMRT78Gy.StrahlentherOnkol 2010;186(April(4)):197–202.

34. CeylanC,KucukN,BasAyataH,GudenM,EnginK.

DosimetricandphysicalcomparisonofIMRTandCyberKnife plansinthetreatmentoflocalizedprostatecancer.RepPract OncolRadiother2010;15(6):181–9.

35. AshmanJB,ZelefskyMJ,HuntMS,LeibelSA,FuksZ.Whole pelvicradiotherapyforprostatecancerusing3Dconformal andintensity-modulatedradiotherapy.IntJRadiatOncolBiol Phys2005;63:765–71;

DeMeerleerG,FonteyneVH,VakaetL,etal.

Intensity-modulatedradiationtherapyforprostatecancer: latemorbidityandresultsonbiochemicalkontrol.Radiother Oncol2007;82:160–6.

36. BollaM,GonzalezD,WardeP,etal.Improvedsurvivalin patientswithlocallyadvancedprostatecancertreatedwith radiotherapyandgoserelin.NEnglJMed1997;337:295–300. 37. BajonT,PiotrowskiT,AntczakA,etal.Comparisonofdose

volumehistogramsforsupineandpronepositioninpatients irradiatedforprostatecancer—apreliminarystudy.RepPract OncolRadiother2011;16:65–70.

38. TyrrellaCH,PaynebH,SeecWA,etal.Bicalutamide (‘Casodex’)150mgasadjuvanttoradiotherapyinpatients withlocalisedorlocallyadvancedprostatecancer:results fromtherandomisedEarlyProstateCancerProgramme Group.RadiotherOncol2005;76:4–10.

39. KeatingNL,O’MalleyAJ,SmithMR.Diabetesand

cardiovasculardiseaseduringandrogendeprivationtherapy forprostatecancer.JClinOncol2006;24:4448–56.

40. SaigalCS,GoreJL,KrupskiTL,HanleyJ,SchonlauM,Litwin MS.Androgendeprivationtherapyincreasescardiovascular morbidityinmenwithprostatecancer.Cancer

2007;110:1493–500.

41. AlibhaiSM,Duong-HuaM,SutradharR,etal.Impactof androgendeprivationtherapyoncardiovasculardiseaseand diabetes.JClinOncol2009;27:3452–8.

42. AlexanderAS,MydinA,JonesSO,etal.Extreme-riskprostate adenocarcinomawithprostate-specificantigen

(PSA)>40ng/ml:prognosticsignificanceofthepreradiation PSAnadir.IntJRadiatOncolBiolPhys2011,

doi:10.1016/j.ijrobp.2010.11.068.January27[Epubaheadof print].