MSAC Application1147:

Final Decision Analytical Protocol (DAP) to guide the assessment of fiducial seeds in image-guided radiotherapy of the prostate

September 2011

Table of Contents

MSAC and PASC

Purpose of this document

Purpose of application

Intervention

Description

Administration, dose, frequency ofadministration, duration of treatment

Subsequent interventions

Background

Current arrangementsfor public reimbursement

Regulatory status

Patient population

Proposed MBS listing

Clinical place for proposed intervention

Comparator

Clinical claim

Outcomesandhealthcareresourcesaffectedbyintroductionofproposed intervention

Outcomes

Safety

Health careresources

Proposed structure of clinical and economic evaluation

References

MSAC and PASC

The Medical ServicesAdvisoryCommittee(MSAC)isanindependentexpertcommitteeappointedby theMinisterforHealthandAgeing(theMinister)tostrengthentheroleofevidenceinhealth financingdecisionsin Australia.MSAC advises the Minister ontheevidence relating tothesafety, effectiveness,andcost-effectiveness of newandexistingmedical technologiesandproceduresand under what circumstancespublic funding should be supported.

TheProtocolAdvisorySub-Committee(PASC)is astandingsub-committee ofMSAC.Itsprimary objectiveisthedeterminationofprotocolstoguideclinicaland economicassessmentsof medical interventionsproposed forpublic funding.

Purpose of this document

Thisdocumentisintendedtoprovideadraftdecision analyticprotocolthatwillbeusedtoguidethe assessmentofaninterventionforaparticularpopulationofpatients.Thedraftprotocolwillbe finalised after invitingrelevant stakeholderstoprovideinputtotheprotocol. Thefinalprotocol will provide the basis for the assessmentofthe intervention.

Theprotocol guidingtheassessment ofthehealth interventionhasbeendevelopedusingthewidely accepted “PICO” approach. The PICO approach involves a clear articulation of the followingaspectsof the researchquestion thatthe assessment is intendedto answer:

Patients–specificationofthecharacteristicsofthepatientsinwhomtheinterventionistobe considered for use;

Intervention– specification of the proposed intervention

Comparator–specificationofthetherapymostlikely tobereplacedbytheproposed intervention

Outcomes–specificationofthehealthoutcomesandthehealthcareresourceslikelytobe affected by the introductionof the proposed intervention.

Purpose of application

AnapplicationrequestingMBSlistingoffiducialmarkerstoguideradiotherapyoftheprostatefor patientswith prostatecancerwasreceivedfrom theRoyalAustralianandNewZealandCollegeof Radiologists (RANZCR) by the Departmentof Healthand Ageing in April 2010.

Intervention

Description

Prostatecanceristhemostcommonly diagnosedcancerinAustralia (excludingbasal and squamous cellskincancers)andthesecondmostcommoncauseofcancerdeathinmenafterlungcancer.In

2007,19,403casesofprostatecancerwerediagnosedinAustralianmenandtherewere2,938

deaths attributed to the disease. The incidence of prostate cancer has fluctuated since the introductionofprostatespecificantigen(PSA)testingwitharapidpeakintheearly1990sfollowing itsintroduction,alevellingoutinthelate1990sand afurtherincreasefrom2002.Theage standardisedincidenceratein2007was182.9per100,000males.Cancerspecificmortality hasfallen steadilyoverthepastdecadeto31.0per100,000males.Themeanageatdiagnosiswas68.4in

2007andthelifetimeriskofdevelopingprostatecancerbeforetheageof75was1in7men

(Australian Institute of Health and Welfare (AIHW) 2010).

External-beamradiotherapy(EBRT)isatreatmentoption formenwith localisedorlocally advanced prostatecancer,howevertheprostateglandisdifficulttoimageusingstandard x-rays andis mobile: itspositionin relationtoexternalmarkersonthe skin ortobonypelvicanatomy canvaryfromdayto dayandalso duringtreatment. Themovementisdueinparttothefillingofadjacentholloworgans (thebladder andrectum) andthese areatrisk ofradiotherapyinducedtoxicity. Theseuncertainties about prostate position mean that treatment planning target volumes (PTV) are typically larger than theclinicaltargetvolumes(CTV)toallowforthe variablepositionoftheprostate.Thereforethe accuratedeliveryofradiotherapytotheprostate andavoidanceof theadjacent organsallowsgreater certainty ofdailytargetingoftheradiotherapytreatmentwhichinturnallowsmarginstobereduced anddoseto adjacentnormalcriticalstructures suchastherectum andbladdertobereduced.Itmay also allow a higher dose tobegiven to the targetorgan.

Theimplantationofradio-opaque, sterilemarkers(usually3or4)intotheprostateisdesignedto providefiducialor fixedreferencepointsduring acourse ofradiotherapywiththeaim ofdelivering radiotherapymoreaccuratelyandefficiently.Themarkersareusuallysmallgoldseeds(typically

~5mm~1mm)thatcanbeeasilyvisualisedusingX-rayimaging.Theseseedsarepreloadedinto

needlesthatareusedtodeliverthesemarkersintotheprostatebeforeradiotherapytreatment. Duringthedeliveryofradiotherapy,thepositionofthemarkersis visuallycheckedagainstreference images derived at the planning processto ensure treatment is accurately delivered.

Image-guidedradiotherapy(IGRT)utilisingdailyon-lineverificationofprostatepositionor surrogate hasbeen showntoreduce systematicandrandomtreatmenterrors,decreasetheriskofgeographic miss(foragivenmargin),andmayallowforsomereductioninPTVmargins(Chungetal2004; O'Danieletal2006;Schallenkampetal2005).Planarkilovoltage(kV)ormegavoltage(MV)imaging ofimplantedprostatefiducialmarkers(Litzenbergetal 2002)isthemostfrequentlyutilisedIGRT techniqueinAustralia.Volumetricverification techniquessuchaskVcone-beamCT,MVCT,andCT- on-rails allowvisualisation of softtissuestructures (Kupelianet al2008),howeverinvestigationis ongoing as to their optimalutilisation and integrationinto clinical practice.

Administration, dose, frequency ofadministration, duration of treatment

Afterconsultation with aradiationoncologist and havingbeenassessed assuitablefor radiotherapy, patientswill beinstructed toceaseany anti-coagulantoranti-platelettherapy fortherecommended periodoftimepriortofiducialmarker implantation.Ifnecessary,appropriateconsultationswiththe patient’s treating physician(s) are undertaken.Prophylactic antibiotics are prescribed according to current guidelines. Patients are also instructed to usea local rectal laxative before the implantation.

Sterilisedfiducialmarkers arepre-loadedintoneedlesthatareusedtodeliver themarkersintothe prostate. Three or4fiducialmarkers(usually gold) are placed as a one-offprocedurepriortothe courseofradiotherapy.Fiducialmarkerscanbeimplantedineithertheambulatorycaresettingorin adaysurgeryfacilitydependingonfactorssuchaspatientpreferenceandinsurancestatusand accesstofacilities.Theprocedureisperformedunder ultrasoundcontrol(mostcommonly trans-rectal ultrasound,MBSItem55603),usingatrans-rectalor trans-perinealneedleinsertionapproach.Inthe ambulatorycaresetting thiswillbeperformedby aradiologist.Theradiologistwouldbe skilledin similar interventional radiological procedures and familiar with ultrasound guided equipment and the sterilisedpre-loadedneedlesused intheimplantation.Theradiologyfacilitywouldhave aradiology nurse skilled inmanagement ofpatients whohave had aminimallyinvasiveprocedure (similar to image-guidedbiopsy).Inadaysurgeryfacilitythe implantationwillbeperformedbyaurologistor radiationoncologistskilled intheuseof trans-rectalultrasound.Urologynursespecialistsareusually involvedinpre-implantandfollow-upofthepatient.Rarelytheseedsarenotoptimallyplacedand the procedure may need to be repeated (expertadvice).

Ananaestheticprocedureisgenerally requiredwhenperformingtheimplantationofthefiducial markers. Thismaybealocal orgeneralanaestheticorconscious sedationdependingonthe assessmentandpreferencesofeachindividualpatient. Patientswithahigherriskofinfectionwill undergoaperinealapproachwhich requiresageneralanaesthetic(expertadvice).Afterthe procedure,thepatientisobservedforaperiodtoensureadequaterecoveryfromtheanaestheticand that there areno immediate adverse side-effectssuch as excessive bleeding.

Table 1 MBS itemdescriptorsfor interventions co-administeredwith theproceduretodeliver themarkers

Category 5 - DIAGNOSTIC IMAGING SERVICES
MBS 55603
PROSTATE, bladder base and urethra, transrectal ultrasound scan of, where performed:
(a) personallybyamedicalpractitionerwhoundertooktheassessmentreferredtoin(c)usingatransducerprobeor probes that:
(i)haveanominalfrequencyof7to7.5megahertzoranominalfrequencyrangewhichincludesfrequenciesof7to7.5 megahertz; and
(ii) can obtain both axial and sagittal scansin 2 planes at right angles; and
(b) following a digital rectal examination of the prostate by that medical practitioner; and
(c) on a patient who has been assessed bya specialist in urology, radiation oncology or medical oncology or a consultant physician in medical oncology who has:
(i)examined the patient in the 60days prior to the scan; and
(ii)recommended the scan for the management of the patient's current prostatic disease (R)
Fee:$109.10 Benefit: 75%= $81.85 85%= $92.75
Category 1 - PROFESSIONAL ATTENDANCES
MBS 104
SPECIALIST, REFERREDCONSULTATION- SURGERY ORHOSPITAL
(Professional attendance at consulting rooms or hospital by aspecialistin the practice of his or her specialty where the patient is referred to him or her)
- INITIAL attendance in a singlecourse of treatment, not being a service to whichophthalmology items 106, 109 or obstetric item 16401 apply.
Fee:$82.30 Benefit: 75%= $61.75 85%= $70.00

Subsequent interventions

Fiducialmarkersareused toguideradiotherapy.EBRTistheirradiationoftheprostatefroman externalsource.TheplanningandtreatmentassociatedwithEBRTcontinuestoevolvetoenable moreaccuratetreatment allowinghigherradiationdoses.Thecurrentstandardofcareis three- dimensional conformalradiotherapy (3DCRT) (MBSitems15248and15263)whichusesthree dimensionalplanningsystemstomaximisedoseto theprostateandattempttosparesurrounding tissues.IntensityModulatedRadiation Therapy(IMRT)isatechnologicaladvancementof3DCRT and iscurrentlyclaimedunderthesameitemnumber.It usesbeamsthatdelivermorethantwointensity levelsforasinglebeamdirectionandasinglesourcepositioninspaceallowingthedeliveryof complex dose distributionsand potentially increased target doses.

Theradiationtreatmenttechniqueshouldbeselected toachievethegoalofdeliveringtheprescribed dosetothetargetvolumeandminimisingdoseto organsatrisk,whiletakingintoconsiderationthe prescribeddose,departmentalresourcesandthecomplexityofindividualpatientanatomy.3DCRT hasbeen showntoreduce theriskofrectal toxicity whencomparedwithconventionalfield based radiationtherapy(Dearnaleyetal1999;Michalskietal2004;Michalskietal2005). IMRThasthe potentialtodeliveramore sculpteddosedistribution than3DCRTresultingin reduceddosetothe rectum and bladder, optimised coverage of the PTV by the prescribed dose, and improved

conformalityofthehighdoseregion(Cahlonetal2008;Zelefskyetal2000).Retrospectiveevidence demonstratesthatIMRTcanreducetheincidenceoflateintestinaltoxicity(Janietal2007;Zelefsky et al 2008) and may allow dose escalation to be employed without corresponding increases in toxicity (Zelefsky etal 2006).

InAustralia, IGRTusingdailypre-treatmentverificationofprostatepositionisrecommendedwhen deliveringdefinitiveEBRTforprostatecancer.3DCRTisregarded astheminimumstandardofcare whendeliveringexternalbeamradiotherapy.IMRTis preferredwhereorganatriskdoseconstraints are not achievable with 3DCRT (Hayden et al 2010). Australian guidelines also recommend a minimumacceptabledoseof70Gyforlow-riskpatients and74Gyforintermediate andhigh-risk patientsand statethatthebenefitof dose-escalation(78-80Gy)isseenacrossallrisk groups; however major clinical disagreement isnoted for this recommendation (Haydenet al 2010).

Patientsmay undergoEBRTaloneorincombination withlowdoseratebrachytherapy(LDRBT,MBS items15338, 37220)or high-doseratebrachytherapy (HDRBT,MBS items37227,15332) asa boost. LDRBT, orpermanent seedBT,istheimplantation ofradioisotopes(iodine-125or palladium-103, although onlyiodine-125 seedsareavailableinAustralia)directlyintothe prostateglandforthe treatmentof localisedprostatecancer. The seeds remainpermanentlyintheprostategland.LDRBT hasbeeninterimfundedontheMBSsince2000.FollowingaMSACassessmentin2010(Tamblynet al2011),LDRBThasbecomepermanentlyfunded sinceDecember2010.HDRBTisthetemporary implantation ofaradiationsource (iridium-192)withintheprostate. Thinplastichollow tubesare insertedthroughtheperinealskinandintotheprostategland.Aradioactivesourceisthen inserted intoeachtube.Followingtreatment,thetubesarepulledout,leavingnoradioactivematerial inthe prostategland.NICEissuedguidanceonHDRBTincombinationwithEBRTin2006supportingthe useofthisprocedureincombinationwithEBRT,butnotedthattheuseofHDRBTasmonotherapy wasthesubjectofresearchstudies(NationalInstituteforHealthandClinicalExcellence(NICE)

2006).

Radicalprostatectomy(MBSitems37210,37211)isan optionforthemanagementoflocalisedand locallyadvancedprostatecancerand involvesthesurgicalremovaloftheprostateglandand reconnectionoftheurethratothebladderneck.EBRT canbeprovidedpost-prostatectomyaseither adjuvanttreatmentforhighriskpatientsorsalvagetreatmentfollowingbiochemicalrelapseand

sometimes implanted fiducial markers are used to guide this treatment.

Table 2 Current MBS item descriptorsfor subsequent interventions

MBS 15248

Category 3 – THERAPUTIC PROCEDURES

RADIATION ONCOLOGYTREATMENT, usingadualphotonenergylinearaccelerator withaminimumhigherenergyofat least10MVphotons,withelectronfacilities-eachattendanceatwhichtreatment isgiven-1field-treatmentdeliveredto primary site (prostate)

Fee:$57.40 Benefit: 75%= $43.05 85%= $48.80

Category 3 – THERAPUTIC PROCEDURES
MBS 15263
RADIATION ONCOLOGYTREATMENT, usingadualphotonenergylinearaccelerator withaminimumhigherenergyofat least 10MV photons, with electron facilities - each attendanceat which treatment is given- 2 or more fields up to a maximum of 5 additional fields (rotational therapy being 3 fields) - treatment delivered to primary site (prostate)
The fee for item15248 plus for each field in excess of 1, an amount of $36.50
Category 3 – THERAPUTIC PROCEDURES
MBS 15338
PROSTATE, radioactiveseed implantation of, radiation oncology component, using transrectal ultrasound guidance, for localisedprostaticmalignancyatclinicalstagesT1(clinicallyinapparenttumournotpalpableorvisible by imaging)orT2 (tumour confined within prostate), with a Gleason score of less than or equal to 7 and a prostate specific antigen(PSA) of lessthanorequalto10ng/mlatthetimeofdiagnosis. The proceduremustbeperformedatanapprovedsitein association witha urologist.
Fee:$900.15 Benefit: 75%= $675.15 85%= $828.95 (See para T2.2of explanatory notes to this Category)
Category 3 – THERAPUTIC PROCEDURES
MBS 37220
PROSTATE,radioactiveseedimplantation of,urological component,usingtransrectalultrasoundguidance, forlocalised prostaticmalignancyatclinicalstagesT1(clinicallyinapparent tumournotpalpableorvisiblebyimaging)orT2 (tumour confined within prostate), with aGleason score of less than or equal to 7and a prostate specific antigen (PSA) of less than orequalto10ng/mlatthetimeofdiagnosis.Theproceduremustbeperformedbyaurologistatanapproved sitein association witha radiation oncologist, and be associated with a service to which item 55603 applies.
Multiple ServicesRule
(Anaes.)
Fee:$1,004.65Benefit: 75%=$753.50
(See para T8.58of explanatory notes to this Category)
Category 3 – THERAPUTIC PROCEDURES
MBS 37210
PROSTATECTOMY,radical,involvingtotalexcisionoftheprostate,sparingofnervesaroundthebladderandbladder neck reconstruction, not being aservice associated with a serviceto which item 35551, 36502 or 37375 applies
Multiple ServicesRule
(Anaes.) (Assist.)
Fee:$1,533.05Benefit: 75%=$1,149.80
Category 3 – THERAPUTIC PROCEDURES
MBS 37211
PROSTATECTOMY,radical,involvingtotalexcisionoftheprostate,sparingofnervesaroundthebladderandbladder neckreconstruction,withpelviclymphadenectomy,notbeingaserviceassociatedwithaservicetowhichitem35551,
36502 or 37375 applies
Multiple ServicesRule
(Anaes.) (Assist.)
Fee:$1,861.85Benefit: 75%=$1,396.40
Category 3 – THERAPUTIC PROCEDURES
MBS 37227
PROSTATE, transperineal insertion of catheters into, for high dose rate brachytherapy using ultrasound guidance including any associated cystoscopy. The procedure must be performed at an approved site in association with a radiation oncologist, andbe associated with a service to which item 15331or 15332 applies.
Multiple ServicesRule
(Anaes.)
Fee:$544.40 Benefit: 75%= $408.30 85%= $473.20 (See para T8.59of explanatory notes to this Category)
Category 3 – THERAPUTIC PROCEDURES
MBS 15332
IMPLANTATIONOFASEALED RADIOACTIVE SOURCE(havingahalf-lifeoflessthan115daysincludingiodine,gold, iridiumortantalum)toasite(includingthetongue,mouth,salivarygland,axilla,subcutaneoussites),wherethe volume treated involvesmultiple planesbut does not require surgical exposure and usingautomatic afterloading techniques
(Anaes.)
Fee:$717.55 Benefit: 75%= $538.20 85%= $646.35

Background

Current arrangementsfor public reimbursement

UntilJune30 2011,theproposedservicewasbeing claimedunderexistingMBSitemnumber37218. Asof1July2011,aninterimMBSitemnumber37217wasintroducedtocover theproposedservice and item number 37218 was modifiedto exclude this use (Table3).

Table 3:Current MBS item descriptorfor proposed service

Category 3 – THERAPEUTIC PROCEDURES
MBS 37218 (to June 30 2011)
PROSTATE, needle biopsy of, or injection into (Anaes.)
Fee:$133.05 Benefit: 75%= $99.80 85%= $113.10
Category 3 – THERAPEUTIC PROCEDURES
MBS 37217 (From 1 July 2011)
Prostate, implantation of gold fiducial markers into the prostate gland or prostatesurgical bed
Multiple ServicesRule (Anaes.)
Fee:$133.05 Benefit: 75%= $99.80 85%= $113.10 (See para T8.56of explanatory notes to this Category)
T 8.56
Item37217isfortheinsertionofgoldfiducialseedsintotheprostateasmarkersforradiotherapy. Theservicecannotbe claimed under item 37218 or any other surgical item.
ThisitemisintroducedintotheScheduleonaninterimbasispendingtheoutcomeofanevaluationbeingundertakenby the Medical Services Advisory Committee (MSAC).
Further information on the review of this service is available from the MSAC Secretariat.
Category 3 – THERAPEUTIC PROCEDURES
MBS 37218 (From 1 July 2011)
PROSTATE, needle biopsy of, or injection into, excluding for insertion of radiopaque markers (Anaes.)
Fee:$133.05 Benefit: 75%= $99.80 85%= $113.10

Regulatory status

TheBestMedicalInternational,Inc.(Best)RadiopaqueStrands and Markershavereceived TGAlisting (registration number143069). They areindicatedforusein softtissue or organtissueradiation therapyprocedures.Other manufacturersarelikelytomakesimilarmarkersforimplantationintothe targetareaavailableinduecourse.Fiducialmarkersmayalsobemanufacturedinhousewhichmay bemorecost-effective;however,thequalityassuranceprocessesandregulatorystatuswillneedto be considered.

TheMBSitemcoversthecostsoftheprocedure.Thecostoftheseedsiscoveredbyeitherthe patient(privatepatients)orthehospital (publicpatients).Fiducialseedsarenoteligibleforlistingon the prosthesis listand were declined forlisting as recently as February 2010.

Patient population

Proposed MBS listing

Theproposed MBSdescriptorhasbeen modifiedfromtheinterim descriptor. Thespecificationofthe typeofmarker(gold)hasbeenremovedasotherradio-opaquematerialsarealsoconsidered suitable.Furthermore,technologiescurrentlyindevelopmentsuch asmarkerscontainingtransducers, suchastheCalypso™4DLocalizationSystem,arenot excludedbythisdescriptoralthoughthehigher costsofthe markers andsystemstotrackthemwouldneedtobebornebythehospitalandpatient. Nocaponthenumberofseedsimplanted(3to4) hasbeenincludedinthedescriptor;thiswasnot considered necessary given the descriptor is for the implantation procedure andcannot be claimed for eachfiducial marker implanted.The proposeditemdescriptor hasbeen modifiedto narrowthe purposeof themarkersfrom“assistinthedeliveryofradiotherapy”to“assistin thedeliveryof external-beamradiotherapy”morespecifically;withoutthis,thedescriptorwouldenablethemarkers

to be implanted for purposes such as HDRBT as monotherapy.

Table 4:Proposed MBSitemdescriptorfor proposed service

Category 3 – THERAPEUTIC PROCEDURES

MBS [item number]

Prostate,implantationofradio-opaquefiducialmarkersintotheprostateglandorprostatesurgicalbedtoassistinthe delivery of external-beam radiotherapy

Multiple Operation Rule (Anaes) Fee: $133.05

Clinical place for proposed intervention

Initialcancerdiagnosisand clinicalassessmentincludesprostatespecificantigen(PSA)bloodtesting, digitalrectal examination (DRE) andneedlebiopsy.Ahistoryandexaminationperformedbya radiationoncologistisalsomandatory.Optionalinvestigationsincludewholebodybonescan,CTof the abdomenand pelvis, and prostateMRI.

Toidentifypatients eligiblefor EBRT,thepatient’slifeexpectancy,overallhealthstatusandtumour characteristicsneedto beassessed. Thecombination ofpathologicalgrade(Gleasonscore), biochemicalinformation(PSAlevel)andstageof thetumour (tumor,node,metastasis(TNM) classification system)caneffectively stratifypatientsintocategoriesassociatedwith different probabilities ofachieving acure. Thechoiceofinitialtreatmentisinfluencedgreatlybyestimatedlife expectancy,co-morbidities, potential therapy side effects, and patient preference.

Australianguidelinesonthemanagementofpatientswithlocalisedprostatecancerwerepublishedin

2002(AustralianCancerNetwork WorkingPartyon Management ofLocalised ProstateCancer2002) andarenolongercurrent.Guidelineshavesince beenpublishedonthemanagementoflocally advanced andmetastatic prostatecancer(AustralianCancerNetwork ManagementofMetastatic ProstateCancerWorking Party2010);however,thisisnot thepopulation mostrelevanttothe implantationoffiducialmarkers.Tworecentinternationalguidelinesprovidethebestunderstanding ofcurrent clinicalpractice:theNCCNClinicalPracticeGuidelines forProstate Cancer(2011)andthe NICEGuidelineonProstateCancer:diagnosisand treatment (2008).Inbothguidelines,anumberof treatmentoptionsareavailabletomendiagnosedwith low,intermediateorhigh-riskprostatecancer and the choiceoftreatmentwilldependonindividualfactors. These treatment optionsaresummarisedin Figure 1.

Low Risk
PSA ≤10ng/ml and Gleason score ≤6 and T1-T2a / IntermediateRisk PSA 10-20ng/ml or Gleason score 7 or T2b-T2c / HighRisk
PSA ≥20ng/ml or Gleason score ≥8 or T3-T4
Active surveillance /  /  / 
LDRBT / monotherapy / boost / 
HDRBT(boostor monotherapy) /  /  / 
Radical prostatectomy /  /  / 
Externalbeam radiotherapy1 /  /  / 

1.Mayincludeneoadjuvant,concomitantoradjuvantandrogendeprivationtherapy(ADT)forhighriskandsomeintermediaterisk

men

Figure1Treatmentoptionsforlow,intermediateandhighriskprostatecancer(basedonAustralianCancer Network Management of Metastatic Prostate Cancer Working Party 2010; Australian Cancer Network WorkingParty onManagementofLocalisedProstateCancer2002;NationalComprehensiveCancer Network 2011;NICE 2008)

Patients with low,intermediate orhigh riskof recurrenceareall potentiallyeligiblefora courseof EBRTaloneorincombinationwithbrachytherapyasaboost.Nevertheless,lowriskpatients aremost commonly treated withonly one treatment modality;either EBRTor brachytherapy.

The recentAustralian Guidelines on the management of locally advanced prostate cancer make the following recommendations regarding EBRT.

Whenradiationtherapyaloneisused,limitedfieldradiotherapyhassimilarefficacyandhas less toxicity thanwhole pelvisandthereforeisrecommended.Therole ofwholepelvis radiationisyettobedefined.Considerationshould begiventodoseescalation(74Gyor higher)ifitcanbedeliveredsafely.Patientswithlocallyadvancedprostatecancershould receive3Dconformalradiationtominimisetoxicity.GradeC(Bodyofevidenceprovides some support for recommendation(s) but careshould be taken in its application)

Radiationinadditiontohormonetherapyimprovessurvivalandisrecommended.GradeB (Bodyofevidencecanbetrustedto guidepracticeinmostsituations)(AustralianCancer NetworkManagementof Metastatic Prostate CancerWorking Party 2010).

Theprimary eligiblepatientpopulation thereforeis menwithprostatecancerwhoareeligiblefora courseofradicalEBRT as thedefinitivetreatment; thesemenmay havelocalisedorlocally advanced diseaseandmayhavelow,intermediateorhighriskofrecurrence.TheymayhaveEBRTaloneor with lowor high dose brachytherapy asa boost.

Therearealsosomepatientswithinthispatient populationwho maybeexpectedtoderivegreater benefit from the accurate delivery of radiotherapy, including thosewith:

‐Previousirradiationofthepelvissuchthatitisnecessarytoavoidirradiatednormaltissues(ie

very tight margins are to be used in treating the prostate).

‐Menwhohaveinflammatoryboweldiseasesuchthatveryaccurateradiotherapyisrequiredto minimise normal tissue toxicity.

Although patients may be stratified into low, intermediate, and high risk, reflecting their risk of recurrenceandtreatmentoptionsvary forthesedifferentpatientgroups,thedecisionoptiontobe considered, that is, whether IGRT usingfiducial markers should be used in place of conventional IGRT usingintermittentimagingofthebonypelviswillbethesameacrossdifferentriskgroups.The relativedifferencesofIGRTwithfiducialmarkers andconventionalIGRTintermsofextentofany improvementin effectiveness may differ across theserisk subgroups.

Biopsy-confirmed prostate cancer

(Digital Rectal Examination (DRE), PSA blood testing, History and examination,Needle biopsy)

Treatment decision

Activesurveillance,radical prostatectomy or brachytherapy as

monotherapy

Radical EBRT

± brachytherapy boost

(± ADT)

PROPOSED INTERVENTION

EBRT (3DCRT/IMRT) using intermittent imaging of the bony pelvis

EBRT (3DCRT/IMRT) using fiducial markers

(FM)

FM implant in ambulatory care setting.

FM implant in day surgery facility.

EBRT delivery +/- brachytherapy boost

EBRT delivery +/- brachytherapy boost

Primary outcomes:Toxicity, Tumourcontrol, Survival, Quality of Life

Secondary outcomes: Biochemical control

Figure 2 Proposed clinical algorithmfor radical EBRT

Fiducialmarkersareproposedasareplacementforimagingusing bonylandmarks;itisexpectedthat utilisationoffiducialmarkerswouldincreasesuch thattheybecomestandardpracticemeanwhile imagingusingbonylandmarkswould decrease. However, a small percentage of patients (<1% estimatedbytheapplicant)willbeconsideredinappropriatetoundergoimplantation offiducial markersbecauseof either apreviousorconcurrentinfection ortheneedtobeoncontinuous anti- coagulant therapy.

Theapplicantestimates,basedonunpublisheddatafromNSWshowingthat1710coursesofEBRT

weredeliveredperyear,thatthenumberofprostatecancerpatientsacrossAustraliawhoare

suitableforEBRTwhereimplantationoffiducial markersisdeemedappropriateisapproximately5000 for 2009/10 or approximately 30.5% ofall newly diagnosed prostate cancers.

Thereare other patient populations in which fiducial markers maybe used:

‐Implantationoffiducialmarkersintothepelvicsofttissue(ie“prostatebed”)afterradical prostatectomy in adjuvantand in salvage post-radicalprostatectomy radiotherapy.

‐Implantationoffiducialmarkersintotheprostatetoguidehighdoseratebrachytherapyas monotherapy.

‐Menwithadvancedormetastaticdisease(ienotsuitablefordefinitiveradiotherapy)whohave had bowelsurgery such that riskof normal tissue toxicity is increased.

With respectto EBRT post-prostatectomy, the Australian Guidelines state:

Itisrecommendedthatpatientswithextracapsularextension,seminalvesicleinvolvementor positive surgicalmarginsreceivepostoperativeEBRT withinfourmonthsofsurgery.Therole of activesurveillance andearly salvage radiotherapy has not been defined. (Grade B)

Thenumber ofmenwho undergoradicalprostatectomyisestimatedfromtheAIHW(includespublic as well as private patients) and Medicare Australia (Table ). The applicant estimates that approximately20%of patientswhoundergothistreatment would besuitableforpost-prostatectomy EBRTandthat<5%wouldbenefitfromfiducial markers.Usingafigureof 6000menundergoing radicalprostatectomyperyear,anestimated1,200wouldbesuitableforpost-prostatectomyEBRT and approximately 300 may utilise fiducial markers. However,it is notedthat thisfigure is likely to be anunderestimateandisexpectedtoriseasthefieldisrapidlychanging;thenumberofpatients receiving post-prostatectomy EBRT isincreasing and the use of fiducial markers to guide this is likely tobecomemorewidespread(expert opinion).Thedecision tousefiducialmarkersin thisindication is drivenbytheexperienceandpracticeof theprovidermorethanby patientfactorswithsomecentres using fiducialmarkers routinely.

Table 5 Number of radical prostatectomies

Source / Item numbers / Year
2005/06 / 2006/07 / 2007/08 / 2008/09 / 2009/10
AIHW / Radical prostatectomy subset of 1167 / 6,179 / 6,671 / 6,178 / 5,913
MBS / 37210/37211 / 4,011 / 4,599 / 5,017 / 6,115 / 6,479

(AustralianGovernmentDepartmentofHumanServices2011;AustralianInstituteofHealthandWelfare(AIHW)2011)

Therefore,a secondarypatientpopulationismen whohavehad aradicalprostatectomyfor primary treatment of prostate cancerandwho areundergoingeither adjuvant orsalvageEBRTdue toeither highrisk pathologicalfactors(extracapsularextension,seminalvesicleinvasionand/orinvolved surgicalmargins)orarisingPSAlevel.Ineachpersontreated,fiducialmarkersareproposed asa replacement forimaging usingbony landmarks.However,a smallerproportion oftheoverall populationreceivingpost-prostatectomyEBRTisexpectedtohaveEBRTwithfiducialmarkersthan

theoverallpopulationreceivingradicalEBRTintheprimarytreatmentofprostatecancer.Inaddition, fewpatientsreceivingpost-prostatectomyEBRTareexpectedtoalsoreceiveloworhighdose

brachytherapy as a boost.

Biopsy-confirmed prostate cancer

(Digital Rectal Examination (DRE), PSA blood testing, History and examination, Needle biopsy)

Treatment decision

Activesurveillance,radicalEBRTor brachytherapy as monotherapy

Radical Prostatectomy

High risk pathological factors (extracapsular extension,seminal vesicle invasion and/or involved surgical margins)

Low risk pathological features

PROPOSED INTERVENTION

Activesurveillance

Activesurveillance

RisingPSA,noevidence

of metastasis

RisingPSA,noevidence

of metastasis

AdjuvantEBRT (3DCRT/IMRT)

SalvageEBRT (3DCRT/IMRT)

AdjuvantEBRT (3DCRT/IMRT) using

fiducialmarkers

SalvageEBRT (3DCRT/IMRT) using

fiducialmarkers

Primary outcomes:Toxicity, Tumourcontrol, Survival, Quality of Life

Secondary outcomes: Biochemical control

Figure 3Proposed clinical algorithmforpost-prostatectomy EBRT

HDRBTislikelytobegiveninconjunctionwith EBRT;fiducialseedsusedtoguidetheEBRT component are included in the primary indication. However, HDRBT can also be given as monotherapy and may also benefit from fiducial seeds to guide the implantation of the brachytherapy.ThenumberofpatientswhoundergoHDRBTinAustraliacurrentlyislikelytobe

small. TheAIHWNationalHospital MorbidityDatabaseincludes acodefor‘brachytherapywith implantation ofremovablemultipleplanesorvolume implant,high doserate’(15327-07),thenumber ofproceduresunderthiscodein2007/08was264ofwhom 243were male. Thismayinclude proceduresforconditions otherthanprostatecancer.ThenumberofMedicareitemsprocessedfor itemnumber 37227inthe2009/10financialyear was361.Additional analysesprovided bythe DepartmentofHealthandAgeingshowthat343 ofthesewereuniqueservicesofwhich272were patientswhoalsoclaimedeitheritem15248or15263(EBRT)withineithertheprecedingorfollowing

31days.Itcantherefore beestimated,that71of the343uniqueclaimsforitem37227in2009/10 mayhavebeenforHDRBTasmonotherapy. These datareflectpatientsundergoingthisprocedurein privatehospitals,themajorityofpatientsmaybe treatedatpublic hospitalsandtherefore,theseare likely to be underestimates.

Table 6 Estimated utilisation of HDRBT

Source / Item numbers / Year
2006/07 / 2007/08 / 2008/09 / 2009/10
AIHW / 15327-07 (male) / 216 / 243
MBS / 37227 / 183 / 399 / 389 / 361

(AustralianGovernmentDepartmentofHumanServices2011;AustralianInstituteofHealthandWelfare(AIHW)2011)

HDRBT asmonotherapyisnotyetconsideredstandardclinicalpractice(Expert adviceandNational Institutefor Health andClinicalExcellence(NICE)2006)andits utilisationin Australiaappears tobe low, thereforeitisnotconsidered suitableas asolepurposeof fiducialmarkerimplantationatthis time, despiteits proposal by the applicant.

Comparator

Radiotherapyforprostatecancerhasalwaysbeenundertakenwith“image-guidance”.Duringa courseofradiotherapy,verificationoftheplacementoftheradiotherapybeam(s)isperformed visuallybytakinganx-rayimageoftherelevantpartofthebody.Theaccuracydependsonthe matching of bony landmarks obtained atthe time oftreatment planning (that is,prior to the courseof treatment)and comparing the daily images.

Other imaging techniques, including ultrasound, electromagnetic targeting and tracking, or endorectal balloon,can alsobeused,butare lesscommon in Australia and notconsideredcomparators.The comparator istherefore intermittent imaging using bony landmarks.

Clinical claim

Comparedwithintermittentimagingofthebony pelvis,possibleimmediatecomplicationsofthe implantationof fiducial markers are:

Riskof infection due tosurgical implantation

Riskof haematuria

Riskof haemotospermia

Riskof dysuria

Riskof rectalbleeding

Riskof pain

Riskof fever

Riskof urinary incontinence

Compared withIGRTfollowingintermittentimagingof thebonypelvis,IGRTwithfiducialmarkershas the followingpotentialbenefits:

Ability to deliver EBRT more accurately,which may lead to:

oReduced toxicity

Reduction ofradiation proctitis

Reduction ofmedical treatment

Reduction ofradiation cystitis

Abilitytoescalatethedoseofradiotherapywithoutequivalentincreaseintoxicity,whichmay lead to:

oImproved tumour control.

Compared withIGRTfollowingintermittentimagingof thebonypelvis,IGRTwithfiducialmarkershas the potentialto reduce PTV marginswith the followingpotentialharm: