Is IORT Ready for Roll-Out?

Is IORT ready for roll-out?

Emanuela Esposito1, 2, 3, Bauke Anninga1, Ian Honey4, Gillian Ross5, Dick Rainsbury6, Siobhan Laws6, Sygriet Rinsma1 and Michael Douek1

1Research Oncology, Division of Cancer Studies, King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK 2Department of Breast Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ – IRCCS, Naples 80131, Italy 3Department of Clinical Medicine and Surgery, Breast Unit, University of Naples Federico II, Naples 80131, Italy 4Department of Medical Physics Floor 3, Henriette Raphael House, Guy’s and St Thomas Hospital, London SE1 9RT, UK 5Clinical Oncology, Royal Marsden Hospital and Institute of Cancer Research, London SW3 6JJ, UK 6Oncoplastic Breast Unit, Royal Hampshire County Hospital, Winchester SO22 5DG, UK

Correspondence to: Emanuela Esposito and Michael Douek. Email: [email protected] and [email protected]

Abstract

Two large randomised controlled trials of intraoperative radiotherapy (IORT) in breast-conserving surgery (TARGIT-A and ELIOT) have been published 14 years after their launch. Neither the TARGIT-A trial nor the ELIOT trial results have changed the current clinical practice for the use of IORT. The in-breast local recurrence rate (LRR) after IORT met the pre-specified non-inferiority margins in both trials and

was 3.3% in TARGIT-A and 4.4% in the ELIOT trial. In both trials, the pre-specified estimates for local recurrence (LR) with external beam Review radiation therapy (EBRT) significantly overestimated actual LRR. In the TARGIT-A trial, LR with EBRT was estimated at the outset to be 6%, and in the ELIOT trial, it was estimated to be 3%. Surprisingly, LRR in the EBRT groups has been found to be significantly lower, 1.3% in the EBRT arm of the TARGIT-A and 0.4% in the EBRT arm of the ELIOT trial, respectively. Median follow-up was 2.4 years for the TARGIT-A trial and 5.8 years for the ELIOT trial. However, the initial cohort of patients in the TARGIT-A trial (reported in 2010) now have a median follow-up of 3.8 years and data on LR were available at 5 years follow-up on 35% of patients (18% who received IORT). Although further follow-up will increase confidence with the data, it will also further delay clinical implementation. By carefully weighing the risks and benefits of a single-fraction radiation treatment with patients, IORT should be offered within agreed and strict protocols. Patients deemed at low risk of LR or those deemed suitable for partial breast irradiation, according to the GEC-ESTRO and ASTRO recommendations, could be considered as candidates for IORT. These guidelines apply to all partial breast irradiation techniques, and more specific guidelines for IORT would assist clinicians.

Keywords: breast cancer, intraoperative radiotherapy, IORT

Published: 12/03/2015 Received: 23/10/2014 ecancer 2015, 9:516 DOI: 10.3332/ecancer.2015.516

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 disadvantage ofIORT isthelongeroperatingtimerequired,equipmentcost,serviceandcost oftheadditionalstaffing. plex radiotherapy treatments, since over 30% of the workload of RT departments constitutes EBRT for breast cancer. On the other hand, a com- more on focus can departments and IORT,reduced, employing EBRTare By for quadrant. times index waiting the or cavity tumour the surgery,either of into time directly the RT at of fraction single a of delivery the IORTis of advantages important most the of One [27]. (TARGIT-A)trial radiotherapy-alone intraoperative targeted the recruitment, completed and launched been have trials phase-III two only IORT,but on published been have studies cohort institution single Several IORT. on conducted were trials possible to use existing operating rooms. Before introducing the Intrabeam the introducing Before rooms. operating existing use to possible and it thus, is X-rays, often for the low-energy shielding sufficient provide will often walls Existing physicists. and medical the anaesthetist the operatingroomremainpotentiallysignificantandnecessitate controlofaccesstotheroomduringtreatmentandfurthershieldingfor within doses radiation but radiation, of 95% block These treatment. to prior wound the shield to used are sheets Tungsten-impregnated depth. cm 1 at Gy 5–6 and applicator the of surface the at Gy 20 is dose delivered minutes, 40 to 20 from ranges time treatment device Germany). It is a miniature low-energy X-ray source employed for IORTfor employed tumour.source the X-ray of low-energy removal miniature after a surgery is during It Germany). Intrabeam the With loaders systems X-ray low-energy IORTare delivering of methods available The Available devicesandtechniquesforIORT LR of 90% over cancer breast contralateral of that observed is it Firstly, BCS. following site treatment operation original the near or at occur BCS radiation after local in interest an to led observations clinical Several The rationaleforIORT growing bodyofscientificevidence,inwhichIORT was givenasaboost,hasprovidedoutstandinglylowlocalrecurrencerates[11,] 12 IORT can techniques be delivereddisplacement tissue prior with to especially tissue boost, displacementdelivered andexternally a by direct missed visualisationpartially be of may the tumourvolume target bed canThe boost. guarantee bed an accurate dose delivery. The would have a poor cosmetic result but provides a challenge for the subsequent radiation planning, particularly for the delivery of the tumour Moreover,recently, excisionlocalwide(WLE) aoffered expansion oncoplasticwhom patientsthebeofin to breast tosurgery allows BCS this, IORT andsomeothershortenedlocalised radiotherapytreatmentswereevaluated. EBRT avoid to order in mastectomy choose even or RT decline patients countries, some In people. elderly the for RTdaily attend cannot and BCS for early breast cancer in North America do not receive post-operative breast irradiation because they live far from a treatment centre EBRT are required to attend the radiation treatment 5 days a week for 3–5 weeks consecutively. Almost one-third of patients who undergo survival overall improve and (LR) recurrence local reduce to shown been has It tumours. breast External beam radiation therapy (EBRT) following breast-conserving surgery (BCS) is the standard of care for the treatment of early-stage Background brachytherapy, intracavitary brachytherapy, three-dimensional conformal radiotherapy (3D-CRT), stereotactic body radiation therapy therapy radiation multicatheter body include stereotactic treatments (3D-CRT), PBI (SBRT) radiotherapy investigation. conformal clinical under three-dimensional been brachytherapy, has intracavitary quadrant breast brachytherapy, index partial the regimens, RT targets localised more directly and that shortened (PBI) both offer to irradiation effort an In breast. contralateral the to apply should principle the operatingroom,toundertakeashieldingassessmentand tomeasureenvironmentalradiationdoseratesaroundthetheatre. [19, 20] [28] or specific balloon devices balloon specific or , and intraoperative radiotherapy (IORT) . This issue affects patients suffering from breast cancer all over the world and is particularly challenging particularly is and world the over all cancer breast sufferingfrom affectspatients issue 6]. This [5, [16– 18] . Lastly, if whole EBRT is used to reduce the occurrence of new breast primaries, then this same same this then primaries, breast new of occurrence the reduce to used is EBRT whole if Lastly, . [29] . Low-energy X-ray IORT is delivered by the Intrabeam the by delivered is IORT X-ray Low-energy . [13–15] [21–25] . Secondly, the risk of ipsilateral new breast primaries is equal to the risk risk the to equal is primaries breast new ipsilateral of risk the Secondly, . . Among the various PBI techniques, the largest randomised controlled controlled randomised largest the techniques, PBI various the . Among 2 [26] ® system, it is thus important to consider control of access to to access of control consider to important thus is it system, and the electron intraoperative treatment (ELIOT) trial (ELIOT) treatment intraoperative electron the and [26] , electron beam radiation therapy radiation beam electron , . Women undergoing post-operative Womenundergoing [1–4]. ® device (Carl Zeiss, Oberkochen, Oberkochen, Zeiss, (Carl device [27] ecancer . Consistent with Consistent [7–9]. , high dose rate after after rate dose high , www.ecancer.org 2015,9:516 [10] . ® .

Review

Liac had an extensive cance level), based on an estimated LRR of 6% with EBRT. Patients were ineligible if they were diagnosed with a lobular tumour or if they with old years 45 clinically over T1–T2 patients ≤ 3.5 2,232 cm, N0–1 invasive enrolling tumours. 2000, The pre-specified March non-inferiority margin was in 2.5% (80% commenced of statistical that power at trial 5% signifi phase-III prospective a was It BCS. after EBRT of as a single fraction, totally intraoperatively, at the same dose used with the Intrabeam the with used dose same the intraoperatively,at totally fraction, single a as must be manually positioned. Three mobile linear accelerators can deliver IOERT,deliver Novac7 can the accelerators linear mobile Three positioned. manually be must is designed to track the movement of gantry in all directions so that it will always intercept the primary beam, whereas other beam stoppers to deliver radiation in non-shielded operating rooms and are provided with a beam stopper. The beam stopper for certain mobile IORT units treat breast tumours, it has been estimated that 12 MeV energy is sufficient. These systems are designed with the concept of Mostly,being devices. to utilised other than rapidly more much dose required the deliver can surgery.beams of Electron time the at bed tumour the to Electron beam radiation therapy (EBRT) or intraoperative electron radiation therapy (IOERT) is the application of electron radiation directly The TARGIT-A trial compared a strategy of a single fraction of IORT delivered using the Intrabeam TARGIT-A trial bed by an iridium 192 ( 192 iridium an by bed tumour the to delivered is (HDR-IORT) radiotherapy surgery,intraoperative of HDR time the BCS. At with treated years) 67 age (median (Brachytherapy Unit) was evaluated by Memorial Sloan–Kettering Cancer Centre (MSKCC), New York, USA in patients older than 60 years Vernon,Mount Instruments, Inc., Radio-Nuclear (Mick afterloader (HDR) High-dose-rate facility operating shielded dedicated a within NY) of 90%isodoserangingfrom13(3MeV)to24mm(9MeV). a phase-III trial, the ELIOT trial. The entire irradiation procedure is completed in 2 minutes, and the delivered dose is 21 Gy with the depth electronic brachytherapy (eBx brachytherapy electronic A prospective phase-IV (post-marketing) trial is underway is trial (post-marketing) phase-IV Aprospective clinical practice. practice. clinical time of surgery or postoperatively. Typically, RT is delivered by balloons in 10 fractions twice a day over five consecutive days. Xoft days. consecutive five over day a twice postoperatively.fractions or 10 surgery Typically, in of balloons time by delivered RTis the at bed tumour the into inserted be can They PBI. for devices brachytherapy intracavitary as employed been have catheters Balloon specialised shieldedoperatingroomfacilities. the rate one would expect with no radiation treatment as shown in the CALGB 9343 trial 7% was rate recurrence local minutes. months), 40 68 and follow-up 20 (median between years varies five At study pilot prior a in effects side of rate higher a with associated were doses Gy 20 since used was Gy 18 Aof dose In June 2010, the first results were published were results first the 2010, June In boost [26]. tumour-bed a as final served IORT cases, the these surgery.In if after administered that was EBRT features, meaning adverse IORTpre-specified showed for pathology used was approach’ ‘risk-adapted A cohort). (post-pathology surgery after or cohort) (pre-pathology (RTOG) grade3–4side effects andahigherrate ofwoundcomplicationsincludingseroma. treatment radiation after years 20 and 10 between occur to expected be would which RT) to (attributable deaths cardiac in differences observe to short too was patients most of follow-up median the Additionally,irradiation. breast to unrelated events other and ischaemia, bowel stroke, included also deaths these arm, IORT the in reduced be to found were that deaths cancer non-breast differencein significant a show statistics log-rank the although survival, of terms deaths were found to be significantly reduced in the IORT arm [1.4% (95% CI: 0.8–2.5%) versus 3.5% (95% CI: 2.3–5.2%) p = 0.0086]. In 0.56] = p EBRTarm; the in 1.1–3.2%) CI: [(95% 1.9% versus 1.5–4.3%) CI: (95% 2.6% was IORTarm the in mortality cancer breast Overall, outset. the at set 2.5%, of margin non-inferiority the met but 0.042] = p a with 0.7–2.5%) CI: [(95% EBRT,with 1.3% and 2.1–5.1%) CI: (95% 3.3% was IORT with LRR The extension. recruitment trial the to due months) 4 and years (2 continued until 2012. In November 2013, the latest results from the TARGIT-A trial recruitment were and published 3,451 to 2,232 from extended was size sample further,the matured data while subprotocols, in accrual allow to order In LRR in the conserved breast was 1.20% (95% CI: 0.53–2.71) in the IORT arm and 0.95% (95% CI: 0.39–2.31) in the EBRT arm (p = 0.41). ® (Sordina, Padova- Italy), and the Mobetron the and Italy), Padova- (Sordina, in situ component. Eligible patients were treated with BCS and were randomised to either IORT or EBRT prior to surgery 192 Ir) source connected to a quadrangular silastic template applicator named Harrison–Anderson–Mick (H.A.M. Harrison–Anderson–Mick named applicator template silastic quadrangular a to connected source Ir) ® , Xoft, Fremont, CA, USA) CA, Fremont, Xoft, , with a median follow-up of 25 months, which was criticised for its shortness its for criticised was which months, 25 of follow-up median a with [34] ® (IntraOP Medical Inc, Sunnyvale, CA). Both Novac7 Both (IntraOPCA). Sunnyvale, Inc, Medical . With IORT, there was a lower rate of Radiation Therapy Oncology Group Oncology Therapy Radiation of rate lower a IORT,was With there [36]. [32] [33] represents the balloon device which is now being tested to deliver RTdeliver to tested being now is which device balloon the represents , but data are still immature, to introduce Xoft introduce to immature, still are data but , 3 [31]. HDR-IORT is also limited by the high cost of ® system (50 kpV low-energy X-rays, 20 Gy). Gy). 20 X-rays, low-energy kpV (50 system ® (Hitesys S.p.A., Aprilia, Latina, Italy), the Italy), Latina, S.p.A., Aprilia, (Hitesys ® [26], again with a short median follow-up system ® and Liac and . However,cancer [26]. non-breast [34] to conventional 3–6 weeks , and this was similar to similar was this and [30], ® ® as IORT, in the current current the IORT,in as have been employed in employed been have ecancer . Treatment[28]. time www.ecancer.org 2015,9:516 . The [35]. ® ). ® -

Review Alvarado cost-effective analysesisrequired,sinceIORT devicesremainunaffordable formanyhospitalsworldwide linear accelerators is effective when considering the reduction in radiotherapy waiting lists, pre-treatment planning and delay, but a specific In terms of cost-effectiveness, despite the higher initial device-related costs, the cost per patient treated with IORT by using electron beams characteristics. respectively 1.9%, and 1.5% of LRR a have to found were guidelines, group ‘low-risk’ GEC-ESTRO the and guidelines group ‘suitable’ ASTRO the fit who Patients 2009. in available EuropèendeCurietherapie ofthe European Society of TherapeuticRadiology and Oncology (GEC-ESTRO) recommendations were made ELIOTthe IORTwith technique treated after published, off-trialwas EIO Groupe at and (ASTRO) Oncology Radiation for Society American of 1.5% LR (p < 0.0001) emerged as a key finding in the ELIOT population. Moreover, a noteworthy retrospective analysis of 1,822 occurrence patientsyears 5 showing group, low-risk a with Consistent LRR. of risk the doubling in resulted subtypes negative triple and nodes tive the for account may which positive) nodes tumours,increased LRR (largerobserved with prognosisIORT. worse In withthe multivariable patientsanalysis, carcinoma greater of than 2 cm 10% and poorly thandifferentiated, more than more four posi- included trial ELIOT The 96.9% (95%CI:95.5–98.3)intheEBRT arm(p=0.59)[27]. there was no significant difference in the 5-year overall survival rate in two arms, that is, 96.8% (95% CI: 95.3–98.3) in the ELIOT arm and EBRTreceive to allocated those IOERTwith receive to compared allocated women for 3.3–26.3) CI: (95% 9.3 was ELIOTtrial the in LRR for (HR) ratio hazard 4.5%. The of margin non-inferiority pre-defined the within fell just LRR follow-up. The median LRR was found to be 4.4% (95% CI: 2.7–6.1) in the ELIOT arm and 0.4% (95% CI: 0.0–1.0) in the EBRT arm (p = 0.0001) in this study. A diagnosis of invasive lobular carcinoma did not affect eligibility. The trial was closed for recruitment in December 2007. The carcinoma, lobular or ductal either were Tumours,BCS. which for suitable cancers breast cm 2.5 ≤ T1–T2 invasive 4.5%. of margin non-inferiority a and significance) Aclinically with years 75 and 48 between aged randomised, were women 1,305 of total ELIOT technique the IOERTusing single-dose delivered Gy 21 a compare to was trial this of aim trial. The equivalence phase-III randomised single-centre The ELIOT trial recruited its first patients in November 2000 at the European Institute of Oncology (EIO) in Milan (Italy). It was a prospective ELIOT trial reported been have analyses cost-effective two States, United In countries. European other or (UK) Kingdom United the (NHS) in Service Health National the across available technology IORT make to required be would equipment in investment Asignificant Cost-effective analysis is also important in view of the equipment cost and potentially small number of eligible patients at some centres. EBRT 1.7%(95%CI:0.6–4.9;p=0.069)].However, thedataarestill too immaturetodrawadefinitiveconclusiononLR. versus 3.0–9.7) CI: (95% 5.4% [IORT met not did post-pathology the while (0.5–2.5)], 1.1% EBRT versus (1.1–4.2) 2.1% [IORT non-inferiority margin 2.5% the met group this and stratum, pre-pathology the for favourable more were results IORT.These received these of TARGIT-A trial lacks long-term follow-up data specifically on LRR. Only 1,222 patients (35%) completed 5 years of follow-up, and 611 (18%) cost perQALY analyses[38] on based cost-effectivemodality EBRTthe in, represents IORTfactored with are associated costs non-medical and medical additional when because misleading, is reimbursement absolute cancer. However, breast early-stage of management the in savings cost potential Shah by analyses cost-minimisation on Based mastectomy. salvage a have EBRT undergo who women all IORT,after whereas lumpectomy salvage have who women of proportion the for values utility improved the by driven was result This over the preferred whole EBRT breast in when measured strategy QALYs slightly (a of QALYs,difference 0.00026 days). was or IORT0.95 quality-adjusted that showed analysis effectiveness The regimen. EBRT 6-week the than (QALYs) years life quality-adjusted more concluded that when considered against the cost of EBRT,of Intrabeam cost the the against considered when that concluded al et [39] to conventional whole breast EBRT. The pre-specified equivalence margin was 7.5% (90% of statistical power at 5% . [40, 41] [40, , confirming, IORTthat restrictedshouldbeselected tumour tobasis patientsof the on 4 ® system is more cost-effective more is system [42]. , IORT represents a represents IORT al, et ecancer . It was found that found was It [27]. were excluded were situ in www.ecancer.org [27], at 5.8 years [37] 2015,9:516 . It offered offered It . [37, 38] [37, .

Review tively andmightbeusefultoaccumulatedata. clinical implementation. National registries should be set up in order to monitor LR events occurring after IORT treatments off-trial,delay further also prospec will it data, the with confidence increase will follow-up further although and ago, years 14 over launched trials phase-III TARGIT-ABoth within selection. evaluated optimal been patient have in techniques ELIOTclinicians and assist to helpful be IORTwould for guidelines specific more though even protocol, strict under delivered IORT for candidates as considered be could recommendations, significant is IORTenough to on share with available them. Patients evidence deemed at of low risk level of LR the or those and deemed suitable patients, for PBI, for according RTto the single-fraction GEC-ESTRO and of ASTRO advantages clear some are there However, devices novel of rest the of evidence clinical of introduced intothemarket. level the clear not is it whereas validated, been have trials these in employed devices The authorsthanktheVito DistanteProjectforsupporting thiswork. Acknowledgments could that inappropriately influencetheirwork. organisations or people other with relationships personal and financial concerning make to disclosures no have authors The Conflicts ofinterest and withthisinmind,itisnecessarytoinformsuitablepatients aboutthenoveloptionsfortreatmentoftheircancer. cancer,effectivetreatment’with ‘minimum patients deliver to to striving of that is paradigm current treatment. The radiation single-fraction a of advantage great the with compared and discussed widely be should recurrence local of risk higher The patients. well-informed and selected specifically EBRTfor to alternative an as considered now be IOERTIORTshould and data, existing the of light in conclusion, In Conclusion that ASTRO recommendations are ineffective for patients treated with this approach. Moreover, Intrabeam demonstrated HDR-IORT while immature, still are technology Xoft by application balloon intracavitary trial. intraoperative totally from ELIOT Data the from emerged has follow-up median of is required. IORT,with follow-up years longer follow-up but of median at 29 months 5.8 promising and at the TARGIT from encouraging are Data trial LRR of terms in acceptable is IOERT whom for women low-risk patients selected EBRTin to inferior TARGIT-AThe not IOERTare IORTand that demonstrated trials ELIOT and Clinical applicationofTARGIT-A andtheELIOTtrials specific guidelinesonIORT areneeded. worldwide, used being increasingly are previously. IORT Since techniques mentioned criteria selection in differences the to due be might 1.9%, 7.4%, and 7.7%, respectively. The slightly higher risk of recurrence was in guidelines the GEC-ESTRO the to ‘low-risk’ according groups and ‘high-risk’ and ‘intermediate-risk’ groups ‘intermediate-risk’, from ‘low-risk’, for GEC-ESTROLRR 5-year the while respectively), 8.8%, and 4.4%, (1.5%, groups ‘unsuitable’ to ‘cautionary’ to ‘suitable’ ASTRO from moved patients as increased showed LRR 5-year technique the ELIOT that of analysis retrospective Italian IORT.The to specifically refer guidelines GEC-ESTRO nor ASTRO neither However, groups. risk lowest the among status receptor oestrogen and size, tumour age, patients’ of terms in differ recommendations The GEC-ESTRO panel stratified patients undergoing PBI into low, characteristics intermediate, clinical and high-risk panel and categories diseases of ASTRO variety The a of PBI. basis to the on PBI approach for unsuitable cautionary,and pragmatic suitable, into a patients grouped clinicians give to up drawn been have recommendations GEC-ESTRO and ASTRO ASTRO andGEC-ESTROrecommendationsin2009 5 [44] ® and both Liac . . ASTRO and GEC-ESTRO ecancer [45, 46] [45, www.ecancer.org ® 2015,9:516 and Novac7 . Aof subset [43] ® - .

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