Baum, M

Tobias, JS

Vaidya, J

English

UCL Discovery

RAD Magazine, May, 2021  27Single-dose intra-operative breast cancer  radiotherapy (TARGIT-IORT) – innovative,  effective, far less trouble to the patientThe September 2020 issue of RAD Magazine and the frontpage of The Times on August 20, 2020, both featured theexcellent long term results of the TARGIT-A trial of  intra-operative radiotherapy (TARGIT-IORT) for early  breast cancer that were published in The BMJ1(https://www.bmj.com/content/370/bmj.m2836.full.pdf). Theseresults had widespread international media coverage – veryunusual in trials of radiotherapy.The study concept was straightforward: since almost alllocal recurrences of early breast cancer occur at the initialsite – the index quadrant – rather than other parts of thesame breast, might it be sufficient to target radiotherapyonly at the initial site and deliver it immediately afterlumpectomy, under the same anaesthetic? The great advan-tage, of course, would be the avoidance of unnecessary treat-ment to the rest of the breast. It would also avoid scatteredirradiation to other organs such as the lung and heart. Working with colleagues in the USA and Germany, wedeveloped the Zeiss Intrabeam system, a type of miniaturelinear accelerator producing 50kV x-rays. This low energyradiation is delivered from the centre of various sized spher-ical applicators that can be introduced into the surgical cav-ity immediately after the cancer has been excised (figure1A). The idea is that the device is placed into the tumourbed and left for 20 to 40 minutes depending on the size ofthe applicator. Various sizes (1.5-5cm diameter) can be useddepending of course on the specific requirement in each  individual patient. The length of exposure is set to providea very high dose at the surface of the applicator (20Gy,which gives a depth-dose of 6Gy at 1cm beyond the surgicalcavity). We gave the procedure a name: TARGIT, forTARGeted Intraoperative radioTherapy, which is now morecommonly called TARGIT-IORT (www.targit.org.uk) to dif-ferentiate it from other forms of IORT.Because of efficient exponential decay, substantiallyenhanced by absorption by the tissues, the dose to otherorgans especially heart and lung is virtually zero. As thelinear energy transfer of kV photons is considerably higherthan for megavoltage, the biologically effective dose fromthis single treatment has been shown to be greater than itmight seem at first sight. RAD Magazine, 47, 552, 27-28Professor Jeffrey S TobiasProfessor of oncologyProfessor Jayant S VaidyaProfessor of surgery and oncologyProfessor Michael Baum Emeritus professor surgeryUniversity College LondonWe started with a pilot study in 1998 and from 2000onwards we designed a pragmatic multicentre internationalrandomised trial – the TARGIT-A trial – using this  approach as the ‘experimental arm’, with conventional exter-nal beam whole breast radiotherapy (EBRT), normally givendaily for three to six weeks, as the ‘control arm’. We werefortunate in working with a large collaborative network ofcentres of excellence and patient representatives were onthe steering group from very early on. The TARGIT-A  trial was academically driven and mainly funded by a  large grant from the HTA programme of NIHR and otherinternational bodies.The cohort group we studied was as follows: eligiblepatients were aged 45 years and older and had to be suitablefor breast conservation, with a unifocal invasive ductal  carcinoma on conventional imaging preferably up to 3.5cmin diameter. MRI was not necessary and was indeed  performed in less than 6% of cases. There were no otherabsolute stipulations. This means that several patients hadtumour prognostic factors putting them at medium or evenhigh risk of local recurrence. More than three-quarters ofpatients had high risk factors that would make them  ineligible for participation in ‘low risk’ population trials suchas PRIME-II and other partial breast irradiation trials usingEBRT or brachytherapy.2,3As part of the design of the study and as a precautionarymeasure, we recognised that there might occasionally besome histological surprises after the full pathology review.So we stated in the protocol that if invasive lobular canceror positive margins were found, collaborating centres  were recommended to offer additional whole breast radio-therapy to the experimental arm, given in the conventionalway, where the local multidisciplinary team felt it to  be appropriate. We expected this to happen in 15-20% ofcases, in which case the intra-operative radiotherapy  already given at the time of surgery would act as the localboost to the tumour bed. It is really important to note thatthis was neither a ‘crossover’ nor a ‘protocol violation’ sincethis EBRT addition was part of the ‘risk-adapted’ experi-mental treatment. We felt it was both sensible and  ethically sound, and it was formally approved as part of thetrial protocol. We mention this in detail here, because misunderstand-ings have sometimes arisen. It was a legitimate part of thestudy design. The randomised trial therefore compared risk-adapted single-dose TARGIT-IORT (20% of whom receivedadditional EBRT) versus conventional whole breast radio-therapy-for-all. So in the experimental arm, 80% of patientssimply did not need to attend further for treatment. Forthem, the large majority, all the treatment – at least as faras the surgery and radiotherapy were concerned – had beenachieved at that one single session, under anaesthetic. Doneand dusted. Early on, the TARGIT-IORT approach stimulated a gooddeal of media interest: TIME, Reader’s Digest and BBC’sTomorrow’s World. Patients started seeking this new treat-ment. We were very firm that the the only way they couldhave the TARGIT-IORT ‘one-shot’ treatment was if they par-ticipated in the TARGIT-A trial. From a single centre in theUK (University College London and associated hospitals),the number of centres in Europe, USA and Australia grewquite rapidly. The recruitment target number was reachedin 2012; a total of 2,298 patients enrolled from 32 centresin 10 countries. The first results were published by  The Lancet in 2010 (figure 1b). The first survival resultswere published in 2013 and by 2018 NICE recommended  TARGIT-IORT in centres that already have the equipment,while awaiting long term results. Other countries were  more forthcoming. By 2019, TARGIT-IORT was included  in national and international guidelines of many countriesin Europe, the USA, the Far East and Australia  (www.targit.org.uk/targit-iort-in-guidelines), and 260 centresin 38 countries worldwide have treated more than 45,000patients (www.targit.org.uk/travel). Scientific papers can beaccessed at www.targit.org.uk/publications.As the long term outcomes are even more important forbreast cancer, we set the bar for completeness of follow-upvery high. By the time of the latest analysis published in2020, we had achieved a very high level of completeness offollow-up (95%). What were the long term results of this large inter-national randomised controlled trial – the highest level ofevidence one can get? In a nutshell, there was simply nodifference in the breast cancer-related outcomes of the twoarms of the study, none at all. Local recurrence-free survival,mastectomy-free survival, distant disease-free survival,breast cancer specific survival – all the same (figure 2). Radiotherapy and surgery both completed in one sitting.In these days of the COVID-19 pandemic, this an extremelyattractive solution to a common and labour-intensive radio-therapy problem. Bearing this in mind, the additional  feature to remember here is that for a typical radiotherapydepartment, about 30% of the workload is made up of treat-ment of this single diagnosis. The resources freed up couldbe used in so many ways, including a substantial reductionin waiting times.As a patient, what would you prefer? The approach out-lined above, which gives you an eight out of 10 chance ofnot needing EBRT at all after your breast-conserving  Figure 1(A) Position of the  TARGIT-IORT applica-tor in the breasttumour bed and aview of the operationtheatre. (B) The frontpage masthead of  The Lancet 2010  publication.Figure 2Long term outcomes of the TARGIT-A trial (from The BMJ 2020;370:m2836.  https://www.bmj.com/content/370/bmj.m2836.full.pdf).Continued on next pagePage 27-28 ok.qxp_Layout 1  05/05/2021  11:56  Page 27       28  RAD Magazine, May, 2021surgical excision, or the traditional approach? This wouldinvolve, at the very least, using the recently introducedwhole breast FAST-Forward regimen (itself a highly com-pressed type of EBRT), which requires a minimum of fivetreatment visits to the radiotherapy department (10 to 15in a quarter of cases in whom a tumour bed boost is given),preceded by a radiotherapy planning session. All this takestime to organise, and most departments would insist on atwo or three-week period of post-surgical recovery evenbefore planning the patient, to ensure that everything hadsettled down, that the patient’s chest contour was stable,and that the ipsilateral arm was not tethered or restrictedin raising or abduction. Perhaps a total of two months atbest between surgery and completion of the radiotherapyand, sadly, often longer. And the result of such an intensivewhole breast regimen even at a short follow-up shows ahigher incidence (25%) of patients reporting a ‘hardened/firm’breast. By contrast, we know that patients treated by  TARGIT have less in the way of long term side effects, witha better cosmetic outcome and a higher level of patient sat-isfaction as well – all well documented and published.4-7There is another major point not yet mentioned. Wefound that the risk of death from other (ie non-breast cancer)causes is substantially lower with TARGIT-IORT than withconventional EBRT. Many still find this a surprising resulteven though excess cardiovascular and other cancer mortal-ity among patients receiving EBRT has been recognisedsince the 1980s. The effect was first seen in the analysispublished in 2013. The long term data have strengthenedthe results: by 12 years the reduction in non-breast cancermortality is 4.4% (from 9.85% with whole breast radio-therapy to 5.41% with TARGIT-IORT). If this level of reduc-tion had been observed in a chemotherapy drug trial, onemight imagine it would have been rapidly adopted.We feel that TARGIT-IORT offers the benefits of otherpartial breast irradiation (PBI) approaches plus severalmore, notably the total integration of surgery and radio-therapy, with completion of all the local (ie non-systemic)treatment all at once, in eight out of every 10 patients.3 Itgives the lowest possible scattered radiation to organs atrisk (OAR). One interesting result from the much awaitedPRIME-II trial is that the local recurrence rate withoutradiotherapy is as high as 9.8% at 10 years (compared with0.9% with radiotherapy), even in an ultra low risk group(65 years and older, less than 3cm, mostly grade 1 and 2,all node negative and ER positive) (Kunkler et al, SABCS2020 www.abstractsonline.com/pp8/#!/9223/presentation/579).By contrast, the TARGIT-A eligibility was much broaderand applicable to most standard risk patients in our breastclinics, such that over three-quarters of these patients wouldnot even have been eligible for participation in PRIME-II.Of the TARGIT-A patients, 64% were ≤65 years, 22% hadnode-positive disease and 20% had grade 3 tumours, makingthem ineligible for PRIME-II. Despite this, there was no dif-ference found in the long term local control between  TARGIT-IORT and EBRT. The new approach with ‘single pit-stop’ intra-operativeradiotherapy is certainly an example of ‘disruptive tech- nology’. The plain fact is that by removing much of thebreast cancer treatment, a significant reduction of the work-load of a typical radiotherapy department would eventuallybe bound to alter the work pattern and therefore incomegeneration in a major way. Equipment would of course befreed up for other uses, and this should be recognised as abenefit. There is already a recommendation by NICE(January 2018) that this treatment should be offered topatients in departments that have the equipment and exper-tise. The recently published long term data robustly  confirmed and even amplified the initial results, as we pointout above in more detail. Elsewhere in the world (figure 3), the treatment hasbeen enthusiastically received, and more than 45,000patients have now been treated in 260 centres in this way.8To satisfy ‘valid consent’, doctors in the UK are now obligedto follow the new GMC guidelines underlining the essentialnature of adequate patient information (https://www.gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/consent).In the UK this powerful principle is now fully enshrined inlaw (Montgomery v Lanarkshire Health Board, 2015). Toooften in this country we have shown ourselves as pretty  good at creativity but far less fleet-footed when it comes toimplementation.Figure 3 Screenshot of the map ofthe world with each dotrepresenting a centre thathas treated breast cancerwith TARGIT-IORT. Thename of the centre andnumber of cases treated bythe centre (if available) isseen in the left-hand panewhen you click on the  centre. This map is inter-active and available atwww.targit.org.uk/travel.rad review of radiotherapy and oncologyContinued from preceding pageReferences 1, Vaidya J S, Bulsara M, Baum M et al. Long term survival and local con-trol outcomes from single dose targeted intraoperative radiotherapy duringlumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A ran-domised clinical trial. BMJ 2020;370:m2836. https://www.bmj.com/ content/370/bmj.m2836.full.pdf.2, Vaidya J S, Bulsara M, Baum M et al. Intraoperative radiotherapy forbreast cancer: powerful evidence to change practice. Nature ReviewsClinical Oncology 2021. https://doi.org/10.1038/s41571-021-00471-7.https://rdcu.be/cfgrz.3, Vaidya J S, Bulsara M, Baum M et al. Single-dose intraoperative radio-therapy during lumpectomy for breast cancer: an innovative patient-centredtreatment. Br J Cancer 2021. https://doi.org/10.1038/s41416-020-01233-5.https://rdcu.be/cfgdK4, Coombs N J, Coombs J M, Vaidya U J et al. Environmental and socialbenefits of the targeted intraoperative radiotherapy for breast cancer: datafrom UK TARGIT-A trial centres and two UK NHS hospitals offeringTARGIT IORT. BMJ Open 2016;6(5):e010703. https://doi.org/10.1136/ bmjopen-2015-010703. https://bmjopen.bmj.com/content/6/5/e010703.5, Corica T, Nowak A K, Saunders C M et al. Cosmesis and breast-relatedquality of life outcomes after intraoperative radiation therapy for earlybreast cancer: a substudy of the TARGIT-A trial. Int J Radiat.Oncol BiolPhys 2016;96(1):55-64. https://doi.org/10.1016/j.ijrobp.2016.04.024.https://www.redjournal.org/article/S0360-3016(16)30135-3/fulltext.6, Corica T, Nowak A K, Saunders C M et al. Cosmetic outcome as rated bypatients, doctors, nurses and BCCT.core software assessed over 5 years ina subset of patients in the TARGIT-A Trial. Radiat Oncol 2018;13(1):68.https://doi.org/10.1186/s13014-018-0998-x.7, Welzel G, Boch A, Sperk E et al. Radiation-related quality of life param-eters after targeted intraoperative radiotherapy versus whole breast  radiotherapy in patients with breast cancer: results from the randomizedp h a s e  I I I  t r i a l  T A R G I T - A .  R a d i a t  O n c o l  2 0 1 3 ; 8 ( 1 ) : 9 .https://doi.org/10.1186/1748-717X-8-9. https://rdcu.be/cfgrQ.8, Vaidya J S, Vaidya U J, Baum M et al. Global adoption of single-shottargeted intraoperative radiotherapy (TARGIT-IORT) to improve breastcancer treatment – better for patients, better for health care systems. UCLPress preprint 2021. https://doi.org/10.14324/000.wp.10121050. Publishedonline first: 5 Feb 2021.Subscribe  today In the UK and Ireland RAD Magazine is delivered free ofcharge to the heart of hospitals.Want to receive a fresh copy at your home address?  Subscribe now for only £9.75 a month.Subscribe toCall : (01371) 812960email: katherine@radmagazine.comI       Page 27-28 ok.qxp_Layout 1  05/05/2021  11:57  Page 28

Single-dose intra-operative breast cancer radiotherapy (TARGIT-IORT) - innovative, effective, far less trouble to the patient

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Single-dose intra-operative breast cancer radiotherapy (TARGIT-IORT) - innovative, effective, far less trouble to the patient

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