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: emanuela.esposito@kcl.ac.uk and michael.douek@kcl.ac.uk
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 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
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.
Background
External beam radiation therapy (EBRT) following breast-conserving surgery (BCS) is the standard of care for the treatment of early-stage breast tumours. It has been shown to reduce local recurrence (LR) and improve overall survival [1–4]. Women undergoing post-operative EBRT are required to attend the radiation treatment 5 days a week for 3–5 weeks consecutively. Almost one-third of patients who undergo BCS for early breast cancer in North America do not receive post-operative breast irradiation because they live far from a treatment centre and cannot attend daily RT [5, 6]. This issue affects patients suffering from breast cancer all over the world and is particularly challenging for the elderly people. In some countries, patients decline RT or even choose mastectomy in order to avoid EBRT [7–9]. Consistent with this, IORT and some other shortened and localised radiotherapy treatments were evaluated.
Moreover, recently, the expansion of oncoplastic breast surgery allows BCS to be offered to patients in whom a wide local excision (WLE) would have a poor cosmetic result but provides a challenge for the subsequent radiation planning, particularly for the delivery of the tumour bed boost. The target volume may be partially missed by externally delivered boost, especially with tissue displacement techniques [10]. IORT can be delivered prior to tissue displacement and a direct visualisation of the tumour bed can guarantee an accurate dose delivery. The growing body of scientific evidence, in which IORT was given as a boost, has provided outstandingly low local recurrence rates [11, 12].
The rationale for IORT
Several clinical observations led to an interest in local radiation treatment following BCS. Firstly, it is observed that over 90% of LR after BCS occur at or near the original operation site [13–15]. Secondly, the risk of ipsilateral new breast primaries is equal to the risk of contralateral breast cancer [16–18]. Lastly, if whole EBRT is used to reduce the occurrence of new breast primaries, then this same principle should apply to the contralateral breast. In an effort to offer both shortened and more localised RT regimens, partial breast irradiation (PBI) that directly targets the index quadrant has been under clinical investigation. PBI treatments include multicatheter brachytherapy, intracavitary brachytherapy, three-dimensional conformal radiotherapy (3D-CRT), stereotactic body radiation therapy (SBRT) [19, 20], and intraoperative radiotherapy (IORT) [21–25]. Among the various PBI techniques, the largest randomised controlled trials were conducted on IORT.
Several single institution cohort studies have been published on IORT, but only two phase-III trials have been launched and completed recruitment, the targeted intraoperative radiotherapy-alone (TARGIT-A) trial [26] and the electron intraoperative treatment (ELIOT) trial [27]. One of the most important advantages of IORT is the delivery of a single fraction of RT at the time of surgery, directly into either the tumour cavity or the index quadrant. By employing IORT, waiting times for EBRT are reduced, and departments can focus on more complex radiotherapy treatments, since over 30% of the workload of RT departments constitutes EBRT for breast cancer. On the other hand, a disadvantage of IORT is the longer operating time required, the equipment cost, the service cost, and the cost of the additional staffing.
Available devices and techniques for IORT
The available methods of delivering IORT are low-energy X-ray systems [26], electron beam radiation therapy [27], high dose rate after loaders [28] or specific balloon devices [29]. Low-energy X-ray IORT is delivered by the Intrabeam® device (Carl Zeiss, Oberkochen, Germany). It is a miniature low-energy X-ray source employed for IORT during surgery after removal of the tumour. With the Intrabeam® device treatment time ranges from 20 to 40 minutes, delivered dose is 20 Gy at the surface of the applicator and 5–6 Gy at 1 cm depth. Tungsten-impregnated sheets are used to shield the wound prior to treatment. These block 95% of radiation, but radiation doses within the operating room remain potentially significant and necessitate control of access to the room during treatment and further shielding for the anaesthetist and medical physicists. Existing walls will often provide sufficient shielding for the low-energy X-rays, and thus, it is often possible to use existing operating rooms. Before introducing the Intrabeam® system, it is thus important to consider control of access to the operating room, to undertake a shielding assessment and to measure environmental radiation dose rates around the theatre.
Electron beam radiation therapy (EBRT) or intraoperative electron radiation therapy (IOERT) is the application of electron radiation directly to the tumour bed at the time of surgery. Electron beams can deliver the required dose much more rapidly than other devices. Mostly, to treat breast tumours, it has been estimated that 12 MeV energy is sufficient. These systems are designed with the concept of being utilised to deliver radiation in non-shielded operating rooms and are provided with a beam stopper. The beam stopper for certain mobile IORT units is designed to track the movement of gantry in all directions so that it will always intercept the primary beam, whereas other beam stoppers must be manually positioned. Three mobile linear accelerators can deliver IOERT, the Novac7® (Hitesys S.p.A., Aprilia, Latina, Italy), the Liac® (Sordina, Padova- Italy), and the Mobetron® (IntraOP Medical Inc, Sunnyvale, CA). Both Novac7® and Liac® have been employed in 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 of 90% isodose ranging from 13 (3 MeV) to 24 mm (9 MeV).
High-dose-rate (HDR) afterloader (Mick Radio-Nuclear Instruments, Inc., Mount Vernon, NY) within a dedicated shielded operating facility (Brachytherapy Unit) was evaluated by Memorial Sloan–Kettering Cancer Centre (MSKCC), New York, USA in patients older than 60 years (median age 67 years) treated with BCS. At the time of surgery, HDR intraoperative radiotherapy (HDR-IORT) is delivered to the tumour bed by an iridium 192 (192Ir) source connected to a quadrangular silastic template applicator named Harrison–Anderson–Mick (H.A.M.®). A dose of 18 Gy was used since 20 Gy doses were associated with a higher rate of side effects in a prior pilot study [28]. Treatment time varies between 20 and 40 minutes. At five years (median follow-up 68 months), local recurrence rate was 7% [30], and this was similar to the rate one would expect with no radiation treatment as shown in the CALGB 9343 trial [31]. HDR-IORT is also limited by the high cost of specialised shielded operating room facilities.
Balloon catheters have been employed as intracavitary brachytherapy devices for PBI. They can be inserted into the tumour bed at the time of surgery or postoperatively. Typically, RT is delivered by balloons in 10 fractions twice a day over five consecutive days. Xoft® electronic brachytherapy (eBx®, Xoft, Fremont, CA, USA) [32] represents the balloon device which is now being tested to deliver RT as a single fraction, totally intraoperatively, at the same dose used with the Intrabeam® system (50 kpV low-energy X-rays, 20 Gy). A prospective phase-IV (post-marketing) trial is underway [33], but data are still immature, to introduce Xoft® as IORT, in the current clinical practice.
TARGIT-A trial
The TARGIT-A trial compared a strategy of a single fraction of IORT delivered using the Intrabeam® system [34] to conventional 3–6 weeks of EBRT after BCS. It was a prospective phase-III trial that commenced in March 2000, enrolling 2,232 patients over 45 years old with clinically T1–T2 ≤ 3.5 cm, N0–1 invasive tumours. The pre-specified non-inferiority margin was 2.5% (80% of statistical power at 5% significance level), based on an estimated LRR of 6% with EBRT. Patients were ineligible if they were diagnosed with a lobular tumour or if they had an extensive in situ component. Eligible patients were treated with BCS and were randomised to either IORT or EBRT prior to surgery (pre-pathology cohort) or after surgery (post-pathology cohort). A ‘risk-adapted approach’ was used for IORT meaning that if the final pathology showed pre-specified adverse features, EBRT was administered after surgery. In these cases, IORT served as a tumour-bed boost [26].
In June 2010, the first results were published [34] with a median follow-up of 25 months, which was criticised for its shortness [35]. The 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). In order to allow accrual in subprotocols, while data matured further, the sample size was extended from 2,232 to 3,451 and recruitment continued until 2012. In November 2013, the latest results from the TARGIT-A trial were published [26], again with a short median follow-up (2 years and 4 months) due to the trial recruitment extension. The LRR with IORT was 3.3% (95% CI: 2.1–5.1%) and with EBRT, 1.3% [(95% CI: 0.7–2.5%) with a p = 0.042] but met the non-inferiority margin of 2.5%, set at the outset. Overall, breast cancer mortality in the IORT arm was 2.6% (95% CI: 1.5–4.3%) versus 1.9% [(95% CI: 1.1–3.2%) in the EBRT arm; p = 0.56] [26]. However, non-breast cancer 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 terms of survival, although the log-rank statistics show a significant difference in non-breast cancer deaths that were found to be reduced in the IORT arm, these deaths also included stroke, bowel ischaemia, and other events unrelated to breast irradiation. Additionally, the median follow-up of most patients was too short to observe differences in cardiac deaths (attributable to RT) which would be expected to occur between 10 and 20 years after radiation treatment [36]. With IORT, there was a lower rate of Radiation Therapy Oncology Group (RTOG) grade 3–4 side effects and a higher rate of wound complications including seroma.
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%) of these received IORT. These results were more favourable for the pre-pathology stratum, and this group met the 2.5% non-inferiority margin [IORT 2.1% (1.1–4.2) versus EBRT 1.1% (0.5–2.5)], while the post-pathology did not met [IORT 5.4% (95% CI: 3.0–9.7) versus EBRT 1.7% (95% CI: 0.6–4.9; p = 0.069)]. However, the data are still too immature to draw a definitive conclusion on LR.
Cost-effective analysis is also important in view of the equipment cost and potentially small number of eligible patients at some centres. A significant investment in equipment would be required to make IORT technology available across the National Health Service (NHS) in the United Kingdom (UK) or other European countries. In United States, two cost-effective analyses have been reported [37, 38]. Alvarado et al concluded that when considered against the cost of EBRT, the Intrabeam® system is more cost-effective [37]. It offered more quality-adjusted life years (QALYs) than the 6-week EBRT regimen. The effectiveness analysis showed that IORT was slightly preferred over the whole breast EBRT strategy when measured in QALYs (a difference of 0.00026 QALYs, or 0.95 quality-adjusted days). This result was driven by the improved utility values for the proportion of women who have salvage lumpectomy after IORT, whereas all women who undergo EBRT have a salvage mastectomy. Based on cost-minimisation analyses by Shah et al, IORT represents a potential cost savings in the management of early-stage breast cancer. However, absolute reimbursement is misleading, because when additional medical and non-medical costs associated with IORT are factored in, EBRT represents the cost-effective modality based on cost per QALY analyses [38].
ELIOT trial
The ELIOT trial recruited its first patients in November 2000 at the European Institute of Oncology (EIO) in Milan (Italy). It was a prospective single-centre randomised phase-III equivalence trial. The aim of this trial was to compare a 21 Gy single-dose IOERT delivered using the ELIOT technique [39] to conventional whole breast EBRT. The pre-specified equivalence margin was 7.5% (90% of statistical power at 5% significance) and a non-inferiority margin of 4.5%. A total of 1,305 women were randomised, aged between 48 and 75 years with clinically invasive T1–T2 ≤ 2.5 cm breast cancers suitable for BCS. Tumours, which were either ductal or lobular carcinoma, in situ were excluded in this study. A diagnosis of invasive lobular carcinoma did not affect eligibility. The trial was closed for recruitment in December 2007. The 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) [27], at 5.8 years median follow-up. The LRR just fell within the pre-defined non-inferiority margin of 4.5%. The hazard ratio (HR) for LRR in the ELIOT trial was 9.3 (95% CI: 3.3–26.3) for women allocated to receive IOERT compared with those allocated to receive EBRT [27]. It was found that 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 96.9% (95% CI: 95.5–98.3) in the EBRT arm (p = 0.59) [27].
The ELIOT trial included more than 10% of patients with worse prognosis (larger tumours, nodes positive) which may account for the increased LRR observed with IORT. In the multivariable analysis, carcinoma greater than 2 cm and poorly differentiated, more than four positive nodes and triple negative subtypes resulted in doubling the risk of LRR. Consistent with a low-risk group, showing 5 years occurrence of 1.5% LR (p < 0.0001) emerged as a key finding in the ELIOT population. Moreover, a noteworthy retrospective analysis of 1,822 patients treated with the ELIOT technique IORT off-trial at EIO was published, after American Society for Radiation Oncology (ASTRO) and Groupe Europèen de Curietherapie of the European Society of Therapeutic Radiology and Oncology (GEC-ESTRO) recommendations were made available in 2009. Patients who fit the ASTRO ‘suitable’ group guidelines and the GEC-ESTRO ‘low-risk’ group guidelines, were found to have a LRR of 1.5% and 1.9%, respectively [40, 41], confirming that IORT should be restricted to selected patients on the basis of tumour characteristics.
In terms of cost-effectiveness, despite the higher initial device-related costs, the cost per patient treated with IORT by using electron beams linear accelerators is effective when considering the reduction in radiotherapy waiting lists, pre-treatment planning and delay, but a specific cost-effective analyses is required, since IORT devices remain unaffordable for many hospitals worldwide [42].
ASTRO and GEC-ESTRO recommendations in 2009
ASTRO and GEC-ESTRO recommendations have been drawn up to give clinicians a pragmatic approach to PBI. The ASTRO panel grouped patients into suitable, cautionary, and unsuitable for PBI on the basis of a variety of diseases and clinical characteristics [43]. The GEC-ESTRO panel stratified patients undergoing PBI into low, intermediate, and high-risk categories [44]. ASTRO and GEC-ESTRO recommendations differ in terms of patients’ age, tumour size, and oestrogen receptor status among the lowest risk groups. However, neither ASTRO nor GEC-ESTRO guidelines refer specifically to IORT. The Italian retrospective analysis of ELIOT technique showed that the 5-year LRR increased as patients moved from ASTRO ‘suitable’ to ‘cautionary’ to ‘unsuitable’ groups (1.5%, 4.4%, and 8.8%, respectively), while the 5-year LRR for ‘low-risk’, ‘intermediate-risk’, and ‘high-risk’ groups according to the GEC-ESTRO guidelines was 1.9%, 7.4%, and 7.7%, respectively. The slightly higher risk of recurrence in the ‘low-risk’ and ‘intermediate-risk’ groups from GEC-ESTRO might be due to the differences in selection criteria mentioned previously. Since IORT techniques are increasingly being used worldwide, specific guidelines on IORT are needed.
Clinical application of TARGIT-A and the ELIOT trials
The TARGIT-A and ELIOT trials demonstrated that IORT and IOERT are not inferior to EBRT in selected patients [45, 46]. A subset of low-risk women for whom IOERT is acceptable in terms of LRR at 5.8 years of median follow-up has emerged from the ELIOT trial. Data from the TARGIT trial are encouraging and promising at 29 months of median follow-up with IORT, but longer follow-up is required. Data from totally intraoperative intracavitary balloon application by Xoft technology are still immature, while HDR-IORT demonstrated that ASTRO recommendations are ineffective for patients treated with this approach. Moreover, Intrabeam® and both Liac® and Novac7® devices employed in these trials have been validated, whereas it is not clear the level of clinical evidence of the rest of novel devices introduced into the market.
However, there are some clear advantages of single-fraction RT for patients, and the level of evidence available on IORT is significant enough to share with them. Patients deemed at low risk of LR or those deemed suitable for PBI, according to the GEC-ESTRO and ASTRO recommendations, could be considered as candidates for IORT delivered under strict protocol, even though more specific guidelines for IORT would be helpful to assist clinicians in patient optimal selection. Both TARGIT-A and ELIOT techniques have been evaluated within phase-III trials launched over 14 years ago, and although further follow-up will increase confidence with the data, it will also further delay clinical implementation. National registries should be set up in order to monitor LR events occurring after IORT treatments off-trial, prospectively and might be useful to accumulate data.
Conclusion
In conclusion, in light of the existing data, IORT and IOERT should be now considered as an alternative to EBRT for specifically selected and well-informed patients. The higher risk of local recurrence should be widely discussed and compared with the great advantage of a single-fraction radiation treatment. The current paradigm is that of striving to deliver ‘minimum effective treatment’ to patients with cancer, and with this in mind, it is necessary to inform suitable patients about the novel options for the treatment of their cancer.
Conflicts of interest
The authors have no disclosures to make concerning financial and personal relationships with other people or organisations that could inappropriately influence their work.
Acknowledgments
The authors thank the Vito Distante Project for supporting this work.
References
1. Veronesi U et al (2002) Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer New Engl J Med 347 1227–1232 DOI: 10.1056/NEJMoa020989 PMID: 12393819
2. Clarke M et al (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials Lancet 366 2087–2106 DOI: 10.1016/S0140-6736(05)67887-7 PMID: 16360786
3. Fisher B et al (2002) Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer New Engl J Med 347 1233–1241 DOI: 10.1056/NEJMoa022152 PMID: 12393820
4. Darby S et al (2011) Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials Lancet 378 1707–1716 DOI: 10.1016/S0140-6736(11)61629-2 PMID: 22019144 PMCID: 3254252
5. Tuttle TM, Jarosek S, Habermann EB, Yee D, Yuan J and Virnig BA (2012) Omission of radiation therapy after breast-conserving surgery in the United States: a population-based analysis of clinicopathologic factors Cancer 118 2004–2013 DOI: 10.1002/cncr.26505
6. Athas WF, Adams-Cameron M, Hunt WC, Amir-Fazli A and Key CR (2000) Travel distance to radiation therapy and receipt of radiotherapy following breast-conserving surgery J Natl Cancer Inst 92 269–271 DOI: 10.1093/jnci/92.3.269 PMID: 10655446
7. Kirby RM, Basit A and Manimaran N (2008) Patient choice significantly affects mastectomy rates in the treatment of breast cancer Int Semin Surg Oncol 5 20 DOI: 10.1186/1477-7800-5-20 PMID: 18694514 PMCID: 2518550
8. Lazovich DA, White E, Thomas DB and Moe RE (1991) Underutilization of breast-conserving surgery and radiation therapy among women with stage I or II breast cancer JAMA 266 3433–3438 DOI: 10.1001/jama.1991.03470240055032 PMID: 1688350
9. Nold RJ, Beamer RL, Helmer SD and McBoyle MF (2000) Factors influencing a woman’s choice to undergo breast-conserving surgery versus modified radical mastectomy Am J Surg 180 413–418 DOI: 10.1016/S0002-9610(00)00501-8
10. Malter W et al (2014) Single center experiences with intraoperative radiotherapy as a boost during oncoplastic breast-conserving surgery Oncol Res Treat 37 15–16
11. Vaidya JS et al (2011) Long-term results of targeted intraoperative radiotherapy (Targit) boost during breast-conserving surgery Int J Radiat Oncol 81 1091–1097 DOI: 10.1016/j.ijrobp.2010.07.1996
12. Sedlmayer F et al (2014) Boost IORT in breast cancer: body of evidence Int J Breast Cancer 2014 472516 DOI: 10.1155/2014/472516
13. Clark RM, Wilkinson RH, Mahoney LJ, Reid JG and MacDonald WD (1982) Breast cancer: a 21 year experience with conservative surgery and radiation Int J Radiat Oncol 8 967–979 DOI: 10.1016/0360-3016(82)90163-8
14. Fisher ER, Anderson S, Redmond C and Fisher B (1992) Ipsilateral breast tumor recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06 Semin Surg Oncol 8 161–166 PMID: 1496227
15. Veronesi U et al (1993) Radiotherapy after breast-preserving surgery in women with localized cancer of the breast New Engl J Med 328 1587–1591 DOI: 10.1056/NEJM199306033282202 PMID: 8387637
16. Bartelink H et al (2007) Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881–10882 trial J Clin Oncol 25 3259–3265 DOI: 10.1200/JCO.2007.11.4991 PMID: 17577015
17. Fisher B and Anderson S (1994) Conservative surgery for the management of invasive and noninvasive carcinoma of the breast: NSABP trials National surgical adjuvant breast and bowel project World J Surg 18 63–69 DOI: 10.1007/BF00348193 PMID: 8197778
18. Fisher ER, Anderson S, Tan-Chiu E, Fisher B, Eaton L and Wolmark N (2001) Fifteen-year prognostic discriminants for invasive breast carcinoma: national surgical adjuvant breast and bowel project protocol-06 Cancer 91 1679–1687 PMID: 11309768
19. Feasibility study of stereotactic body radiotherapy for early breast cancer (ARTEMIS) (2014) Available at https://clinicaltrials.gov/ct2/show/NCT02065960 [cited 2015 28 January]
20. Xu Q et al (2012) Dosimetric investigation of accelerated partial breast irradiation (APBI) using cyberknife Med Phys 39 6621–6628 DOI: 10.1118/1.4757616 PMID: 23127056
21. Polgar C, Fodor J, Major T, Sulyok Z and Kasler M (2013) Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial Radiother Oncol 108 197–202 DOI: 10.1016/j.radonc.2013.05.008 PMID: 23742961
22. Veronesi U et al (2003) Intraoperative radiation therapy for breast cancer: technical notes Breast J 9 106–112 DOI: 10.1046/j.1524-4741.2003.09208.x PMID: 12603383
23. Vicini F et al (2011) Five-year analysis of treatment efficacy and cosmesis by the American society of breast surgeons mammosite breast brachytherapy registry trial in patients treated with accelerated partial breast irradiation Int J Radiat Oncol 79 808–817 DOI: 10.1016/j.ijrobp.2009.11.043
24. Baglan KL et al (2003) Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT) Int J Radiat Oncol 55 302–311 DOI: 10.1016/S0360-3016(02)03811-7
25. Vaidya JS et al (2001) Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer Ann Oncol 12 1075–1080 DOI: 10.1023/A:1011609401132 PMID: 11583188
26. Vaidya JS et al (2014) Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial Lancet 383 603–613 DOI: 10.1016/S0140-6736(13)61950-9
27. Veronesi U et al (2013) Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial Lancet Oncol 14 1269–1277 DOI: 10.1016/S1470-2045(13)70497-2 PMID: 24225155
28. Sacchini V, Beal K, Goldberg J, Montgomery L, Port E and McCormick B (2008) Study of quadrant high-dose intraoperative radiation therapy for early-stage breast cancer Brit J Surg 95 1105–1110 DOI: 10.1002/bjs.6208 PMID: 18690634
29. Dooley WC et al (2011) Surgical perspectives from a prospective, nonrandomized, multicenter study of breast-conserving surgery and adjuvant electronic brachytherapy for the treatment of breast cancer World J Surg Oncol 9 30 DOI: 10.1186/1477-7819-9-30
30. Beal K SV, Zelefsky M, Rogers KH and McCormickl B (2011) 5 year update on intraoperative radiation therapy for breast cancer American society for radiation oncology (ASTRO) 53rd annual meeting Int J Radiat Oncol Biol Phys Suppl S241–S242 DOI: 10.1016/j.ijrobp.2011.06.1709
31. Hughes KS et al (2013) Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343 J Clin Oncol 31 2382–2387 DOI: 10.1200/JCO.2012.45.2615 PMID: 23690420 PMCID: 3691356
32. Dickler A, Ivanov O and Francescatti D (2009) Intraoperative radiation therapy in the treatment of early-stage breast cancer utilizing xoft axxent electronic brachytherapy World J Surg Oncol 7 24 DOI: 10.1186/1477-7819-7-24 PMID: 19254369 PMCID: 2651878
33. Safety and efficacy study of the Xoft® Axxent® eBx™ IORT system Available at http://www.cancer.gov/clinicaltrials/search/view?cdrid=737392&version=HealthProfessional&protocolsearchid=6281961 [updated 4 July 2014; cited 2015 28 January]
34. Vaidya JS et al (2010) Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial Lancet 376 91–102 DOI: 10.1016/S0140-6736(10)60837-9 PMID: 20570343
35. Cuzick J (2014) Radiotherapy for breast cancer, the TARGIT-A trial Lancet 383 1716 DOI: 10.1016/S0140-6736(14)60825-4 PMID: 24835608
36. Yarnold J, Offersen BV, Olivotto I, Poortmans P and Sarin R (2014) Radiotherapy for breast cancer, the TARGIT-A trial Lancet 383 1717–1718 DOI: 10.1016/S0140-6736(14)60828-X PMID: 24835611
37. Alvarado MD et al (2013) Cost-effectiveness analysis of intraoperative radiation therapy for early-stage breast cancer Ann Surgical Oncol 20 2873–2880 DOI: 10.1245/s10434-013-2997-3
38. Shah C et al (2014) Evaluating radiotherapy options in breast cancer: does intraoperative radiotherapy represent the most cost-efficacious option? Clini Breast Cancer 14 141–146 DOI: 10.1016/j.clbc.2013.10.005
39. Veronesi U et al (2010) Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons Breast Cancer Res Treat 124 141–151 DOI: 10.1007/s10549-010-1115-5 PMID: 20711810
40. Leonardi MC et al (2012) How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology Int J Radiat Oncol 83 806–813 DOI: 10.1016/j.ijrobp.2011.08.014
41. Leonardi MC et al (2013) Accelerated partial breast irradiation with intraoperative electrons: using GEC-ESTRO recommendations as guidance for patient selection Radiother Oncol 106 21–27 DOI: 10.1016/j.radonc.2012.10.018
42. Frasson AL, Zerwes FP, Braga AP, Barbosa FS and Koch HA (2007) Intraoperative radiotherapy in the conventional linear accelerator room for early breast cancer treatment: an alternative choice in developing countries J Exp Clin Canc Res 26 379–384
43. Smith BD et al (2009) Accelerated partial breast irradiation consensus statement from the American society for radiation oncology (ASTRO) Int J Radiat Oncol 74 987–1001 DOI: 10.1016/j.ijrobp.2009.02.031
44. Polgar C et al (2010) Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009) Radiother Oncol 94 264–273 DOI: 10.1016/j.radonc.2010.01.014
45. Silverstein MJ et al (2014) Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials Part 1–ELIOT Ann Surg Oncol 21 3787–3792 DOI: 10.1245/s10434-014-3998-6 PMID: 25160734 PMCID: 4189005
46. Silverstein MJ et al (2014) Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials Part 2–TARGIT Ann Surg Oncol 21 3793–3799 DOI: 10.1245/s10434-014-3999-5 PMID: 25138079 PMCID: 4189006
