Keywords ISSN accelerated partial breast irradiation boost breast cancer intraoperative radiotherapy late effects quality of life

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1 SPECIAL REPORT Intraoperative radiotherapy during breast conserving surgery using a miniature x ray generator (Intrabeam ): theoretical and experimental background and clinical experience Frederik Wenz* 1, Elena Blank 1, Grit Welzel 1, Frank Hofmann 1, Daniela Astor 1, Christian Neumaier 1, Carsten Herskind 1, Axel Gerhardt 2, Marc Suetterlin 2 & Uta Kraus-Tiefenbacher 1 Breast cancer is currently the most frequent indication for intraoperative radiotherapy with increasing numbers worldwide. Intraoperative radiotherapy can be used as a tumor bed boost followed by whole breast radiotherapy, or as a distinct form of accelerated partial breast irradiation in selected patients. This article summarizes the theoretical background including pattern of recurrence and distribution of tumor cell foci in the breast and discusses the rationale for intraoperative radiotherapy, especially using a miniature x ray generator (Intrabeam ). The concepts of how to avoid geographic and temporal miss by giving radiotherapy during surgery to the open wound cavity are described. Experimental and clinical experience is presented based on in vitro experiments and more than 3 treated patients in a single department with mature follow-up. Intraoperative radiotherapy (IORT) has increased tremendously in clinical use and significance with the development of mobile radiotherapy devices (e.g., Liac, Novac 7, Mobetron and Intrabeam ) approximately 1 15 years ago. Breast cancer has become the most frequent indication for IORT over the last decade. Meanwhile, more than 1 centers worldwide use a miniature x ray generator (e.g., Intrabeam, Carl Zeiss Surgical, Oberkochen, Germany) (Figure 1) [1 3] for IORT of early breast cancer during breastconserving surgery (BCS) [11]. This article summarizes the theoretical and experimental background for this approach and presents our clinical experience. Theoretical background BCS followed by external beam radiotherapy (EBRT) to the whole breast has almost completely replaced radical mastectomy in suitable patients. EBRT following BCS using a dose of 5 Gy in standard fractions improves local control, breast cancer-specific survival and overall survival in these patients compared with BCS alone [4]. At present, local recurrence rates of less than 5% after 5 years are typically achievable (Figure 2). Most of the problems, especially acute skin toxicity and late cardiac toxicity have been improved by technical optimizations of dose delivery [5 7]. Nevertheless, in recent years, several studies have questioned the role of standard EBRT to the whole breast in selected patients, because most of the recurrent tumors appeared in the vicinity of the initial tumor bed [2]. It was, therefore, hypothesized that there is a spectrum of breast cancers regarding risk of local recurrence, and that more risk-adapted radiotherapy strategies should be investigated (Figure 3). For high-risk patients (i.e., younger patients, larger tumor and node positivity), it was shown that an additional dose to the tumor bed could improve local control. Therefore, the tumor bed boost is widely accepted as standard of care [8]. For low-risk patients, the situation is still controversial. It was speculated that radiotherapy may be omitted completely in selected patients. However, all randomized studies have shown significantly poorer local control rates when EBRT after BCS was omitted even in low-risk patients (Table 1) [9 12]. At present, several randomized studies are investigating the concept of a limited radiotherapy dose to the tumor bed and its immediate surroundings (e.g., TARGIT [12], ELIOT [13], GEC-ESTRO [13], NSABP B-39 [14]). 1 Department of Radiation Oncology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany 2 Department of Gynecology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany *Author for correspondence: Tel.: Fax: frederik.wenz@umm.de Keywords accelerated partial breast irradiation boost breast cancer intraoperative radiotherapy late effects quality of life part of /WHE Future Medicine Ltd Women's Health (212) 8(1), ISSN

2 SPECIAL REPORT Wenz, Blank, Welzel et al. The concept of temporal miss is based on the fact that a delay of radiotherapy by several weeks reduces local control significantly [15] and that the IORT boost reduces overall treatment time by 1 2 weeks compared with a percutaneous fractionated boost. Furthermore, there is no tumor cell proliferation before and/or during radiotherapy, which can be observed before and during fractionated radiotherapy which is protracted over several weeks and is started several weeks to months after surgery. In addition, there is the theoretical concept of local cure by the IORT boost, which is depicted and explained in Figure 4 [16]. Figure 1. Miniature x ray generator (Intrabeam, Carl Zeiss Surgical, Oberkochen, Germany) in preparation for intraoperative radiotherapy during breast-conserving surgery. Rationale for IORT The elimination of geographic and temporal miss are the two most important advantages of delivering radiotherapy during BCS. Geographic miss is a relevant challenge in day-to-day clinical practice, especially for the localization of the tumor bed boost when radiotherapy is given after chemotherapy, which may last several months, or when oncoplastic reconstruction methods have been used during BCS [14]. Targeting the tumor bed during surgery before oncoplastic reconstruction with the surgeon and radiation oncologist both present in the operating room eliminates this source of reduced local control. Rationale for Intrabeam There is an ongoing controversial debate based on the considerable uncertainty regarding the optimal target volume concepts and the target volume definition for partial breast radiotherapy [17 21]. There are some widely accepted facts, based on systematic pathologic studies, about tumor cell foci outside of the macroscopic tumor [16]. Approximately 4% of all breast cancer patients have no additional disseminated tumor cell foci in the ipsilateral breast. Around 2% have tumor cell foci within a radius of 2 cm and approximately 4% of the patients have tumor cell foci disseminated in the whole breast (Figure 5A). However, this number is certainly lower in patients with small ductal invasive tumors lacking an extensive intraductal component. Regarding the most common histo logical subtype (i.e., ductal invasive carcinoma), it is reasonable to assume that due to the ductal growth and distribution pattern, there is an exponential decline of tumor cell density outside of the macroscopic tumor (Figure 5B). There is obviously no clear border or infiltration zone, and therefore, the classical target volume concept in radiation oncology has to be modified in the case of partial breast radiotherapy. We have, therefore, developed the concept of a sphere of equivalence [16]. This novel target volume concept considers that the dose distribution (i.e., dose fall-off of the Intrabeam) is similar to the decreasing probability of remaining tumor cell foci and the decreasing tumor cell density outside of the macro scopic tumor. Areas of high probability and density are treated with a high dose, whereas areas of low probability and density are treated with a lower dose. Experimental background Traditionally, radiation oncologists are reluctant to apply high single doses, especially to 4 future science group

3 Intraoperative radiotherapy during breast-conserving surgery using Intrabeam SPECIAL REPORT late-reacting tissues such as brain, spinal cord or breast. However, clinical experience from radiosurgery and stereotactic ablative radiotherapy has demonstrated that, as long as the volume is small, high single doses are highly efficient in sterilizing even macroscopic tumors while being well tolerated. There is a special radiobiological situation in IORT with the Intrabeam system regarding the expected normal tissue toxicity [22 24]: A high single dose is delivered with a low dose rate (2 5 min) allowing significant repair in normal tissues during IORT; The dose is limited to a small volume due to the steep dose drop off of 5 kv x rays; The relative biological effectiveness of 5 kv x rays is higher compared with standard 6 MV x rays from linear accelerators. After extensive radiobiological modeling, these results have been experimentally validated [22,23]. One may assume that the chest wall thickness completely shields the lung and heart from relevant radiation doses, and that the skin should be kept at least 5 1 mm away from the applicator to avoid the induction of fibrosis. Clinical experience The clinical experience using low-energy x rays for IORT in breast cancer has now lasted for more than 1 years, when the procedure was pioneered by the Vaidya et al. [3]. Several pilot studies, case series and the randomized Phase III TARGIT trial have been published [25 34]. In this section, we summarize our updated experience regarding the clinical indications for IORT as a boost, IORT as accelerated partial breast irradiation only and IORT during a second BCS in patients with previous radiotherapy to the breast. Cases: Local recurrence-free survival (%) Censored Time after BCS (months) Figure 2. The local recurrence rate in all 337 breast cancer cases undergoing external beam radiotherapy after standard breast-conserving surgery in the Department of Radiation Oncology, University Medical Centre Mannheim (Germany) in the years 25 and 26. Median age: 6 years; 55% T1, 35% T2, 35% N + and 46% chemotherapy. The local recurrence rate was 1.5% after 4 years. BCS: Breast-conserving surgery. future science group Women's Health (212) 8(1) 41

4 SPECIAL REPORT Wenz, Blank, Welzel et al BCS BCS + RT BCS + RT + boost 7 Recurrence rate (%) Risk-adapted de-escalation 2 1 Risk-adapted escalation 5 1 Time after BCS (years) Figure 3. Risk-adapted strategies for radiotherapy after breast-conserving surgery. External beam radiotherapy (EBRT) following breast-conserving surgery reduces the rate of local recurrence at 1 years from 3 4% to approximately 1%. However, 6 7% of the patients would never develop a local recurrence, even without EBRT, and 1% relapse despite EBRT. For low-risk patients, a de-escalation of radiotherapy (e.g., reduction of radiation dose and/or volume) is currently being investigated in Phase III studies. For patients with a high-risk of local recurrence, a dose escalation using a tumor bed boost has been shown to be beneficial. BCS: Breast-conserving surgery; RT: Radiotherapy. Adapted with permission from [4]. IORT as a boost The TARGIT study group (with centers in London, Mannheim, Perth, New York and Aviano) has prospectively treated and followed approximately 3 pilot patients receiving IORT as a tumor bed boost followed by EBRT. It was a group with a relatively high-risk for local recurrence (~3% younger than 5 years of age; ~3% T2 tumors; and ~3% node positive). The median follow-up was more than 5 years. The 5-year local recurrence rate was only approximately 2% [29,31 33], demonstrating the efficacy of this approach. We now have a single center experience of more than 2 patients with a median follow-up of 48 months (Table 2), the local recurrence rate is also in the range of 2%. It is also important to consider the toxicity of a novel approach. We, among others [25,26], have reported that perioperative complications are not increased when prophylactic anti biotics are given. The frequency and volume of postoperative seroma being palpable and visible on imaging studies appeared to be slightly increased after an IORT boost. By contrast, the number of seromas requiring puncture was lower than in a comparable group of patients receiving no IORT [28]. Long-term toxicity was moderate and in the range of the expected rates. Moderate-to-severe fibrosis was not higher than expected. Skin toxicity, including telangiectasias and hyperpigmentation, was in the lower range of comparable studies. Patient satisfaction and quality of life assessments showed very good results [35]. It is of interest for the diagnostic radiologist that imaging changes during followup are different from standard radiotherapy, 42 future science group

5 Intraoperative radiotherapy during breast-conserving surgery using Intrabeam SPECIAL REPORT Table 1. Can we do without external beam radiotherapy after breast-conserving surgery? Trial Author (year) n Criteria Follow-up (years) NSABP B21 Canada CALGB ABCSG 8A Fisher et al. (22) Fyles et al. (24) Hughes et al. (24) Pötter et al. (27) 19 Tumor diameter <1 cm, pn, on TAM 769 Age >5 years, ER +, tumor diameter <2 cm, pn, on TAM 628 Age >7 years, ER +, tumor diameter <2 cm, on TAM 869 Tumor diameter <3 cm, ER +, pn, on TAM/AI IBTR with RT (%) IBTR without RT (%) Ref [9] [11] [1] [12] All randomized trials comparing TAM alone with TAM + external beam radiotherapy in highly selected patients showed significantly inferior local control rates. AI: Aromatase inhibitor; IBTR: In breast tumor recurrence; RT: Radiotherapy; TAM: Tamoxifen. but do not interfere with the detection of recurrences. Imaging changes appear sooner after IORT as compared with external beam. In the long-term, there are comparable rates of imaging changes but more oil cysts and fewer dystrophic calcifications after IORT [36 38]. IORT as accelerated partial breast irradiation only TARGIT was initially given during a pilot phase as a boost to the tumor bed to assess its safety and feasibility, and immediately following this the TARGIT A trial was launched in March 2 [29,31]. IORT alone was initially given in parallel to 8 patients in whom no EBRT was possible [34]. This included patients with comorbidities such as collagen vascular disease or metastases at first presentation. After a follow-up of more than 3 years, the local recurrence rate in these patients was 1.5%. The international prospectively randomized Phase III trial (TARGIT A) recruited more than 22 patients over 1 years [3]. Older patients with small, bioptically verified ductal invasive breast cancer that appeared unifocal on imaging studies were entered. Patients Tumor cell proliferation before and during fractionated radiotherapy Treatment time 6 7 weeks IORT Lower tumor cell number at radiotherapy start after IORT in all patients or local cure in some Treatment time 4.5 weeks Reduction of overall treatment time lowers the in breast tumor recurrence at 5 years by approximately 1 2% Figure 4. The concept of local cure by intraoperative radiotherapy boost. The shortening of the overall treatment time in comparison to external beam radiotherapy including a percutaneous boost by 1 2 weeks reduces the rate of in breast tumor recurrences by approximately 1 2% (reduction of tumor cell proliferation during fractionated radiotherapy). In addition, the application of the tumor bed boost during surgery reduces the number of tumor cells that are present at the beginning of radiotherapy in all patients and even to zero in some patients. One can estimate that an IORT dose of 1 2 Gy will sterilize approximately 3 5% of the remaining tumor stem cells. IORT: Intraoperative radiotherapy. future science group Women's Health (212) 8(1) 43

6 SPECIAL REPORT Wenz, Blank, Welzel et al cm 4.5 cm 4. cm 3.5 cm Patients with foci (%) Dose (Gy) Distance (cm) Distance (cm) Figure 5. The tumor foci probability and tumor cells distribution is mimicked by the dose distribution of Intrabeam (Carl Zeiss Surgical, Oberkochen, Germany). (A) Decreasing percentage of patients with tumor cells at a certain distance. (B) The radial/ductal tumor cell growth pattern leads to an exponential decrease of the tumor cell density with increasing distance from the border of the macroscopic tumor. (C) This behavior is mimicked by the radial drop off of the dose produced by the Intrabeam system. (A) Adapted with permission from [21]. were randomized into the standard arm (BCS followed by EBRT and systemic therapy) or into the risk-adapted experimental arm. These patients received IORT during BCS and when the final histopathological report revealed additional risk factors that were not known before surgery, EBRT was added as per protocol. The first analysis of the trial was published in June 21 and demonstrated a 4-year local recurrence rate of approximately 1% in both arms [3]. The noninferiority criteria for the novel risk-adapted approach were met. In Germany, the inclusion criteria were stricter as compared with other countries, and we have not seen any recurrence in our single-center experience (Table 2). Also, toxicity rates were comparable between both arms. The rate of clinically relevant toxicity was approximately 3% for both approaches. IORT during a second BCS Patients suffering from recurrent breast cancer in a previously irradiated breast (e.g., from previous breast cancer or Hodgkin s disease), are typically recommended to undergo mastectomy even when the second cancer is detected at a Table 2. Rates of ipsilateral breast recurrences after intraoperative radiotherapy during breast-conserving surgery. Treatment n Events 4 years free of IBTR (%) IORT (TARGIT trial) 34 1 IORT (off study) IORT + EBRT Second BCS + IORT (previous RT to breast) Rates are in more than 3 patients with a follow-up of more than 18 months (median follow-up of 48 months). BCS: Breast-conserving surgery; EBRT: External beam radiotherapy; IBTR: In breast tumor recurrence; IORT: Intraoperative radiotherapy; RT: Radiotherapy future science group

7 Intraoperative radiotherapy during breast-conserving surgery using Intrabeam SPECIAL REPORT TARGIT G (German) TARGIT E (elderly) Breast carcinoma, unifocal, ductal invasive, age 5 years, 2 cm tumor diameter Breast carcinoma, unifocal, ductal invasive, age 7 years, 2 cm tumor diameter Wide excision and sentinel node excision and/or axillary dissection + IORT Histopathology: Positive/close margins re-op Extensive intraductal component (>25% of tumor volume) Lymph vessel invasion (L1) Randomization Wide excision and sentinel node excision and/or axillary dissection Whole-breast radiotherapy Wide excision and sentinel node excision and/or axillary dissection + IORT Histopathology: Positive/close margins re-op Extensive intraductal component (>25% of tumor volume) Lymph vessel invasion (L1) Yes No Yes No Whole-breast radiotherapy (4.5 weeks) No further treatment Whole-breast radiotherapy (4.5 weeks) No further treatment Adjuvant systemic therapy Adjuvant systemic therapy Adjuvant systemic therapy Figure 6. Methodology of selected ongoing clinical studies for patients with early breast cancer. IORT: Intraoperative radiotherapy; re-op: Re-operation. very small size. This is based on the expected toxicity of a second course of whole breast radiotherapy. We have offered a second, breastconserving approach with IORT to 22 patients and could demonstrate that conservation of the breast can be achieved in 9% of the cases at 4 year follow-up (Table 2) [39,4]. Conclusion Although there are already several consensus statements of national and international societies regarding the use of accelerated partial breast irradiation only outside of clinical studies (e.g., ASTRO, ASBS, ABR, GEC-ESTRO and DEGRO), the TARGIT study group is currently still offering the possibility to enter patients in the trials to prolong follow-up and to fill additional subprotocols. At the end of May 211, there have been almost 3 patients randomized in the TARGIT A trial. There will be a subanalysis of the German modification ( 5 years, 2 cm), and elderly patients can be entered in the single-arm TARGIT E trial (NCT ) (Figure 6) [15]. Based on the analysis of 76 consecutive patients undergoing BCS from our breast cancer center, we estimated that approximately 96% of the patients are eligible for an IORT boost ( 3.5 cm), future science group Women's Health (212) 8(1) 45

8 SPECIAL REPORT Wenz, Blank, Welzel et al. approximately 35% are eligible for the TARGIT A trial (German version: 5 years, invasive ductal cancer and ct1cn) and 1% qualify for TARGIT E ( 7 years, invasive ductal, ct1cn). Based on these estimations, we see a growing demand for IORT in breast cancer in the future. Future perspective Accelerated partial breast irradiation only using IORT with low-energy photons will become the standard of care for selected patients with early breast cancer, assuming that the noninferiority to EBRT will be demonstrated with mature follow-up. Financial & competing interests disclosure Carl Zeiss Surgical/Oberkochen supports radiobiologial research at the University Medical Centre Mannheim (F Wenz). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Executive summary Intraoperative radiotherapy as a tumor bed boost: the rationale is the lack of geographic and temporal miss. Clinical experience shows very low local recurrence rates with an acceptable rate of side effects. Intraoperative radiotherapy as accelerated partial breast irradiation only : the rationale is the predominance of local recurrences at the initial tumor bed in selected patients. First results from randomized trials demonstrated noninferiority to the standard approach. Further studies are ongoing. References Papers of special note have been highlighted as: of interest of considerable interest 1. Kraus-Tiefenbacher U, Steil V, Bauer L, Melchert F, Wenz F. A novel device for intraoperative radiotherapy (IORT). Onkologie 26, (23). 2. Vaidya JS, Tobias JS, Baum M et al. Intraoperative radiotherapy for breast cancer. Lancet Oncol. 5, (24). 3. Vaidya J, Tobias JS, Baum M et al. Targeted intraoperative radiotherapy (TARGIT) an innovative approach to partial breast irradiation. Semin. Radiat. Oncol. 15, (25). 4. Clarke M, Collins R, Darby S et al.; Early Breast Cancer Trialists Collaborative Group. Effect of radiotherapy and of differences in extent of surgery for early breast cancer on local recurrence and 15 year survival: an overview on randomized trials. Lancet 366, (25). 5. Abo Madyan Y, Polednik M, Rahn A et al. Improving dose homogeneity in large breast by IMRT: efficacy and dosimetric accuracy of different techniques. Strahlenther. Onkol. 184, (28). 6. Lohr F, Heggemann F, Papavassiliu T et al. Ist die kardiotoxizität der radiotherapie im rahmen des brusterhalts überhaupt noch relevant, und könnte sie durch mehrfelder- IMRT gesenkt werden? Strahlenther. Onkol. 185, (29). 7. Lohr F, El-Haddad M, Dobler B et al. Potential impact of a robust and simple IMRT approach for left sided breast cancer on cardiac mortality Int. J. Radiat. Oncol. Biol. Phys. 74, 73 8 (29). 8. Bartelink H, Horiot JC, Poortmans P et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N. Engl. J. Med. 345, (21). 9. Fisher B, Bryant J, Dignam JJ et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J. Clin. Oncol. 2, (22). 1. Hughes KS, Schnaper LA, Berry D et al. Lumpectomy plus Tamoxifen with or without irradiation in women 7 years of age or older with early breast cancer. N. Engl. J. Med. 351, (24). 11. Fyles AW, McCready DR, Manchul LA et al. Tamoxifen with or without breast irradiation in women 5 years of age or older with early breast cancer. N. Engl. J. Med. 351, (24). 12. Pötter R, Gnant M, Kwasny W et al. Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 68, (27). 13. Veronesi U, Orecchia R, Luini A et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res. Treat. 124(1), (21). 14. Benda RK, Yasuda G, Sethi A et al. Breast boost: are we missing the target? Cancer 97, (23). 15. Huang J, Barbera L, Brouwers M et al. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J. Clin. Oncol. 21, (23). 16. Herskind C, Griebel J, Kraus-Tiefenbacher U, Wenz F. Sphere of equivalence a novel target volume concept for intraoperative radiotherapy using low-energy x rays. Int. J. Radiat. Oncol. Biol. Phys. 72, (28). 17. Sautter-Bihl ML, Budach W, Dunst J et al. DEGRO practical guidelines for radiotherapy of breast cancer I. Strahlenther. Onkol. 183, (27). 18. Wenz F, Budach W, Dunst J et al. Accelerated partial breast irradiation (APBI) ready for prime time? Strahlenther. Onkol. 185, (29). 19. Souchon R, Wenz F, Sedlmayer F et al. DEGRO practice guidelines for palliative radiotherapy of metastastic breast cancer. Strahlenther. Onkol. 185, (29). 2. Sautter-Bihl ML, Sedlmayer F, Budach W et al. Intraoperative radiotherapy as accelerated partial breast irradiation for early breast cancer beware of one-stop shops? Strahlenther. Onkol. 186, (21). 21. Holland R, Veling SH, Mravunac M et al. Histologic multifocality of Tis, T1 2 breast carcinomas. Implications for clinical trials of breast-concerving surgery. Cancer 56, (1985). 22. Herskind C, Steil V, Tiefenbacher U, Wenz F. Radiobiologic aspects of intraoperative radiotherapy (IORT) with isotropic low-energy x rays for early-stage breast cancer. Radiat. Res. 163, (25) future science group

9 Intraoperative radiotherapy during breast-conserving surgery using Intrabeam SPECIAL REPORT 23. Herskind C, Schalla S, Hahn EW, Höver KH, Wenz F. Influence of different dose rates on cell recovery and RBE at different spatial positions during protracted conformal radiotherapy. Radiat. Protect. Dosim. 122, (26). 24. Herskind C, Wenz F. Radiobiological comparison of hypofractionated accelerated partial breast irradiation (APBI) and single-dose intraoperative radiotherapy (IORT) with 5-kV x rays. Strahlenther. Onkol. 186, (21). 25. Kraus-Tiefenbacher U, Scheda A, Steil V et al. Intraoperative radiotherapy (IORT) for breast cancer using the INTRABEAM system. Tumori 91, (25). 26. Kraus-Tiefenbacher U, Scheda A, Bauer L, Kehrer T, Melchert F, Wenz F. Intraoperative radiotherapy (IORT) as a boost in patients with early stage breast cancer acute toxicity. Onkologie 29, (26). 27. Kraus-Tiefenbacher U, Bauer L, Scheda A et al. Long-term toxicity of an intraoperative radiotherapy (IORT) boost using low energy x rays during breast conserving surgery (BCS). Int. J. Radiat. Oncol. Biol. Phys. 66, (26). 28. Kraus-Tiefenbacher U, Welzel G, Brade J et al. Postoperative seroma formation after intraoperative radiotherapy (IORT) using low KV x rays given during breast conserving surgery. Int. J. Radiat. Oncol. Biol. Phys. 77, (21). 29. Vaidya J, Baum M, Tobias JS et al. Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost. Int. J. Radiat. Oncol. Biol. Phys. 66, (26). 3. Vaidya JS, Joseph DJ, Tobias JS et al. TARGeted Intraoperative radiotherapy Alone versus whole breast radiotherapy for breast cancer (TARGIT-A trial)- results of an international prospective randomised Phase III trial. Lancet 376, (21). First randomized study on intraoperative radiotherapy (IORT) as accelerated partial breast irradiation in comparison to standard external beam radiotherapy showing noninferiority in 2232 patients. Local recurrence rates in both arms were approximately 1% after 4 years. 31. Vaidya JS, Baum M, Tobias JS et al. Long term results of targeted intraoperative radiotherapy (TARGIT) boost during breast conserving surgery. Int. J. Radiat. Oncol. Biol. Phys. 81(4), (211). Reports the long-term results of IORT as a tumor bed boost with 4 5 years of follow-up. Local recurrence rates were below 2% in a cohort of high-risk patients (~3% node positive and ~3% T2 tumors). 32. Wenz F, Welzel G, Blank E et al. Intraoperative radiotherapy (IORT) as a boost during breast conserving surgery (BCS) using low kv x rays the first five years of experience with a novel approach. Int. J. Radiat. Oncol. Biol. Phys. 77, (21). Reports the long-term results of IORT as a tumor bed boost with 4 5 years of follow-up. Local recurrence rates were below 2% in a cohort of high-risk patients (~3% node positive and ~3% T2 tumors). 33. Blank E, Kraus-Tiefenbacher U, Keller A et al. Single center long term follow-up after intraoperative radiotherapy as a boost during breast-conserving surgery using lowkilovoltage x rays. Ann. Surg. Oncol. 17(Suppl. 3), (21). 34. Keshtgar M, Vaidya JS, Tobias JS et al. Targeted intra-operative radiotherapy (TARGIT) for breast cancer in patients where external beam radiation is not possible. Int. J. Radiat. Oncol. Biol. Phys. 8, (211). 35. Welzel G, Hofmann F, Blank E et al. Health related quality of life after breast conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovolt x rays. Ann. Surg. Oncol. 17(Suppl. 3), (21). 36. Wasser K, Schoeber C, Kraus-Tiefenbacher U et al. Early mammographic and sonographic findings after intraoperative radiotherapy (IORT) as a boost in patients with breast cancer. Eur. J. Radiol. 17, (27). 37. Ruch M, Brade J, Schoeber C et al. Long-term follow-up findings in mammography and ultrasound after intraoperative radiotherapy (IORT) for breast cancer. Breast 18, (29). 38. Wasser K, Ruch M, Brade J et al. Do structural changes in the tumor bed after intraoperative radiotherapy (IORT) of breast cancer complicate the evaluation of mammograms in a long-term follow-up? Eur. J. Radiol. doi:1.116/j. ejrad (211) (Epub ahead of print). 39. Kraus-Tiefenbacher U, Bauer L, Schöber C, Schaefer J, Steil V, Wenz F. Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy. BMC Cancer 7, 178 (27). 4. Kraus-Tiefenbacher U, Blank E, Wenz F. Intraoperative Radiotherapy (IORT) during a second breast-conserving procedure for relapsed breast cancer after previous external beam radiotherapy (EBRT). Int. J. Radiat. Oncol. Biol. Phys. 8, (211). Websites 11. Targeted intraoperative radiotherapy (IORT) for breast cancer: intrabeam The Clinical Trials Group, University College London Groupe Européen de Curietherapie (GEC), European Society for Therapeutic Radiology and Oncology (ESTRO). GEC ESTRO APBI Trial Radiation Therapy Oncology Group (RTOG). RTOG 413 Protocol Information. StudyDetails.aspx?study= ClinicalTrials.gov. Prospective Phase II Study of Intraoperative Radiotherapy (IORT) in Elderly Patients With Small Breast Cancer (TARGIT E). NCT future science group Women's Health (212) 8(1) 47