Accelerated partial breast irradiation using external beam conformal radiation therapy: A review

Critical Reviews in Oncology/Hematology 81 (2012) 1–20

Accelerated partial breast irradiation using external beam conformal radiation therapy: A review Christopher F. Njeh a,∗ , Mark W. Saunders a , Christian M. Langton b b

a Radiation Oncology Department, Texas Oncology Tyler, TX, USA Physics, Faculty of Science and Technology, Queensland University of Technology, Brisbane, Australia

Accepted 25 January 2011

Contents 1.

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6.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Rationale for breast conservation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Rationale for accelerated partial breast irradiation (APBI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Accelerated partial breast irradiation (APBI) techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . External beam conformal radiation therapy techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. 3D-CRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Intensity modulated radiation therapy (IMRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Tomotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Volumetric modulated arc therapy (VMAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Proton therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Comparison of EBCRT techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Patient setup: supine position and prone position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Target delineation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Patient set-up errors and organ motion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. IGRT and APBI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Dose fractionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Hypofractionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. APBI in Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Patient selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Published randomized clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. On going randomized clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Health economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Optimal technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Patient selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Target volume definition and delineation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Optimal dose and fractionation scheme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Imaging and pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +1 9035799896; fax: +1 9035927741. E-mail address: [email protected] (C.F. Njeh).

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.01.011

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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Lumpectomy followed by whole breast radiation therapy (i.e. breast conservation therapy (BCT)) is the standard of care for management of early stage breast cancer. However, its utilization has not been maximized because of a number of reasons including the logistic issues associated with the 5–6 weeks of radiation treatment. Also, pathological and clinical data suggest that most ipsilateral breast cancer recurrences are in the vicinity of the lumpectomy. Accelerated partial breast irradiation (APBI) is an approach that treats only the lumpectomy bed plus a 1–2 cm margin, rather than the whole breast with higher doses of radiation in a shorter period of time. There has been growing interest for APBI and various approaches have been developed and are under phase I–III clinical studies. This paper reviews external beam conformal radiation therapy (EBCRT) as a possible technique to APBI. The various EBCRT approaches such as 3D conformal radiation therapy, IMRT, proton therapy, tomotherapy, and volumetric arc therapy are discussed. Issues with the implementation of these techniques such as target volume delineation and organ motion are also presented. It is evident that EBCRT has potential for APBI of a selected group of early breast cancer patient. However, issues with setup errors and breathing motions need to be adequately addressed. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Early stage breast cancer; Radiation therapy; Accelerated partial breast irradiation; External beam conformal radiation therapy; Lumpectomy; Target delineation; Fractionation; Whole breast radiation therapy

1. Introduction 1.1. The problem Breast cancer is a worldwide problem, accounting for 10.4% of all cancer incidence among women, making it the second most common type of non-skin cancer (after lung cancer) and the fifth most common cause of cancer death. In the USA, breast cancer has the highest incidence among all cancer types in females with one in every eight to ten women being affected during her lifetime [1]; it is estimated that 192,370 women will be diagnosed with, and 40,170 women will die of, cancer of the breast in 2009 [2–4]. The ‘surveillance, epidemiology and end results’ (SEER) program reported that 60% of diagnosed breast cancer is early stage [2,3]. Similarly in Japan, the fraction of early stage breast cancer was reported to be 40.6% in 1996 [5]. With the increase of breast cancer screening by mammography, more and more patients will have their breast cancer diagnosed at an early stage. Hence, there is a need for proper clinical management of early stage breast cancer. Most women who are newly diagnosed with early-stage breast cancer have a choice of: breast-conserving surgery (such as lumpectomy), a mastectomy (also called a modified radical mastectomy), radiation therapy and systemic treatments [6]. 1.2. Rationale for breast conservation therapy Breast conservation therapy (BCT) is the procedure of choice for the management of the early stage breast cancer. This was endorsed as far back as 1990 by the United States National Institute of Health consensus statement, recommending breast conserving treatment as the preferable option for women with early-stage breast cancer [7] and updated in 2001 [8]. BCT consists of resection of the primary

breast tumor (lumpectomy, segmental mastectomy or wide local excision) followed by whole breast irradiation (WBI). A total dose of 45–50 Gy is delivered to the entire breast over 5–6 weeks (1.8–2 Gy per fraction). In most patients, a boost dose of 10–16 Gy to the tumor bed is added. The establishment of BCT as the standard of care resulted from many years of prospective studies such as the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 studies [9–11]. These studies found equivalent survival and local control rates among women treated with BCT compared to those treated with mastectomy. The value of radiation therapy as a breast conservation component has been further validated by studies comparing lumpectomy alone to lumpectomy and radiation therapy. These studies demonstrate a threefold reduction in recurrence with the use of radiation therapy following breast conserving surgery [9,12–15]. For patients with ductal carcinoma in situ (DCIS), randomized studies comparing lumpectomy alone to lumpectomy plus radiation therapy, conducted by the NSABP and European organization for research and treatment of cancer (EORTC) found a 55% and 47% reduction in the ipsilateral breast cancer events, respectively, with the addition of radiation therapy [15,16]. Recently Clarke et al. [13] (Early Breast Cancer Trialist Collaborative GroupEBCTCG), Vinh-Hung and Verschraegen [14] and Viani et al. [17] have presented pooled meta-analysis of these randomized clinical studies. Vinh-Hung’s analysis found that the relative risk of ipsilateral breast tumor recurrence after breast-conserving surgery, comparing patients treated with or without radiation therapy, was 3.00 (95% confidence interval CI = 2.65–3.40). Further, the relative risk of mortality was 1.086 (95% CI = 1.003–1.175), corresponding to an estimated 8.6% (95% CI = 0.3–17.5%) relative excess mortality if radiation therapy was omitted. BCT is well tolerated with minimal long-term complications, favorable cosmetic out-

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come and reduced psychological trauma [9,11]. Radiation therapy therefore is an essential component of BCT. It not only decreases local recurrence but improves overall survival [13,14]. 1.3. Rationale for accelerated partial breast irradiation (APBI) Despite the advantages of BCT, its utilization remains a problem [18]. It has been reported that of the women who are candidates for BCT, 10–80% actually receive it [19–21]. In addition, 15–30% of patients who undergo lumpectomy do not receive radiation therapy [22–24]. Similarly, in Japan, radiation therapy is performed in approximately 70% of patients following breast conservation surgery [25]. The under utilization of BCT has been associated with the fact that some women cannot or will not commit to the usual 6–7 week course of adjunct conventional radiation therapy that is part of the BCT package [26]. It has been further hypothesized that convenience, access, cost and other logistical issues are major contributing factors. Other logistical issues include: distance from the radiation therapy facility, lack of transportation, lack of social support structure, and poor ambulatory status of the patient [20,27,28]. Other reasons that may steer women away from BCT that have been identified include: physician bias, patient age, and fear of radiation treatments [24,29]. There has been an interest therefore to identify a subset of women who may not benefit from the addition of radiation therapy after lumpectomy for early stage breast cancer [30]. Early studies were not able to identify a subset of women that will not benefit from radiation therapy [31,32]. However, there is now some indication that RT may be avoided in a selected group of elderly patients after breast conservative surgery without exposing these patients to an increased risk of distant-disease recurrence [33] but the jury is still out. Another criticism of BCT relates to consumption of resources because breast irradiation may constitute 25–30% of patient visits and can stress a health-care delivery system. However radiation therapy facilities in the USA have largely kept up with demand for post-lumpectomy radiation therapy but not all countries have such adequate resources. For example Palacios Eito et al. [34] reported that the number of external irradiation units available in Spain in 2004 (177) was clearly lower than the number desirable (266–316). There is significant shortage of radiation therapy equipment in most of Asia and pacific regions [35], Latin America [36], Africa [37] and Eastern Europe [38]. In Africa, the actual supply of megavoltage radiation therapy machines (cobalt or linear accelerator) was only 155 in 2002, 18% of the estimated need. In 12 Asia-Pacific countries with available data, 1147 MV machines were available for an estimated demand of nearly 4000 MV machines [38]. The question that arises therefore is ‘can similar rates of local control be achieved with radiation therapy delivered only to the area at highest risk for recurrence?’ If so, radiation could be delivered in a significantly shortened period, thereby

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potentially making the BCT option available and attractive to more women. This is the concept of accelerated partial breast irradiation (APBI) [28,39,40]. The stronger case for APBI has come from both retrospective and prospective studies; reporting that 44–86% of local recurrence occurs close to the tumor bed [12,41–43]. Ipsilateral breast recurrences, in areas other than the tumor bed, occurred in 3–4% of the cases [40]. An update of the NSABP B-06 trial also confirmed this pattern of local recurrences, with 75% of them at or near the lumpectomy site. Also noted was the fact that ipsilateral recurrences, away from the lumpectomy, are similar to the recurrences of contralateral breast cancer [31]. Based upon this evidence, BCT, with whole breast irradiation has been criticized as an overtreatment. Whole breast treatments incorporate the entire breast (including the surgical cavity), overlying skin, lower axilla and even small portions of the heart and lung in the treatment fields; this may introduce avoidable toxicity [44] whereas partial breast irradiation spares more normal tissue. An additional theoretical advantage of APBI is a decreased dose to normal tissue. With a smaller target volume, it may be expected that adjacent organs such as the heart and lungs will receive less radiation. Radiation-induced lung injury after treatment for breast cancer, such as pneumonitis, lung fibrosis and pulmonary function test changes, are well documented in the literature [45,46]. An increase in lung cancer incidence and mortality after irradiation for breast cancer has also been reported in large studies [47–50]. It worth noting that the increase risk of long-term cardiac-related mortality after BCT may not be significant with modern breast radiotherapy [51]. A number of pathology studies have also researched local breast recurrence [52,53]. In the study by Holland et al., mastectomy specimens from more than 300 women diagnosed with invasive breast carcinoma, who fulfilled the criteria for breast conserving therapy, were systematically investigated [53]. They found that of the 282 invasive cancers, 105 (37%) showed no tumor foci in the mastectomy specimen around the reference mass. In 56 cases (20%) tumor foci were present within 2 cm, and in 121 cases (43%) the tumor was found more than 2 cm from the reference tumor [53]. This study supported the concept that whole-breast treatment either with surgery or radiation therapy is necessary to achieve local control. Supporters of APBI argue that this study was flawed in its patient selection and that the quality of mammography used at the time may have missed radiographic evidence of multicentric disease that would today be detected [54]. Vaidya et al. [52] also found a similar distribution of multicentric foci (MCF) in terms of their distances from the primary tumor as in the Holland study. However, Vaidya and co-workers carried out further two–dimensional and three-dimensional analyses and took the size of the breast into account. They showed that the distributions of primary tumors and MCF in the four breast quadrants differed significantly (p = 0.034). Vaidya and colleagues further hypothesized that in light of large studies showing 90% recurrences occurring in the index quadrant, MCF probably do not give rise to these recurrences. Studies

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from women considered appropriate for breast-conservation therapy reveal that the microscopic extension of malignant cells is unlikely to be beyond 1 cm [55–57]. 1.4. Accelerated partial breast irradiation (APBI) techniques APBI is an approach that treats only the lumpectomy bed plus a 1–2 cm margin, rather than the whole breast. By increasing the radiation fraction size and decreasing the target volume, this technique allows the treatment to be accomplished in a shorter period. APBI is generally defined as radiation therapy that uses daily fraction doses greater than 2.0 Gy delivered in less than 5 weeks. There are a number of approaches now available for the implementation of APBI [58], these include multicatheter interstitial brachytherapy [59], balloon catheter brachytherapy [60], conformal external beam radiation therapy [61] and intra-operative radiation therapy (IORT) [62,63]. These techniques have recently been reviewed by Njeh et al. [58]. There are a few balloon based brachytherapy devices that have been approved by the FDA including Mammosite (Hologic, Marlborough, MA), Axxent electronic brachytherapy (Xoft, Fremont, CA), and Contura (SenoRx, Inc., Aliso Viejo, CA). Hybrid brachytherapy devices have also been developed to take advantages of the versatility and dosimetric conformity of multicatheter interstitial brachytherapy with the convenience and aesthetics of a single entry device. There are currently two devices in this category namely the Struts Adjusted Volume Implant (SAVI) (Cianna Medical, Aliso, Viejo, Ca) and the ClearPath (North American Scientific, Chatsworth, CA) [58]. Intra-operative radiation therapy (IORT) refers to the delivery of a single fractional dose of radiation (using either electrons or X-rays) directly to the tumor bed during surgery. These techniques have been reviewed by Reitsamer et al. [64], Vaidya et al. [65,66] and Orecchia and Veronesi [67]. Intra-operative radiation therapy was first used in 1998 with a device called the Intrabeam, since then, two other mobile linear accelerators have become available (the Mobetron and Novac-7 systems). These systems either generate megavoltage electrons (Mobetron and Novac-7) or kilovoltage photons (intrabeam). Each of these techniques is vastly different from one another in terms of degree of invasiveness, radiation delivery, operator proficiency, acceptance between radiation oncologist and length of treatment. This paper reviews only external beam conformal radiation therapy (EBCRT), identifying the weaknesses and strengths of this approach and proposes a direction for future research and development.

2. External beam conformal radiation therapy techniques Several techniques can be classified as ‘external beam conformal radiation therapy’ including: 3D-conformal radiation

therapy (3D-CRT), with multiple static photons, and/or electrons fields; intensity modulated radiation therapy (IMRT); tomotherapy; volumetric arc therapy (VMAT); and proton beams therapy [68]. External beam conformal radiation therapy has many potential advantages, over the other techniques [61]; these include: The technique is non-invasive and the patient is not subjected to a second invasive surgical procedure or anesthesia, thereby reducing the potential risk of complications. The treatment can wait until completion of pathological analysis regarding the original tumor and the status of the resection margins are available. The technique has potential for widespread availability since most radiation therapy centers already perform 3D-CRT for other cancers and the radiation oncologist is familiar with the technical demands and quality assurance issues. It is intrinsically likely to generate better dose homogeneity and thus may result in a better cosmetic outcome when compared with brachytherapy techniques. However, compared to other APBI techniques, the improved target coverage comes at the cost of a higher integral dose to the remaining normal breast [69]. Preliminary data with external beam conformal radiation therapy (EBCRT) have been encouraging. Its feasibility was demonstrated in the radiation Therapy Oncology Group (RTOG) 0319 protocol, a phase II/III RTOG trial [70]. Jain et al. [71] demonstrated that 3D-CRT partial breast irradiation has the potential to expose a smaller volume of lung tissue to high dose radiation compare to whole breast irradiation (WBI). Similarly for patients with lateralized tumor beds, EBCRT–APBI offers significant cardiac sparing compared with WBI [72]. Some of the recent clinical studies evaluating the efficacy and safety of conformal external beam radiation therapy for CEBRT–APBI are presented in Table 1. 2.1. 3D-CRT The most widely used 3D-CRT approach was initially described by investigators at the William Beaumont Hospital [83,84]. This technique uses three to five tangentially positioned non-coplanar beams. The tumor bed is defined by the computed tomography visualized seroma cavity, postoperative changes, and surgical clips, when available. The clinical target volume (CTV) is defined as the tumor bed with a 1.5 cm margin limited by 0.5 cm from the skin and chest wall. The planning tumor volume (PTV) is defined as the CTV with a 1.0 cm uniform three-dimensional expansions. This expansion accounts for potential breathing and setup errors and hence this approach might deliver higher doses to normal breast tissue than IMRT–APBI [85]. This technique was adopted for use as one of the allowed treatment modalities for patients randomized to APBI in the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology group (NSABP/RTOG) 0413 phase III trial [70,81]. The prescription dose used for NSABP/RTOG protocol is 3.85 Gy twice daily (separated by at least 6 h) to a total dose of 38.5 Gy delivered within 1 week [81].

Good/Excellent cosmesis

n/a 90% 89% 97% 100% n/a n/a n/a 81.7% 79.5%

IBF

6% 0% 1.1% 2% 0% 0% 25% 0% n/a n/a

Fractionation scheme

3.85 Gy × 10 (bid) 3.85 Gy × 10 (bid) 3.85 Gy × 10 (bid) 3.2 Gy × 4 (bid)$ 5.0, 5.5, 6.0 Gy × 5 (10 days) 6.0 Gy × 5 (10 days) 5.0–5.31 Gy × 8 (10 days)& 3.85 Gy × 10 (bid) 3.85 Gy × 10 (bid) 3.85 Gy × 10

Follow up (months)

54 24 51 36 36 (minimum) 18 96 (mean) 34 median 15 >24

No of cases

52 91 94 99 10 47 353 55 60 34 Vicini et al. [73] Vicini et al. [74] Chen et al. [75] Taghian et al. [76] Formenti et al. [77] Formenti et al. [78] Magee et al. [79] Leonard et al. [80] Hepel et al. [81] Jagsi et al. [82]

Author

Table 1 Accelerated partial breast irradiation clinical studies using external beam radiation: $ Technique used were: mixed photons and electrons (63 patients), photons alone (16 patients), and protons (20), & Technique was electron field with a beam energy of 8–14 MeV, the majority being treated with 10 MeV, IBF = ipsilateral breast failure, n/a = data not available.

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Vicini et al. [74] have recently updated their study whereby ninety-one consecutive patients were treated with 3D-CRT–APBI, with a median follow up of 24 months. They observed no local recurrences. Cosmetic results were rated as good/excellent in 100% of patients at 6 months (n = 47), 93% at 1 year (n = 43), 91% at 2 years (n = 21), and in 90% at ≥3 years (n = 10). Only 2 patients (3%) developed grade III toxicity (breast pain), which resolved with time [74]. Further analysis of the RTOG 0319 phase II trial has also been recently reported [73]. 52 patients were studied for a median follow-up is 4.5 years (1.7–4.8). The total number of ipsilateral breast failures (IBF) were 3 giving a four year estimate of 6% (95% CI = 0–12%)). One IBF was outside of the field, making the within field failure rate of 4% (CI = 0–9%). Only two (4%) Grade 3 toxicities were observed [73]. Taghian et al. [86] have proposed a simpler easily replicated conformal approach that employs traditional supine positioning. This is a combination of photons and en-face electrons. The arrangement is aimed to provide the best PTV coverage. In their study a three-field technique consisting of 6 MV or 10 MV opposed conformal tangential photons (“minitangents”) and enface electrons was employed on 70% of the patients [68]. The average contribution of the electron field was 20%. They also suggested that for some patients with large breast size or deep seroma location, an en-face photon field or multiple additional fields may be needed to achieve PTV coverage. Mydin et al. [87] reported that a three-field electron/minitangent photon technique was more conformal and reduced the dose to the ipsilateral breast, but had the disadvantage of exposing increased volumes of heart and ipsilateral lung to low-dose radiation compared with the photon-only technique. Recht et al. [88] recently suggested that the risk of radiation pneumonitis in patient treated with APBI was related to the ipsilateral lung volume (ILV) treated. It has been demonstrated that the ILV exposure is minimized by the used of mixed photon and electron APBI technique rather than photons alone [68]. Rechts et al. [88] have further recommended the following dosimetric constraints: ILV 20 Gy should be lower than 3%, the ILV 10 Gy lower than 10%, and the ILV 5 Gy lower than 20% when purely coplanar techniques are used. 2.2. Intensity modulated radiation therapy (IMRT) Intensity modulated radiation therapy (IMRT) is a form of EBRT that uses complex structure-based planning techniques and variable intensity beam fluencies to optimize dose delivery. The major value of IMRT for breast radiotherapy is reduction of dose inhomogeneity within the target volume. A secondary advantage is the reduction of high dose irradiation to some normal tissues and organ at risk (OAR) such as the heart and ipsilateral lung. These have been supported by several studies comparing IMRT with standard 3D tangential field radiation therapy for breast can-

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cer [89–91]. However, the multiple beams in IMRT could results in a substantial volume of normal tissue receiving a low or moderate radiation dose (i.e. increase in integral dose) [92]. IMRT is being considered as an option for APBI and its feasibility has been reported in the literature [93–98]. In a prospective phase II trial of APBI IMRT, the outcome of breast cosmesis at short-term follow up compared favorably with a previous series that used 3D-CRT–APBI [94]. Similarly, Livi et al. [93] recently reported on their randomized phase III clinical trial, with APBI using IMRT producing very low acute toxicity compare WBI (5% grade 1 and 0.8% grade 2 compare to 22% and 19%). On the contrary however, Jagsi and colleagues from University of Michigan [82] recently reported that after a median follow up time of 2.5 years, seven (20.6%) patients treated with APBI IMRT with active breathing control developed new unacceptable cosmesis. They also found that the percentage of breast reference volume receiving 50% (V50) and 100% (V100) of the prescribed dose correlated with cosmetic outcome. The V50 were statistically significantly lower in patients with acceptable cosmesis (mean V50 = 34.6% range 16.6–49.2%) than in those who developed unacceptable cosmesis (mean V50 = 46.1%, range 31.3–64.5%). The same trend was observed for V100 [82]. 2.3. Tomotherapy Helical tomotherapy (“slice therapy”) combines helical intensity modulated delivery with an integrated image guided system [99–101]. In tomotherapy the patient moves through the bore of the gantry simultaneously with gantry rotation. Radiation is delivered by a narrow 6 MV beam rotating around the patient analogous to computed tomography. As the machine is specifically designed for IMRT delivery there is no flattening filter. The couch moves continuously as the gantry rotates, thus delivering radiation in a helical manner [101]. Online imaging is achieved by using megavoltage computed tomography (MVCT) scans acquired with the linear accelerator slightly detuned to reduce the mean beam energy to 0.75 MeV [102]. The beam is modulated across the patient by a pneumatically driven binary 64 leaf multileaf collimator, and is collimated longitudinally by a set of moveable jaws to give field length of 1, 2.5 and 5 cm [100]. The Tomotherapy HiARtTM system incorporates a rapid auto-matching system, so that daily positional corrections before treatment delivery is possible. Because of the integration of IMRT and image guided radiation therapy (IGRT), tomotherapy has potential for breast treatment and especially APBI [97,103–107]. The visibility of the lumpectomy seroma and the postsurgical clips on MVCT image may not be optimal, hence alignment might depend on anatomical locations such as the chest wall/lung interface. This implies that MVCT guidance for APBI may be appropriate for cases where the PTV is located closer to the chest wall [105], but not for all cases.

2.4. Volumetric modulated arc therapy (VMAT) Volumetric modulated arc therapy (VMAT) also known as, intensity-modulated arc therapy (IMAT), delivers highly conformal dose distributions by combining gantry rotation and dynamic multileaf collimation. Instead of delivering intensity-modulated beams with fixed gantry angles, VMAT delivers optimized dose distributions by rotating the radiation beam around the patient. During delivery, the field shape, which is formed by a multileaf collimator (MLC), changes continuously as determined by the treatment plan. Intensity distributions at all angles around the patient are achieved with multiple overlapping arcs, with each arc having a different set of field apertures. The weight or the total monitor units (MUs) delivered in each arc, are typically different. VMAT uses intensity-modulated fan beams rotating around the patient, delivering the treatment slice by slice. As with tomotherapy, VMAT combines intensity modulation and rotational delivery [108,109]. Recently several VMAT delivery techniques have been developed for clinical applications, including RapidArc (Varian, CA) [110] and VMAT (Elekta AB, Stockholm, Sweden) [111]. The feasibility of VMAT for APBI has been demonstrated by Qiu et al. [112]. Compared to a conventional 3D-CRT technique they found VMAT to be more efficient, rendering equivalent or better dose conformity, delivers lower doses to the ipsilateral lung and breast [112]. 2.5. Proton therapy Protons beams, unlike X-rays, have a low entrance dose, followed by a region of uniform high dose (the spread-out Bragg peak) at the target, and then a steep fall-off to zero dose. As a result, the physical dose distribution with protons is both highly conformal and homogeneous. These characteristics minimize the dose delivered to normal tissues while maximizing the dose delivered to the tumor. APBI using proton beam therapy (PBT) has been reported to achieve excellent PTV coverage and dose homogeneity while significantly reducing the volume of irradiated target breast tissue by an average of 36% compared to the 3D-CRT based APBI [68,113,114]. Protons deliver a lower integral dose to the patient compared to photons; the production of secondary neutrons by the proton beam (with a scatter foil technique) could however increase this integral dose and thus reduce substantially the advantage of proton beam therapy for breast cancer [115,116]. The contribution of neutrons to the integral dose using the spot scanning technique has been shown to be very low [117]. Interfraction and intrafraction tumor motion during scanned proton beam therapy can introduce substantial heterogeneities in the dose distribution throughout the target volume [118]. Proton beam therapy is also more costly than conventional treatment and any potential benefits must be assessed in the light of the associated costs to the healthcare system. The use of proton for breast therapy has been reviewed by Weber et al. [119].

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3. Discussions External beam conformal radiation therapy APBI has a lot of potential for wide spread clinical applications; however, many issues and unanswered question remain. These include breathing motion, treatment setup variation, the appropriate fractionation scheme and patient selection. The target may move during breathing and the patient may be positioned differently for different fractions. The following section will address some of these issues. 3.1. Comparison of EBCRT techniques Dosimetric comparison of the various external beam conformal APBI has been reported by various researchers including Moon et al. [106] and Oliver et al. [97]. Moon et al. [106] found that all modalities satisfied the homogeneity requirement by RTOG protocol; however, IMRT provided the most homogeneous plan. In terms of isodose conformity to the PTV, tomotherapy was significantly better than the other techniques (3D-CRT, IMRT, PBT) with 3D-CRT having the worst conformal plan. Among all the EB–APBI techniques, PBT had the lowest volume of ipsilateral breast exposed to a lower dose levels of 25% of prescribed; hence the best technique for sparing ipsilateral normal breast [106]. The reported average ipsilateral lung volume percentage receiving 20% of the prescribed dose was significantly lower in IMRT (2.3%) and PBT (0.4%) compared to 3D-CRT (6.0%) and tomotherapy (14.2%) [106]. When comparing WBI, IMRT and tomotherapy, Oliver et al. [97] found that a four field IMRT plan produced the best dosimetric results. They noted however that for IMRT to be clinically effective, an appropriate respiratory motion management protocol would have to be implemented. 3.2. Patient setup: supine position and prone position The standard patient setup is supine, on a carbon fiber breast board. Normally, both arms are extended above the head. Prone positioning in the application of APBI may however offer specific advantages, particularly for patients with large pendulous breasts [105]. This is because large-breasted patients have been shown to experience more acute skin reactions and inferior cosmetic outcome following BCT [120]. Prone positioning may also separate the lumpectomy site farther from the ipsilateral lung and reduce the ipsilateral lung dose. Furthermore, Formenti et al. have suggested that a prone patient position may also minimize target tissue movement during breathing [77,78]. For their initial pilot study, at minimum follow-up of 36 months (range, 36–53 months), they reported all patients to be alive and disease free with good to excellent cosmesis [77]. In their subsequent study, 47 patients were treated in the prone position with threedimensional conformal radiotherapy after breast-conserving surgery. They found acute toxicity in this study group to be

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modest and limited mainly to Grade 1–2 erythema. With a median follow-up of 18 months, only Grade 1 late toxicity occurred, and no patient developed local recurrence [78]. The prone position also provides exceptional sparing of the heart and lung tissues. Kainz et al. [105] have also studied the feasibility of prone position using tomotherapy for APBI and found conformal and uniform target–dose coverage with adequate sparing of critical structures. They found however that the contralateral breast dose exceeded the RTOG 0413 guidelines [105]. Unfortunately, the prone position is not widely used because it requires a special immobilization device and is uncomfortable for some patients. Also, it is questionable whether it can be effectively applied to patients with small breast volume or with a challenging anatomy. 3.3. Target delineation Current practice in radiation therapy uses the definition of target volume proposed by the International Commission on Radiation Units and Measurements (ICRU) [121]. They proposed the following terminology: gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). The GTV is the part of the tumor that is visible with the use of 3D imaging so that the actual volume delineated is dependent on the imaging modality utilized and the data acquisition process. However, the clinically relevant volume (CTV) includes the GTV as well as sub-clinical and microscopic anatomical spread patterns. However, these patterns are currently below the resolution limits of most modern imaging techniques. This problem is accounted for by adding margins around the GTV based on assumptions built from clinical or pathological experience, but is subject to high degrees of uncertainty, making target delineation highly imprecise [122]. For APBI, the GTV is the lumpectomy cavity (LC) or the seroma volume and the CTV is generally defined as the contouring of a seroma within the lumpectomy cavity, expanded by some margin, usually 1 to 2 cm [83,123]. The rationale for universal expansion of the CTV is that a full tumor excision by a skilled breast surgeon should leave a minimal safety margin of equal distance in all directions. However, this has been questioned by some researchers [106], arguing that universal expansion of the lumpectomy cavity sometimes results in a PTV too large to be accommodated in patients with small breasts. Furthermore, the seroma identification and contouring can be problematic because treatment delivery is delayed after breast surgery. In general, the identification of the location of the lumpectomy cavity is done using a combination of information: preoperative radiological imaging, surgical annotation, clinical palpation of the surgical defect, position of the breast scar and CT-based planning [124,125]. In the past, the position of the scar has been relied on heavily to assist with locating the tumor bed. However, breast surgical techniques have changed, with the scar frequently

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being placed some distance from the site of the tumor in order to achieve a better cosmetic result. CT-based planning is now the widely used for breast treatment. However, the limitation of CT-based planning is the inability to consistently and accurately delineate the lumpectomy cavity, because of poor visibility on the CT. Hepel et al. [125] found out that 50% of the tumor beds were poorly defined on the planning CT. These findings have been confirmed by Landis et al. [126] and also in the recent UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial [127]. Because of this and other reasons, the delineation of the lumpectomy cavity (or seroma) on CT images could vary among different observers and even among experienced ones [126]. It has been suggested by Dzhugashvili et al. [128] and Coles and Yarnold [129] that the use of surgical clips may reduce such observer variability. Researchers have documented in the literature the superiority of using surgical clips to locate the tumor bed compared with clinical methods [130–136]. However, a consistent policy of clip placement at the time of surgery is necessary. An example of this is to place a clip at the medial, lateral, superior and inferior extent of the tumor bed and a fifth clip at the deepest extent of the tumor bed in the direction of the surgical excision [137]. Shaikh et al. [138] have further argued that gold fiducial markers (fiducial markers are artificial landmarks added to a scene to facilitate locating point correspondences between images, or between images and a known model), because of their improved contrast on KV images compared to surgical clips, may further improve identification and delineation of the seroma cavity Training, contouring guidelines and computer-based educational tools have been demonstrated to be practical measures that can improve consistency in seroma delineation and hence reduce inter and intra-operator variability [122]. Wong et al. [139] found that when a group of oncologists were given contouring guidelines, compared to those without guidelines, the seroma target volume was statistically significantly larger in the group without guidelines. However, when both groups were given guidelines, there was not statistically significant difference between the seroma target volume of the two groups [139]. Another potential measure to improve consistency is to evaluate geometric parameters and clinical features that may be associated with greater observer variability. Peterson et al. [140] identified the clinical features associated with reduced inter-observer concordance to include low seroma clarity score, small volume, tissue extension from the surgical cavity, proximity to the pectoralis muscle, dense breast parenchyma, and the presence of benign calcifications. Technical parameters such CT slice thickness and contrast can also impact the variability. Knowledge of these features may be applied to train radiation oncologists and radiation therapy staff who participate in trials of APBI and to refine contouring guidelines and quality assurance processes for APBI protocols.

In the age of multi-modality imaging, the application of modalities such as breast ultrasound and breast magnetic resonance imaging in seroma delineation may also improve delineation consistency. Distinct from CT imaging, breast ultrasound (US) can differentiate solid from fluidfilled structures with high specificity [141]. Conventional two-dimensional (2D) US is still the standard in the diagnostic setting, but is limited by a lack of spatial orientation information in three dimensions [141]. High-resolution threedimensional (3D) US, has the potential for applications in APBI. Berrang et al. [142] have recently demonstrated the feasibility of using 3D US for image the breast for APBI [142]. They used the Restitu (Resonant Medical Inc., US) system and image fusion methods to co-register 3D US and CT images. In their feasibility study, radiation oncologists were able to use US images to contour the seroma target, with improved interobserver consistency compared with CT in cases with dense breast parenchyma and poor CT seroma clarity [142]. 3.4. Patient set-up errors and organ motion Immobilization and geometric uncertainty are also important issues for APBI. The breast can move throughout a treatment regimen. These displacements and deformations of the breast may occur between fractions (referred to as interfraction) and/or during beam delivery (intrafraction) due to cardiac action and respiration actions. The location of the target relative to the predetermined treatment isocenter may also change during treatment due to setup uncertainties. A number of researchers including Langen and Jones [143], Booth and Zavgorodni, [144] and Jaffray et al. [145] have reviewed these issues extensively. A study by Kron et al. [146] has shown that intra-fraction breathing motion was less than inter-fraction setup uncertainty indicating that patient setup should have a higher priority than breathing. The traditional way to deal with, or account for, these uncertainties is by extending the CTV with an appropriate safety margin, generating the planning target volume (PTV) [121]. These margins are again, based on clinical experience even though theoretical margins based on the observed variations have been suggested by McKenzie et al. [147]. The concept of CTV to PTV is less commonly used for breast radiation therapy, in which the whole breast is treated. APBI using more complex 3D radiation therapy techniques, however requires the use of this concept to ensure accurate target coverage. Baglan et al. [83] reported the average positional difference between normal inhalation and exhalation to be between 0.6 and 0.9 cm [83]. Based on these results, Baglan et al. [83] used a 5 mm margin to expand the CTV into a PTV. 3.5. IGRT and APBI More often than not, in an effort to avoid missing the planned target, the PTV includes a large amount of normal

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healthy tissue within the high dose volume; thus limiting the total dose that can be delivered to the PTV. Furthermore, the breast is a peripheral organ and often the CTV will extend to the skin surface. In these cases, the restriction of the PTVEVAL (the evaluated PTV) to 5 mm from the skin surface will not provide an adequate margin for intra-fraction breathing motion. To address the problem of organ motion, many imaging techniques have recently been introduced to track the motion of tumors. Treatment delivery using these techniques is collectively called image-guided radiation therapy (IGRT) [148]. Some of the most available IGRT methods for APBI include; electronic portal imaging devices (EPID) [149,150], implanted fiducial markers within room megavoltage (MV) or kilovoltage (kV) X-rays [98,138], and in room CT such as the cone beam CT [151,152], tomotherapy [104,105] and digital tomosynthesis [153]. Cone beam CT options are based on either an additional kV system or the use of megavoltage radiations from a therapy source [154]. IGRT technologies provide volumetric imaging of both the targeted structures and the surrounding normal tissue and hence, provide patientspecific verification that the intention has been satisfied. Recent studies have shown that CB–CT imaging can achieve 1–2 mm positioning accuracy for APBI set up [151,152,155]. Similar positioning accuracy can be achieved with tomotherapy [104]. Optical [156] and video imaging [157] methods that rely on imaging the patient’s surface have also been suggested for breast alignment. Optical methods of localizing the breast typically rely on passive markers placed on the skin surface as reference points for patient alignment. In video systems this method is extended to use the entire surface topology of the breast for patient positioning. In a comparative study some of the above alignment techniques (lasers, kV with chest wall, kV with clips and 3D surface imaging), Gierga et al. [158] found the most accurate method, defined in terms of target registration error (TRE), to be kV with surgical clips. In a similar comparative study, Yue et al. [159] and Hassan et al. [160] found that the use of either breast surface or surgical clips as surrogates for cavity results in improved localization in most patients compared to bony registration. Hassn et al. [160] presented two possible types of change in anatomy to account for setup errors; the first is a whole breast shift with respect to bony anatomy, the cavity moving with the breast; the second is the change in the cavity within the breast and independent of breast tissue. Breast surface techniques work well for the first scenario but not the second, while clips perform well for all situations [160]. One may take into account breathing motion in two ways. The first is to implement an active breathing control that ensures that the patient’s breast and hence lumpectomy cavity motion is minimized while the beam is on by controlling the amount of air inhaled and exhaled [161]. An alternative way is to gate the dose delivery, by allowing the patient to breathe freely but deliver radiation when the PTV-EVAL is in a predetermined phase of the breathing cycle.

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3.6. Dose fractionation There is still the question of the appropriate dose and fractional scheme for 3D-CRT–APBI. As evident in Table 1, different doses and fractionation schemes have been reported in the literature. Rosenstein et al. [162] assessed the biologically equivalent doses (BEDs) of several APBI schedules using a linear quadratic model. Using an ␣/␤ ratio of 10, they found that the Vicini [84] fractionation scheme provided a BED of 53 Gy, the Formenti [78] fractionation scheme gave 48 Gy and the 32-Gy dose used by Taghian et al. [86] gave a BED of 45. However, Cuttino et al. [163] utilizing a wide range of established radiobiological parameters, determined that the maximum fraction size needed to deliver a biologically equivalent dose using 3D-CRT is 3.82 Gy, supporting the continued use of 3.85 Gy BID in the current national cooperative trial. 3.7. Hypofractionation Hypofractionation refers to irradiation schemes with less than 5 fractions per week and larger doses per fraction than 2 Gy. APBI can be considered as an advanced form of hypofractionated treatment, wherein further acceleration of the dose is possible as the irradiated volume is less. Hypofractionation is a very interesting topic from both radiobiological and clinical perspectives. Although not the focus of this review a brief discussion will be presented here. The initial reluctance in adopting hypofractionation was guided by the traditional dogma that higher fraction size was associated with higher incidence of late adverse effects. Also, breast cancer and healthy tissue were previously thought to be insensitive to fraction size and best treated with fractions of 2.0 Gy or less. Current evidence indicates that this might not be true [164]. Furthermore, four large randomized clinical trials in Canada [165] and the UK [166–168] have demonstrated equivalence between WBI and hypofractionation schemes, recently reviewed by Holloway et al. [169]. For example, the Standardization of Breast Radiotherapy (START) Trial B accrued 2215 women in the UK between 1999 and 2001 [167]: patients were randomized to either 50 Gy in 25 fractions over 5 weeks or 40 Gy in 15 fractions over 3 weeks. After a median follow-up of 6.0 years (IQR 5.0–6.2) the rate of local-regional tumor recurrence at 5 years was 2.2% (95% CI 1.3–3.1) in the 40 Gy group and 3.3% (95% CI 2.2–4.5) in the 50 Gy group, representing an absolute difference of −0.7% (95% CI −1.7% to 0.9%). Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy [167]. The randomized control trials (RCT) provide level 1 evidence of the efficacy and safety of hypofractionation for selected patients with early stage breast cancer. How this is accepted within the scientific community is still debatable. It has to be noted however that hypofractionation has been used in the UK off clinical trial as a means to com-

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bat the shortage of radiation therapy facilities for a while now [170]. A national survey of radiotherapy fractionation in the UK in 2003 found three regimens were in use: 40 Gy in 15 fractions; 45 Gy in 20 fractions; and 50 Gy in 25 fractions [171]. The rest of Europe has mainly followed the traditional fractionation as confirmed by a survey conducted between August 2008 and January 2009 on behalf of the Breast Working Party within the EORTC-ROG: that found that the standard fraction dose was generally 2 Gy for both breast and boost treatment [172]. The UK National Institute of Clinical Excellence (NICE), further recommended a fractionation of 40 Gy in 15 fraction for the treatment of adjuvant post-mastectomy and post conservation therapy [173,174]. For selected patients the ASTRO task force also support the use of hypofractionation in their recent published guideline [175]. 3.8. APBI in Asia Breast conservation therapy (BCT) in the Asia region has not observed the level of interest and growth observed in the western countries. In Hong Kong, the limited usage of BCT has been associated with limited number of radiation therapy facilities [176]. However, because of the increasing local experience in the administration of BCT, increasing numbers of young patients in the population and increasing efforts to promote breast cancer awareness in recent years, the use of BCT is steadily increasing [176]. For example, in Western Australia the proportion of women under going initial BCT doubled from 33% in 1982–1985 to 72% in 1998–2000 [177]. One will further expect that APBI to increase the use of BCT in the management of early breast cancer. However, there is another issue in the application of APBI to the Asian population which is breast size. Asian women generally have smaller breast compare to European. Some of the APBI techniques might be challenging to apply to this patient group. In Japan for example, excision involving 2 cm free margin from the tumor is most commonly performed. In many cases mammary gland tissue does not remain on the dermal or pectoralis muscle sides of the tumor. The target of irradiation is only the lateral stump [25]. When irradiation is performed in the supine position, flat extension of the breast reduces the distance between the target of the irradiation and the skin, leading to excessive exposure of the skin. However, using the 4-field technique of 3D-CRT, Kosata et al. [178] demonstrated that in Japanese women, patients with a laterally located small tumor can be candidates for APBI, although patients with medially located tumor cannot. They also noted that a new beam arrangement using a combination of photons and electrons (a three-field technique that consisted of opposed, conformal tangential photons and enface electrons) recently proposed by Massachusetts General Hospital [86] may be more suited to Japanese women than that of the NSABP B-39/RTOG 0413 protocol [178].

4. Clinical issues 4.1. Patient selection Patient selection is critical to the successful application of APBI [179]. In a recent review, Polgar et al. [180] argued that the relatively poorer results of early APBI studies, with high local recurrence rates exceeding 1% per year, could be attributed to inadequate patient selection criteria and/or suboptimal treatment technique and lack of appropriate QA procedures. Various societies have now published recommendations for patient selection criteria for APBI. These include, the American Society of Breast surgeons (ASBS), the American Brachytherapy Society (ABS), American Society for Radiation Oncology (ASTRO) and European Society for therapeutic Radiology and Oncology (ESTRO) [54,180,181]. The recent GEC-ESTRO recommendations ([180] have stratified the patients into three groups: low risk, intermediate and high risk (contraindication for APBI); similarly, ASTRO [181] has stratified them into suitable, cautionary and unsuitable. The low risk (suitable) group describes patients where APBI outside of a clinical trial would be considered acceptable (see Table 2); these criteria are stricter than those recommended by the ASBS or ABS. However, less restrictive criteria could be applied to patients who enrolled in a clinical trial. Generally young patients (<50 years) and those who may harbor disease a significant distance from the edge of the excision cavity or potentially have multi-centric disease should not be treated with APBI off-protocol. It also worth noting that these recommendations were determined from a systematic review of the APBI literature. The groupings were based primarily on an analysis of the characteristics of patients most frequently included in trials of APBI and not on data that identified subsets of patients with higher rates of ipsilateral breast tumor recurrence (IBTR) when treated with APBI. Recent analysis using ASBS registry trial [182,183] and using data from University of Wisconsin [184] show that the ASTRO consensus groupings may not be optimal in identifying patients for APBI. 4.2. Published randomized clinical trials Level 1 clinical evidence of efficacy, validity and safety is obtained from randomized control trials (RCT). There are currently four reported APBI RCTs [185–188]. In the Christie Hospital Manchester, UK trial, 708 (355 in each arm) patients with tumors 4 cm or smaller of infiltrating ductal or lobular histology were randomized after segmental mastectomy to undergo radiation to a small breast field, including the tumor bed (the limited field arm (LF) or to the whole breast and regional nodes (the wide field WF, arm)) [185]. The dose to the LF was 40–42.5 Gy delivered in 8 fractions over 10 days using 8–14 MeV electrons. With a median follow up of 65 months, the 8-years actuarial overall survival rates were comparable between the two arms (73% and 71% for the LF and WF group, respectively). However, the actuarial breast

Negative (at inked) Allows for 0–3 nodes involved (with negative sentinel lymph node or >6 nodes sampled

Negative (>2 mm) Negative (by sentinel lymph node or axillary dissection)

Negative (>2 mm) Negative (by sentinel lymph node or axillary dissection)

Margin status

Negative (at inked margin) Negative (>2 mm) Negative (by sentinel lymph node or axillary dissection) Negative (by sentinel lymph node or axillary)

Lymph node status

≤2

≤3

≤3

≥60

≥50

≥18

ASTRO [181]

GEC-ESTRO [180]

NSABP B39/RTOG-0413

Histology

ABS ASBS

Infiltrating ductal carcinoma Invasive ductal carcinoma or ductal carcinoma in situ Invasive ductal carcinoma or or other favorable subtypes (mucinous, tubular and colloid) Invasive ductal carcinoma or or other favorable subtypes (mucinous, tubular and colloid) Invasive ductal carcinoma or ductal carcinoma in situ

Tumor size (cm)

≤3 ≤2

Patient age (year)

≥50 ≥45

Organization

Table 2 Recommended patient selection criteria for accelerated partial breast irradiation off-protocol: ABS, American Brachytherapy Society; ASBS, American Society of Breast Surgeons; ASTRO: American Society for Radiation Oncology; ASTRO is the suitable patients and GEC-ESTRO is the low risk group.

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recurrence rate were 20% for the LF and 11% for the WF arm (p = 0.008). There were many limitations/shortcomings to this study that could account for the high rates of local failure. Firstly, the average field size used in the LF arm was 6 × 8 cm and no attempt was made to localize the excision cavity, making geographic miss a possibility. Secondly, patients with tumor size up to 4 cm were enrolled on the study, axillary staging was omitted and specimen margins were not evaluated microscopically. In the Yorkshire Breast Cancer Group (YBCG) study, 174 patients were enrolled (90 in WBI, and 84 in tumor bed radiation therapy (TBRT) arm) between 1986 and 1990 [187]. The WBI consisted of breast-tangents treated to 40 Gy in 15 fractions and a tumor bed boost of 15 Gy in 5 fractions. TBRT was delivered at 55 Gy in 20 fractions using either photon, or electron, beam irradiation targeting a clinically defined area including the scar position. The trial was closed early due to poor accrual rates. At median follow-up of 8 years, the loco-regional recurrence rates in the WBI arm were 9% compared with 24% in the TBRT arm (p = 0.05). Again, the overall survival was not significantly different between the two arms. This study also had many short comings: a variety of out of date RT techniques were used, including a direct cobalt or cesium beam. Also, tumor bed was defined clinically using a combination of preoperative information, scar position and patient recollection. Furthermore, the protocol did not define an appropriate safety margin to cover the high risk area for possible microscopic residual disease. The Christie Hospital and the Yorkshire trials, due to the various limitations, are not truly comparable to current techniques used for APBI. However, they highlight the importance of appropriate patient selection, thorough patient workup and pathologic tumor assessment and the application of precision radiation therapy [189]. The National Institute of Oncology Hungary conducted a randomized trial of 258 patients with stage I (or N1) breast cancer from 1998 to 2004 [186]. Patients in the partial breast treatment arm were primarily treated with multicatheter interstitial brachytherapy (see the review by Patel [59] for more on the technique). However, 40 patients (31%) in the APBI arm were technically ineligible for the brachytherapy and were therefore treated with partial breast electron beam irradiation, although in conventional fractionation of 50 Gy in 25 fractions. Surgical clips were used to define the tumor bed, with a 2 cm margin applied around the tumor bed target. At median follow up of 66 months, this trial has found a similar local recurrence rate of 3.4% in the whole breast treatment arm and 4.7% in the partial breast treatment arm. A phase III, prospective randomized non-inferiority trial called TARGIT (targeted intraoperative radiation therapy) was started in March 2000 (this is not an EBCRT technique but it provides the first level 1 evidence for APBI). This trial compared single dose intraoperative radiation therapy (IORT) using 50 kV X-rays targeted to the tumor bed to conventional whole breast external beam radiation therapy in

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early breast cancer [66,190]. Patients were enrolled from 28 centers in nine countries including UK, Germany, Italy, USA and Australia. Data accrual was closed in May 2010 and the results of this trial have recently been published by Vaidya et al. [188]. In this trial 1113 patients were randomly assigned to the targeted intraoperative radiotherapy group and 1119 to the whole breast external beam radiation therapy group. From this, 854 patients received targeted intraoperative radiotherapy, only 142 received targeted intraoperative radiotherapy with external beam radiotherapy and 1025 patients in the external beam radiotherapy group receiving the allocated treatment. They observed at 4 year follow-up, six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan–Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53–2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39–2.31) in the external beam radiotherapy group. The rate of recurrence between the two groups was not statistically significant. Similarly the total rate of major toxicities was similar in the two groups [188]. This study presents the first level 1 evidence of the equivalence of APBI using IORT to WBI and confirms that targeted IORT allows the entire dose of radiation therapy to be administered in a single fraction at the time of breast-conserving surgery, thus avoiding the need for repeated radiation therapy treatments or placement of in dwelling radiation therapy devices. Similar positive results for IORT have recently been published by Veronesi and colleagues [191] from the ELIOT study. In this study, 1822 patients received 21 Gy prescribed to the 90% isodose, using 5–10 MeV electrons, delivered by a mobile linear accelerator. The median follow up was 36 months. At 6 years after treatment, an actuarial IBTR rate of 6.4% was observed. The YBCG (Yorkshire Breast Cancer Group) [187] and Christie Hospital [185] trials lack consistency in terms of patient selection and appropriate target definition. So, these two trials only provides level 3 evidence of efficacy. The Hungary trial [186] lacks the sample size to detect a difference. Hence, the only RCT that provides level 1 evidence is the recently published TARGIT study [188]. It is not surprising that a recent meta-analysis by Valachis [192] has been criticized for combining two unsuccessful trials with a more rigorous trial [193]. Nonetheless caution should be exercised in interpreting the TARGIT and ELIOT results considering the limited follow up (median follow up of 24 and 36 months, respectively). This is because IBTR and its impact on survival cannot be reliably assessed before a minimum follow up of 10 years [194]. 4.3. On going randomized clinical trials In light of the interest in APBI, seven phase III randomized clinical trials are currently evaluating the clinical efficacy of these APBI techniques; these studies include the National Surgical Adjuvant Breast and Bowel Project

(NSABP) B-39/Radiation therapy oncology group (RTOG) 0413 trial, RAPID (randomized trial of accelerated partial breast irradiation)/Ontario clinical oncology group, IRMA (Innovazioni nella Radioterapia della MAmmella), GECESTRO, IMPORT-LOW (Intensity Modulated and Partial Organ RadioTherapy) trial in the UK [195], electron intraoperative therapy (ELIOT) trial and targeted intra-operative radiotherapy (TARGIT) [196]. These trials have been examined in details recently by Mannino and Yarnold [197] identifying the differences between them: these trials differing in patient selection criteria, radiotherapy technique used in the experimental (APBI) arm, radiation dose and fractionation scheme [197,198]. The NSABP-B-39/RTOG 0413, RAPID, IRMA and IMPORT LOW are the trials with 3D EBCRT as the experimental arm and will be described briefly. The NSABPB-39/RTOG 0413 trail opened accrual in 2005 with a target of 4300 patients. The experimental arm tests three APBI techniques: multi-catheter brachytherapy, MammoSite balloon catheter and 3D conformal radiotherapy. The APBI technique is chosen according to technical considerations such as radiation facility technique credentialing and patient preference. Partial breast PTV definition and fractionation scheme vary depending on the type of APBI used. For EBCRT, a 15 mm margin is added to the tumor bed to define the CTV and further 10 mm added to account for organ motion to define the PTV. The prescribed dose for EBCRT group is 38.5 Gy in 10 fractions delivered twice a day in 5–10 days. The prescribed dose in the two brachytherapy groups is 34 Gy in 10 fractions delivered twice a day over 5–10 days. In order to assess the effectiveness of partial breast irradiation in a variety of clinical scenarios, the patient inclusion has been more liberal than those employed in previous phase I/II trials, incorporating patients with microscopically negative margins, any histology 0–3 positive lymph nodes and age of at least 18 years. As of January 2007, low risk patients were no longer being recruited. The RAPID and IRMA trials were launched in 2006 and 2007, respectively. Both studies compare WBI and 3D conformal radiation therapy to a partial breast PTV. In the IRMA trial the PTV is defined by adding 5 mm to the CTV which is obtained by the uniform expansion of the GTV by 15 mm. The fractionation schedule in the APBI arm is 38.5 Gy in 10 fractions delivered twice a day over a period of 5–8 days in RAPID and over 5 consecutive days in IRMA. The WBI arm the RAPID fractionation is 42.5 Gy in 16 fractions. The IMPORT LOW trial was launched in the UK in 2006 as an extension to the START trials with an accrual target of 1935 [195]. All patients (experimental and control arms) are prescribed a 15-fraction regimen, the control group receiving 40 Gy to the whole breast in 15 fractions over three weeks (no boost) using simple forward-planned IMRT. There are two control arms: arm 1, receives synchronous 40 Gy in 15 fractions to the partial breast PTV, plus 36 Gy in 15 fractions to the remainder of the whole breast. Arm 2, receives 40 Gy in 15 fractions to the partial breast PTV only. Comparison of

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IBTR between the two test arms will provide a direct measure of radiotherapy effect against other quadrant relapses. It is recommended that the tumor bed be identified by imaging surgical markers (titanium or gold) in the wall of the excision cavity. A minimum CTV margin of 15 mm is added to the tumor bed and modified according to the position of underlying deep fascia and overlying skin. A PTV margin of 10 mm is added to both partial and whole breast CTV to allow for breast swelling, breathing and setup variations [195]. The inclusion criteria were low risk early stage breast cancer to include: ≥50 years, tumor size ≤2 cm, invasive adenocarcinoma (excluding invasive lobular carcinoma) and minimum margins of ≥2 mm. If these trials accrue to target, almost 16,000 women will be followed, hence providing level I evidence for or against the application of APBI in women with early stage breast cancer. Also because of the heterogeneity of the trials (different inclusion criteria, different APBI techniques, etc.), many questions might be answered. 4.4. Health economics In the present age of rapidly increasing healthcare costs, evaluation of techniques has to include cost effectiveness. Cost might play a key role in the rapid adaptation of a new technology or technique. However, cost analysis is country specific because reimbursement or how healthcare is financed varies from country to country. In the USA for example, re-imbursement changes continually and rates of reimbursement vary substantially between the different APBI and WBI techniques. Hence, this makes the appropriate presentation of a comprehensive cost analysis challenging and its accuracy short-lived. Nevertheless, cost comparisons have been reported by Suh et al. [199,200] and Sher et al. [201]. Sher and colleagues [201] modelled treatment planning and delivery for different WBI fractionation schemes: Mammosite, MIB, APBI–3D-CRT and APBI–IMRT. They found that the least expensive partial breast-based radiation therapy approaches were the external beam techniques (APBI–3DCRT and APBI–IMRT); any reduced cost to patients for the HDR brachytherapy-based APBI regimens were overshadowed by substantial increases in cost to payers, resulting in higher total societal costs. The cost of HDR treatment delivery was primarily responsible for the increased direct medical cost. APBI approaches in general were favored over whole-breast techniques when only considering costs to patients. However, if one were to pursue a partial-breast radiation therapy regimen to minimize patient costs, it would be more advantageous from a societal perspective to pursue external beam-based approaches such as APBI–3D-CRT or APBI–IMRT in lieu of the brachytherapy-based regimens [200]. Similarly, Sher et al. [201] reported that APBI–3DCRT was the most cost-effective strategy for postmenopausal women with early-stage breast cancer. Unless the quality of life after MSB proves to be superior, it is unlikely to be cost-effective [201]. Vaidya and colleagues [66] made a con-

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servative estimates of 66% man hours saving, if intraoperative radiation therapy using intrabeam was used instead of WBI. They went on to estimate the savings to the UK national health service of about 18 millions dollars. So, in general one could expect savings in costs of treatment to be closely related to fraction number.

5. Further research As eluded in this review, there are still a few unanswered questions including optimal technique, patient selection, target volume definition and delineation, optimal dose and fractionation scheme. 5.1. Optimal technique As reviewed herein, there are quite a variety of techniques available for APBI, but with insufficient clinical and dosimetric data to determine the optimal technique. It is worth noting that none of the current RCT will address this issue since a direct comparison of the technique is not part of any of the current trials. So further research is required to determine: (a) what is the optimal technique? (b) what technique is best for which patient? Breast size and location of the lumpectomy cavity might dictate which technique to use. 5.2. Patient selection There is yet to be a consensus in terms of which patients characteristics are suitable for APBI. Different societies have come up with varying patient selection criteria [54,180,181]. Current data analyses [182–184] show that these recommendations might not be optimal. Therefore there is a need for a definitive clinical and pathological criteria for APBI patient selection. 5.3. Target volume definition and delineation As reviewed herein, the volume of breast tissue irradiated varies with the technique used. Empirical and pathological studies are required to determine the level and degree of spread of micro-calcification. This will give a definitive guidance on how much tissue needs to be irradiated. Also a better understanding of breathing motion and how to minimize its impact on the target is required. 5.4. Optimal dose and fractionation scheme There is growing evidence that the linear quadratic model (LQM) may not be appropriate for modeling high dose per treatment [202,203]. It has been suggested that LQM consistently overestimates cell killing at high single doses because

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it predicts a survival curve that continuously bends downward, whereas the experimental data are consistent with a constant slope (D0) at high doses. Furthermore, high-dose radiotherapy is achieving higher local control than could be explained by our current knowledge of radiation killing of cancer cells in a tumor. Proper radiobiological modeling is required to determine the optimal dose and fractionation scheme for APBI.

5.5. Imaging and pathology The role of imaging in the management of most diseases is unquestionable. This is also true for breast cancer management. The success of APBI depends highly on the ability to identify patients at low risk of multi-centric disease. Hence, the appropriate imaging technique has to be determined. For example, the value of adding a preoperative breast MRI to conventional mammography remains controversial [204]. Hence, an imaging technique is required to increase the specificity and sensitivity of multi-centric disease diagnosis.

6. Conclusions APBI has a role in the management of a select group of early stage breast cancer patients. External beam conformal radiation therapy has significant potential for APBI but further research is required to identify the optimal approach, or to determine the type of patient that will benefit from a particular approach. Issues associated with accurate target delineation are critical for the application of EBCRT; with the optimal approach to minimize setup errors yet to be established. Finally, the medical community awaits the phase III clinical trails demonstrating the efficacy and safety of EBCRT for early breast cancer.

Conflict of interest No conflict of interest and no disclosure from any of the authors, no funding source for this article.

Reviewers Jacques Bernier, Professor, Clinique de Genolier, Dept of Radio Oncology, 1 route du Muids, CH-1272 Genolier, Switzerland. Abdul Rashid, Ph.D., Georgetown University Hospital, Radiation Medicine, Washington, DC 20007, United States.

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Biographies Christopher Njeh, Ph.D. is currently Chief Medical Physicist at Texas Oncology Tyler, TX, a subsidiary of US Oncology and holds an adjunct assistant professor at the University of California at Fresno, California. Dr. Njeh obtained his Ph.D. degree in Medical Physics from Sheffield Hallam University, U.K. and, after graduation, he worked at Addenbrooke’s Hospital in Cambridge, U.K. and Queen Elizabeth’s Hospital in Birmingham, U.K. He then went to the US as a Visiting Postdoctoral Fellow at the University of California, San Francisco, CA where he was subsequently appointed an Assistant Professor of Radiology. He later completed a Medical Physics Residency at

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Johns Hopkins University, Baltimore, MD and. Dr. Njeh is certified in Therapeutic Radiologic Physics by the American Board of Radiology (ABR). Dr. Njeh is a member of the American Association of Physicist in Medicine (AAPM) and the American Society of Radiation Oncology (ASTRO). He is member of the minority recruitment at AAPM and education community at ASTRO. Dr. Njeh is a manuscript reviewer for a number of international journals including: Medical dosimetry, Physics in medicine and biology and Osteoporosis international. Dr. Njeh is the author of over 60 peer reviewed articles, more than 10 book chapters and 2 books. His research interest includes image guided radiation therapy and accelerated partial breast irradiation. Mark W. Saunders received his medical degree in 1988 from the University of Arkansas for Medical Science in Little Rock, where he also completed an internship in 1989. He then completed a residency at Brown Cancer Center in Louisville, Kentucky, in 1992, where he served as chief resident. Is a certified Radiation Oncologist and Adjunct Professor at the University of Texas at Tyler. He has been involved in the clinical application of APBI and has treated numerous patients with Mammosite. He is also involved with Radiation Therapy Oncology Group (RTOG) research protocols. Christian M. Langton is Professor of Medical Physics and Head of Physics at Queensland University of Technology in Brisbane, Australia. He also serves as Director of the Queensland Cancer Physics Collaborative, which has already secured over $2 million of financial support; the website for the Collaborative is located at www.qld-cpc.org.au. Christian Langton studied for his Joint Honours B.Sc. in Physics and Chemistry at University of Hull and M.Sc. in Medical Physics at University of Aberdeen before returning to University of Hull to study for his Ph.D. He was awarded his DSc by University of Hull in 2007. Professor Langton was awarded Chartered Engineer status from the Institute of Materials in 1994, He is a Fellow of the Institute of Physics, Institute of Physics & Engineering in Medicine (IPEM), American Institute for Medical and Biological Engineering

(AIMBE), Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM), and Australian Institute of Physics (AIP) in 2009, along with being made an Affiliate of the Royal College of Physicians in 2001. He was awarded the IPEM’s ‘Manufacturer’s Award for 1995–96’. Following two years in industry, developing the BUA technique with Walker Sonix in Worcester, MA, he returned to UK academia, with Senior Lectureships in Applied Physics at City of London Polytechnic and Sheffield Hallam University. In 1992, he was appointed Director of the Health Research Centre at Sheffield. In 1994, he again returned to University of Hull, as the Senior Lecturer in Medical Physics within the School of Medicine, Faculty of Health. He was awarded the Personal Titles of Reader and Professor of Medical Physics in 1999 and 2007, respectively. His work on the science, technology and clinical utility of ultrasound assessment of cancellous bone and osteoporosis has resulted in over 1500 publication citations with a current h-index of 21. He is named inventor on six related patents; there are 7 commercial devices currently available adopting the BUA technique, with over 12,000 systems utilised worldwide. Professor Langton’s research has been recognised (EurekaUK) by Universities UK as one of the top “100 discoveries and developments in UK Universities that have changed the world” over the past 50 years, covering the whole spectrum from the arts and humanities to science and technology. The UK’s Department of Health has also recognised Professor Langton’s contributions in a publication highlighting eleven projects that have contributed to ‘60 years of NHS research benefiting patients’. Professor Langton previously served as Sub-Dean for Research and Reach-Out within University of Hull’s Postgraduate Medical Institute, and Director of R&D Performance within Hull & East Yorkshire Hospitals NHS Trust. He coordinated the 2008 Research Assessment Exercise (RAE) submission under Allied Health Professions and Studies (UoA12) which achieved the highest rating within the university, being 6th out of 68 submissions nationally.