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

Transcription

1 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 a Radiation Oncology Department, Texas Oncology Tyler, TX, USA b Physics, Faculty of Science and Technology, Queensland University of Technology, Brisbane, Australia Accepted 25 January 2011 Contents 1. Introduction The problem Rationale for breast conservation therapy Rationale for accelerated partial breast irradiation (APBI) Accelerated partial breast irradiation (APBI) techniques External beam conformal radiation therapy techniques D-CRT Intensity modulated radiation therapy (IMRT) Tomotherapy Volumetric modulated arc therapy (VMAT) Proton therapy Discussions Comparison of EBCRT techniques Patient setup: supine position and prone position Target delineation Patient set-up errors and organ motion IGRT and APBI Dose fractionation Hypofractionation APBI in Asia Clinical issues Patient selection Published randomized clinical trials On going randomized clinical trials Health economics Further research Optimal technique Patient selection Target volume definition and delineation Optimal dose and fractionation scheme Imaging and pathology Conclusions Conflict of interest Corresponding author. Tel.: ; fax: address: christopher.njeh@usoncology.com (C.F. Njeh) /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 2 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 1 20 Reviewers References Biographies 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 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] 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 Gy is delivered to the entire breast over 5 6 weeks (1.8 2 Gy per fraction). In most patients, a boost dose of 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 Group- EBCTCG), 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 = ). Further, the relative risk of mortality was (95% CI = ), corresponding to an estimated 8.6% (95% CI = %) relative excess mortality if radiation therapy was omitted. BCT is well tolerated with minimal long-term complications, favorable cosmetic out-

3 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 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] 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 ( ). 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 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

4 4 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 1 20 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] 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 D-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].

5 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 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. Author No of cases Follow up (months) Fractionation scheme IBF Good/Excellent cosmesis Vicini et al. [73] Gy 10 (bid) 6% n/a Vicini et al. [74] Gy 10 (bid) 0% 90% Chen et al. [75] Gy 10 (bid) 1.1% 89% Taghian et al. [76] Gy 4 (bid) $ 2% 97% Formenti et al. [77] (minimum) 5.0, 5.5, 6.0 Gy 5 (10 days) 0% 100% Formenti et al. [78] Gy 5 (10 days) 0% n/a Magee et al. [79] (mean) Gy 8 (10 days) & 25% n/a Leonard et al. [80] median 3.85 Gy 10 (bid) 0% n/a Hepel et al. [81] Gy 10 (bid) n/a 81.7% Jagsi et al. [82] 34 > Gy 10 n/a 79.5% 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 ( ). 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 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-

6 6 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 1 20 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 %) than in those who developed unacceptable cosmesis (mean V50 = 46.1%, range %). The same trend was observed for V100 [82] 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 HiARt TM 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, ]. 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 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] 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].

7 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 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 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 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, 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 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 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

8 8 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 1 20 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 [ ]. 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] 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 IGRT and APBI More often than not, in an effort to avoid missing the planned target, the PTV includes a large amount of normal

9 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 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 PTV- EVAL (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 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 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 [ ] 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 ) the rate of local-regional tumor recurrence at 5 years was 2.2% (95% CI ) in the 40 Gy group and 3.3% (95% CI ) 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-

10 10 C.F. Njeh et al. / Critical Reviews in Oncology/Hematology 81 (2012) 1 20 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] 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 to 72% in [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 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 [ ]. 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 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