Radiotherapy and Oncology

Radiotherapy and Oncology 106 (2013) 15 20 Contents lists available at SciVerse ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com Review Accelerated fractionation with a concurrent boost for early stage breast cancer Gary M. Freedman a,, Julia R. White b, Douglas W. Arthur c, X. Allen Li d, Frank A. Vicini e a University of Pennsylvania, Philadelphia; b Ohio State University, Columbus; c Virginia Commonwealth University, Richmond; d Medical College of Wisconsin, Milwaukee; and e Michigan Healthcare Professionals/21st Century Oncology, Royal Oak, United States article info abstract Article history: Received 4 August 2012 Received in revised form 25 November 2012 Accepted 6 December 2012 Available online 17 January 2013 Keywords: Breast cancer Radiation therapy Hypofractionation Radiation fractionation Concurrent boost Hypofractionated radiation refers to treatment with greater than 2 Gy per fraction, usually in fewer number and an overall shorter treatment period, compared to conventional radiation fractionation. Randomized prospective trials of hypofractionated whole breast irradiation (WBI) have demonstrated comparable outcomes as conventional fractionation in early stage postlumpectomy radiation in selected groups of patients. These data have changed the traditional radiobiology estimation of the alpha/beta ratio that predicted fractionation sensitivity for breast cancer, suggesting that further increase in dose per fraction is possible for early stage breast cancer without significantly increasing late effects. Many questions remain regarding hypofractionated WBI and span from optimal patient selection to radiation technique including dose planning optimization and the incorporation of a tumor bed boost. A concurrent radiation boost has been studied in a number of single institution studies and has shown to be feasible with acceptable acute and short-term late toxicity. A phase III trial by the Radiation Therapy Oncology Group (RTOG 1005) in North America and other trials in Europe are currently studying in-breast cancer control from hypofractionated WBI with a concurrent tumor bed boost. Results from these current trials could improve the acceptance and broaden the applicability of hypofractionation treatment courses for the treatment of patients with early stage breast cancer. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 106 (2013) 15 20 Breast-conserving surgery and radiation is a standard alternative to mastectomy for most patients with stage I and II invasive breast cancer [1]. Postlumpectomy whole breast irradiation (WBI) is now associated with very high local control rates of 90 95%, rates that are higher than those seen in the early randomized trials due to improvements in early detection, patient selection, surgical and radiation techniques, and use of systemic therapy [2,3]. This reduction in local recurrence because of postlumpectomy radiation is also associated with improved overall survival [4]. Yet in spite of these benefits of postlumpectomy radiation, the number of women treated with breast-conserving surgery (BCS) but without radiation in the United States is approximately 15 20%, and the percentage of women in whom radiation is omitted is even higher for patients aged P70 80 years [5 7]. One reason for this may be the extended 6 7 week length of treatment. Delivering postoperative WBI in a shorter period of time could result in greater convenience for patients and greater utilization of postoperative radiation. Cost to the individual and third-party payers, governmental or private insurers, could also be significantly reduced by delivering an effective course of postlumpectomy radiation in half the time as a traditional 30 35 treatment course. Corresponding author. Address: Department of Radiation Oncology, Perelman Center for Advanced Medicine, TRC 4 West, 3400 Civic Center Blvd., Philadelphia, PA 19104, United States. E-mail address: gary.freedman@uphs.upenn.edu (G.M. Freedman). Hypofractionation, or use of larger dose radiation treatments compared to conventional radiation fraction sizes of 1.8 2 Gy per day, has been shown in randomized prospective trials to not be inferior to conventional fractionation for WBI in selected patients with early stage breast cancer. Hypofractionation also generally implies (but not always) the delivery of fewer radiation fractions over a shorter elapsed time interval, i.e. fewer number of weeks to complete treatment than conventional WBI schedules. This review will focus on studies of hypofractionated WBI, and whole breast hypofractionation with concurrent boost, in early stage breast cancer. Articles on partial breast irradiation will not be covered. Hypofractionated WBI for early stage breast cancer Rationale Early laboratory and clinical studies in radiobiology showed that tissues could be generally divided into early responding (tumors and tissues responsible for acute effects observed during radiation) and late responding (responsible for late effects of radiation). Modeling of dose response showed that early responding tissues were less sensitive to effects of radiation fraction size than late responding tissues. The linear quadratic (LQ) radiobiology model predicted that the effect of radiation is different for cell killing by two different components alpha (single hit killing) and 0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2012.12.001

16 Whole Breast Hypofractionation ± Boost beta (two hit killing) [8]. In the LQ model, a tissue that is late responding has a dose response curve modeled best by a low alpha to beta ratio, and one that is early responding a higher alpha to beta ratio. Early radiobiology studies, mostly from squamous cell cancers of the cervix or head and neck, determined that tumor tissue behaved mostly like an acute responding tissue with a high alpha/beta ratio of 10 and normal tissue like a late responding tissue with a low alpha/beta ratio of 3. In that way, smaller fraction sizes of 1.8 2 Gy became customary for radiotherapy in order to exploit this biological differential maximize local control in tumor tissue while minimizing late effects in late responding normal tissue over a course of fractionated radiation. Hypofractionation using a larger radiation fraction size and fewer number of fractions under these assumptions of alpha/beta ratios 10 for tumor effects and 3 for late effects would result in relatively greater late tissue effects for the same tumor control effect. This is generally what was observed clinically in early experiences with large fraction sizes [9]. For the treatment of breast cancer, the early experiences with hypofractionation were also associated with more severe late sequelae [10 12]. The clinical experience with whole breast hypofractionation in breast cancer subsequently improved after better understanding of the LQ model led to a decrease in the total radiation dose to approximately 40 Gy [13,14]. This premise was confirmed clinically by the outcome from a series of randomized clinical trials from the United Kingdom from Royal Marsden Hospital (RMH) and the Standardization of Breast Radiotherapy (START) Group [15 18]. These trials concluded that breast cancer has an alpha/beta ratio for tumor control of 4.6, and normal breast tissue an alpha/beta ratio of 3.4 [17]. When the alpha/beta ratios of the tumor and normal tissue are more approximate to one another such as this, the relative benefit of normal tissue sparing with conventional fractionation is diminished and there is more of a rationale for hypofractionation [19]. Radiobiologic models using this newer understanding of the alpha/beta ratio for breast cancer show that increasing fraction size with a sufficiently large reduction of the total radiation dose can keep late toxicity comparable to that seen with conventional fractionation without decreasing the rates of tumor control [20]. Prospective randomized trials of hypofractionated WBI The prospective randomized clinical trials evaluating efficacy of hypofractionated WBI for in-breast cancer control in comparison to standard WBI are shown in Table 1 [15 18,21]. These phase III randomized trials were similar in their design to test that in-breast cancer recurrence at 5 years in the hypofractionated arms was not inferior to that achieved by standard fractionated WBI. The Royal Marsden Hospital (RMH), Sutton and Gloucestershire Oncology Centre used a hypofractionated WBI schedule that maintained the same 5 week length of treatment for all three arms [15,16]. The local recurrence rates at 10 years were 12.1% for 50 Gy, 14.8% for 39 Gy, and 9.6% for 42.9 Gy (p = 0.027). There was a statistically significant change in breast appearance with the largest daily fraction size of 3.3 Gy to a total of 42.9 Gy compared with the other treatment arms. However, this change in baseline size and shape of the breast was considered mild in most patients, and the number with a severe difference was relatively low (10.1%, 3.4% and 5.6%, respectively). The START trials consisted of two separate studies evaluating different hypofractionation schedules; START trial A and START trial B [17,18]. There were no differences in 5 year local control between the hypofractionation arms and standard fractionation in each trial (Table 1). Rates of distant relapse, disease-free and overall survival were also similar. There was no significant difference in patient-reported breast, arm, or shoulder-related symptoms between regimens in trial A or B [22]. The rate of moderate or marked change in skin appearance after radiation was significantly lower for 39 Gy versus 50 Gy in trial A (41.6 Gy and 50 Gy did not vary significantly) and for 40 Gy versus 50 Gy in trial B. Symptoms related to the arm and shoulder did not differ significantly between regimens in trial A or B. This is important in addressing potential concerns about increased late effect risks that have historically been associated with larger daily radiation fraction sizes. In Canada, the Ontario Clinical Oncology Group (OCOG) trial randomized patients to 42.5 Gy in 16 (2.67 Gy) fractions over 22 days versus 50 Gy in (2 Gy) 25 fractions over 35 days without boost [21]. These two radiation schedules were associated with equivalent 10-year local recurrence risks of 6.2% and 6.7%, respectively. The trial also addressed late effect risks and reported that the cosmetic appearance was considered good or excellent in approximately 70% of women in both groups. There were similarly no reported differences in 10-year skin and subcutaneous tissue and cardiac complications. More recently, the UK FAST trial looked at photographic breast appearance as the primary endpoint (not local control) to evaluate more abbreviated WBI hypofractionation schedules [23]. Patients were randomized to 50 Gy in 25 fractions over 5 weeks, versus a schedule of one fraction a week for 5 weeks using 5.7 Gy per fraction (total 28.5 Gy) or 6.0 Gy per fraction (total 30 Gy). There was a lower incidence of acute RTOG grade 2 and 3 radiation dermatitis in the weekly five fraction regimens compared to conventional fractionation (grade 2/3 35.5/10.9% for 50 Gy versus 11.7/2.7% for 30 Gy versus 8.5%/1.9% for 28.5 Gy). For late effects, there was a significant worsening in 2 year photographic breast appearance and 3 year cosmetic assessment with hypofractionation onceweekly as compared to the conventional fractionation arm. The risk ratio for mild or marked change on photographic breast appearance was 1.7 (p < 0.001), and 1.15 (p = 0.489), respectively. The cosmetic assessments showed a moderate/marked adverse effect of the breast in 17.3% for 30 Gy (p < 0.001), 11.1% for 28.5 Gy Table 1 Trials of hypofractionated WBI versus conventional fractionation in early stage breast cancer. Trial Years conducted # Fractionation Gy/# of fractions Boost (%) Local recurrence (%) Time point RMH/GOC) [15,16] 1986 1998 470 50/25 74 12.1 10 years 466 42.9/13 75 9.6 474 39/13 74 14.8 START A [17] 1998 2002 749 50/25 60 3.6 5 Years 750 41.6/13 61 3.5 737 39/13 61 5.2 START B [18] 1999 2001 1105 50/25 41 3.3 5 Years 1110 40/15 44 2.2 OCOG [21] 1993 1996 612 50/25 0 6.7 10 Years 622 42.5/16 0 6.2 RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre; START: Standardization of Breast Radiotherapy; OCOG: Ontario Clinical Oncology Group.

G.M. Freedman et al. / Radiotherapy and Oncology 106 (2013) 15 20 17 (p = 0.18), and 9.5% for 50 Gy. Most of these late effects were breast shrinkage or induration. After a median follow-up of 3 years, there have been only 2 local recurrences. 2010 American Society of Radiation Oncology Consensus Statement The American Society of Radiation Oncology (ASTRO) convened a task force of experts to make consensus recommendations on the use of hypofractionated WBI in early stage breast cancer [24]. After a review of the available literature and randomized trials, there was consensus that hypofractionated WBI was suitable outside of a clinical trial in the following patients: breast cancer patients with pt1 2 tumor size, N0 nodal disease, age greater than 50 years old, patients who do not receive chemotherapy and in patients where acceptable dose homogeneity can be achieved. Questions that remain about hypofractionated WBI There has not been significant adoption of hypofractionated WBI in the United States. This may in part be due to many clinical questions that remain concerning hypofractionated WBI that existing data from randomized trials do not address. These questions include whether the range of patients acceptably treated with a hypofractionated WBI treatment course can be widened to include patients with large breast sizes, those at higher risk of in-breast failure and receiving chemotherapy. Additionally there remain questions surrounding late effects of these accelerated treatment courses. A frequent question is whether the inclusion criteria for hypofractionated WBI can be widened. The randomized trials of hypofractionated WBI treated few women with large breast sizes, and in the OCOG study used large patient chest wall separation (a surrogate for large breast size) as an exclusion criterion. Radiation dermatitis and late fibrosis have both been linked to radiation dose inhomogeneity, large breast size, and larger radiation fraction size [25 27]. In addition, the trials of whole-breast hypofractionation consisted of mostly lower-risk patients, so as a result the applicability and safety of hypofractionation in women treated with adjuvant systemic chemotherapy is not well known. Use of chemotherapy was associated with worse long-term fibrosis and cosmetic outcome in the past [28], and it is unknown whether this is still the case in patients treated with hypofractionated radiation and modern anthracycline- and taxane-based regimens in use today. There is also a concern for late effects with hypofractionation even with the 5 10 year follow-up in existing studies. Cardiac disease, as an example, from radiation has a particularly late interval to onset with a mean of about 10 20 years. In the Surveillance Epidemiology and End Results (SEER) database from 1973 to 1992, there was an excess rate of fatal myocardial infarction of 1 2% over the course of 8 18 years from treatment for patients receiving leftsided versus right-sided adjuvant radiation [29]. Hypofractionated WBI and concurrent boost Another major factor limiting the use of WBI and hypofractionation is the use of a lumpectomy cavity boost. In two prospective randomized studies in invasive breast cancer, the use of a boost after WBI reduced the risk of local recurrence even in patients with negative resection margins [30,31]. In both studies, the boost was given sequentially after WBI. An international survey of Radiation Oncologists in 2001 2002 showed that 85% of American and 75% of European respondents would deliver a boost even with negative margins after WBI [32]. None of the 5 prospective studies for hypofractionated WBI in Table 1 examined a hypofractionated dose schedule that is biologically equivalent to the cumulative dose from a tumor bed boost (typically 60 66 Gy in 30 33 fractions). A standard fractionated sequential boost (5 fractions of 2 Gy) was optional per the investigator in the START A and B trials, so it was delivered in only a percentage of patients and in a nonrandomized fashion. The use of a sequential boost of 1 2 weeks in these studies extended the overall treatment time reducing the potential time-saving benefit to patients from hypofractionation. In regard to the use of a tumor bed boost, the ASTRO task force concluded that there were few data to define the indications for and toxicity of a tumor bed boost in patients treated with hypofractionated WBI [24]. The task force recommended that hypofractionated WBI not be used when a tumor bed boost was thought to be indicated. When the boost was indicated, there was lack of consensus regarding the appropriateness of hypofractionation. The current concern about the use of hypofractionated WBI when a boost is indicated has led to research into methods for integrating the tumor bed boost with hypofractionated radiation. This has the potential of expanding the indications for hypofractionation beyond that recommended by the 2010 ASTRO consensus conference statement. Studies of WBI and concurrent boost There have been several comparative planning studies of simultaneous boost with WBI for postlumpectomy radiation (Table 2). Guerrero et al. [33] estimated using the LQ model that a treatment course delivering 1.8 Gy 25 treatments to the whole breast while delivering a simultaneous integrated boost (SIB) of 2.4 Gy 25 treatments to the tumor bed was biologically equivalent to 45 Gy (1.8 Gy 25) whole breast plus a sequential boost of 20 Gy (2 Gy 10). Among their findings was that IMRT could often improve lung and heart dose compared with a simultaneous electron beam boost, but delivered higher dose to normal breast tissue. However, for deeper tumor locations, the IMRT boost improved dose homogeneity and normal breast tissue receiving high doses. Hurkmans et al. [34] reported a planning study of SIB using inverse optimization compared to a sequential 3-field boost. There was similar volume of PTV breast or PTV boost receiving >95% of the prescribed dose. There was also similar mean heart and lung dose. The SIB was more conformal than sequential boost and the dosimetric planning revealed that the SIB plans reduced the volume of breast PTV excluding the boost PTV that received >95% of the prescribed boost dose. Singla et al. [35] compared SIB plans using IMRT versus 3D conformal radiation that delivered a simultaneous boost of 16 Gy above the whole breast dose of 50.4 Gy. SIB using IMRT was able to reduce mean lung dose and maximum heart dose, with a nonsignificant increase in the contralateral breast dose. Furthermore a significant improvement in target dose conformality by up to 67% was documented. Van der Laan et al. reported a comparative planning study of simultaneous integrated boost in 30 patients with left-sided breast cancer [36]. The whole breast planning target volume (PTV) received 1.81 Gy and boost PTV received 2.3 Gy, respectively, with concurrent boost. These plans were compared with a sequential boost technique. With the integrated boost, the mean volume receiving P107% of the breast dose was reduced by 20%, the mean volume of breast tissue outside the boost PTV receiving P95% of the boost dose was reduced by 54%, and the mean heart and lung dose was reduced by 10%. Clinical outcomes have now been reported with techniques of conventionally fractionated whole breast irradiation of 1.8 Gy per fraction and simultaneous integrated boost. McDonald et al. [37] reported retrospectively the 3-year outcomes of 354 patients treated with 1.8 cgy whole breast fractionation and a simultaneous boost to 2.14 2.4 Gy to the tumor bed (cumulative 45 50.4 Gy in 25 28 fractions whole breast and 59.92 60 Gy in 25 28 fractions tumor bed). The 3-year local recurrence rate was 2.8%. In a subgroup of 142 cases followed up for a minimum of three years the

18 Whole Breast Hypofractionation ± Boost Table 2 Selected comparative planning studies of whole breast irradiation with simultaneous boost. Author and Year Whole breast fractionation Lumpectomy volume fractionation Guerrero 2004 [33] 1.8 Gy 25 = 45 Gy 2.4 Gy 25 = 60 Gy Hurkmans 2006 [34] 1.66 Gy 31 = 51.46 Gy 2.38 Gy 31 = 73.78 Gy Singla 2006 [35] 1.8 Gy 28 = 50.4 Gy 2.37 Gy 28 = 66.36 Gy van der Laan 2007 [36] 1.81 Gy 28 = 50.68 Gy 2.3 Gy 28 = 64.4 Gy cosmetic result was good or excellent in 96.5%. The Netherlands group of Bantema-Joppe et al. have also reported clinical outcomes with this conventional whole breast fractionation schedule and concurrent boost. They have reported 3-year local control of 99.6% in 752 patients treated in 28 fractions (1.8 Gy whole breast with a simultaneous boost of 2.3 2.4 Gy tumor bed) [38]. They have also reported toxicity and cosmetic outcomes at 3 years [39]. Out of 436 available patients, the rate of grade P2 fibrosis in the boost area was 8.5% and non-boost 49.4%. There was a fair poor cosmetic result in 39.7 cases. The rate of fibrosis in the boost was associated with having radiotherapy prior to chemotherapy, and fibrosis outside of the boost was associated with reresection and larger tumor size. Clinical studies of hypofractionated WBI with concurrent boost There have been several single institution studies of hypofractionated WBI with a concurrent boost for early stage breast cancer. The prospective clinical trials have relatively short-term follow up and not all have reported in-breast local recurrence rates (Table 3). These trials did not include regional lymph node irradiation. Formenti et al. [40] reported a clinical trial of IMRT, hypofractionation, and a concomitant boost that shortened treatment length to 3 weeks. Ninety-one patients were treated with a whole-breast dose of 40.5 Gy delivered in 15 fractions with a concomitant boost of 0.5 Gy per day for a total tumor bed dose of 48 Gy. There were 2 acute grade 3 toxicities that did not require treatment breaks. Late soft tissue fibrosis was grade 1 in 48% and grade 2 in 3%. Grade 1 pigmentation change was noted in 70%. Breast pain was grade 1 in 8% and grade 2 in 2%. Skin telangiectasias were grade 1 in 3% and grade 2 in 2%. There was 1 regional node recurrence with a median follow-up of 12 months. From the same institution, Ciervide et al. [41] reported the 5-year results of 145 patients with ductal carcinoma in situ treated on two consecutive trials of whole breast hypofractionation with concurrent boost. The fractionation was 40.5 42 Gy in 15 fractions to the whole breast with a concurrent daily boost of 0.5 Gy (total 48 49.5 Gy). After a median follow-up of 5 years there was a 4.1% rate of local recurrence. Chadha et al. [42] reported on the acute toxicity in the first 50 patients enrolled on a prospective trial. The whole breast dose was 2.7 Gy per fraction in 15 fractions to a total dose of 40.5 Gy with a concomitant boost dose of 0.3 Gy per fraction to a total dose of 45 Gy. These were compared to a control group of patients treated in the same time period with a sequential boost. There was a lower incidence of Pgrade 2 skin toxicity with a concurrent boost (4% versus 24%, p = 0.0015) and a lower incidence of breast pain (p = 0.045). There were no acute grade 3 or 4 toxicities or reported late soft tissue toxicities. Freedman et al. [43] reported a prospective trial of 75 patients treated with a whole breast dose of 2.25 Gy per day for 20 fractions for a total of 45 Gy over 4 weeks. An incorporated tumor bed boost gave simultaneously to the tumor bed 2.8 Gy per fraction for a total of 56 Gy. All breast sizes and women treated with adjuvant chemotherapy before radiation were permitted on study. The maximum acute skin toxicity by the end of treatment was grade 0 in 9 patients (12%), grade 1 in 49 (65%), and grade 2 in 17 (23%). There was no grade 3 or higher skin toxicity. After radiation, all grade 2 toxicities had resolved by 6 weeks. The 5-year local recurrence rate is 2.7%. The cosmetic outcomes when reported in these trials have been good or excellent in 91 100% of patients [41,44,45]. Current large cooperative group randomized trials of simultaneous boost and WBI The Radiation Therapy Oncology Group has opened a phase III randomized trial (RTOG 1005) in May 2011 that proposes to establish the hypofractionated dose to the highest risk portion of the breast around the lumpectomy cavity delivered as a concurrent boost over 3 weeks that results in local in-breast cancer control that is not inferior to standard WBI with sequential boost (Table 4). Patient inclusion criteria are defined to include patients at higher than average risk for local recurrence who could most benefit from the addition of a tumor bed boost age less than 50 years, node positive breast cancer, lymphovascular space invasion, presence of an extensive in situ ductal component (EIC), close resection margins, focally positive resection margins, and/or non-hormone sensitive breast cancer as examples. The primary endpoint is non-inferiority of local control, with secondary endpoints examining survival, breast-related symptoms and cosmesis, cost, and radiation physics and biological correlative studies. The control arm is WBI, with a standard sequential tumor bed boost. The WBI fractionation for the control arm can be either Table 3 Phase I/II trials of whole-breast hypofractionation and concurrent boost reporting in-breast recurrence rates in early stage breast cancer. Trial Accrued Median F/U (yr.) Fractionation In-breast recurrence Whole breast fractionation Lumpectomy volume Fractionation Formenti [40] 91 1 2.7 Gy 15 = 40.5 Gy 3.2 Gy 15 = 48 Gy 0 Teh [47] 15 1 2.65 Gy 16 = 42.2 Gy 3.28 Gy 16 = 52.48 Gy 0 Cante [44] 463 2.3 2.25 Gy 20 = 45 Gy 2.75 Gy 20 = 55 Gy 0 Morganti [48] 201 2.6 2.5 Gy 16 = 40 Gy 2.75 Gy 16 = 44 Gy 0 2Gy25 = 50 Gy 2.4 Gy 25 = 60 Gy Corvo [45] 377 3 2.3 Gy 20 = 46 Gy 3.5 Gy 5 = 52 Gy 0 Ciervide [41] 145 5 2.8 Gy 15 = 42 Gy2.7 Gy 15 = 40.5 Gy 3.3 Gy 15 = 49.5 Gy3.2 Gy 15 = 48 Gy 4.1% Freedman [43] 75 5.8 2.25 Gy 20 = 45 Gy 2.8 Gy 20 = 56 Gy 2.7%

G.M. Freedman et al. / Radiotherapy and Oncology 106 (2013) 15 20 19 Table 4 Phase III randomized trials of whole breast irradiation comparing sequential boost to concurrent boost in early stage breast cancer. Trial Primary endpoint Targeted accrual Concurrent boost arm Whole breast dose (Gy) Lumpectomy PTV dose (Gy) RTOG 1005 In-breast cancer recurrence 2300 40 (2.67 Gy 15 F) 48 (3.2 Gy 15 F) IMPORT HIGH Palpable induration 820 I: 36 (2.3 15 F) 48 (3.2 Gy 15 F) II: 36 (2.3 15 F) 53 (3.53 15 F) IMRT MC2 Breast Appearance 500 50.4 (1.8 Gy 28 F) 64.4 (2.3 28 F) conventional 50 Gy in 25 (2 Gy) fractions or 42.5 Gy in 16 (2.67 Gy) fractions. The sequential tumor bed boost in the control arm is 12 14 Gy in 6 7 fractions, or a total of 62 64 Gy. The WBI dose-fractionation in the experimental arm is 40 Gy in 15 fractions, 2.67 Gy per fraction with the tumor bed boost volume concurrently receiving 3.2 Gy per fraction and a total tumor bed dose after 15 fractions of 48 Gy. This would result in an equivalent tumor bed dose (assuming an alpha beta ratio of 4, and correcting for proliferation effects) of approximately 63 66 Gy in 2 Gy fractions. A range of equivalent dose is necessary due to an estimate for increased biologic effectiveness due to the fewer weeks of treatment with a concurrent rather than sequential boost. There is no regional lymph node irradiation in either study arm. Participating institutions have several acceptable technique options including use of 3D conformal or IMRT techniques [46]. The IMPORT (Intensity Modulation and Partial Organ) High trial in the United Kingdom was opened in 2009 by the investigators who ran the START trials (Table 4). This trial s goal is to evaluate two different hypofractionated concurrent boost regimens for the effect on breast appearance in comparison to those received sequential boost. The 3 arm trial has a control arm of 40 Gy WBI in 15 fractions with a sequential boost of 16 Gy in 8 fractions over 4½ weeks. The two experimental arms specify a whole breast dose, quadrant dose and then the lumpectomy volume site dose; postulating different dose levels based on regions of risk within the breast. Similarly, the IMRT-MC2 trial was opened in 2011 by the University of Heidelberg with the goal to determine impact of the concurrent boost regimens effect on breast appearance in comparison to those who have received a sequential boost following WBI (Table 4). This study is unique in that it uses conventionally fractionated WBI at 1.8 Gy and only the lumpectomy site volume is hypofractionated with the concurrent boost. Results from these accruing trials will enable all patients requiring WBI to have an option of a shorter radiation course without sacrificing efficacy or negatively impacting breast appearance. Conclusions Prospective randomized trials have established the principle that hypofractionation may be used for WBI with acceptable toxicity and equal local control as conventional fractionation in appropriately selected patients. However, for hypofractionation to become more widely applied in the United States, more data are needed about the use and integration of a boost, treatment of higher risk women receiving neoadjuvant or adjuvant chemotherapy, or results in special subgroups such as women with a large breast size. Use of a concurrent boost is a promising method of maintaining a shorter radiation schedule of whole breast hypofractionation, but also gaining the local control benefit of a lumpectomy cavity boost. A phase III trial RTOG 1005 is studying hypofractionated WBI with a concurrent boost over 3 weeks in such higher risk patients. 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