Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy

The Breast 24 (2015) 739e744

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Original article

Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy Jessica L. Wobb a, *, Chirag Shah b, Maha S. Jawad c, Michelle Wallace c, Joshua T. Dilworth c, Inga S. Grills c, Hong Ye c, Peter Y. Chen c a

Dept of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA Cleveland Clinic, Dept of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH, USA c Dept of Radiation Oncology, Beaumont Health System, Royal Oak, MI, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 April 2015 Received in revised form 21 July 2015 Accepted 12 September 2015 Available online 12 October 2015

Purpose: Brachytherapy-based APBI (bAPBI) shortens treatment duration and limits dose to normal tissue. While studies have demonstrated similar local control when comparing bAPBI and whole breast irradiation using intensity modulated radiotherapy (WBI-IMRT), comparison of late side effects is limited. Here, we report chronic toxicity profiles associated with these two treatment modalities. Methods: 1034 patients with early stage breast cancer were treated at a single institution; 489 received standard-fractionation WBI-IMRT between 2000 and 2013 and 545 received bAPBI (interstitial 40%, applicator-based 60%) between 1993 and 2013. Chronic toxicity was evaluated
6 months utilizing CTCAE version 3.0; cosmesis was evaluated using the Harvard scale. Results: Median follow-up was 4.6 years (range 0.1e13.4) for WBI-IMRT versus 6.7 years (range 0.1e20.1) for bAPBI (p < 0.001). Compared to WBI-IMRT, bAPBI was associated with higher rates of
grade 2 seroma formation (14.4% vs 2.9%, p < 0.001), telangiectasia (12.3% vs 2.1%, p ¼ 0.002) and symptomatic fat necrosis (10.2% vs 3.6%, p < 0.001). Lower rates of hyperpigmentation were observed (5.8% vs 14.5%; p ¼ 0.001). Infection rates were similar (3.3% vs 1.3%, p ¼ 0.07). There was no difference between rates of fair (6.1% vs. 4.1%, p ¼ 0.30) or poor (0.2% vs. 0.5%, p ¼ NS) cosmesis. Mastectomy rates for local recurrence (3.1% for WBI-IMRT and 1.2% for bAPBI, p ¼ 0.06), or for other reasons (0.8% and 0.6%, p ¼ 0.60) were similar between groups. Conclusion: With 5-year follow-up, WBI-IMRT and bAPBI are associated with similar, acceptable rates of toxicity. These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in a safe and efficacious manner. © 2015 Elsevier Ltd. All rights reserved.

Keywords: APBI IMRT Chronic toxicity Breast cancer

Introduction Multiple randomized controlled trials comparing mastectomy to breast conserving therapy (BCT), consisting of lumpectomy followed by whole breast irradiation (WBI), have consistently demonstrated equivalent clinical outcomes for definitive management of early stage breast cancer [1e4]. As such, a focus on treatments that maintain quality of life without jeopardizing cancer control or survival rates has become of increasing interest. Studies

* Corresponding author. Tel.: þ1 724 272 6143. E-mail address: [email protected] (J.L. Wobb). http://dx.doi.org/10.1016/j.breast.2015.09.004 0960-9776/© 2015 Elsevier Ltd. All rights reserved.

have shown that up to 20% of patients fail to receive adjuvant radiotherapy due to a variety of factors, including travel distance to a radiation facility and protracted treatment schedules, which are traditionally 3e6.5 weeks in duration [5,6]. Accelerated partial breast irradiation (APBI) represents a treatment modality that shortens adjuvant radiotherapy to five days or less [7]. This modality may translate into improved quality of life by reducing treatment duration, increasing the accessibility of BCT, and potentially reducing toxicities by treating smaller volumes of normal breast tissue, heart, and regional lymphatics. Commonly utilized APBI techniques include three-dimensional conformal external beam (3D-CRT) and brachytherapy-based (bAPBI) radiotherapy. While prospective studies and matched-

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pair analyses comparing APBI to WBI have demonstrated excellent long-term clinical outcomes [8,9], documentation of late toxicities remains relatively sparse. It is known, however, that toxicity profiles can vary significantly between APBI techniques. An interim analysis of 3 years of follow-up from the RAPID trial, which randomized patients to 3D-CRT or WBI, demonstrated inferior cosmetic outcomes (29% fair to poor vs 17%; p < 0.001) with increased rates of grade 1 (53% vs 43%; p < 0.001), and 2 (12% vs 3%; p < 0.001) chronic toxicity in the APBI group compared to WBI [10]. On the other hand, Polgar et al. reported more favorable cosmesis with bAPBI (18.8% fair to poor vs 34.4%; p ¼ 0.009) compared to photon-based WBI with an average of 5 years of follow-up [11]. The administration of WBI has evolved over the past decade, incorporating 3dimensional-conformal techniques and intensity modulation. WBI-IMRT has been shown in prospective and randomized trials to decrease both acute and chronic toxicity when compared to more conventional WBI techniques, such as standardized 2D planning with wedge-based external beam radiotherapy [12e14]. To date, there are no data comparing bAPBI to WBI-IMRT in the context of toxicity and cosmetic outcomes with prolonged followup. Therefore, the purpose of this study is to compare chronic toxicity rates for patients treated with these two modalities. Materials/methods

brachytherapy consisting of 50 Gy (0.52/Gy/h over a 96 h period) or high-dose-rate (HDR; N ¼ 99) brachytherapy to a total of 32e34 Gy given twice daily (BID) in 8e10 fractions. Single-lumen MammoSite (Hologic, Inc., Bedford, MA; N ¼ 207), multi-lumen MammoSite and Contura (SenoRx, Inc., Aliso Viejo, CA; N ¼ 101) balloons, and SAVI strut-based (Cianna Medical, Aliso Viejo, CA; N ¼ 19) applicators were used to deliver HDR brachytherapy with a dose of 34 Gy given BID in 10 fractions. Cosmesis and toxicity assessment Chronic toxicity was defined as an event occurring
6 months after treatment completion. Toxicity was assessed by the treating radiation oncologist at regularly scheduled follow-up visits. Scoring was performed utilizing the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0 (CTCAE www. eortc.be/services/doc/ctc/ctcaev3.pdf) on a scale of 0e4 based on clinician assessment. Events included breast pain, hyperpigmentation, hypopigmentation, breast edema, induration/fibrosis, volume reduction, and telangiectasia. Of note, there are no CTCAE v3.0 “grade 3” designations for hypopigmentation, edema, fat necrosis, or seroma formation. Fat necrosis was graded as a “1” if asymptomatic, found only on mammogram, and as a “2” if symptomatic. Seroma formation was graded in a similar fashion. Cosmesis was evaluated on a four-category scale, including excellent, good, fair and poor, using the Harvard criteria [17].

Patient population Statistical methods A total of 1034 patients with early stage breast cancer, stage 0 to IIB, were treated with adjuvant breast irradiation at a single institution from 1993 to 2013 as part of their breast conserving therapy. Four hundred eighty-nine patients received WBI-IMRT from 2000 to 2013, and 545 received bAPBI from 1993 to 2013. Patients who received WBI prior to 2000 were treated with opposed tangents with or without wedges and were not included in this analysis. This study was approved by the WBH Institutional Review Board (HIC no. 2012-220).

Categorical variables were analyzed using the Pearson ChiSquare test and continuous variables using the independent samples T-test. The KaplaneMeier method was utilized to calculate ipsilateral breast tumor recurrence (IBTR). Time to IBTR was calculated from the date of radiotherapy completion to the date of the event. Analyses were performed using SPSS version 20 (SYSTAT Software, Chicago, IL). P values of 0.05 were considered statistically significant.

Details of radiotherapy

Results

Patients treated with WBI-IMRT first underwent a 3D CT scan in the supine position for planning purposes with Alpha Cradle immobilization (Smithers Medical Products, Canton, OH). Active Breathing Control was used for left-sided tumors at the discretion of the treating physician [15]. A median of 45 Gy was delivered to the whole breast (range 40.05e50.4 Gy) with a median 16 Gy supplemental boost to the surgical cavity (range 0e22 Gy, 98% receiving boost). 9.4% of patients received radiotherapy either to the level III/supraclavicular nodes (N ¼ 39; 8.0%) or full axilla (N ¼ 7; 1.4%). Radiation plans between 2000 and 2002 were created with the use of forward planning, utilizing a “field in field” technique delivered with multiple static multi-leaf collimator segments (MLC) with optimized dose homogeneity (Pinnacle, ADAC laboratories, Milpitas, CA), the details of which have been published previously [16]. After 2002, planning was performed with inverseplanned multi-segment IMRT, with objectives to limit the volume of the breast receiving 105% of the prescription dose to 15% (V105 < 15%), the V110 < 10%, and the V115 < 5%. Brachytherapy-based APBI consisted of multi-planar interstitial needle placement, single-and multi-lumen balloons, and strutbased implants Patients who received 3D-CRT (N ¼ 217) were excluded from this analysis, as recently published randomized data has shown inferior rates of chronic toxicity and cosmesis with this technique compared to WBI [10]. Patients treated with interstitial needles received either low-dose-rate (LDR; N ¼ 119)

Patient characteristics, including clinical, pathologic, and treatment-related factors, are presented in Table 1. WBI-IMRT patients were significantly younger (median 61 vs 65 years old, p < 0.001), with larger tumors volumes (median size 13.8 vs 10.9 mm; p < 0.001) and were more likely to be node positive (15% vs 7.3%; p < 0.001) and with higher-grade disease (20% vs 18%, p ¼ 0.03). WBI-IMRT patients were also more likely to receive adjuvant hormonal therapy (70% vs 59%; p < 0.001) and chemotherapy (70% vs 15%; p < 0.001). Median follow up time was 6.7 years (range 0.1e20.1) and 3.9 years (range 0.1e13.4) for bAPBI and WBI-IMRT, respectively (p < 0.001); median follow-up for interstitial APBI was 13.0 years as compared with 5.1 years for applicator based APBI. Rates of Grade 2 or greater maximum chronic toxicity by technique are presented in Table 2. WBI-IMRT was associated with higher rates of hyperpigmentation (14.5% vs 5.8%; p ¼ 0.001), whereas bAPBI had higher rates of telangiectasia (12.3% vs 2.1%; p < 0.001), symptomatic fat necrosis (10.2% vs 3.6%; p < 0.001), and seroma formation (14.4% vs 2.9%; p < 0.001). There were no significant differences noted regarding rates of hypopigmentation, edema, pain, induration/fibrosis, or volume reduction (all p > 0.05). Infection rates were similar (1.3% vs 3.3%, p ¼ 0.07) between groups. Table 3 presents rates of grade 3 or greater toxicity by technique. No differences in rates of hyperpigmentation, breast pain, induration/fibrosis, volume reduction,

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Table 1 Patient characteristics.

Age at diagnosis (years) Mean Median Range Follow up (years) Mean Median Range Menopausal status Pre Peri Post Tumor size (mm) Mean Median Range T stage T0 T1 T2 T3 Histology DCIS Invasive ductal Invasive lobular Other Tumor grade I II III Unk N-stage N0 N1 Nx ER status Positive Negative Unknown PR status Positive Negative Unknown Her2 status Positive Negative Unknown Triple negative No Yes Unknown Margin status Negative Close/Positive Unknown Brachytherapy Interstitial LDR Interstitial HDR Single-lumen Multi-lumen SAVI Adjuvant endocrine Yes No Unknown Adjuvant chemotherapy Yes No Unknown

All patients (N ¼ 1034)

bAPBI (N ¼ 545)

WBI-IMRT (N ¼ 489)

p-value

63 63 32e91

65 65 40e91

61 61 32e88

<0.001

6.3 5.2 0.1e20.1

7.9 6.7 0.1e20.1

4.6 3.9 0.1e13.4

<0.001

127 (12%) 36 (4%) 866 (84%)

38 (7%) 19 (4%) 483 (89%)

89 (18%) 17 (4%) 383 (78%)

<0.001

12.3 10.0 0.5e60.0

10.9 10.0 0.5e35.0

13.8 12.0 1.0e60.0

<0.001

230 (22%) 680 (66%) 121 (11.7%) 3 (0.3%)

76 (14%) 425 (78%) 44 (8%) 0

154 (31.4%) 255 (52%) 77 (16%) 3 (0.6%)

<0.001

230 (22%) 710 (69%) 46 (4%) 48 (5%)

76 (14%) 420 (77%) 16 (3%) 33 (6%)

154 (32%) 290 (59%) 30 (6%) 15 (3%)

<0.001

293 425 194 122

180 (33%) 256 (47%) 97 (18%) 12 (2%)

113 (23%) 169 (35%) 97 (20%) 110 (22%)

0.03

916 (88.5%) 113 (11%) 5 (0.5%)

502 (92.1%) 40 (7.3%) 3 (0.6%)

414 (84.6%) 73 (15%) 2 (0.4%)

<0.001

848 (82%) 135 (13%) 51 (5%)

453 (83%) 66 (12%) 26 (5%)

395 (81%) 69 (14%) 25 (5%)

0.33

654 (63%) 246 (24%) 134 (13%)

328 (60%) 121 (22%) 96 (18%)

326 (67%) 125 (25%) 38 (8%)

0.80

48 (5%) 581 (56%) 405 (39%)

25 (4%) 282 (52%) 238 (44%)

23 (5%) 299 (61%) 167 (34%)

0.64

921 (89%) 74 (7%) 39 (4%)

508 (93.2%) 34 (6.2%) 3 (0.6%)

413 (84%) 40 (8%) 36 (7%)

0.13

965 (93%) 68 (6.6%) 4 (0.4%)

506 (92.8%) 38 (7%) 1 (0.2%)

459 (94%) 30 (6%) 0

0.06

N/A

119 (22%) 99 (18%) 207 (38%) 101 (19%) 19 (3%)

N/A

N/A

666 (65%) 293 (28%) 75 (7%)

322 (59%) 178 (33%) 45 (8%)

344 (70%) 115 (24%) 30 (6%)

<0.001

206 (20%) 774 (75%) 54 (5%)

80 (15%) 432 (79%) 33 (6%)

342 (70%) 126 (26%) 21 (4%)

<0.001

(28%) (41%) (19%) (12%)

ER: estrogen receptor; PR: progesterone receptor.

or telangiectasia were noted. No difference in cosmesis was noted with respect to rates of fair (4.1% vs. 6.1%, p ¼ 0.30) or poor (0.5% vs. 0.2%, p ¼ NS) cosmesis with WBI-IMRT and bAPBI, respectively.

Univariate analysis of Grade 2 or greater toxicity was performed on patients with 3 years or greater follow-up and is presented in Table 4.

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Table 2 Grade 2þ maximum chronic toxicity. Toxicity

Cosmesis (fair/poor) Hyperpigmentation Hypopigmentation Edema Pain Induration/fibrosis Volume reduction Telangiectasia Fat necrosisa Seromaa

bAPBI (N ¼ 545)

WBI (N ¼ 489)

N (%)

N (%)

26 25 5 22 17 100 23 54 44 61

16 56 4 17 10 22 11 8 14 11

(6.1%) (5.8%) (1.2%) (5.1%) (3.9%) (23.2%) (5.3%) (12.3%) (10.2%) (14.4%)

p-value

(4.1%) (14.5%) (1.0%) (4.4%) (2.6%) (5.7%) (2.9%) (2.1%) (3.6%) (2.9%)

0.30 0.001 ns ns 0.31 0.72 0.49 0.002 <0.001 <0.001

APBI (N ¼ 545)

WBI (N ¼ 489)

p-value

N (%)

N (%)

1 0 7 3 1 8

2 (0.5%) 10 (2.6%) 3 (0.8%) 1 (0.3%) 0 5 (1.3%)

Bold represents statistical significance. a Pearson Chi-Square test.

Table 3 Grade 3þ maximum chronic toxicity. Toxicity

Cosmesis (poor) Hyperpigmentation Pain Induration/fibrosis Volume reduction Telangiectasia

(0.2%) (1.6%) (0.7%) (0.2%) (1.8%)

ns ns 0.08 ns ns ns

As there are differences in brachytherapy techniques with interstitial and applicator-based treatment, toxicity was evaluated by brachytherapy modality. Rates of grade 2 or greater toxicity are presented in Table 5; hyperpigmentation was seen more frequently with interstitial brachytherapy as was breast edema, volume reduction, fat necrosis, seroma, infection, and induration/fibrosis. Limited differences were seen in the rates of grade 3 or greater toxicity with the exception of increased telangiectasias with applicator-based APBI. At 5 and 10 years, ipsilateral breast tumor recurrence (IBTR) rates were 2.6% and 4.8% with WBI-IMRT and 2.2% and 4.6% with bAPBI, respectively (p ¼ 0.64). No significant differences in mastectomy rates for IBTR (3.1% for WBI-IMRT and 1.2% for bAPBI, p ¼ 0.06), or for reasons other than IBTR (0.8% and 0.6%, p ¼ 0.60) were seen. Discussion With 5-year follow-up, few differences in the rates of chronic toxicity were noted between bAPBI and WBI-IMRT. Significant toxicities (grade 3) were no different by technique, and no grade 4 toxicities were noted. Importantly, in light of recently published data [18e20], no differences in the rate of infections or salvage mastectomies, whether because of IBTR or otherwise, were seen. Also, rates of fair and poor cosmesis, which would be expected to increase with higher rates of chronic toxicity, were comparable

between the techniques. Taken together, these data support the safety of bAPBI and with long term clinical data, support the continued utilization of this technique on and off-protocol. Local control data is limited by the short follow-up in this study and the difference in prognostic factors between groups. Previously, two population-based studies had suggested that bAPBI was associated with higher rates of toxicity compared to WBI. Smith et al. evaluated over 92,000 women treated between 2003 and 2008, utilizing fee-for-service Medicare data with close to 7000 women receiving bAPBI. With short follow up of only one year, the study found bAPBI to be associated with higher rates of subsequent mastectomy (4.0% vs 2.2%), infectious complications (8.1% vs 4.5%), and non-infectious complications including breast pain (14.9% vs 11.7%), fat necrosis (9.1% vs 5.7%), and rib fracture (4.2% vs 3.6%) compared and WBI [18]. Similarly, Presley et al. evaluated over 29,000 women using Medicare data, approximately 4600 of whom received brachytherapy, and found that after 1 year of follow-up, bAPBI was associated with higher rates of complications compared to WBI, particularly wound complications (35.2% vs 18.4%; p < 0.0001) [19]. While provocative in light of the large numbers of patients evaluated, significant limitations of these studies are well documented, including their retrospective nature, short follow up time, lack of clinical and pathologic data, use of billing codes as surrogates for clinical outcomes, and the overall technique which has been shown to lead to widely variable results with the same data sets employed [21,22]. While retrospective, the results of our study demonstrate that when using prospectively collected clinical data with long-term follow up, few differences exist overall, with no significant differences existing in the rate of infectious complications (1.3% vs 3.3%; p ¼ 0.07) or subsequent mastectomy secondary to reasons other than IBTR (0.8% vs 0.6%; p ¼ 0.60). Further, it should be noted that the above studies included all WBI techniques (as they were unable to ascertain the precise radiotherapy technique), while our study used only WBIIMRT, the newest WBI technique that has been shown to reduce rates of toxicity compared with older techniques [12e14]. Additionally, our bAPBI cohort was found to have very low rates of chronic toxicities overall. Only the rates of symptomatic seroma (14.4%), fat necrosis (10.2%), and telangiectasia (12.3%) were significantly elevated compared to WBI-IMRT (2.9% seroma, 3.6% fat necrosis, telangiectasia 2.1%). The results of this study are consistent with data from the initial single-lumen MammoSite trial, which demonstrated similar rates of symptomatic seroma formation (12%) and radionecrosis (9.3%) [23]. Rates of telangiectasia were higher (39.5%) than the current study. One explanation for this may be our inclusion of multi-lumen and interstitial techniques, which can provide superior dosimetry and avoidance of increased skin dosing. Further, long-term follow up of the Hungarian randomized trial found that bAPBI delivered with multi-catheter interstitial brachytherapy was associated with a higher rate of good to excellent cosmesis (81.2%) compared to WBI (65.6%) [24], which is comparable to our rate of 93.9% for bAPBI. However, our rates of good to excellent cosmesis were significantly higher in the WBIIMRT cohort (95.9%), likely secondary to the use of IMRT in the current study. It should be noted that our data is based on physician

Table 4 Univariate analysis of grade 2þ chronic toxicity with minimum 3 year follow-up.

Telangiectasia Hyperpigmentation Seroma Fat necrosis Bold represents statistical significance.

Interstitial (n ¼ 181)

Applicator-based (n ¼ 207)

WBI (n ¼ 226)

0.640 0.194 0.002 0.015

0.053 <0.001 0.014 0.818

0.043 <0.001 0.008 0.002

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Table 5 Toxicity by brachytherapy modality. Toxicity Grade 2 or greater Cosmesis (fair/poor) Hyperpigmentation Hypopigmentation Edema Pain Induration/fibrosis Volume reduction Telangiectasia Fat necrosis Seroma Infection Grade 3 or greater Cosmesis (poor) Hyperpigmentation Pain Induration/fibrosis Volume reduction Telangiectasia

Interstitial (n ¼ 218)

Applicator-based (n ¼ 327)

WBI (n ¼ 489)

p-value

8 16 1 18 5 44 17 0 25 23 7

(4%) (9%) (1%) (10%) (3%) (24%) (9%) (0%) (13%) (12%) (4%)

18 9 4 4 12 56 6 8 19 38 7

(7%) (4%) (2%) (2%) (5%) (23%) (2%) (3%) (8%) (16%) (3%)

16 56 4 17 10 22 11 5 14 11 5

(4%) (15%) (1%) (4%) (3%) (6%) (3%) (1%) (4%) (3%) (1%)

0.17 <0.001 0.55 0.001 0.23 <0.001 0.001 <0.001 <0.001 <0.001 0.16

1 0 1 1 1 17

(1%) (0%) (1%) (1%) (1%) (9%)

0 0 6 2 0 37

(0%) (0%) (3%) (1%) (0%) (15%)

2 10 3 1 0 8

(1%) (3%) (1%) (1%) (0%) (2%)

0.52 0.003 0.11 0.62 0.19 0.02

Bold represents statistical significance.

scoring method and CTCAE rather than patient reported outcomes though recent data has shown consistency between techniques. Data documenting the late effects of WBI-IMRT is relatively sparse. One randomized trial from Donovan et al. [14] compared conventional 2D-WBI with WBI-IMRT and showed that at five years, 10.2% of WBI-IMRT patients demonstrated a “marked” visual change in the treated breast (vs 13.9% in the 2D-WBI group) when compared to pre-treatment photographs. This change was based on size and shape as determined by a panel of clinicians. Clinically palpable induration was also decreased with IMRT. Specific toxicities, such as hyperpigmentation, hypopigmentation, edema, volume reduction, and telangiectasia, were not reported. A more recent study from Cambridge with a similar randomization reported that improved dose homogeneity with IMRT led to superior overall cosmesis at 5 years. However, rates of specific toxicities other than telangiectasia (8% of whom had “quite a bit” or “very much” in the IMRT arm) were also not reported [25]. In both cases, more subjective grading scales were used compared to the current study, which has implemented specific definitions by CTCAE grading criteria. Thus, comparing our study's incidence of late toxicity with WBI-IMRT in published reports is difficult. One concern regarding bAPBI is the potential increase in cost; however, it should be noted that this is based on absolute cost differences that mitigate the improvements in quality of life (shorter treatment duration, less missed work, travel costs) as well as potential improvements in toxicity. A previous analysis from our group demonstrated that when incorporating such factors into a cost/QALY model, bAPBI was cost effective as compared with WBI when accounting for factors such as the increased cost to the patient with protracted courses of radiotherapy with improved quality of life using QALYs as a surrogate [26]. Further, when evaluating bAPBI with WBI-IMRT, all bAPBI techniques were cost effective based on absolute costs and cost per quality adjusted life year. While it is essential to evaluate the cost effectiveness of techniques such as bAPBI, cost analyses must incorporate the inherent benefits of techniques such as bAPBI in terms of treatment duration reduction, improved utilization of BCT, and potential improvements in toxicity. With increased utilization of hypofractionated WBI schedules, cost-efficacy will continue to be evaluated particularly as the duration of WBI approaches APBI and as such the cost benefit of the shorter APBI treatment is lessened. There are limitations to the present analysis, including the inherent pitfalls of a retrospective study. Further, despite large

numbers of patients, the total number of events remains small, limiting definitive conclusions. Also, while a standardized toxicity grading system was utilized, the system is subjective and is thus physician-dependent as there was no blinding to treatment technique. Likewise, bAPBI patients differed with respect to follow-up time; therefore, there may be under-reporting of toxicity rates. Skin toxicity is dependent on follow-up time; telangiectasias for example are late events while seroma and hyperpigmentation are seen earlier; as such, differences in follow up may lead to under reporting of late toxicities in groups with shorter follow-up. Those patients undergoing WBI-IMRT also had significant differences in patient and treatment characteristics (tumor size, chemotherapy receipt, margin status, etc) which also might have potentially altered chronic toxicity rates and cosmesis. Finally, though not the primary purpose of the study, recurrence outcomes were presented but may be limited by differences in follow-up, and limited numbers of events with a need for long-term follow up [27,28]. Although these limitations are noted, this study adds to the literature supporting the safety of bAPBI with long term follow up of randomized trials awaited for final confirmation. Conclusion These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in patients treated with breastconserving therapy with comparable rates of late toxicity, high rates of good to excellent cosmesis, and no difference in rates of infection or mastectomy. Moving forward, this may translate into improved quality of life and higher rates of breast conservation as a safe and efficacious modality. Conflict of interest statement None declared. References [1] Van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester R, Tong D, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92(14):1143e50. [2] Poggi MM, Danforth DN, Sciuto LC, Smith SL, Steinberg SM, Liewehr DJ, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. Cancer 2003;98(4):697e702.

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