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Long-Term Outcomes with 3-Dimensional Conformal External Beam Accelerated Partial Breast Irradiation
Practical Radiation Oncology (2019) xx, e1-e8
www.practicalradonc.org
Basic Original Report
Long-Term Outcomes with 3-Dimensional Conformal External Beam Accelerated Partial Breast Irradiation William R. Kennedy MD a,*,1, Michael C. Roach MD a,1, Maria A. Thomas MD, PhD a, Laura Ochoa DNP, PhD a, Michael B. Altman PhD a, Leonel F. Hernandez-Aya MD b, Amy E. Cyr MD c, Julie A. Margenthaler MD c, Imran Zoberi MD a a
Department of Radiation Oncology, bDivision of Oncology, and cDepartment of Surgery, Washington University School of Medicine, St Louis, Missouri
Received 24 May 2019; revised 29 August 2019; accepted 6 September 2019
Abstract Purpose: Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up. Methods and Materials: All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (<2 mm, 2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable). Results: Two hundred ninety-three patients were identified, of whom 266 had >1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO “suitable,” 87 (32.7%) were “cautionary,” and 17 (6.4%) were “unsuitable.” Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%). Conclusions: External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in “cautionary” and “unsuitable” consensus groupings do not appear to have inferior outcomes. Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Sources of support: This work had no specific funding. Disclosures: none. * Corresponding author. E-mail address: [email protected] (W.R. Kennedy). 1 W.R.K. and M.C.R. contributed equally to this work. https://doi.org/10.1016/j.prro.2019.09.007 1879-8500/Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Introduction For early-stage breast cancer, breast-conserving surgery followed by radiation therapy (RT) to the whole breast has oncologic outcomes equal to that of removing the entire breast.1,2 However, the standard postoperative radiation course of 3 to 6 weeks can create problems with toxicity, convenience, access, and cost. These issues prohibit many women from completing or even starting adjuvant RT, which has been proven to decrease recurrences for invasive disease and improve overall survival.3,4 By shortening the overall course of adjuvant radiation and decreasing the amount of irradiated breast volume, accelerated partial breast irradiation (APBI) aims to improve patient compliance and quality of life without compromising oncologic outcomes. Several APBI methods are available, including interstitial brachytherapy, intracavitary brachytherapy applicators, and external beam RT using 3-dimensional conformal RT (3D-CRT). Partial breast irradiation with 3D-CRT has the potential to be widely adopted because it is noninvasive and does not typically require additional specialized equipment to deliver. However, most series evaluating 3DCRT APBI have relatively small cohorts with limited follow-up, demonstrating heterogeneous local failure rates between 0% and 25%.5-9 Furthermore, there are potential issues of poor cosmesis with 3D-CRT APBI, possibly owing to variations in technique, treated volume, prescribed dose, and fractionation.10,11 Although initial results of randomized studies evaluating once-daily 3D-CRT APBI over 1 to 3 weeks at the University of Florence and United Kingdom (IMPORT-LOW) show excellent cosmetic results, preliminary reports of the Randomized Trial of Accelerated Partial Breast Irradiation (RAPID), using twice-daily fractionation, have raised concerns about cosmesis.9,12,13 The 2 questions of tumor control and cosmetic outcomes must be better answered before further implementation of this technique in general practice. We sought to address these concerns by reporting long-term outcomes of 3D-CRT APBI at our institution, a highvolume early adopter of this treatment modality.
Methods and Materials Institutional review board approval was obtained for this single-institution retrospective review of all patients treated with APBI with 3D-CRT from January 2006 to December 2012. All patients had disease limited to 3 cm and had breast-conserving surgery with negative surgical margins. APBI was routinely offered to all eligible patients. Magnetic resonance imaging of the breast was not routinely used to evaluate candidacy for APBI in this cohort. No patients received neoadjuvant therapy. All patients were treated supine with arms above the head either in an alpha cradle or on a slant board
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before computed tomography simulation. At the time of computed tomography simulation, wires were placed by treating physicians to delineate any surgical scars. The lumpectomy cavity was then expanded by 15 mm to create the clinical target volume. Skin and chest wall contours were subtracted from this volume. The final clinical target volume was then expanded by 10 mm to account for setup variation to create the planning target volume (PTV). Treatment was delivered using a combination of 6-, 10-, and 18-MV photon beams. Planning constraints included limiting the ipsilateral lung V20 to 20% and the heart V25 to 25%. At the start of our study period, data on which to base these constraints were unavailable. The planning constraints used in the current study were set to minimize dose to the heart and lungs in an achievable manner. Patients enrolled on an institutional dose-escalation protocol received either 36 Gy in 9 twice-daily fractions of 4 Gy or 40 Gy in 10 twice-daily fractions of 4 Gy. For patients treated off-protocol, dose to the PTV was 38.5 Gy in 10 twice-daily fractions of 3.85 Gy. Treatment localization was with simultaneous 2-dimensional radiographs and Align RT, an optical system that uses patterned light to reconstruct and analyze 3-dimensional surface data. Patient characteristics collected included age at diagnosis, type of axillary surgery, and use of adjuvant hormonal therapy or chemotherapy. Pathology characteristics recorded included tumor histology, size, grade, and receptor status, as well as the distance from the closest surgical margin. Treatment characteristics included total radiation dose and radiation fraction size and number. Patients were sorted into the 3 categories from the 2016 update to the American Society for Radiation Oncology (ASTRO) APBI consensus group, namely “suitable,” “cautionary,” and “unsuitable.”14 Clinical outcomes were obtained from medical, surgical, and radiation oncology follow-up notes through April 19, 2019. These outcomes included ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), and distant PFS. Death without evidence of disease or severe toxicity was censored but not counted as an event for PFS. Likewise, subsequent contralateral breast cancer diagnoses were not counted as events for any outcome. Cosmesis and pain were evaluated by comparing both patient and physician language from follow-up notes to that in Common Toxicity Criteria for Adverse Events version 4.0. The highest grade toxicity at any time was used for each patient. All time intervals were calculated from the final day of APBI. Recurrence and survival were calculated using the KaplaneMeier method. Differences in recurrence and survival between patient groups were compared with the log-rank test. The c2 test was used to compare total dose and fractionation as well as dosimetric measures to dichotomized posttreatment cosmetic outcomes. A 2sided P value of <.05 was considered statistically
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Long-term 3DCRT APBI outcomes
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Patient and treatment-related characteristics (n Z 266) All patients, n Z 266
Age, median (range), y T stage Tis T1 T2 (<3 cm) Histology Ductal Lobular Grade 1 2 3 Estrogen receptor status Positive Negative HER2 status Amplified Nonamplified Unknown Triple-negative disease Axillary sampling Sentinel node Axillary dissection None Margin status Negative (2 mm) Close (<2 mm) ASTRO suitability group Suitable Cautionary Unsuitable Radiation dose 38.5 Gy in 10 fractions 36 Gy in 9 fractions 40 Gy in 10 fractions Adjuvant therapy Tamoxifen Aromatase inhibitor Chemotherapy None
Invasive, n Z 188
In situ, n Z 78
61 (39-88)
64 (39-88)
58 (41-83)
78 (29.3%) 179 (67.3%) 9 (3.4%)
0 (0%) 179 (95.2%) 9 (4.8%)
78 (100%) 0 (0%) 0 (0%)
259 (97.4%) 7 (2.6%)
181 (96.3%) 7 (3.7%)
78 (100%) 0 (0%)
117 (44.0%) 116 (43.6%) 33 (12.4%)
87 (46.3%) 78 (41.5%) 23 (12.2%)
30 (38%) 38 (49%) 10 (13%)
248 (93.2%) 18 (6.8%)
175 (93.1%) 13 (6.9%)
73 (94%) 5 (6%)
11 228 27 11
11 169 8 10
0 59 19 1
(4.1%) (85.7%) (10.2%) (4.1%)
(5.9%) (89.9%) (4.3%) (5.3%)
(0%) (76%) (24%) (1%)
194 (72.9%) 2 (0.8%) 70 (26.3%)
184 (97.9%) 2 (1.1%) 2 (1.1%)
10 (13%) 0 (0%) 68 (87%)
260 (97.7%) 6 (2.3%)
183 (97.3%) 5 (2.7%)
77 (99%) 1 (1%)
162 (60.9%) 87 (32.7%) 17 (6.4%)
133 (70.7%) 48 (25.5%) 7 (3.7%)
29 (37%) 39 (50%) 10 (13%)
138 (51.9%) 79 (29.7%) 49 (18.4%)
99 (52.7%) 54 (28.7%) 35 (18.6%)
39 (50%) 25 (32%) 14 (18%)
79 126 23 49
(29.7%) (47.4%) (8.6%) (18.4%)
37 118 23 22
(19.7%) (62.8%) (12.2%) (11.7%)
42 8 0 27
(54%) (10%) (0%) (35%)
Abbreviation: ASTRO Z American Society for Radiation Oncology.
significant for all tests. Linear regression was used to obtain odds ratios of irradiated breast volume predictive of poor cosmesis. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corporation, Armonk, NY).
Results A total of 293 women were identified who met the aforementioned inclusion and exclusion criteria. Patient characteristics are presented in Table 1. Of these patients, 266 had more than a year of follow-up within the
institution. None of the 27 patients excluded from longterm analysis had evidence of disease at their last follow-up. Median follow-up for the 266 patients with >1 year of follow-up was 87 months (range, 13-156). The median age at diagnosis was 61 years (range, 39-88). There were 188 patients (71%) with invasive disease and 78 (29%) with ductal carcinoma in situ (DCIS). Of those with invasive disease, 184 (97.9%) underwent a sentinel node procedure and 2 (1.1%) an axillary dissection. No lymph node sampling was done in 2 (1.1%). A total dose of 40 Gy in 10 twice-daily fractions of 4 Gy was given to 49 patients (18.4%), 38.5 Gy in 10 twice-daily fractions of 3.85 Gy to 138 (51.9%), and 36 Gy in 9 twice-daily
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Figure 1
Cumulative ipsilateral breast tumor recurrence (IBTR) for the entire cohort.
Figure 2
Progression-free survival for the entire cohort.
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fractions of 4 Gy to 79 (29.7%). Adjuvant hormone therapy was given to 196 (77.1%) and adjuvant chemotherapy to 23 (8.6%). Overall, 162 (60.9%) patients were ASTRO “suitable,” 87 (32.7%) were “cautionary,” and 17 (6.4%) were “unsuitable.” One patient was unsuitable owing to age <40 years (age 39) and 2 owing to having invasive disease and no nodal sampling. The other 14 patients were unsuitable owing to age 40 to 49 years and not otherwise meeting “suitable” criteria. No patients had positive surgical margins, positive nodes, neoadjuvant therapy, extensive lymphovascular space invasion, known BRCA mutation, or disease >3 cm, all of which are risk factors ASTRO considers “unsuitable.” Among the patients with DCIS, half were “cautionary.” The overall IBTR rate at 7 years was 1.8% (Fig 1), and PFS at 7 years was 95.2% (Fig 2). Close margins (P Z .77), invasive disease (P Z .76), dose prescribed (P Z .69), and ASTRO suitability guidelines (P Z .73) were not prognostic of IBTR. Likewise, close margins (P Z 66), invasive disease (P Z .16), dose prescribed (P Z .35), and ASTRO suitability guidelines (P Z .72) were not prognostic of PFS in this cohort. There were 3 distant failures at 63, 70, and 73 months, all in patients with invasive disease, yielding a 7-year distant metastasesefree survival rate of 98.5%. There were no differences in IBTR, regional recurrence, and PFS in our cohort based on estrogen receptor status (P Z .77, .61, .90, respectively), HER2 (P Z .65, .48, .53), age <50 years (P Z .27, .91, .48), chemotherapy use (P Z .59, .90, .59), or hormone use (P Z .20, .17, .67). With a median follow-up of 88 months (range, 15-156) for the 78 patients in the DCIS cohort, there were 2 cases of IBTR and 4 contralateral events. Both cases of IBTR were found by routine mammogram at 9.3 and 9.5 years after APBI. Both patients developed new early-stage invasive cancers in previously untreated quadrants of the ipsilateral breast. Both patients were successfully salvaged and were disease-free at their most recent follow-up. There were no recurrences in the treated quadrant, regional lymph nodes, or distantly in the DCIS cohort. With a median follow-up of 87 months (range, 14-156) for the 188 patients in the invasive cohort, there were 5 cases of IBTR, 3 isolated regional recurrences, 3 distant recurrences, and 6 contralateral events. All patients with regional or distant recurrences had estrogen- or progesterone-receptor positive, HER2-negative disease. The median time to IBTR for the invasive cohort was 7.2 years (range, 6.2-11.3). All recurrences were diagnosed on routine mammogram. Of these, a single case of IBTR occurred in the previously treated quadrant. This patient experienced a recurrence within this same quadrant and in the axilla simultaneously. She underwent mastectomy for her pT2N1 disease, adjuvant chemotherapy, hormonal therapy, and RT to the chest wall and regional lymphatics. She developed metastatic disease 1 year after this local and regional recurrence. The remaining 4 patients
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developed new disease in a previously untreated quadrant of the ipsilateral breast; all were successfully salvaged with either lumpectomy plus adjuvant whole-breast RT or mastectomy and were disease-free at their most recent follow-up. The 3 isolated regional recurrences in the invasive cohort occurred at 46, 54, and 83 months after APBI. These were found by routine mammography, patient selfexamination, and elevated CA 15-3 between annual mammography, respectively. The first was treated with axillary dissection, adjuvant hormonal therapy, and adjuvant RT to the breast and regional lymphatics; she is disease-free 6 years after this recurrence. The second has been treated with hormone therapy alone for 2 years given her age and comorbidities, with no distant progression. The third was initially salvaged with axillary dissection, adjuvant RT to the whole breast and regional nodes, and letrozole plus palbociclib, but she developed osseous metastases shortly thereafter and is currently receiving capecitabine. The 3 distant recurrences were found 63, 70, and 73 months after APBI owing to abdominal pain, neurologic symptoms, and bone pain, respectively. The proportion of patients with good to excellent cosmesis before RT was 95.5%, with the remaining 4.5% having fair to poor pretreatment cosmesis. After RT, there were 22 documented patient-reported complaints of grade 1 chronic skin toxicity, 4 grade 2, and 3 grade 3. Two patients in the cohort expressed interest in seeing a plastic surgeon after completion of RT to address poor cosmesis. There were 120 grade 1, 64 grade 2, and 2 grade 3 physician reports of chronic skin toxicity. Thus, there was a resulting 75.2% rate of post-RT good to excellent and 24.8% fair to poor cosmesis according to documentation by physicians. Among the 3 total doses of 3600 cGy, 3850 cGy, and 4000 cGy, there was no difference in good versus poor cosmetic outcomes (P Z .10). When comparing fraction size of 385 cGy versus 400 cGy; 385 cGy had significantly better cosmesis (22% fair or poor vs 33% fair or poor, P Z .039). There were 38 grade 1 pain, 4 grade 2 pain, and 2 grade 3 pain complaints documented by physicians. Rib fractures, pericardial fibrosis, radiation pneumonitis, and seroma infections occurred in a single patient each. Dose-volume histogram data were obtained on all patients. At least 95% of the PTV was covered by 100% of the prescription dose in all patients. The median PTV was 161.1 cm3 (range, 34.0-591.1). The median ipsilateral breast volume was 1149.0 cm3 (range, 326.7-2635.5), with the median percentage of breast irradiated being 15.9% (range, 5.5%-40.3%). Linear regression revealed that the odds of having adverse cosmesis was greater with increasing percentage of irradiated breast (odds ratio 1.101; 95% CI, 1.015-1.194; P Z .021). The maximum skin dose was a median of 41.9 Gy (range, 37.9-45.35). The ipsilateral lung V20 Gy was a median 2.1% (range 0%-9.6%) and ipsilateral mean lung dose was 3.7 Gy (range, 0.31-6.61).
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Table 2 Studies of external beam accelerated partial breast irradiation with 5 y or more of follow-up, listed in chronologic order of publication Reference
Median follow-up, mo
Patients, n
DCIS, %
Total dose, Gy
Fractions
IBTR, %
Good or excellent cosmesis, %
15 19 21 8 18 17 7 12 16 13 Current
64 71 64 60 58 60 58 60 60 72 87
98 98 52 51 192 30 44 260 141 669 266
0 0 0 0 21 53 0 9 36 0 29
30 32 38.5 37.5 34 or 38.5 38.5 36.9 30 34 or 38.5 40 36, 38.5, or 40
5 QD 8 bid 10 bid 10 bid 10 bid 10 bid 9 bid 5 QD 10 bid 15 QD 9 or 10 bid
1 5 NR 0 0 3 2 2 3 0.5 1.8
89 NR 83 75 81 73 84 100 94 86 75
Abbreviations: bid Z twice daily; DCIS Z ductal carcinoma in situ; IBTR Z ipsilateral breast tumor recurrence; NR Z not reported; QD Z once daily.
The median heart V25 Gy was 0% (range 0%-0.2%). The mean heart dose was a median of 0.43 Gy (range, 0.05-3.48) for all patients, 0.71 Gy (range, 0.07-3.48) for patients with left-sided breast cancers, and 0.33 Gy (range, 0.05-1.17) for patients with right-sided cancers. None of these dosimetric measures were associated with the single cases of rib fractures, pericardial fibrosis, radiation pneumonitis, or seroma infections.
Discussion External beam APBI has the potential to be widely implemented in general radiation oncology practice to increase compliance and quality of life of breast conservation therapy, but mostly studies with limited follow-up and wide ranges of IBTR and cosmesis have been published to date. We report acceptably low IBTR and high levels of good to excellent cosmesis in a large cohort of patients at an extended median follow-up of over 7 years, with patients being followed for up to 13 years in the current series. Furthermore, we found that carefully selected patients who were classified as ASTRO “cautionary” or “unsuitable” APBI candidates did not fare worse than those meeting “suitable” criteria, providing important implications for subsequent APBI patient selection guidelines. Finally, we found that higher fraction sizes of 400 cGy negatively affected cosmesis compared with 385 cGy. APBI is increasingly being used for women with earlystage breast cancer after breast-conserving surgery. Guidelines for the use of APBI off a clinical trial were updated by ASTRO in 2016. Compared with APBI via interstitial or intracavitary brachytherapy, APBI with 3DCRT avoids the risks associated with an invasive procedure and can be performed with equipment present at virtually all radiation oncology centers. However, APBI with 3D-CRT exposes more of the breast tissue to
radiation than do brachytherapy techniques, and reports on long-term cosmesis and toxicity are conflicting. This cohort of 266 patients who underwent 3D-CRT APBI with a median follow-up of 7 years reflects one of the largest series with extended follow-up to date. Our series showed an IBTR of 1.8% at 7 years. This is comparable to several series with 5-year outcomes, such as Formenti et al at 1%, Livi et al at 1.5%, Mozsa et al at 2.3%, Horst et al at 2.4%, and Liss et al at 3%.7,12,15-17 Two series have reported no recurrences.8,18 One has reported a slightly higher rate of 5%.19 It should be noted that only 3 of these studies have more than 100 patients, and only 1 has more than 200. For comparison, we await the published outcomes from RAPID, which has randomized over 2000 women to APBI with 3D-CRT versus whole-breast radiation, as well as Radiation Therapy Oncology Group 0413. A summary of studies with reported long-term (5 years) follow-up is presented I Table 2. Given the low rates of regional and distant recurrence in our cohort, it is unsurprising that the use of chemotherapy or hormone therapy did not have a significant impact on PFS in our select low-risk cohort. Of note, 2 of the 5 patients with invasive disease who developed an IBTR in our cohort opted for mastectomy. This 1% rate of mastectomy in those with invasive disease receiving external beam APBI is lower than the rate of 4% reported by Smith et al in a retrospective review of the Surveillance, Epidemiology, and End ResultseMedicare database of women who underwent APBI via brachytherapy.20 APBI with 3D-CRT was well tolerated in this series. The rate of good to excellent posttreatment cosmesis from physician documentation was 75% overall compared with 95.5% before APBI, with only 2 of the 266 women expressing interest in meeting with a plastic surgeon for poor cosmesis. Notably, the rates of good to excellent cosmesis differed based upon fraction size, with patients
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receiving fractions of 385 cGy having a lower proportion of fair or poor cosmetic outcomes than those receiving fractions of 400 cGy (22% vs 33%, P Z .039). In addition to fraction size, we found that increasing irradiated breast volume predicted for adverse cosmesis, although no other dosimetric measures predicted for adverse events, highlighting the need for methods to minimize setup uncertainty and therefore decrease PTV. Our rate of 75% with good to excellent cosmesis is on the low end of the retrospective 3D-CRT APBI series with long-term follow-up discussed earlier, reporting a range of 73% to 100% for good to excellent cosmesis. However, our observed rate is higher than the 3-year results of 64% reported in Radiation Therapy Oncology Group 0319 and similar to 71% at 3 years reported in RAPID.21,22 It is notably similar to the rates of 70% to 71% seen in the 10-year results of a large randomized trial of hypofractionated once-daily whole-breast radiation versus conventionally fractionated whole-breast radiation.23 This is one of the first reported studies of APBI with 3D-CRT after the 2016 ASTRO update to consensus guidelines on APBI suitability criteria. The major changes included dropping the lower age bound for “suitable” from 60 to 50 years and allowing some treatment of DCIS as “suitable.”14 In our cohort, 32.7% of patients were “cautionary” and 6.4% were “unsuitable.” Importantly, these patients did not have a statistical difference in IBTR or PFS. Although the proportion of “unsuitable” patients was small, it is reassuring that the larger proportion of “cautionary” patients appears to be able to be treated effectively with APBI. We await confirmation of this from other groups with the new categories. There are several limitations to this study. First, it is retrospective, with all the biases inherent to this technique. This makes categorizing patient and physician statements regarding toxicity more difficult than if they were provided with a standard and validated evaluation form, as is being done in many prospective studies. Additionally, 29% of our patients had received a diagnosis of DCIS, which could make our results more favorable than those in other studies. However, our outcomes were not significantly different between patients with DCIS and those with invasive disease <3 cm. Other reported studies with long-term follow-up have a similar proportion of DCIS in their cohorts.12,15-17 Strengths of this study include the length of follow-up, the number of patients, and the exploration of different dose regimens, between which there was no significant difference in disease outcomes, though worse cosmesis with increasing fraction size was suggested.
Conclusions In this large cohort of patients treated with the 3DCRT technique for APBI, the risk of developing an
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IBTR was <2% at 7 years. In the select group of patients with ASTRO “cautionary” or “unsuitable” disease, both IBTR and PFS, outcomes were not worse than those in the “suitable” category. Increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. This technique was overall well tolerated, though prospective, multi-institutional outcomes are needed for confirmation.
References 1. National Institutes of Health Consensus Development Panel. NIH Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr. 2001:5-15. 2. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med. 2002;347:1233-1241. 3. Acharya S, Hsieh S, Michalski JM, et al. Distance to radiation facility and treatment choice in early-stage breast cancer. Int J Radiat Oncol Biol Phys. 2016;94:691-699. 4. Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol. 2001;19:2254-2262. 5. Njeh CF, Saunders MW, Langton CM. Accelerated partial breast irradiation using external beam conformal radiation therapy: A review. Crit Rev Oncol Hematol. 2012;81:1-20. 6. Ott OJ, Strnad V, Stillkrieg W, et al. Accelerated partial breast irradiation with external beam radiotherapy: First results of the German phase 2 trial. Strahlenther Onkol. 2017;193:55-61. 7. Mózsa E, Mészáros N, Major T, et al. Accelerated partial breast irradiation with external beam three-dimensional conformal radiotherapy. Five-year results of a prospective phase II clinical study. Strahlenther Onkol. 2014;190:444-450. 8. Rodríguez N, Sanz X, Dengra J, et al. Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol0 Biol Phys. 2013;87:1051-1057. 9. Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: A randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol. 2013;31:4038-4045. 10. Hepel JT, Tokita M, MacAusland SG, et al. Toxicity of threedimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2009;75:1290-1296. 11. Jagsi R, Ben-David MA, Moran JM, et al. Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76:71-78. 12. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015;51:451-463. 13. Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017; 390:1048-1060. 14. Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: Executive summary for the update of an ASTRO evidencebased consensus statement. Pract Radiat Oncol. 2017;7:73-79.
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15. Formenti SC, Hsu H, Fenton-Kerimian M, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: Five-year results of 100 patients. Int J Radiat Oncol Biol Phys. 2012;84: 606-611. 16. Horst KC, Fasola C, Ikeda D, et al. Five-year results of a prospective clinical trial investigating accelerated partial breast irradiation using 3D conformal radiotherapy after lumpectomy for early stage breast cancer. Breast. 2016;28:178-183. 17. Liss AL, Ben-David MA, Jagsi R, et al. Decline of cosmetic outcomes following accelerated partial breast irradiation using intensity modulated radiation therapy: Results of a single-institution prospective clinical trial. Int J Radiat Oncol Biol Phys. 2014;89:96-102. 18. Shah C, Wilkinson JB, Lanni T, et al. Five-year outcomes and toxicities using 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Clin Breast Cancer. 2013;13:206-211. 19. Pashtan IM, Recht A, Ancukiewicz M, et al. External beam accelerated partial-breast irradiation using 32 Gy in 8 twice-daily
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Basic Original Report
Long-Term Outcomes with 3-Dimensional Conformal External Beam Accelerated Partial Breast Irradiation William R. Kennedy MD a,*,1, Michael C. Roach MD a,1, Maria A. Thomas MD, PhD a, Laura Ochoa DNP, PhD a, Michael B. Altman PhD a, Leonel F. Hernandez-Aya MD b, Amy E. Cyr MD c, Julie A. Margenthaler MD c, Imran Zoberi MD a a
Department of Radiation Oncology, bDivision of Oncology, and cDepartment of Surgery, Washington University School of Medicine, St Louis, Missouri
Received 24 May 2019; revised 29 August 2019; accepted 6 September 2019
Abstract Purpose: Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up. Methods and Materials: All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (<2 mm, 2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable). Results: Two hundred ninety-three patients were identified, of whom 266 had >1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO “suitable,” 87 (32.7%) were “cautionary,” and 17 (6.4%) were “unsuitable.” Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%). Conclusions: External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in “cautionary” and “unsuitable” consensus groupings do not appear to have inferior outcomes. Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Sources of support: This work had no specific funding. Disclosures: none. * Corresponding author. E-mail address: [email protected] (W.R. Kennedy). 1 W.R.K. and M.C.R. contributed equally to this work. https://doi.org/10.1016/j.prro.2019.09.007 1879-8500/Ó 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Introduction For early-stage breast cancer, breast-conserving surgery followed by radiation therapy (RT) to the whole breast has oncologic outcomes equal to that of removing the entire breast.1,2 However, the standard postoperative radiation course of 3 to 6 weeks can create problems with toxicity, convenience, access, and cost. These issues prohibit many women from completing or even starting adjuvant RT, which has been proven to decrease recurrences for invasive disease and improve overall survival.3,4 By shortening the overall course of adjuvant radiation and decreasing the amount of irradiated breast volume, accelerated partial breast irradiation (APBI) aims to improve patient compliance and quality of life without compromising oncologic outcomes. Several APBI methods are available, including interstitial brachytherapy, intracavitary brachytherapy applicators, and external beam RT using 3-dimensional conformal RT (3D-CRT). Partial breast irradiation with 3D-CRT has the potential to be widely adopted because it is noninvasive and does not typically require additional specialized equipment to deliver. However, most series evaluating 3DCRT APBI have relatively small cohorts with limited follow-up, demonstrating heterogeneous local failure rates between 0% and 25%.5-9 Furthermore, there are potential issues of poor cosmesis with 3D-CRT APBI, possibly owing to variations in technique, treated volume, prescribed dose, and fractionation.10,11 Although initial results of randomized studies evaluating once-daily 3D-CRT APBI over 1 to 3 weeks at the University of Florence and United Kingdom (IMPORT-LOW) show excellent cosmetic results, preliminary reports of the Randomized Trial of Accelerated Partial Breast Irradiation (RAPID), using twice-daily fractionation, have raised concerns about cosmesis.9,12,13 The 2 questions of tumor control and cosmetic outcomes must be better answered before further implementation of this technique in general practice. We sought to address these concerns by reporting long-term outcomes of 3D-CRT APBI at our institution, a highvolume early adopter of this treatment modality.
Methods and Materials Institutional review board approval was obtained for this single-institution retrospective review of all patients treated with APBI with 3D-CRT from January 2006 to December 2012. All patients had disease limited to 3 cm and had breast-conserving surgery with negative surgical margins. APBI was routinely offered to all eligible patients. Magnetic resonance imaging of the breast was not routinely used to evaluate candidacy for APBI in this cohort. No patients received neoadjuvant therapy. All patients were treated supine with arms above the head either in an alpha cradle or on a slant board
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before computed tomography simulation. At the time of computed tomography simulation, wires were placed by treating physicians to delineate any surgical scars. The lumpectomy cavity was then expanded by 15 mm to create the clinical target volume. Skin and chest wall contours were subtracted from this volume. The final clinical target volume was then expanded by 10 mm to account for setup variation to create the planning target volume (PTV). Treatment was delivered using a combination of 6-, 10-, and 18-MV photon beams. Planning constraints included limiting the ipsilateral lung V20 to 20% and the heart V25 to 25%. At the start of our study period, data on which to base these constraints were unavailable. The planning constraints used in the current study were set to minimize dose to the heart and lungs in an achievable manner. Patients enrolled on an institutional dose-escalation protocol received either 36 Gy in 9 twice-daily fractions of 4 Gy or 40 Gy in 10 twice-daily fractions of 4 Gy. For patients treated off-protocol, dose to the PTV was 38.5 Gy in 10 twice-daily fractions of 3.85 Gy. Treatment localization was with simultaneous 2-dimensional radiographs and Align RT, an optical system that uses patterned light to reconstruct and analyze 3-dimensional surface data. Patient characteristics collected included age at diagnosis, type of axillary surgery, and use of adjuvant hormonal therapy or chemotherapy. Pathology characteristics recorded included tumor histology, size, grade, and receptor status, as well as the distance from the closest surgical margin. Treatment characteristics included total radiation dose and radiation fraction size and number. Patients were sorted into the 3 categories from the 2016 update to the American Society for Radiation Oncology (ASTRO) APBI consensus group, namely “suitable,” “cautionary,” and “unsuitable.”14 Clinical outcomes were obtained from medical, surgical, and radiation oncology follow-up notes through April 19, 2019. These outcomes included ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), and distant PFS. Death without evidence of disease or severe toxicity was censored but not counted as an event for PFS. Likewise, subsequent contralateral breast cancer diagnoses were not counted as events for any outcome. Cosmesis and pain were evaluated by comparing both patient and physician language from follow-up notes to that in Common Toxicity Criteria for Adverse Events version 4.0. The highest grade toxicity at any time was used for each patient. All time intervals were calculated from the final day of APBI. Recurrence and survival were calculated using the KaplaneMeier method. Differences in recurrence and survival between patient groups were compared with the log-rank test. The c2 test was used to compare total dose and fractionation as well as dosimetric measures to dichotomized posttreatment cosmetic outcomes. A 2sided P value of <.05 was considered statistically
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Long-term 3DCRT APBI outcomes
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Patient and treatment-related characteristics (n Z 266) All patients, n Z 266
Age, median (range), y T stage Tis T1 T2 (<3 cm) Histology Ductal Lobular Grade 1 2 3 Estrogen receptor status Positive Negative HER2 status Amplified Nonamplified Unknown Triple-negative disease Axillary sampling Sentinel node Axillary dissection None Margin status Negative (2 mm) Close (<2 mm) ASTRO suitability group Suitable Cautionary Unsuitable Radiation dose 38.5 Gy in 10 fractions 36 Gy in 9 fractions 40 Gy in 10 fractions Adjuvant therapy Tamoxifen Aromatase inhibitor Chemotherapy None
Invasive, n Z 188
In situ, n Z 78
61 (39-88)
64 (39-88)
58 (41-83)
78 (29.3%) 179 (67.3%) 9 (3.4%)
0 (0%) 179 (95.2%) 9 (4.8%)
78 (100%) 0 (0%) 0 (0%)
259 (97.4%) 7 (2.6%)
181 (96.3%) 7 (3.7%)
78 (100%) 0 (0%)
117 (44.0%) 116 (43.6%) 33 (12.4%)
87 (46.3%) 78 (41.5%) 23 (12.2%)
30 (38%) 38 (49%) 10 (13%)
248 (93.2%) 18 (6.8%)
175 (93.1%) 13 (6.9%)
73 (94%) 5 (6%)
11 228 27 11
11 169 8 10
0 59 19 1
(4.1%) (85.7%) (10.2%) (4.1%)
(5.9%) (89.9%) (4.3%) (5.3%)
(0%) (76%) (24%) (1%)
194 (72.9%) 2 (0.8%) 70 (26.3%)
184 (97.9%) 2 (1.1%) 2 (1.1%)
10 (13%) 0 (0%) 68 (87%)
260 (97.7%) 6 (2.3%)
183 (97.3%) 5 (2.7%)
77 (99%) 1 (1%)
162 (60.9%) 87 (32.7%) 17 (6.4%)
133 (70.7%) 48 (25.5%) 7 (3.7%)
29 (37%) 39 (50%) 10 (13%)
138 (51.9%) 79 (29.7%) 49 (18.4%)
99 (52.7%) 54 (28.7%) 35 (18.6%)
39 (50%) 25 (32%) 14 (18%)
79 126 23 49
(29.7%) (47.4%) (8.6%) (18.4%)
37 118 23 22
(19.7%) (62.8%) (12.2%) (11.7%)
42 8 0 27
(54%) (10%) (0%) (35%)
Abbreviation: ASTRO Z American Society for Radiation Oncology.
significant for all tests. Linear regression was used to obtain odds ratios of irradiated breast volume predictive of poor cosmesis. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corporation, Armonk, NY).
Results A total of 293 women were identified who met the aforementioned inclusion and exclusion criteria. Patient characteristics are presented in Table 1. Of these patients, 266 had more than a year of follow-up within the
institution. None of the 27 patients excluded from longterm analysis had evidence of disease at their last follow-up. Median follow-up for the 266 patients with >1 year of follow-up was 87 months (range, 13-156). The median age at diagnosis was 61 years (range, 39-88). There were 188 patients (71%) with invasive disease and 78 (29%) with ductal carcinoma in situ (DCIS). Of those with invasive disease, 184 (97.9%) underwent a sentinel node procedure and 2 (1.1%) an axillary dissection. No lymph node sampling was done in 2 (1.1%). A total dose of 40 Gy in 10 twice-daily fractions of 4 Gy was given to 49 patients (18.4%), 38.5 Gy in 10 twice-daily fractions of 3.85 Gy to 138 (51.9%), and 36 Gy in 9 twice-daily
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Figure 1
Cumulative ipsilateral breast tumor recurrence (IBTR) for the entire cohort.
Figure 2
Progression-free survival for the entire cohort.
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fractions of 4 Gy to 79 (29.7%). Adjuvant hormone therapy was given to 196 (77.1%) and adjuvant chemotherapy to 23 (8.6%). Overall, 162 (60.9%) patients were ASTRO “suitable,” 87 (32.7%) were “cautionary,” and 17 (6.4%) were “unsuitable.” One patient was unsuitable owing to age <40 years (age 39) and 2 owing to having invasive disease and no nodal sampling. The other 14 patients were unsuitable owing to age 40 to 49 years and not otherwise meeting “suitable” criteria. No patients had positive surgical margins, positive nodes, neoadjuvant therapy, extensive lymphovascular space invasion, known BRCA mutation, or disease >3 cm, all of which are risk factors ASTRO considers “unsuitable.” Among the patients with DCIS, half were “cautionary.” The overall IBTR rate at 7 years was 1.8% (Fig 1), and PFS at 7 years was 95.2% (Fig 2). Close margins (P Z .77), invasive disease (P Z .76), dose prescribed (P Z .69), and ASTRO suitability guidelines (P Z .73) were not prognostic of IBTR. Likewise, close margins (P Z 66), invasive disease (P Z .16), dose prescribed (P Z .35), and ASTRO suitability guidelines (P Z .72) were not prognostic of PFS in this cohort. There were 3 distant failures at 63, 70, and 73 months, all in patients with invasive disease, yielding a 7-year distant metastasesefree survival rate of 98.5%. There were no differences in IBTR, regional recurrence, and PFS in our cohort based on estrogen receptor status (P Z .77, .61, .90, respectively), HER2 (P Z .65, .48, .53), age <50 years (P Z .27, .91, .48), chemotherapy use (P Z .59, .90, .59), or hormone use (P Z .20, .17, .67). With a median follow-up of 88 months (range, 15-156) for the 78 patients in the DCIS cohort, there were 2 cases of IBTR and 4 contralateral events. Both cases of IBTR were found by routine mammogram at 9.3 and 9.5 years after APBI. Both patients developed new early-stage invasive cancers in previously untreated quadrants of the ipsilateral breast. Both patients were successfully salvaged and were disease-free at their most recent follow-up. There were no recurrences in the treated quadrant, regional lymph nodes, or distantly in the DCIS cohort. With a median follow-up of 87 months (range, 14-156) for the 188 patients in the invasive cohort, there were 5 cases of IBTR, 3 isolated regional recurrences, 3 distant recurrences, and 6 contralateral events. All patients with regional or distant recurrences had estrogen- or progesterone-receptor positive, HER2-negative disease. The median time to IBTR for the invasive cohort was 7.2 years (range, 6.2-11.3). All recurrences were diagnosed on routine mammogram. Of these, a single case of IBTR occurred in the previously treated quadrant. This patient experienced a recurrence within this same quadrant and in the axilla simultaneously. She underwent mastectomy for her pT2N1 disease, adjuvant chemotherapy, hormonal therapy, and RT to the chest wall and regional lymphatics. She developed metastatic disease 1 year after this local and regional recurrence. The remaining 4 patients
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developed new disease in a previously untreated quadrant of the ipsilateral breast; all were successfully salvaged with either lumpectomy plus adjuvant whole-breast RT or mastectomy and were disease-free at their most recent follow-up. The 3 isolated regional recurrences in the invasive cohort occurred at 46, 54, and 83 months after APBI. These were found by routine mammography, patient selfexamination, and elevated CA 15-3 between annual mammography, respectively. The first was treated with axillary dissection, adjuvant hormonal therapy, and adjuvant RT to the breast and regional lymphatics; she is disease-free 6 years after this recurrence. The second has been treated with hormone therapy alone for 2 years given her age and comorbidities, with no distant progression. The third was initially salvaged with axillary dissection, adjuvant RT to the whole breast and regional nodes, and letrozole plus palbociclib, but she developed osseous metastases shortly thereafter and is currently receiving capecitabine. The 3 distant recurrences were found 63, 70, and 73 months after APBI owing to abdominal pain, neurologic symptoms, and bone pain, respectively. The proportion of patients with good to excellent cosmesis before RT was 95.5%, with the remaining 4.5% having fair to poor pretreatment cosmesis. After RT, there were 22 documented patient-reported complaints of grade 1 chronic skin toxicity, 4 grade 2, and 3 grade 3. Two patients in the cohort expressed interest in seeing a plastic surgeon after completion of RT to address poor cosmesis. There were 120 grade 1, 64 grade 2, and 2 grade 3 physician reports of chronic skin toxicity. Thus, there was a resulting 75.2% rate of post-RT good to excellent and 24.8% fair to poor cosmesis according to documentation by physicians. Among the 3 total doses of 3600 cGy, 3850 cGy, and 4000 cGy, there was no difference in good versus poor cosmetic outcomes (P Z .10). When comparing fraction size of 385 cGy versus 400 cGy; 385 cGy had significantly better cosmesis (22% fair or poor vs 33% fair or poor, P Z .039). There were 38 grade 1 pain, 4 grade 2 pain, and 2 grade 3 pain complaints documented by physicians. Rib fractures, pericardial fibrosis, radiation pneumonitis, and seroma infections occurred in a single patient each. Dose-volume histogram data were obtained on all patients. At least 95% of the PTV was covered by 100% of the prescription dose in all patients. The median PTV was 161.1 cm3 (range, 34.0-591.1). The median ipsilateral breast volume was 1149.0 cm3 (range, 326.7-2635.5), with the median percentage of breast irradiated being 15.9% (range, 5.5%-40.3%). Linear regression revealed that the odds of having adverse cosmesis was greater with increasing percentage of irradiated breast (odds ratio 1.101; 95% CI, 1.015-1.194; P Z .021). The maximum skin dose was a median of 41.9 Gy (range, 37.9-45.35). The ipsilateral lung V20 Gy was a median 2.1% (range 0%-9.6%) and ipsilateral mean lung dose was 3.7 Gy (range, 0.31-6.61).
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Table 2 Studies of external beam accelerated partial breast irradiation with 5 y or more of follow-up, listed in chronologic order of publication Reference
Median follow-up, mo
Patients, n
DCIS, %
Total dose, Gy
Fractions
IBTR, %
Good or excellent cosmesis, %
15 19 21 8 18 17 7 12 16 13 Current
64 71 64 60 58 60 58 60 60 72 87
98 98 52 51 192 30 44 260 141 669 266
0 0 0 0 21 53 0 9 36 0 29
30 32 38.5 37.5 34 or 38.5 38.5 36.9 30 34 or 38.5 40 36, 38.5, or 40
5 QD 8 bid 10 bid 10 bid 10 bid 10 bid 9 bid 5 QD 10 bid 15 QD 9 or 10 bid
1 5 NR 0 0 3 2 2 3 0.5 1.8
89 NR 83 75 81 73 84 100 94 86 75
Abbreviations: bid Z twice daily; DCIS Z ductal carcinoma in situ; IBTR Z ipsilateral breast tumor recurrence; NR Z not reported; QD Z once daily.
The median heart V25 Gy was 0% (range 0%-0.2%). The mean heart dose was a median of 0.43 Gy (range, 0.05-3.48) for all patients, 0.71 Gy (range, 0.07-3.48) for patients with left-sided breast cancers, and 0.33 Gy (range, 0.05-1.17) for patients with right-sided cancers. None of these dosimetric measures were associated with the single cases of rib fractures, pericardial fibrosis, radiation pneumonitis, or seroma infections.
Discussion External beam APBI has the potential to be widely implemented in general radiation oncology practice to increase compliance and quality of life of breast conservation therapy, but mostly studies with limited follow-up and wide ranges of IBTR and cosmesis have been published to date. We report acceptably low IBTR and high levels of good to excellent cosmesis in a large cohort of patients at an extended median follow-up of over 7 years, with patients being followed for up to 13 years in the current series. Furthermore, we found that carefully selected patients who were classified as ASTRO “cautionary” or “unsuitable” APBI candidates did not fare worse than those meeting “suitable” criteria, providing important implications for subsequent APBI patient selection guidelines. Finally, we found that higher fraction sizes of 400 cGy negatively affected cosmesis compared with 385 cGy. APBI is increasingly being used for women with earlystage breast cancer after breast-conserving surgery. Guidelines for the use of APBI off a clinical trial were updated by ASTRO in 2016. Compared with APBI via interstitial or intracavitary brachytherapy, APBI with 3DCRT avoids the risks associated with an invasive procedure and can be performed with equipment present at virtually all radiation oncology centers. However, APBI with 3D-CRT exposes more of the breast tissue to
radiation than do brachytherapy techniques, and reports on long-term cosmesis and toxicity are conflicting. This cohort of 266 patients who underwent 3D-CRT APBI with a median follow-up of 7 years reflects one of the largest series with extended follow-up to date. Our series showed an IBTR of 1.8% at 7 years. This is comparable to several series with 5-year outcomes, such as Formenti et al at 1%, Livi et al at 1.5%, Mozsa et al at 2.3%, Horst et al at 2.4%, and Liss et al at 3%.7,12,15-17 Two series have reported no recurrences.8,18 One has reported a slightly higher rate of 5%.19 It should be noted that only 3 of these studies have more than 100 patients, and only 1 has more than 200. For comparison, we await the published outcomes from RAPID, which has randomized over 2000 women to APBI with 3D-CRT versus whole-breast radiation, as well as Radiation Therapy Oncology Group 0413. A summary of studies with reported long-term (5 years) follow-up is presented I Table 2. Given the low rates of regional and distant recurrence in our cohort, it is unsurprising that the use of chemotherapy or hormone therapy did not have a significant impact on PFS in our select low-risk cohort. Of note, 2 of the 5 patients with invasive disease who developed an IBTR in our cohort opted for mastectomy. This 1% rate of mastectomy in those with invasive disease receiving external beam APBI is lower than the rate of 4% reported by Smith et al in a retrospective review of the Surveillance, Epidemiology, and End ResultseMedicare database of women who underwent APBI via brachytherapy.20 APBI with 3D-CRT was well tolerated in this series. The rate of good to excellent posttreatment cosmesis from physician documentation was 75% overall compared with 95.5% before APBI, with only 2 of the 266 women expressing interest in meeting with a plastic surgeon for poor cosmesis. Notably, the rates of good to excellent cosmesis differed based upon fraction size, with patients
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receiving fractions of 385 cGy having a lower proportion of fair or poor cosmetic outcomes than those receiving fractions of 400 cGy (22% vs 33%, P Z .039). In addition to fraction size, we found that increasing irradiated breast volume predicted for adverse cosmesis, although no other dosimetric measures predicted for adverse events, highlighting the need for methods to minimize setup uncertainty and therefore decrease PTV. Our rate of 75% with good to excellent cosmesis is on the low end of the retrospective 3D-CRT APBI series with long-term follow-up discussed earlier, reporting a range of 73% to 100% for good to excellent cosmesis. However, our observed rate is higher than the 3-year results of 64% reported in Radiation Therapy Oncology Group 0319 and similar to 71% at 3 years reported in RAPID.21,22 It is notably similar to the rates of 70% to 71% seen in the 10-year results of a large randomized trial of hypofractionated once-daily whole-breast radiation versus conventionally fractionated whole-breast radiation.23 This is one of the first reported studies of APBI with 3D-CRT after the 2016 ASTRO update to consensus guidelines on APBI suitability criteria. The major changes included dropping the lower age bound for “suitable” from 60 to 50 years and allowing some treatment of DCIS as “suitable.”14 In our cohort, 32.7% of patients were “cautionary” and 6.4% were “unsuitable.” Importantly, these patients did not have a statistical difference in IBTR or PFS. Although the proportion of “unsuitable” patients was small, it is reassuring that the larger proportion of “cautionary” patients appears to be able to be treated effectively with APBI. We await confirmation of this from other groups with the new categories. There are several limitations to this study. First, it is retrospective, with all the biases inherent to this technique. This makes categorizing patient and physician statements regarding toxicity more difficult than if they were provided with a standard and validated evaluation form, as is being done in many prospective studies. Additionally, 29% of our patients had received a diagnosis of DCIS, which could make our results more favorable than those in other studies. However, our outcomes were not significantly different between patients with DCIS and those with invasive disease <3 cm. Other reported studies with long-term follow-up have a similar proportion of DCIS in their cohorts.12,15-17 Strengths of this study include the length of follow-up, the number of patients, and the exploration of different dose regimens, between which there was no significant difference in disease outcomes, though worse cosmesis with increasing fraction size was suggested.
Conclusions In this large cohort of patients treated with the 3DCRT technique for APBI, the risk of developing an
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IBTR was <2% at 7 years. In the select group of patients with ASTRO “cautionary” or “unsuitable” disease, both IBTR and PFS, outcomes were not worse than those in the “suitable” category. Increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. This technique was overall well tolerated, though prospective, multi-institutional outcomes are needed for confirmation.
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