ORIGINAL ARTICLE
Brachytherapy-based Accelerated Partial Breast Irradiation Provides Equivalent 10-Year Outcomes to Whole Breast Irradiation A Matched-Pair Analysis Jessica L. Wobb, MD,* Chirag Shah, MD,w Peter Y. Chen, MD, FACR,* Michelle Wallace, RN,* Hong Ye, MS,* Maha S. Jawad, MD,* and Inga S. Grills, MD*
Introduction: Although whole breast irradiation (WBI) represents the standard radiotherapy technique in breast conserving therapy, accelerated partial breast irradiation (APBI) has emerged as an option to reduce treatment duration with comparable clinical outcomes. The purpose of this analysis is to present long-term clinical outcomes between WBI and APBI. Methods: A total of 3009 patients were treated with breast conserving therapy at a single institution between 1980 and 2012. Among them, 2528 patients received WBI and 481 received APBI (interstitial or balloon based). A matched-pair analysis was performed with patients matched by age ( ± 3 years), stage (T-stage vs. T1 vs. T2), and estrogen receptor status (+ / ). All patients had a minimum of 12 months follow-up. A total of 274 matches (ratio 1:1) were made. Results: No differences between groups were noted with respect to clinicopathologic features; WBI patients demonstrated a trend for slightly larger tumors (1.3 vs. 1.1 cm, P = 0.06). At 10 years, no differences were noted with respect to rates of ipsilateral breast tumor recurrence (4% vs. 4%, P = 0.11), regional recurrence (1% vs. 1%, P = 0.20), contralateral breast failure (9% vs. 3%, P = 0.06), or distant metastases (3% vs. 6%, P = 0.47) for WBI and APBI, respectively. In addition, 10-year disease-free survival (93% vs. 91%, P = 0.10) and overall survival (83% vs. 75%, P = 0.34) were similar. Long-term cosmesis was good to excellent in 94% of WBI patients versus 95% of APBI patients (P = 0.78). Conclusions: At 10 years, no differences in recurrence or survival were found between patients undergoing WBI or brachytherapy-based APBI. Key Words: accelerated partial breast irradiation, APBI, breast cancer, breast conserving therapy, matched pair
(Am J Clin Oncol 2015;00:000–000)
From the *Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI; and wDepartment of Radiation Oncology, Summa Cancer Institute, Summa Health System, Akron, OH. Presented as an oral presentation at the American Society for Radiation Oncology 2013 Annual Meeting and the Best of ASTRO 2013 Meeting in San Diego, CA. The authors declare no conflicts of interest. Reprints: Peter Y. Chen, MD, FACR, Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, 3601 West 13 Mile Road, Royal Oak, MI 48073. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000082
American Journal of Clinical Oncology
B
reast conserving therapy (BCT) represents a standard of care in the management of early-stage breast cancer. Twenty-year follow-up from the NSABP and EORTC trials established BCT as an equivalent alternative to mastectomy, utilizing 2D whole breast irradiation (WBI).1,2 More recently, the importance of adding breast radiotherapy to maximize local control was documented in the EBCTCG meta-analysis showing that the addition of radiotherapy to breast conversing surgery decreased the risk of LR in half and reduces the risk of dying from breast cancer by one sixth.3 Despite providing equivalent clinical outcomes and improved quality of life, BCT and radiation therapy following breast conserving surgery remain underutilized. One rationale is that WBI, the standard for several decades, entails 6 to 7 weeks of daily treatment with newer shortened WBI schedules still requiring 3 weeks.4,5 In patients with significant distances to radiation centers or socioeconomic factors limiting travel, this would limit BCT as an option for the management of their earlystage breast cancers.4,5 Accelerated partial breast irradiation (APBI) offers the potential for a shorter duration of treatment, with treatment delivered in r1 week. In the 20-year follow-up from studies comparing mastectomy to BCT, the rates of breast tumor recurrence outside of the lumpectomy site and contralateral breast failure were equivalent.6 This key finding provides the justification for APBI which focuses radiation therapy only to the lumpectomy site plus a 1 cm margin. APBI was initially performed with interstitial catheters,7 but more recently technological advances have allowed for APBI to be delivered through 3D conformal radiotherapy8 or applicator brachytherapy minimizing the need for general anesthesia or invasive procedures.9 The shortened duration of treatment and limited field of treatment allow for a potential increase in quality of life and decrease in toxicity profile.10 At this time, there remains a paucity of data comparing longterm clinical outcomes between patients treated with APBI or WBI. Although randomized trials have been completed or are underway, it will be several years before mature results are available. Therefore, the purpose of this study is to analyze outcomes of patients treated with WBI versus brachytherapy-based APBI with long-term follow-up using a matched-pair analysis to control for differences in patient and pathologic characteristics.11
MATERIALS AND METHODS Patient Population A total of 481 patients with early-stage breast cancer were prospectively treated at a single institution with brachytherapybased APBI, receiving interstitial or balloon brachytherapy to
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Wobb et al
the tumor bed as part of their BCT from June 1993 to September 2011. Treatment techniques included a low-dose rate implant which delivered 50 Gy over 96 hours at 0.52 Gy/h and a high-dose rate implant that delivered either 32 Gy in 8 fractions twice daily (bid), or 34 Gy in 10 fractions bid. All balloon brachytherapy patients received 34 Gy in 10 fractions bid. Patients with balloon applicators were treated with either Mammosite Radiation Therapy System/Multilumen Catheter (Hologic Inc., Bedford, MA) or Contura Multi-Lumen Balloon (SenoRx Inc., Aliso Viejo, CA). This research was approved by the hospital Human Investigation Committee. There were a total of 2528 women with early-stage breast cancer who were treated with WBI at our institution between June 1983 and December 2011. Follow-up was complete through February 2012. Radiotherapy was delivered using standard fractionation WBI, consisting of 6 weeks of daily radiation, delivered Monday through Friday. WBI patients received a mean WB dose of 46 Gy (range, 42.6 to 70.9 Gy) and a mean boost dose of 14.8 Gy (range, 0 to 20.5 Gy).
Statistical Analyses To evaluate clinical outcomes between comparable groups of patients, each APBI patient was matched with 1 WBI patient. Patients were matched according to age (± 3 y), T stage (Tis vs. T1 vs. T2), and estrogen receptor status (positive vs. negative). Demographics, pathologic data, and clinical outcomes were gathered. Margins were considered “close” if tumor was found to be < 2 to 0.1 mm from ink. Time intervals were calculated from the date of RT completion. Outcomes included ipsilateral breast tumor recurrence (IBTR), contralateral breast failure (CLBF), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS). IBTR was defined as a cancer recurrence in the treated breast either before or concurrent with regional or distant failure. The Kaplan-Meier method was used to calculate clinical outcomes, and univariate analysis was performed by the Cox Proportional Hazards test. A P-value of r0.05 was considered significant, and all tests were 2-sided. Analyses were performed using SPSS version 20 (SYSTAT Software, Chicago, IL).
RESULTS A total of 274 matches were made per treatment modality after matching for age (± 3 y), T stage, and estrogen receptor status. Patients treated with APBI included 127 (46%) treated with interstitial-based brachytherapy and 147 (54%) with applicator-based irradiation. Clinical and pathologic features for both groups are shown in Table 1. Tumors in the WBI group were slightly larger than in the APBI cohort; however, this did not reach statistical significance (1.3 vs. 1.1 cm, P = 0.06). No other differences were noted, with the exception of use of adjuvant hormonal therapy, which was higher in the WBI patients (68% vs. 54%; P = 0.001). Mean follow-up was 8.1 years (range, 1 to 29 y) in the WBI group and 7.8 years (range, 1 to 19 y) in the APBI group (range, 1 to 19 y; P < 0.001). Cosmesis was good to excellent in 94% of patients treated with WBI versus 95% of patients who received APBI (P = 0.78). Clinical outcomes are presented in Table 2. Ten-year rates of IBTR (4.2% vs. 3.7%; P = 0.11), CLBF (3% vs. 9%; P = 0.06), RR (1% vs. 1%; P = 0.20), and DM (6% vs. 3%; P = 0.47) were not statistically different between APBI and WBI, respectively. With respect to IBTR, failure within the lumpectomy cavity was 1.4% for APBI patients and 0.9% for
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TABLE 1. Patient Characteristics
n (%) APBI (N = 274)
WBI (N = 274)
P
63 (44-84) 1.1 (0.1-3.3)
63 (40-85) 1.3 (0.1-4.6)
0.88 0.06
48 (18) 195 (71) 31 (11)
48 (18) 195 (71) 31 (11)
1.00
247 (91) 25 (9)
235 (86) 37 (14)
0.07
257 (94) 16 (6)
261 (95) 13 (5)
0.35
240 (88) 34 (12)
240 (88) 34 (12)
1.00
162 (59) 63 (23) 49 (18)
177 (65) 69 (25) 28 (10)
0.99
81 132 55 6
74 104 46 50
0.78
Mean age (y) Tumor size (cm) T-stage Tis T1 T2 Nodes Negative Positive Margins Negative Close/positive ER status Positive Negative PR status Positive Negative Unknown Grade 1 2 3 Unknown Adjuvant therapy Hormones Chemotherapy
(30) (48) (20) (2)
139 (54) 40 (15)
(27) (38) (17) (18)
177 (68) 46 (18)
0.001 0.44
APBI indicates accelerated partial breast irradiation; ER, estrogen receptor; PR, progesterone receptor; WBI, whole breast irradiation.
WBI (P = 0.24). Elsewhere failure within the breast was same in both groups (2.8% vs. 2.8%; P = 0.28). In addition, rates of DFS (91% vs. 93%; P = 0.10), CSS (93% vs. 94%; P = 0.72), and OS (75% vs. 82%; P = 0.34) were comparable between groups. Figure 1 shows Kaplan-Meier curves for IBTR-free and CLBF-free survival. Figure 2 delineates CSS and DFS. Univariate analysis for IBTR is shown in Table 3. Age was a predictor of IBTR in the APBI cohort (P = 0.05) but not among WBI patients (P = 0.97). No other clinical or pathologic feature was associated with IBTR for either cohort of patients and therefore a multivariate analysis was not performed.
TABLE 2. Five- and 10-Year Clinical Outcomes
APBI (N = 274) (%) Overall IBTR Lumpectomy bed IBTR Elsewhere IBTR CLBF RR DM DFS CSS OS
WBI (N = 274) (%)
5y
10 y
5y
10 y
P
3.5 1.4 2.1 1 1 3 93 96 90
4.2 1.4 2.8 3 1 6 91 93 75
0.9 0 0.9 3 1 2 98 98 93
3.7 0.9 2.8 9 1 3 93 94 82
0.11 0.24 0.28 0.06 0.20 0.47 0.10 0.72 0.34
APBI indicates accelerated partial breast irradiation; CLBF, contralateral breast failure; CSS, cause-specific survival; DFS, disease-free survival; DM, distant metastases; IBTR, ipsilateral breast tumor recurrence; OS, overall survival; RR, regional recurrence; WBI, whole breast irradiation.
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APBI vs. WBI Matched Pair
A
A 1.0
1.0
WBI
0.8
Cause-Specific Survival (%)
IBTR-Free Survival (%)
WBI APBI
APBI
P=0.11
0.6
0.4
0.2
0.8
P=0.72
0.6
0.4
0.2 10-year CI (lower 95%, upper 95%) WBI: 93.3 to 99.7 APBI: 93.0 to 98.6
0.0 0
5
10
15
20
10-year CI (lower 95%, upper 95%) WBI: 90.4 to 98.4 APBI: 89.4 to 97.4
0.0 25
0
5
10
Time (years)
No. at risk WBI APBI
274 274
130 154
78 80
58 31
15
20
25
Time (years) No. at risk
22
WBI APBI
274 274
133 161
80 82
60 37
25
B 1.0
APBI
B WBI
Disease-Free Survival (%)
CLBF-Free Survival (%)
1.0 WBI
0.8
P=0.06
0.6
0.4
0.2 10-year CI (lower 95%, upper 95%) WBI: 86.7 to 96.3 APBI: 94.3 to 99.8
0.0 0
5
10
15
20
0.8
APBI P=0.10
0.6
0.4
0.2
25
10-year CI (lower 95%, upper 95%) WBI: 88.4 to 97.2 APBI: 87.5 to 95.5
0.0
Time (years) 0
No. at risk WBI APBI
274 274
126 158
72 80
53 33
5
10
21
FIGURE 1. A, Ipsilateral breast tumor recurrence (IBTR)-free survival. B, Contralateral breast failure (CLBF)-free survival. APBI indicates accelerated partial breast irradiation; CI, confidence interval; WBI, whole breast irradiation.
15
20
25
Time (years) No. at risk WBI APBI
274 274
130 153
79 79
59 31
23
FIGURE 2. A, Cause-specific survival. B, Disease-free survival. APBI indicates accelerated partial breast irradiation; CI, confidence interval; WBI, whole breast irradiation.
DISCUSSION The results from this study demonstrate that adjuvant radiotherapy as part of BCT for early-stage breast cancer with either WBI or APBI provides excellent local control and survival with long-term follow-up. Further, the analysis demonstrates that when comparing a matched cohort of low-risk patients, no difference in clinical outcomes were noted between patients treated with WBI or APBI. In addition, no differences in cosmesis were noted between APBI and WBI with durable cosmesis outcomes noted using brachytherapybased APBI. These findings confirm previous studies in documenting the safety, efficacy, and equivalence of APBI when compared with WBI.10,11 Copyright
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The findings of our study are consistent with 10-year results from a phase 3 randomized clinical trial that was recently published by Polgar et al.10 This study randomized 258 patients to receive either WBI (50 Gy in 25 fractions) or APBI (36.4 Gy in 7 fractions) with multicatheter high-dose rate (69%) or limited electron fields (31%). Results demonstrated equivalent disease control and complication rates in patients who received APBI compared with WBI. As well, cosmetic outcomes were found to be improved in patients who received APBI. Local failure rates were 5.9% in the APBI group and 5.1% in the WBI group, which are similar to the IBTR rates in our study (4.2% APBI vs. 3.7% WBI). There was, however, no
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TABLE 3. Univariate Analysis of Ipsilateral Breast Tumor Recurrence Age Tumor size T-Stage Tis vs. T1 Tis vs. T2 Grade Moderate vs. well Poor vs. well Nodes Margins Negative vs. close/positive ER PR Hormones Chemotherapy
APBI (N = 274)
WBI (N = 274)
0.05 0.32
0.97 0.28
0.68 0.73 0.44 0.43 0.29 0.68
0.72 0.99 0.33 0.45 0.42 0.94
0.44 0.24 0.73 0.15 0.51
0.83 0.16 0.28 0.69 0.48
APBI indicates accelerated partial breast irradiation; ER, estrogen receptor; PR, progesterone receptor; WBI, whole breast irradiation.
difference in cosmesis noted in our series. One explanation for this finding could be that the current study included only interstitial and applicator-based APBI and in the Polgar study, it seems that the cosmesis benefit was limited to the interstitial subset of patients. More recent data suggest inferior cosmetic outcomes with external beam conformal APBI after a median follow-up of 36 months,12 although another randomized trial comparing WBI versus conformal external beam APBI reported conflicting data, reporting similar cosmetic outcomes between those 2 modalities.13 One concern regarding brachytherapy-based APBI is the potential for higher mastectomy rates as well as infectious and noninfectious complication rates, previously reported in several population-based analyses utilizing the SEER-Medicare database.14–16 There were, however, significant limitations regarding these studies. These were observational, retrospective series with relatively short follow-up periods. Outcomes were based on billing codes from Medicare data, which can lead to misclassification bias and gives very little information regarding clinicopathologic features, comorbidities, or systemic treatment. In addition, outcomes are generated from fee-for-service payments rather than health care records. As a result, the mastectomy rates are ambiguous, as Medicare billing data do not discern between local recurrence, contralateral failure, or mastectomy for noncancer reasons.17–20 In addition, critical variables that influence IBTR, such as margin status, presence of lymphovascular invasion, and compliance with systemic/hormone therapy, cannot be extracted.20 Likewise, it is also important to point out that although the most recent data by Smith et al16 report mastectomy rates of brachytherapybased APBI to be 2.8% versus 1.3% with WBI, this demonstrates only a 1.5% difference between the 2 modalities; indeed, in the era of this investigation, no formal guidelines were available for appropriate selection of patients for APBI, as such criteria came after the time interval scrutinized by the authors. Thus, in quantification of mastectomies of WBI versus ABPI patients, a mere 1.5% difference may well be explained by the dearth of any substantial long-term data, during the time period analyzed by Smith et al, for the formulation of evidence-based guidelines for the selection of patients for APBI.20 Taken together, these findings, although interesting, are not compelling enough to be considered practice-changing in the
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face of quality prospective data that supports excellent local control and toxicity profiles with APBI.19 The results from our matched-pair analysis are consistent with the recently reported prospective data demonstrating similar rates of local recurrence and toxicity between brachytherapy-based APBI and WBI that would not likely lead to higher mastectomy rates.21 Although toxicity data are not reported in the current analysis, the equivalence in cosmesis suggests that toxicities would be similar, as cosmetic outcome reflects in large part the reported constellation of local toxicities found with either APBI or WBI.21,22 Although not statistically significant, APBI was associated with a trend for reduced contralateral failures. One potential explanation is a reduction in contralateral breast dose with APBI, reducing the potential for radiation-induced secondary breast cancers. Further studies and longer follow-up are required to validate these findings. There are limitations to our analysis, including the inherent short falls of a nonrandomized retrospective study. In utilizing a matched-pair analysis, we attempted to control for differences in clinical and pathologic risk factors associated with recurrence. Consideration was given to include other factors known to influence local disease control and distant disease spread in the matched criteria, including nodal and margin status, presence of LVSI, Her2/Neu receptor status, tumor grade, and use of systemic therapy. However, increasing the number of variables within the match would significantly decrease the total number of matches, and these variables were not different between the 2 cohorts as a whole, with the exception of endocrine therapy being more common in the WBI group. Further, although our study is one of the largest to date, the relatively small numbers and limited number of events should be noted. Finally, toxicity was not specifically evaluated in this study, which would be important in comparing WBI and APBI. This is being addressed and presently being analyzed with updates on morbidity forthcoming. Despite its limitations, this analysis represents one of only a few matched cohort comparisons of APBI to WBI with substantial long-term outcomes. Although results from the recently closed RTOG 0413/NSABP B-39 trial are anticipated, long-term control rates will not likely be reported for some time and until then, this study adds to the current body of data supporting the potential efficacy of APBI as a safe and efficacious alternative to conventional WBI.
CONCLUSIONS Brachytherapy-based APBI provides excellent local control in appropriately selected patients, and demonstrates equivalent clinical outcomes and cosmesis at 10 years when compared with patients treated with WBI. REFERENCES 1. 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. N Engl J Med. 2002;347:1233–1241. 2. Litiere S, Werutsky G, Fentijman IS, et al. Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13:412–419. 3. Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials. Lancet. 2011;378:1707–1716.
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4. Whelan TJ, Pignol JP, Levin MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2011;362:513–520. 5. Haviland JS, Owen JR, Dewar JA, et al. The UK standardization of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomized controlled trials. Lancet Oncol. 2013; 14:1086–1094. 6. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002; 347:1227–1232. 7. King TA, Bolton JS, Kuske RR, et al. Long-term results of widefield brachytherapy after segmental mastectomy for Tis,1,2 breast cancer. Am J Surg. 2000;180:299–304. 8. Chen PY, Wallace M, Mitchell C, et al. Four-year efficacy, cosmesis, and toxicity using three-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76:991–997. 9. Benitez PR, Keisch ME, Vicini F, et al. Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer. Am J Surg. 2007;19:456–462. 10. Polgar C, Fodor J, Major T, et al. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108:197–202. 11. Shah C, Antonucci JV, Wilkinson JB, et al. Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matchedpair analysis. Radiother Oncol. 2011;100:210–214. 12. 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. 13. Chafe S, Moughan J, McCormick B, et al. Late toxicity and patient self-assessment of breast appearance/satisfaction on RTOG 0319: a phase 2 trial of 3-dimensional conformal radiation therapy-
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APBI vs. WBI Matched Pair
accelerated partial breast irradiation following lumpectomy for stage I and II breast cancer. Int J Radiat Oncol Biol Phys. 2013; 86:854–859. Presley CJ, Soulos PR, Herrin J, et al. Patterns of use and shortterm complications of breast brachytherapy in the national Medicare population from 2008-2009. J Clin Oncol. 2012;30: 4301–4307. Smith GL, Xu Y, Bucholz TA, et al. Association between treatment with brachytherapy vs. whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA. 2012;307: 1827–1837. Smith GL, Jiang J, Buchholz T, et al. Benefit of adjuvant brachytherapy versus external beam radiation for early stage breast cancer: impact of a patient stratification on breast preservation. Int J Radiat Oncol Biol Phys. 2014;88:274–284. Cuttino LW, White JR, Rabinovitch R, et al. Accelerated partialbreast irradiation: trial by media or by science? Int J Radiat Oncol Biol Phys. 2012;83:1075–1077. Shah C, Badiyan S, Khwaja S, et al. Accelerated partialbreast irradiation: does the evidence stack up? Oncology. 2013; 27:1–4. Kuske RR, Young SS. Breast brachytherapy versus whole-breast irradiation: reported differences may be statistically significant but clinically trivial. Int J Radiat Oncol Biol Phys. 2014;88: 266–267. Chen PY. Accelerated partial breast irradiation: keeping guidelines in step with evolving data. Int J Radiat Oncol Biol Phys. 2014;88: 263–265. Vargo JA, Verma V, Kim H, et al. Extended (5-year) outcomes of accelerated partial breast irradiation using MammoSite balloon brachytherapy: patterns of failure, patient selection, and dosimetric correlates for late toxicity. Int J Radiat Oncol Biol Phys. 2014;88: 285–291. Shah C, Vicini F, Keisch M, et al. Outcome after ipsilateral breast tumor recurrence in patients who received accelerated partial breast irradiation. Cancer. 2012;118:4126–4131.
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5
Brachytherapy-based Accelerated Partial Breast Irradiation Provides Equivalent 10-Year Outcomes to Whole Breast Irradiation A Matched-Pair Analysis Jessica L. Wobb, MD,* Chirag Shah, MD,w Peter Y. Chen, MD, FACR,* Michelle Wallace, RN,* Hong Ye, MS,* Maha S. Jawad, MD,* and Inga S. Grills, MD*
Introduction: Although whole breast irradiation (WBI) represents the standard radiotherapy technique in breast conserving therapy, accelerated partial breast irradiation (APBI) has emerged as an option to reduce treatment duration with comparable clinical outcomes. The purpose of this analysis is to present long-term clinical outcomes between WBI and APBI. Methods: A total of 3009 patients were treated with breast conserving therapy at a single institution between 1980 and 2012. Among them, 2528 patients received WBI and 481 received APBI (interstitial or balloon based). A matched-pair analysis was performed with patients matched by age ( ± 3 years), stage (T-stage vs. T1 vs. T2), and estrogen receptor status (+ / ). All patients had a minimum of 12 months follow-up. A total of 274 matches (ratio 1:1) were made. Results: No differences between groups were noted with respect to clinicopathologic features; WBI patients demonstrated a trend for slightly larger tumors (1.3 vs. 1.1 cm, P = 0.06). At 10 years, no differences were noted with respect to rates of ipsilateral breast tumor recurrence (4% vs. 4%, P = 0.11), regional recurrence (1% vs. 1%, P = 0.20), contralateral breast failure (9% vs. 3%, P = 0.06), or distant metastases (3% vs. 6%, P = 0.47) for WBI and APBI, respectively. In addition, 10-year disease-free survival (93% vs. 91%, P = 0.10) and overall survival (83% vs. 75%, P = 0.34) were similar. Long-term cosmesis was good to excellent in 94% of WBI patients versus 95% of APBI patients (P = 0.78). Conclusions: At 10 years, no differences in recurrence or survival were found between patients undergoing WBI or brachytherapy-based APBI. Key Words: accelerated partial breast irradiation, APBI, breast cancer, breast conserving therapy, matched pair
(Am J Clin Oncol 2015;00:000–000)
From the *Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI; and wDepartment of Radiation Oncology, Summa Cancer Institute, Summa Health System, Akron, OH. Presented as an oral presentation at the American Society for Radiation Oncology 2013 Annual Meeting and the Best of ASTRO 2013 Meeting in San Diego, CA. The authors declare no conflicts of interest. Reprints: Peter Y. Chen, MD, FACR, Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, 3601 West 13 Mile Road, Royal Oak, MI 48073. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000082
American Journal of Clinical Oncology
B
reast conserving therapy (BCT) represents a standard of care in the management of early-stage breast cancer. Twenty-year follow-up from the NSABP and EORTC trials established BCT as an equivalent alternative to mastectomy, utilizing 2D whole breast irradiation (WBI).1,2 More recently, the importance of adding breast radiotherapy to maximize local control was documented in the EBCTCG meta-analysis showing that the addition of radiotherapy to breast conversing surgery decreased the risk of LR in half and reduces the risk of dying from breast cancer by one sixth.3 Despite providing equivalent clinical outcomes and improved quality of life, BCT and radiation therapy following breast conserving surgery remain underutilized. One rationale is that WBI, the standard for several decades, entails 6 to 7 weeks of daily treatment with newer shortened WBI schedules still requiring 3 weeks.4,5 In patients with significant distances to radiation centers or socioeconomic factors limiting travel, this would limit BCT as an option for the management of their earlystage breast cancers.4,5 Accelerated partial breast irradiation (APBI) offers the potential for a shorter duration of treatment, with treatment delivered in r1 week. In the 20-year follow-up from studies comparing mastectomy to BCT, the rates of breast tumor recurrence outside of the lumpectomy site and contralateral breast failure were equivalent.6 This key finding provides the justification for APBI which focuses radiation therapy only to the lumpectomy site plus a 1 cm margin. APBI was initially performed with interstitial catheters,7 but more recently technological advances have allowed for APBI to be delivered through 3D conformal radiotherapy8 or applicator brachytherapy minimizing the need for general anesthesia or invasive procedures.9 The shortened duration of treatment and limited field of treatment allow for a potential increase in quality of life and decrease in toxicity profile.10 At this time, there remains a paucity of data comparing longterm clinical outcomes between patients treated with APBI or WBI. Although randomized trials have been completed or are underway, it will be several years before mature results are available. Therefore, the purpose of this study is to analyze outcomes of patients treated with WBI versus brachytherapy-based APBI with long-term follow-up using a matched-pair analysis to control for differences in patient and pathologic characteristics.11
MATERIALS AND METHODS Patient Population A total of 481 patients with early-stage breast cancer were prospectively treated at a single institution with brachytherapybased APBI, receiving interstitial or balloon brachytherapy to
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the tumor bed as part of their BCT from June 1993 to September 2011. Treatment techniques included a low-dose rate implant which delivered 50 Gy over 96 hours at 0.52 Gy/h and a high-dose rate implant that delivered either 32 Gy in 8 fractions twice daily (bid), or 34 Gy in 10 fractions bid. All balloon brachytherapy patients received 34 Gy in 10 fractions bid. Patients with balloon applicators were treated with either Mammosite Radiation Therapy System/Multilumen Catheter (Hologic Inc., Bedford, MA) or Contura Multi-Lumen Balloon (SenoRx Inc., Aliso Viejo, CA). This research was approved by the hospital Human Investigation Committee. There were a total of 2528 women with early-stage breast cancer who were treated with WBI at our institution between June 1983 and December 2011. Follow-up was complete through February 2012. Radiotherapy was delivered using standard fractionation WBI, consisting of 6 weeks of daily radiation, delivered Monday through Friday. WBI patients received a mean WB dose of 46 Gy (range, 42.6 to 70.9 Gy) and a mean boost dose of 14.8 Gy (range, 0 to 20.5 Gy).
Statistical Analyses To evaluate clinical outcomes between comparable groups of patients, each APBI patient was matched with 1 WBI patient. Patients were matched according to age (± 3 y), T stage (Tis vs. T1 vs. T2), and estrogen receptor status (positive vs. negative). Demographics, pathologic data, and clinical outcomes were gathered. Margins were considered “close” if tumor was found to be < 2 to 0.1 mm from ink. Time intervals were calculated from the date of RT completion. Outcomes included ipsilateral breast tumor recurrence (IBTR), contralateral breast failure (CLBF), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS). IBTR was defined as a cancer recurrence in the treated breast either before or concurrent with regional or distant failure. The Kaplan-Meier method was used to calculate clinical outcomes, and univariate analysis was performed by the Cox Proportional Hazards test. A P-value of r0.05 was considered significant, and all tests were 2-sided. Analyses were performed using SPSS version 20 (SYSTAT Software, Chicago, IL).
RESULTS A total of 274 matches were made per treatment modality after matching for age (± 3 y), T stage, and estrogen receptor status. Patients treated with APBI included 127 (46%) treated with interstitial-based brachytherapy and 147 (54%) with applicator-based irradiation. Clinical and pathologic features for both groups are shown in Table 1. Tumors in the WBI group were slightly larger than in the APBI cohort; however, this did not reach statistical significance (1.3 vs. 1.1 cm, P = 0.06). No other differences were noted, with the exception of use of adjuvant hormonal therapy, which was higher in the WBI patients (68% vs. 54%; P = 0.001). Mean follow-up was 8.1 years (range, 1 to 29 y) in the WBI group and 7.8 years (range, 1 to 19 y) in the APBI group (range, 1 to 19 y; P < 0.001). Cosmesis was good to excellent in 94% of patients treated with WBI versus 95% of patients who received APBI (P = 0.78). Clinical outcomes are presented in Table 2. Ten-year rates of IBTR (4.2% vs. 3.7%; P = 0.11), CLBF (3% vs. 9%; P = 0.06), RR (1% vs. 1%; P = 0.20), and DM (6% vs. 3%; P = 0.47) were not statistically different between APBI and WBI, respectively. With respect to IBTR, failure within the lumpectomy cavity was 1.4% for APBI patients and 0.9% for
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TABLE 1. Patient Characteristics
n (%) APBI (N = 274)
WBI (N = 274)
P
63 (44-84) 1.1 (0.1-3.3)
63 (40-85) 1.3 (0.1-4.6)
0.88 0.06
48 (18) 195 (71) 31 (11)
48 (18) 195 (71) 31 (11)
1.00
247 (91) 25 (9)
235 (86) 37 (14)
0.07
257 (94) 16 (6)
261 (95) 13 (5)
0.35
240 (88) 34 (12)
240 (88) 34 (12)
1.00
162 (59) 63 (23) 49 (18)
177 (65) 69 (25) 28 (10)
0.99
81 132 55 6
74 104 46 50
0.78
Mean age (y) Tumor size (cm) T-stage Tis T1 T2 Nodes Negative Positive Margins Negative Close/positive ER status Positive Negative PR status Positive Negative Unknown Grade 1 2 3 Unknown Adjuvant therapy Hormones Chemotherapy
(30) (48) (20) (2)
139 (54) 40 (15)
(27) (38) (17) (18)
177 (68) 46 (18)
0.001 0.44
APBI indicates accelerated partial breast irradiation; ER, estrogen receptor; PR, progesterone receptor; WBI, whole breast irradiation.
WBI (P = 0.24). Elsewhere failure within the breast was same in both groups (2.8% vs. 2.8%; P = 0.28). In addition, rates of DFS (91% vs. 93%; P = 0.10), CSS (93% vs. 94%; P = 0.72), and OS (75% vs. 82%; P = 0.34) were comparable between groups. Figure 1 shows Kaplan-Meier curves for IBTR-free and CLBF-free survival. Figure 2 delineates CSS and DFS. Univariate analysis for IBTR is shown in Table 3. Age was a predictor of IBTR in the APBI cohort (P = 0.05) but not among WBI patients (P = 0.97). No other clinical or pathologic feature was associated with IBTR for either cohort of patients and therefore a multivariate analysis was not performed.
TABLE 2. Five- and 10-Year Clinical Outcomes
APBI (N = 274) (%) Overall IBTR Lumpectomy bed IBTR Elsewhere IBTR CLBF RR DM DFS CSS OS
WBI (N = 274) (%)
5y
10 y
5y
10 y
P
3.5 1.4 2.1 1 1 3 93 96 90
4.2 1.4 2.8 3 1 6 91 93 75
0.9 0 0.9 3 1 2 98 98 93
3.7 0.9 2.8 9 1 3 93 94 82
0.11 0.24 0.28 0.06 0.20 0.47 0.10 0.72 0.34
APBI indicates accelerated partial breast irradiation; CLBF, contralateral breast failure; CSS, cause-specific survival; DFS, disease-free survival; DM, distant metastases; IBTR, ipsilateral breast tumor recurrence; OS, overall survival; RR, regional recurrence; WBI, whole breast irradiation.
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APBI vs. WBI Matched Pair
A
A 1.0
1.0
WBI
0.8
Cause-Specific Survival (%)
IBTR-Free Survival (%)
WBI APBI
APBI
P=0.11
0.6
0.4
0.2
0.8
P=0.72
0.6
0.4
0.2 10-year CI (lower 95%, upper 95%) WBI: 93.3 to 99.7 APBI: 93.0 to 98.6
0.0 0
5
10
15
20
10-year CI (lower 95%, upper 95%) WBI: 90.4 to 98.4 APBI: 89.4 to 97.4
0.0 25
0
5
10
Time (years)
No. at risk WBI APBI
274 274
130 154
78 80
58 31
15
20
25
Time (years) No. at risk
22
WBI APBI
274 274
133 161
80 82
60 37
25
B 1.0
APBI
B WBI
Disease-Free Survival (%)
CLBF-Free Survival (%)
1.0 WBI
0.8
P=0.06
0.6
0.4
0.2 10-year CI (lower 95%, upper 95%) WBI: 86.7 to 96.3 APBI: 94.3 to 99.8
0.0 0
5
10
15
20
0.8
APBI P=0.10
0.6
0.4
0.2
25
10-year CI (lower 95%, upper 95%) WBI: 88.4 to 97.2 APBI: 87.5 to 95.5
0.0
Time (years) 0
No. at risk WBI APBI
274 274
126 158
72 80
53 33
5
10
21
FIGURE 1. A, Ipsilateral breast tumor recurrence (IBTR)-free survival. B, Contralateral breast failure (CLBF)-free survival. APBI indicates accelerated partial breast irradiation; CI, confidence interval; WBI, whole breast irradiation.
15
20
25
Time (years) No. at risk WBI APBI
274 274
130 153
79 79
59 31
23
FIGURE 2. A, Cause-specific survival. B, Disease-free survival. APBI indicates accelerated partial breast irradiation; CI, confidence interval; WBI, whole breast irradiation.
DISCUSSION The results from this study demonstrate that adjuvant radiotherapy as part of BCT for early-stage breast cancer with either WBI or APBI provides excellent local control and survival with long-term follow-up. Further, the analysis demonstrates that when comparing a matched cohort of low-risk patients, no difference in clinical outcomes were noted between patients treated with WBI or APBI. In addition, no differences in cosmesis were noted between APBI and WBI with durable cosmesis outcomes noted using brachytherapybased APBI. These findings confirm previous studies in documenting the safety, efficacy, and equivalence of APBI when compared with WBI.10,11 Copyright
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The findings of our study are consistent with 10-year results from a phase 3 randomized clinical trial that was recently published by Polgar et al.10 This study randomized 258 patients to receive either WBI (50 Gy in 25 fractions) or APBI (36.4 Gy in 7 fractions) with multicatheter high-dose rate (69%) or limited electron fields (31%). Results demonstrated equivalent disease control and complication rates in patients who received APBI compared with WBI. As well, cosmetic outcomes were found to be improved in patients who received APBI. Local failure rates were 5.9% in the APBI group and 5.1% in the WBI group, which are similar to the IBTR rates in our study (4.2% APBI vs. 3.7% WBI). There was, however, no
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American Journal of Clinical Oncology
Wobb et al
TABLE 3. Univariate Analysis of Ipsilateral Breast Tumor Recurrence Age Tumor size T-Stage Tis vs. T1 Tis vs. T2 Grade Moderate vs. well Poor vs. well Nodes Margins Negative vs. close/positive ER PR Hormones Chemotherapy
APBI (N = 274)
WBI (N = 274)
0.05 0.32
0.97 0.28
0.68 0.73 0.44 0.43 0.29 0.68
0.72 0.99 0.33 0.45 0.42 0.94
0.44 0.24 0.73 0.15 0.51
0.83 0.16 0.28 0.69 0.48
APBI indicates accelerated partial breast irradiation; ER, estrogen receptor; PR, progesterone receptor; WBI, whole breast irradiation.
difference in cosmesis noted in our series. One explanation for this finding could be that the current study included only interstitial and applicator-based APBI and in the Polgar study, it seems that the cosmesis benefit was limited to the interstitial subset of patients. More recent data suggest inferior cosmetic outcomes with external beam conformal APBI after a median follow-up of 36 months,12 although another randomized trial comparing WBI versus conformal external beam APBI reported conflicting data, reporting similar cosmetic outcomes between those 2 modalities.13 One concern regarding brachytherapy-based APBI is the potential for higher mastectomy rates as well as infectious and noninfectious complication rates, previously reported in several population-based analyses utilizing the SEER-Medicare database.14–16 There were, however, significant limitations regarding these studies. These were observational, retrospective series with relatively short follow-up periods. Outcomes were based on billing codes from Medicare data, which can lead to misclassification bias and gives very little information regarding clinicopathologic features, comorbidities, or systemic treatment. In addition, outcomes are generated from fee-for-service payments rather than health care records. As a result, the mastectomy rates are ambiguous, as Medicare billing data do not discern between local recurrence, contralateral failure, or mastectomy for noncancer reasons.17–20 In addition, critical variables that influence IBTR, such as margin status, presence of lymphovascular invasion, and compliance with systemic/hormone therapy, cannot be extracted.20 Likewise, it is also important to point out that although the most recent data by Smith et al16 report mastectomy rates of brachytherapybased APBI to be 2.8% versus 1.3% with WBI, this demonstrates only a 1.5% difference between the 2 modalities; indeed, in the era of this investigation, no formal guidelines were available for appropriate selection of patients for APBI, as such criteria came after the time interval scrutinized by the authors. Thus, in quantification of mastectomies of WBI versus ABPI patients, a mere 1.5% difference may well be explained by the dearth of any substantial long-term data, during the time period analyzed by Smith et al, for the formulation of evidence-based guidelines for the selection of patients for APBI.20 Taken together, these findings, although interesting, are not compelling enough to be considered practice-changing in the
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Volume 00, Number 00, ’’ 2015
face of quality prospective data that supports excellent local control and toxicity profiles with APBI.19 The results from our matched-pair analysis are consistent with the recently reported prospective data demonstrating similar rates of local recurrence and toxicity between brachytherapy-based APBI and WBI that would not likely lead to higher mastectomy rates.21 Although toxicity data are not reported in the current analysis, the equivalence in cosmesis suggests that toxicities would be similar, as cosmetic outcome reflects in large part the reported constellation of local toxicities found with either APBI or WBI.21,22 Although not statistically significant, APBI was associated with a trend for reduced contralateral failures. One potential explanation is a reduction in contralateral breast dose with APBI, reducing the potential for radiation-induced secondary breast cancers. Further studies and longer follow-up are required to validate these findings. There are limitations to our analysis, including the inherent short falls of a nonrandomized retrospective study. In utilizing a matched-pair analysis, we attempted to control for differences in clinical and pathologic risk factors associated with recurrence. Consideration was given to include other factors known to influence local disease control and distant disease spread in the matched criteria, including nodal and margin status, presence of LVSI, Her2/Neu receptor status, tumor grade, and use of systemic therapy. However, increasing the number of variables within the match would significantly decrease the total number of matches, and these variables were not different between the 2 cohorts as a whole, with the exception of endocrine therapy being more common in the WBI group. Further, although our study is one of the largest to date, the relatively small numbers and limited number of events should be noted. Finally, toxicity was not specifically evaluated in this study, which would be important in comparing WBI and APBI. This is being addressed and presently being analyzed with updates on morbidity forthcoming. Despite its limitations, this analysis represents one of only a few matched cohort comparisons of APBI to WBI with substantial long-term outcomes. Although results from the recently closed RTOG 0413/NSABP B-39 trial are anticipated, long-term control rates will not likely be reported for some time and until then, this study adds to the current body of data supporting the potential efficacy of APBI as a safe and efficacious alternative to conventional WBI.
CONCLUSIONS Brachytherapy-based APBI provides excellent local control in appropriately selected patients, and demonstrates equivalent clinical outcomes and cosmesis at 10 years when compared with patients treated with WBI. REFERENCES 1. 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. N Engl J Med. 2002;347:1233–1241. 2. Litiere S, Werutsky G, Fentijman IS, et al. Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13:412–419. 3. Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials. Lancet. 2011;378:1707–1716.
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Volume 00, Number 00, ’’ 2015
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APBI vs. WBI Matched Pair
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