Breast Boost Using Noninvasive Image-Guided Breast Brachytherapy vs. External Beam: A 2:1 Matched-Pair Analysis

Original Study

Breast Boost Using Noninvasive Image-Guided Breast Brachytherapy vs. External Beam: A 2:1 Matched-Pair Analysis Kara Lynne Leonard,1,2 Jaroslaw T. Hepel,1,2 John R. Styczynski,2 Jessica R. Hiatt,2 Thomas A. DiPetrillo,1,2 David E. Wazer1,2 Abstract Outcomes were compared for 47 women with breast cancer undergoing breast-conserving therapy with whole breast irradiation (WBI) and noninvasive breast brachytherapy (NIBB) boost and 94 matched control subjects treated with WBI and electron beam (EB) boost. Acute desquamation occurred in 39% and 52% of patients, respectively. There was less skin/subcutaneous toxicity in those treated with NIBB than in those treated with EB (P [ .046). NIBB compares favorably with EB. Background: To compare clinical outcomes and toxicity in patients treated with NIBB boost with those in patients treated with external beam (EB) boost. Patients and Methods: Women with early stage breast cancer treated with WBI and NIBB boost were identified. Control subjects treated with EB boost identified as the best possible match with respect to age, stage, chemotherapy use, and fractionation were chosen for a 2:1 comparison. Acute toxicity, late toxicity, and oncologic outcomes were reviewed. The McNemar nonparametric test was used to evaluate marginal homogeneity between matched pairs. Results: One hundred forty-one patients were included in the analysis: 47 patients treated with NIBB boost and 94 matched control subjects treated with EB boost (electron, n ¼ 93) or 3-D conformal radiation (n ¼ 1). Grade 2þ desquamation developed in 18 patients (39%) treated with NIBB boost and in 49 patients (52%) treated with EB boost (P ¼ .07). Breast size, electron energy, and fractionation predicted for acute desquamation (P < .0001, P < .001, and P ¼ .006). Median follow-up was 13.6 months. One patient (2%) who received NIBB had Grade 2þ skin/subcutaneous fibrosis 15 months after completion of treatment. Among those treated with EB, 9 patients (9.5%) developed Grade 2þ subcutaneous fibrosis, and 1 patient had recurrent cellulitis. There was statistically significantly less combined skin/subcutaneous toxicity in those treated with NIBB than in those treated with EB (P ¼ .046). Conclusion: NIBB boost is associated with favorable short-term clinical outcomes compared with EB. Clinical Breast Cancer, Vol. 13, No. 6, 455-9 ª 2013 Elsevier Inc. All rights reserved. Keywords: AccuBoost, Breast boost, Breast cancer, Brachytherapy, NIBB

Introduction Current noninvasive approaches for partial breast irradiation (PBI) for tumor bed boost use external beam (EB) modalities such as en face electrons and 3-D conformal radiation (3DCRT). The 1 Department of Radiation Oncology, Rhode Island Hospital, Brown Alpert Medical School, Providence, RI 2 Department of Radiation Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA

Submitted: Jun 5, 2013; Revised: Aug 2, 2013; Accepted: Aug 26, 2013; Epub: Oct 4, 2013 Address for correspondence: Kara Lynne Leonard, MD, 800 Washington St, Box 359, Boston, MA 02111 Fax: 617-636-6131; e-mail contact: [email protected]

1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.08.005

application of these techniques typically requires extensive target volume expansion to account for uncertainty in tumor bed localization, intrinsic daily setup error, respiratory motion, and allowances for radiation beam physical penumbra. In order to account for such factors, Bartelink et al used a minimum margin expansion of 1.5 cm in the EORTC (European Organization for Research and Treatment of Cancer) boost vs. no boost trial.1 Noninvasive, image-guided breast brachytherapy (NIBB) is designed to deliver PBI without the uncertainties associated with target delineation, respiratory motion, and daily setup error. NIBB involves target delineation via mammography-based image guidance and treatment of the tumor bed with 192Ir applicators positioned on breast compression paddles along orthogonal axes. Dose is

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NIBB vs. External Beam Boost prescribed to midplane whereby the cumulative dose to skin is minimized by alternating treatments along each orthogonal axis. With this technique, the dose distribution is such that maximum dose is delivered to the tumor bed at depth with a high degree of skin-sparing.2 This technique obviates the necessity for additional margin expansions beyond the tumor bed resulting in boost target volumes that are smaller compared with electron beam and 3DCRT techniques while still maintaining planning target volume (PTV) dosimetric benchmarks.3 Currently, NIBB is being used as an alternative to EB for tumor bed boost in conjunction with whole breast irradiation (WBI).4 The current analysis compares clinical outcomes and acute and late toxicity in patients treated with NIBB boost with those in patients treated with EB.

Patients and Methods Women with early stage breast cancer or duct carcinoma in situ (DCIS) treated with WBI and NIBB boost at Rhode Island Hospital between May 2009 and May 2012 were identified. Patients treated with NIBB were treated with a commercially available system (Accuboost, Advanced Radiation Therapy, Inc, Billerica, MA).4 This NIBB technique has been previously described.3 Briefly, the breast is immobilized via moderate mammographic compression and an image is obtained using approximately 30 kV(p) x-rays. The clinical target volume (CTV) is determined to encompass postoperative changes and clips visualized on the mammographic image. Tungston alloy applicators are mounted on the mammography paddles. The appropriate sized applicator is selected to cover the CTV with no additional margin (Fig. 1). High dose-rate 192Ir photons are delivered along 2 intersecting orthogonal axes. From among all patients treated with WBI and EB at our institution during the same time period, control subjects identified as the best possible match with respect to age, stage, chemotherapy use, fractionation, and when possible with respect to breast size, comorbid illness, and smoking status, were chosen for a 2:1 comparison.

were reviewed for each patient and matched control subject. Acute skin toxicity and late skin and subcutaneous toxicity were assessed by the physician at each visit and retrospectively collected and recorded according to the Common Terminology Criteria for Adverse Events version 3.0. Two-tailed Fisher’s exact test was used to evaluate associations between patient/tumor factors and toxicity. McNemar nonparametric test was used to evaluate for marginal homogeneity between matched pairs with respect to acute and late toxicity.

Results Patient Characteristics One hundred forty-one patients were included in the analysis: 47 patients treated with NIBB boost between May 2009 and May 2012 and 94 control subjects matched 2:1 treated during the same interval. Patient and tumor characteristics are shown in Table 1; as a result of the matched pairing, the 2 groups were nearly identical with respect to age, mean tumor size, breast size, T-stage, N-stage, overall stage, smoking status, and comorbid autoimmune disorders. Mean age was 58 years in each group and most patients had stage I breast cancer (n ¼ 84) or DCIS (n ¼ 36).

Treatment Characteristics Treatment characteristics are shown in Table 2; the NIBB and EB groups were well matched with respect to fractionation and chemotherapy use. Treatment dose and fractionation were chosen at the discretion of the treating physician. Most patients treated with NIBB received 50-50.4 Gy to the whole breast with a 10-Gy boost. Boost was delivered with en face electrons for 93 control subjects and for 1 subject, with 3DCRT mini-tangents. Patients treated with EB were treated most commonly with 46-50.4 Gy to the whole breast followed by a 10-14 Gy boost.

Acute Toxicity Data Collection and Analysis Acute toxicity (during and within 90 days of treatment), late toxicity (90 days or more after treatment), and oncologic outcomes Figure 1 Noninvasive Image-Guided Breast Brachytherapy Imaging and Target Localization

Both NIBB boost and EB were well tolerated. Four patients in the NIBB group and 9 patients in the EB group required a treatment break (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.18-2.6; P ¼ .77). Grade 2þ desquamation developed in 18 patients (39%) treated with NIBB boost and in 49 patients (52%) treated with EB (OR, 0.52; 95% CI, 0.24-1.06; P ¼ .07). Figure 2A shows acute toxicity for each matched pair. Breast size, electron energy, and fractionation predicted for acute desquamation (P < .0001, P < .001, and P ¼ .006, respectively); patient age and use of chemotherapy did not (P ¼ .56, P ¼ .21, respectively).

Late Toxicity

456

-

Median follow-up was 13.6 months for the entire cohort. One patient (2%) who received NIBB boost had Grade 2þ subcutaneous fibrosis 15 months after completion of treatment. Among those treated with EB boost, 9 patients (9.5%) developed Grade 2þ subcutaneous fibrosis and 1 patient had recurrent breast cellulitis. Two patients who received NIBB boost and 1 patient who received EB boost had stable nipple inversion. Among the 70 pairs (105 patients) with  4 months of follow-up, median followup was 12 months for the NIBB boost group and 15.6 months for

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Kara Lynne Leonard et al Table 1 Patient and Tumor Characteristics

Table 2 Treatment Characteristics

Characteristic

NIBB, n [ 47

EB, n [ 94

Mean Age, years

58

58

Mean Tumor Size, cm

1.5

1.4

<1100 cc

24 (51)

50 (53)

>1100 cc

19 (40)

36 (38)

4 (9)

8 (9)

Breast Size, n (%)

Unknown T-Stage, n (%) Tis

12 (26)

24 (26)

Characteristic

NIBB, n [ 47

EB, n [ 94

48.3

47

WBI Dose, Gy Mean 42-43

9 (19)

17 (18)

46-46.8

6 (13)

41 (44)

50-50.4

32 (68 )

35 (37)

1.8-2

38 (81)

77 (82)

2.67

9 (19)

17 (18)

WBI Dose per Fraction, Gy

Boost Dose, Gy

T1a

2 (4)

4 (4)

T1b

9 (19)

19 (20)

Mean

T1c

18 (38)

35 (37)

2-6

T2

3 (6)

6 (6)

7-8

6 (13)

4 (4)

34 (72)

33 (35)

8.8

10.8

7 (15)

16 (17)

ypT0

1 (2)

2 (2)

10

ypT1c

2 (4)

3 (3)

14

e

38 (40)

ypT2

e

1 (1)

16-18

e

3 (3)

Boost Dose per Fraction, Gy

N-Stage, n (%) N0/Nx N1 N2

40 (85)

82 (87)

2

37 (79)

77 (82)

6 (13)

12 (13)

2.4-2.7

10 (21)

17 (18)

1 (2)

e

Mean

57

57.8

Overall Stage, n (%)

Total Dose, Gy

DCIS

12 (26)

24 (26)

60-64

31 (66)

70 (74)

I

28 (60)

54 (57)

54-59

7 (15)

7 (15)

II

6 (13)

16 (17)

44-50

9 (19)

9 (19)

III

1 (2)

e

None

31 (66)

62 (66)

Adjuvant

13 (28)

26 (28)

3 (6)

6 (6)

Smoking Status, n (%) Current smoker Former smoker Nonsmoker Unknown

29 (62)

54 (57)

Chemotherapy, n (%)

4 (8)

7 (7)

Neoadjuvant

13 (28)

25 (27)

Timing of Boost

1 (2)

8 (9)

Autoimmune Disorders, n (%) Sarcoid

1 (2)

e

Fibromyalgia

1 (2)

e

Psoriasis

e

1 (2)

Graves disease

e

1 (2)

Abbreviations: DCIS ¼ duct carcinoma in situ; EB ¼ external beam; NIBB ¼ noninvasive imageguided breast brachytherapy.

the EB boost group. Matched pair comparison revealed that the incidence of subcutaneous fibrosis was borderline statistically significantly less in those treated with NIBB boost compared with those treated with EB boost (OR, 0.14; 95% CI, 0.003-1.1; P ¼ .077). There was statistically significantly less combined skin/ subcutaneous toxicity in those treated with NIBB than in those treated with EB (OR, 0.13; 95% CI, 0.003-0.93; P ¼ .046). Figure 2B shows late skin/subcutaneous toxicity for each matched pair. Breast size and fractionation did not predict for late skin/ subcutaneous toxicity.

Oncologic Outcomes There was 1 internal mammary node failure in the EB group and no other locoregional failures occurred in either group.

1 (2)

e

Started before WBI, completed during

14 (30)

e

Interdigitated

29 (62)

1 (1)

3 (6)

93 (99)

6 MeV

e

14 (15)

9 MeV

e

30 (32)

12 MeV

e

30 (32)

14 MeV

e

1 (1)

16 MeV

e

16 (17)

20 MeV

e

2 (2)

Photons

e

1 (1)

Completed before WBI

Started after WBI complete Electron Energy

Data are presented as n (%) except where otherwise noted. Abbreviations: EB ¼ external beam; NIBB ¼ noninvasive image-guided breast brachytherapy; WBI ¼ whole breast irradiation.

Discussion Large randomized trials have conclusively demonstrated the benefit of the addition of the tumor bed boost to whole breast radiotherapy in the treatment of early stage breast cancer.1,5,6 Limitations of boost irradiation with electrons include a complex beam penumbra, imprecision in the definition of the tumor bed7,8 and

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NIBB vs. External Beam Boost Figure 2 Acute and Late Toxicity With Breast Boost. (A) Acute Toxicity: NIBB Boost vs. EB Boost. (B) Late Skin/ Subcutaneous Toxicity: NIBB Boost vs. EB Boost

Abbreviations: EB ¼ external beam; NIBB ¼ noninvasive image-guided breast brachytherapy.

susceptibility to delivery error because of breast and patient motion. The advent of computed tomography (CT)-based planning for breast tumor bed delineation has not definitively resulted in improved targeting accuracy as suggested by Landis et al, who found up to a 3-fold difference in the volume of tissue that was delineated as target by a group of experienced physicians using CT for definition of the breast excision cavity.9 Further, the use of a CT scan for delineation and treatment planning has been shown to lead to a significant increase of the irradiated boost volume by a factor of 1.5-1.8.10 This larger boost volume appears to unnecessarily increase the risk of side effects especially with a higher boost dose.11,12 Image guidance and methods to account for or reduce target motion have become an integral part of radiation therapy. The application of these principles to breast irradiation using a mammography-based imaging platform and brachytherapy delivery system have been shown to result in markedly improved dosevolume relationships for administration of a tumor bed boost. Sioshansi et al3 reported that target volumes with NIBB were 35% and 65% smaller than respective electron and 3DCRT boost volumes (P ¼ .023 for electrons; P ¼ .008 for 3DCRT). Electron boost plans had a lower Dmin than NIBB boost (1.11 Gy vs. 1.77 Gy; P ¼ .016), but higher volume receiving 100 Gy (V100), dose receiving 90 Gy (D90), and dose receiving 50 Gy (D50). With regard to PTV coverage, the only statistically significant differences between the techniques were slightly higher D90 and V90 with 3DCRT and higher Dmax with NIBB (45.5 Gy vs. 40 Gy; P ¼ .055). The maximum cumulative skin dose using NIBB is 60%

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less than electron boost and 10% less than 3DCRT. Compared with electron and 3DCRT boost, NIBB delivers 70%-90% less dose to the chest wall and lung. The current study compares tumor control and toxicity outcomes in patients treated with NIBB with those treated with EB. A matched-pair method was chosen for this comparison to balance the treatment groups and thereby reduce the influence of confounding factors. This method appeared to be successful with respect to balancing between the 2 cohorts; important factors such as patient age, tumor stage, use of chemotherapy, and fractionation. Although a small proportion of patient pairs were not identically matched for breast size, comorbid illness, or smoking status, overall the groups were well balanced for these factors. Importantly, locoregional control rates were excellent ( 99%) in both groups. The side effect profile for NIBB compared favorably with that for EB with respect to acute and late toxicity. In the present series, only 1 patient (2%) treated with NIBB developed late subcutaneous/skin toxicity, compared with 11% of patients treated with EB. The 9% Grade 2þ subcutaneous fibrosis in patients in this series who were treated with EB was similar to the 11% moderate-to-severe fibrosis reported in the initial 5-year publication of the EORTC 22881-10882 boost vs. no boost trial.1,13 It is important to note that this initial publication of the EORTC boost trial reported no significant difference in fibrosis rates between those treated with and without boost. However, the rate of moderate-to-severe fibrosis in those treated with boost rose substantially to 28.1% when median follow-up was extended to 10.8 years, and there was a significant difference that became apparent between the boost and no boost groups.1 Because the current study has a follow-up of just over 1 year, longer follow-up will be essential to determine if the marked difference in the rate of fibrosis seen between NIBB and EB boost patients will persist. The present study is limited by its retrospective nature and the inherent selection bias. Moreover, the mean WBI and boost doses and timing of the boost differ slightly between the NIBB and EB groups. Nonetheless, with similar total doses delivered to the breast, the toxicity outcomes with NIBB were superior to those when EB was used.

Conclusion In conclusion, NIBB boost was associated with favorable clinical short-term outcomes compared with those when EB boost was used. Further evaluation of this technique as an alternative to EB boost appears warranted.

Clinical Practice Points  Noninvasive, image-guided breast brachytherapy (NIBB) is

currently being used as an alternative to EB for tumor bed boost in conjunction with whole breast irradiation.  NIBB is associated with smaller treatment volumes and lower V100, D90, and D50 than electron boost.  The present series compares toxicity and oncologic outcomes between 47 patients treated with NIBB boost and 94 patients with EB boost.  Grade 2þ desquamation developed in 39% of patients treated with NIBB and in 52% of patients treated with EB.

Kara Lynne Leonard et al  There was statistically significantly less combined skin/subcu-

taneous toxicity in those treated with NIBB than in those treated with EB.  NIBB boost is associated with favorable short-term clinical outcomes compared with EB.

Disclosure David E. Wazer, MD serves on the medical advisory board of Advanced Radiation Therapy, Inc. All other authors have no conflicts of interest.

References 1. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2010; 25:3259-65. 2. Rivard MJ, Melhus CS, Wazer DE, et al. Dosimetric characterization of round HDR 192Ir accuboost applicators for breast brachytherapy. Med Phys 2009; 36: 5027-32. 3. Sioshansi S, Rivard MJ, Hiatt JR, et al. Dose modeling of non-invasive image-guided breast brachytherapy in comparison to electron beam boost and three-dimensional conformal accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011; 80:410-6.

4. Hamid S, Rocchio K, Arthur D, et al. A multi-institutional study of feasibility, implementation, and early clinical results with noninvasive breast brachytherapy for tumor bed boost. Int J Radiat Oncol Biol Phys 2012; 83:1374-80. 5. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997; 15:963-8. 6. Polgar C, Fodor J, Orosz Z, et al. The effect of tumour bed boost on local control after breast conserving surgery. First results of the randomized boost trial of the National Institute of Oncology. Magy Onkol 2001; 45:385-91. 7. Benda RK, Yasuda G, Sethl A, et al. Breast boost: are we missing the target? A dosimetric comparison of two boost techniques. Cancer 2003; 97:905-9. 8. Hepel JT, Evans SB, Hiatt JR, et al. Planning the breast boost: comparison of three techniques and evolution of tumor bed during treatment. Int J Radiat Oncol Biol Phys 2009; 74:458-63. 9. Landis DM, Luo W, Song J, et al. Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity. Int J Radiat Oncol Biol Phys 2007; 67:1299-308. 10. Al Uwini S, Antonini N, Poortmans PM, et al. The influence of the use of CTplanning on the irradiated boost volume in breast conserving treatment. Radiother Oncol 2009; 93:87-93. 11. Vrieling C, Collette L, Fourquet A, et al. The influence of the boost in breastconserving therapy on cosmetic outcome in the EORTC “boost versus no boost” trial. Int J Radiat Oncol Biol Phys 1999; 45:677-85. 12. Vrieling C, Collette L, Fourquet A, et al. The influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving therapy in the EORTC ‘boost vs. no boost’ trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. Radiother Oncol 2000; 55:219-32. 13. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345:1378-87.

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