Outcome of a phase II prospective study on partial breast irradiation with interstitial multi-catheter high-dose-rate brachytherapy

Radiotherapy and Oncology 108 (2013) 236–241

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Phase II trial

Outcome of a phase II prospective study on partial breast irradiation with interstitial multi-catheter high-dose-rate brachytherapy Cynthia Aristei a,⇑, Isabella Palumbo a, Giorgia Capezzali b, Alessia Farneti c, Vittorio Bini d, Lorenzo Falcinelli b, Manuela Margaritelli c, Valentina Lancellotta c, Claudio Zucchetti e, Elisabetta Perrucci b a

Radiation Oncology Section, University of Perugia and Santa Maria della Misericordia Hospital; b Radiation Oncology Division, Santa Maria della Misericordia Hospital, Perugia; Radiation Oncology Section, University of Perugia; d Internal Medicine, Endocrin and Metabolic Sciences Section, University of Perugia; and e Medical Physics Unit, Perugia General Hospital, Italy

c

a r t i c l e

i n f o

Article history: Received 15 June 2012 Received in revised form 23 July 2013 Accepted 5 August 2013 Available online 14 September 2013 Keywords: Breast cancer Conservative surgery Interstitial multi-catheter partial breast irradiation High-dose-rate brachytherapy

a b s t r a c t Background and purpose: Partial breast irradiation (PBI) is an alternative to whole-breast irradiation after breast-conserving surgery in selected patients. Until the results of randomized phase III studies are available, phase II studies inform about PBI. We report the 5 year results of a phase II prospective study with PBI using interstitial multi-catheter high-dose-rate brachytherapy (ClinicalTrials.gov Identifier: NCT00499057). Methods: Hundred patients received PBI (4 Gy, twice a day for 4 days, until 32 Gy). Inclusion criteria were: age P40 years, infiltrating carcinoma without lobular histology, ductal in situ carcinoma, tumor size 62.5 cm, negative surgical margins and axillary lymph nodes. Results: At a median follow-up of 60 months late toxicity occurred in 25 patients; the 5-year probability of freedom from late toxicity was 72.6% (95% CI: 63.7–81.7). Tamoxifen was the only significant risk factor for late toxicity. Cosmetic results, judged by physicians and patients, were good/excellent in 98 patients. Three local relapses (1 true, 2 elsewhere) and 1 regional relapse occurred. The 5-year probability of local or regional relapse-free survival was 97.7% (95% CI: 91.1–99.4) and 99.0% (95% CI: 92.9–99.8), respectively. Conclusion: PBI with interstitial multi-catheter brachytherapy is associated with low relapse and late toxicity rates. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 108 (2013) 236–241

Partial breast irradiation (PBI) with different techniques (interstitial or endocavitary brachytherapy, intra-operative radiotherapy –RT- with electrons or low-energy photons, external beam RT) is increasingly used as an alternative to whole breast irradiation (WBI) after breast conserving surgery (BCS) [1–4]. Furthermore PBI, mainly with interstitial brachytherapy, is under evaluation for the re-irradiation of patients treated with a second BCS after a local relapse [5]. Risk of relapse after PBI was recently stratified by the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) [6] and the American Society of Therapeutic Radiology and Oncology (ASTRO) [7] on the basis of data from a few randomized or prospective single-arm studies. Group 1 includes patients who, if well informed, may receive PBI outside of clinical trials; they are at low-risk for GEC-ESTRO and ⇑ Corresponding author. Address: Radiation Oncology Section, Department of Surgical, Radiological and Odontostomatological Sciences, University of Perugia, Ospedale Santa Maria della Misericordia, Sant’Andrea delle Fratte, 06156 Perugia, Italy. E-mail addresses: [email protected], [email protected] (C. Aristei). 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.08.005

defined as suitable according to ASTRO. Group 2 includes patients at intermediate-risk who should be treated only inside clinical trials according to GEC-ESTRO; ASTRO suggests that caution and concern have to be exercised if PBI is administered outside clinical trials. Group 3 encompasses patients at high-risk for GEC-ESTRO who should receive WBI with or without a boost to the tumor bed. According to ASTRO they are unsuitable for PBI outside of clinical trials. As knowledge about PBI is accumulating rapidly current recommendations will be modified or will serve as a framework to promote additional clinical investigations [8]. In this light, we here report the 5 year results of a phase II prospective study which administered PBI with high-dose-rate (HDR) brachytherapy after BCS (ClinicalTrials.gov Identifier: NCT00499057) to a series of 100 patients. Materials and methods From August 2003 to December 2008, 100 patients aged 49– 84 years (median 66 years) were enrolled. The study was approved

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by the Umbria Region Public Health Ethics Committee and written informed consent was obtained from each patient. Inclusion criteria were age P40 years, ECOG performance status 0–2, infiltrating carcinoma without lobular histology, ductal in situ carcinoma (DCIS), tumor size 62.5 cm, negative surgical margins and axillary lymph nodes, suitable breast for implantation. Criteria for implantation were: breast volume, ratio between breast volume and volume to be irradiated, distance of volume to be irradiated from skin. Exclusion criteria were infiltrating lobular carcinoma, Paget’s disease of the nipple, large areas of lobular carcinoma in situ, extensive intra-ductal component, lymphovascular invasion, multifocality and skin infiltration. All patients underwent wide excision, with sentinel node biopsy in 79 cases and axillary dissection in 14. 7/14 patients with DCIS axilla were not sampled. Patients with positive or close (<2 mm) margins underwent re-excision to ensure margins were negative. Histological findings are reported in Table 1. Implants were positioned during BCS or re-excision in 17 cases and postoperatively, at a median of 8 weeks (range 4–12), in the other 83. The computed-tomography-based procedures for pre-implant CTV definition and implant geometry, and post-implant dosimetry, were described elsewhere [9]. Briefly, images from breast computed tomography (CT) scans were transferred to a treatment planning system (TPS) for external beam (EB) RT. The excision cavity was outlined on each slice and, using the TPS volume expansion feature, expanded by 1–2 cm ensuring a safe distance of 5 mm–1 cm from the skin and chest wall. Through virtual simulation with the TPS for EBRT, the catheter position was defined. On implantation day, needle entrance and exit points were marked on the patient’s skin to serve as landmarks during implantation which was performed under general or local anesthesia. Then a breast CT checked implant geometry and CT images were transferred to the 3D software (PLATO Brachytherapy Insight) to reconstruct the catheters and to outline and expand the surgical cavity. Dwell positions were activated for each catheter, and inactive and active lengths defined. Treatment planning was carried out using the PLATO-Nucletron TPS. The dose was prescribed to 85% of the mean dose in basal points in the whole volume. Dosimetric parameters were volumes receiving 100% and 150% of the prescribed dose (V100 and V150) and the dose homogeneity index DHI = V100 V150/V100. Treatment schedule was 4 Gy twice a day, with a minimum inter-fraction interval of 6 h, for 4 days (total dose 32 Gy). Therapy was delivered using a microSelectron HDR 192Ir remote afterloading system (Nucletron). Eight patients received adjuvant chemotherapy. Six cycles of CMF on days 1 and 8 (cyclophosphamide 600 mg/m2 intravenously [i.v.], methotrexate 40 mg/m2 i.v. and fluorouracil 600 mg/m2 i.v.) were administered to 5 followed by trastuzumab every 3 weeks in 1. Six cycles of FEC (fluorouracil 500 mg/m2 i.v., epirubicin 75 mg/m2 i.v., cyclophosphamide 500 mg/m2 i.v.) were administered to 1 patient; 4 cycles of EC (epirubicin 120 mg/m2 iv, cyclophosphamide 600 mg/m2 i.v.) followed by 4 cycles of paclitaxel 175 mg/m2 i.v. were given to 1 patient and another received 14 weekly administrations of epirubicine (25 mg/m2 i.v.). In 7 patients adjuvant chemotherapy was started at a median of 24 days after RT (range 1–43, mean 21). In 1 patient PBI was administered between the first and second CMF cycles. Hormonal therapy was prescribed for 78 patients (28 tamoxifen, 42 aromatase inhibitors, 8 tamoxifen followed by aromatase inhibitors). Follow-up All patients were monitored three days after catheter removal for wound infection and healing.

Table 1 Histological finding.

*

Histology Infiltrating ductal carcinoma G1 G2 G3 Infiltrating tubular Infiltrating papillary Infiltrating lobular Ductal carcinoma in situ Low-grade Intermediate-grade High-grade

82 28 48 6 2 1 1 14 9 3 2

T stage Median tumor size (range)

9 mm (2–28)

Nodal status N0 N1mi in sentinel node N1 (1/7 positive node) Not determined

91 1 1 7

Estrogen receptor Positive Negative Not determined

85 8 7

Progesterone receptor Positive Negative Not determined

63 30 7

Ki-67 <14% P14% Not determined

59 33 8

cERB-B2 Positive Negative Not determined

10 81 9

Biological subtypes* Luminal A Luminal B (HER2 negative) Luminal B (HER2 positive) Triple negative

58 21 4 3

In 86 infiltrating carcinomas.

Check-ups were scheduled at 15 and 30 days after implant removal, every three months in years 1 and 2, every six months in years 3, 4 and 5, then annually. Patients underwent mammograms and breast ultrasound scans six months after brachytherapy and then yearly. Skin and subcutaneous toxicity, teleangiectasia and pain were classified using the Common Terminology Criteria for Adverse Events (CTCAE v3.0) [10]. Fat necrosis was graded according to the Lövey et al. scoring system [11]. Cosmetic results were evaluated according to the Harvard criteria [12] by radiation oncologists and patients. At present no cut-off for ending the follow-up has been established. Definition of recurrence Local recurrence was a biopsy-detected carcinoma in the treated breast. Within, or immediately adjacent to, the treated volume, it was classified as a ‘‘true recurrence’’. At a distance of a few centimeters or more from the treated volume it was considered as ‘‘elsewhere failure’’. Regional recurrence was defined as biopsyproven carcinoma or clinical evidence of disease within the ipsilateral axilla, supraclavicular, infraclavicular, internal mammary nodes. Distant metastases were radiological and/or pathological evidence of disease at any site other than the ipsilateral or contralateral breast or draining breast lymph nodes. Contralateral disease was biopsy-proven carcinoma in the other breast. All time intervals were calculated from the PBI completion date.

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Statistical analysis The Mann–Whitney non-parametric test compared continuous variables. The Chi squared test analyzed categorical or qualitative data. Survival analysis was estimated using the Kaplan–Meier method. Cohen’s k-test of inter-rater agreement (k-value ranging from 0 to 1) estimated concordance between patient’s and physician’s assessment of cosmesis. Landis and Koch’s grading interpreted strength of agreement: <0.2 = poor, 0.2–0.4 = fair, 0.4– 0.6 = moderate, 0.6–0.8 = good, 0.8–1.0 = very good [13]. A two-sided significance was set at p < 0.05. All calculations were carried out with Predictive Analytic Software (PASW) release 17.0.2, SPSS Inc., Chicago, USA, 2009. Results Median follow-up was 60 months (range 5–92). Except for two patients who died 5 and 7 months after PBI, the minimum followup was at least 3 years in all. A single-plane implant was constructed in 1 case, a 2-plane in 18, a 3-plane in 79 and a 4-plane in 2. A median of 12 catheters were implanted (range 4–15). Catheter repositioning or placement adjustments were not required in any patient. Median V100 was 103 cm3, (range 14.0–271.0), median V150 was 26.7 cm3 (range 5.70–57.1) and median DHI was 0.75 (range 0.59–0.81). Late toxicities occurred in 25 patients at a median of 12 months (range 3–49 months). They included G1 breast pain in 3, G2 skin atrophy in 1, G1 and G2 subcutaneous fibrosis in 8 and 2 patients, respectively, G1 and G2 teleangiectasia in 11 and 4 patients, respectively. Fat necrosis was observed in 9 cases (asymptomatic G1 in 8; symptomatic G2 in 1). Seroma was diagnosed in 3 patients. Late toxicities were 41 in total, as 12 patients developed more than one. As the grade of late side effects may change over time, modifications were assessed at each check-up. One G2 subcutaneous fibrosis doubled in size between months 10 and 53 after PBI. Three cases of teleangiectasias progressed from G1 to G2 after 13, 22 and 27 months, respectively, so at the last check-up there were 8 G1 and 7 G2. Fat necrosis in 2 patients (1 G1, 1 G2) was reduced by 75% 44 months after ending PBI. Seroma was reduced in size by 50% in 1 case after 37 months; it almost disappeared in another in 36 months. In assessing the probability of late toxicity presence vs absence and time of first observation were analyzed. The 5-year probability of toxicities was 27.4% (95% CI: 18.3–36.8). The 5-year probability of teleangiectasia, fat necrosis or fibrosis was 15.8% (95% CI: 8.4– 23.2), 10.0% (95% CI: 3.7–16.2), 10.8% (95% CI: 4.4–17.2), respectively. A plateau was reached after the 4th year (Fig. 1). Univariate analysis investigated the effects of patient-related (age, tumor size) and therapy-related (hormonal therapy, chemotherapy, number of catheters, number of planes, V100, V150, DHI) risk factors for toxicity. Only hormonal therapy with tamoxifen emerged as a significant factor for late toxicity. Patients treated with tamoxifen, either alone or before aromatase inhibitors, had a higher late toxicity rate than patients treated with aromatase inhibitors alone or not treated with any kind of hormonal therapy (p = 0.003). Table 2 reports distribution of the risk factors for late toxicity and late toxicity rates. Judgements of cosmetic results were available from all patients. Outcome was excellent/good in 98/100 physician and patient judgments. For the other two it was judged as fair by patients and physicians. Patient and physician judgements did not agree in two instances which were judged as good by physicians and excellent by patients. Overall inter-rater agreement was very good (k value 1.00). Three local relapses (3%) included 1 ‘‘true recurrence’’ 63 months after PBI and 2 ‘‘elsewhere failures’’ at 19 and

48 months, respectively after PBI. The 5-year probability of local relapse-free survival was 97.7% (95% CI: 91.1–99.4) (Fig. S2, in Supplementary file). One regional relapse was observed in the supraclavicular and axillary nodes 7 months after PBI in a patient with a negative sentinel node. The 5-year probability of regional relapse-free survival was 99.0% (95% CI: 92.9–99.8) (Fig. S2, in Supplementary file). Four patients developed distant metastases, seven patients contralateral breast cancer and eleven patients other primary cancers in diverse sites. At each patient’s last check-up outcomes showed 90 patients were alive: 85 with no evidence of cancer, 2 with metastatic breast cancer, 3 with lung cancer. Ten patients had died: 2 of metastatic breast cancer, 5 of other cancers and 3 of other causes (1 pulmonary embolism, 1 respiratory failure, 1 heart failure). The 5-year probability of cancer specific-free survival was 97.9% (95% CI: 91.7–99.5) (Fig. S2, in Supplementary file).

Discussion Our Radiation-Oncology Centre chose interstitial brachytherapy for PBI treatments in 2003 as it was the most common approach at that time. Most patients with early stage breast cancer were enrolled in interstitial brachytherapy PBI clinical trials, follow-ups were longer than with other techniques, and preliminary results were similar to conventional WBI in selected patients. HDR treatments were chosen to allow irradiation on an outpatient basis. Other techniques have tended to replace brachytherapy, mainly because it is an operator-dependent technique requiring long training and a high degree of user skill. The results of the present single-center study with a 5 year median follow-up show that PBI with multi-catheter interstitial HDR brachytherapy is still a valid approach, offering low relapse and late toxicity rates. Our cohort was very similar to others, as was the 5-year local relapse rate of about 3% [14–17]. Only one regional relapse was observed, concurring with other results [18–20]. It must be admitted we opted for a rather cautious selection as enrolled patients were older (median 66 years) and had smaller tumors (median 9 mm) than indicated in our inclusion criteria (age P40 years, tumor size 62.5 cm). Because of the few relapses in a cohort of this size statistical analysis of risk factors for relapse was not informative. When attempting to match patients in our trial with categories as established by ASTRO and GEC-ESTRO, the first obstacle was lack of knowledge about the BRCA 1/2 mutation which was not determined in any patient of ours, as required by the ASTRO consensus statement. So a correlation could be established only with the GECESTRO categories; 81 of our patients fell within the low-risk group and 19 in the intermediate-risk group. Comparing some features of our series with the GEC-ESTRO and ASTRO criteria for risk stratification seemed interesting. DCIS is in the GEC-ESTRO intermediate-risk category and in the ASTRO cautionary category if the tumor is 63 cm. In our series only 1 patient with G2 DCIS developed ‘‘true relapse’’ which was probably random, and certainly not enough to make us remove DCIS histology as an inclusion criterion. Furthermore, treating selected DCIS patients with different PBI techniques, was associated with a low probability of relapse after follow-ups of up to almost 5 years [16,21–24]. Consequently, we agree that PBI could be a feasible alternative to WBI in patients with unifocal, small DCIS with negative margins. The impact of receptor status on risk of relapse is controversial [8,14,15,25–27]. Divergences might depend on the power of the different studies. In our study none of the 7 receptor negative patients relapsed; relapses occurred in 3 patients who had at least

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0.30

Actuarial rate of toxicity

0.25

0.20

0.15

0.10 Late toxicity Fat necrosis

0.05

Teleangiectasia Fibrosis

0.00 0

12

24

36

48

60

72

84

96

Time in months 100

87

82

69

54

34

16

6

100

96

93

84

68

48

25

6

100

94

89

77

62

42

22

6

100

94

90

83

66

46

23

6

Fig. 1. Actuarial rates (Kaplan–Meier analysis) of late toxicity, fat necrosis, teleangiectasia, fibrosis.

Table 2 Risk factors for late toxicity – univariate analysis. Risk factor

No late toxicity Yes

Age (y)* Tumor size (P1 cm) Hormonal therapy Tamoxifen Chemotherapy Number of catheters* Number of planes* V100* V150* DHI* *

Late toxicity No

Yes

66.0 (49.0–85.0) 29 (40.8%) 58 (78.4%) 21 (36.2%) 4 (5.4%)

p No

64.5 (51.0–80.0) 42 16 37 70

(59.2%) (21.6%) (67.8%) (94.6%)

12 (7–15) 3 (2–4) 103 (16.5–271) 27 (5.9–57.1) 0.75 (0.61–0.81)

10 (38.5%) 22 (84.6%) 16 (72.7%) 4 (15.4%)

16 (61.5%) 4 (15.4%) 6 (27.3%) 22 (84.6%) 12 (4–15) 3 (1–3) 103 (14–184) 25.8 (5.7–50.3) 0.75 (0.59–0.81)

0.832 1.000 0.159 0.003 0.233 0.425 0.112 0.432 0.204 0.494

Median (min–max).

one positive receptor and received hormonal therapy. The numbers are too low to draw any definitive conclusions but, like the GEC-ESTRO low-risk group, our protocol continues enrolling patients independently of receptor status. Lobular histology and metastatic nodes were exclusion criteria in our protocol, as in the GEC-ESTRO low risk and ASTRO suitable categories. However, standard WBI was refused by 3 patients (1 lobular carcinoma, 1 sentinel lymph-node micrometastases, 1 with 1/7 positive node) who opted for PBI after receiving full information about risks. None relapsed. Interestingly lobular histology was not associated with increased risk of relapse in the GermanAustrian phase II trial [14,15]. The issue of nodal status is more complex. When WBI is delivered, nodal irradiation is standard treatment if 4 or more axillary nodes are positive [28], but controversial with 1–3 positive nodes [29–32]. For PBI administration ASTRO includes any positive axillary node in the unsuitable category, while GEC-ESTRO considers 1–3 positive nodes as intermediaterisk. Our present results in 2 patients preclude any comments. Results after PBI in patients with 1–3 positive nodes are conflicting [26,27], as each series reported data from few patients. Therefore, PBI administration to patients with 1–3 positive axillary nodes still needs to be fully clarified.

Finally, our late toxicity rate deserves some consideration. Assessment of late toxicity after PBI is complex, as the incidence of any side effect is highly dependent on time of measurement. Fat necrosis, teleangiectasias and subcutaneous fibrosis, the most common side effects, change over time with the latter two being reported to plateau at the 5–6th year post-therapy [14]. In our series the plateau started in the 4th year. At a median follow-up of 5 years, fat necrosis was observed in 9% of patients and teleangiectasias in 15%, both comparing well with other reports after a minimum 4-year follow-up (fat necrosis: 5–50%) [11,14,33–37], (teleangiectasia 4–34%) [14,33–35,37]. In our series we had no case of G3 subcutaneous fibrosis and only 10% of patients developed G1 and G2, which compares very favorably with reports of up to 46% rates [14,33–37], with about a 2% incidence of G3 [33,36]. Skin atrophy in 1 patient was classified as G3 [38] on the RTOG/EORTC scale and as G2 when CTCAE 3.0 was used. It seems clear that modern 3D planning has reduced the incidence of side effects when brachytherapy is used for PBI. We focused on obtaining good dose distribution in the target volume and on keeping the dose to the skin under 70% of the prescribed dose. Univariate analysis showed tamoxifen was the only significant risk factor for late toxicity, which developed in 16/25 patients

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who received the drug. In some studies the association of RT and tamoxifen determined an increased risk of fibrosis [39–41], which was hypothesized to be caused by a tamoxifen-induced local increase in TGFb [42]. In the present series 10 patients developed fibrosis and 7 had been treated with tamoxifen. Although interesting, this result needs to be confirmed in a larger series of patients. In conclusion, PBI has been intensively evaluated in prospective clinical trials as an alternative to conventional WBI over the last two decades. Although our series included almost 20% of patients at intermediate-risk according to the GEC-ESTRO classification, results are similar to the best relapse and late toxicity rates. They concur in demonstrating that PBI with 192Ir interstitial multi-catheter HDR brachytherapy is feasible for selected patients and the good results justify continuing enrollment. Indeed, results after even longer follow-ups might lead to modifying current recommendations in the ASTRO and GEC-ESTRO consensus recommendations. Furthermore, selection criteria will undoubtedly change as the controversial impact of some risk factors is clarified with data from randomized phase III trials [1,43] and the impact of bio-pathological factors, like receptor status, HER2 and Ki67 [44–46] on prognosis is better assessed. Conflict of interest The authors have declared no conflicts of interest. Acknowledgement The authors would like to thank Dr Geraldine A Boyd for translating and editing this paper. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2013. 08.005. References [1] Offersen BV, Overgaard M, Kroman N, Overgaard J. Accelerated partial breast irradiation as part of breast conserving therapy of early carcinoma: a systematic review. Radiother Oncol 2009;90:1–13. [2] Smith GL, Xu Y, Buchholz TA, et al. Brachytherapy for accelerated partial-breast irradiation: a rapidly emerging technology in breast cancer care. J Clin Oncol 2011;29:157–65. [3] Abbott AM, Habermann EB, Tuttle TM. Trends in the use of implantable accelerated partial breast irradiation therapy for early stage breast cancer in the United States. Cancer 2011;117:3305–10. [4] Hattangadi JA, Taback N, Neville BA, Harris JR, Punglia RS. Accelerated partial breast irradiation using brachytherapy for breast cancer: patterns in utilization and guideline concordance. J Natl Cancer Inst 2012;104:29–41. [5] Hannoun-Levi J-M, Resch A, Gal J, et al. Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumor recurrence: multicentic study of the GEC-ESTRO Breast Cancer Working Group. Radiother Oncol 2013;108:226–31. [6] Polgár C, Van Limbergen E, Pötter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 2010;94:264–73. [7] Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74:987–1001. [8] Vicini F, Arthur D, Wazer D, et al. Limitation of the American Society of Therapeutic Radiology and Oncology consensus panel guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;79:977–84. [9] Aristei C, Tarducci R, Palumbo I, et al. Computed tomography for excision cavity localization and 3D-treatment planning in partial breast irradiation with high-dose-rate interstitial brachytherapy. Radiother Oncol 2009;1:43–7. [10] Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176–81.

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