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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 1, pp , 2007 Copyright 2007 Elsevier Inc. Printed in the USA. All rights reserved /07/$ see front matter CLINICAL INVESTIGATION Breast ANALYSIS OF TREATMENT EFFICACY, COSMESIS, AND TOXICITY USING THE MAMMOSITE BREAST BRACHYTHERAPY CATHETER TO DELIVER ACCELERATED PARTIAL-BREAST IRRADIATION: THE WILLIAM BEAUMONT HOSPITAL EXPERIENCE K. KENNETH CHAO, M.D.,* FRANK A. VICINI, M.D.,* MICHELLE WALLACE, R.N., B.S.N., O.C.N.,* CHRISTINA MITCHELL, R.N., B.S.N.,* PETER CHEN, M.D.,* MICHEL GHILEZAN, M.D.,* SAMUEL GILBERT, B.S., JONATHAN KUNZMAN, B.S., PAMELA BENITEZ, M.D., AND ALVARO MARTINEZ, M.D.* *Department of Radiation Oncology, Beaumont Cancer Institute, William Beaumont Hospital, Royal Oak, MI; University of Michigan, Ann Arbor, MI; Western Michigan University, Kalamazoo, MI; and Department of Surgery, William Beaumont Hospital, Royal Oak, MI Purpose: To review our institution s experience of treating patients with the MammoSite (Cytyc Corp., Marlborough, MA) breast brachytherapy catheter to deliver accelerated partial-breast irradiation (APBI), for determining short-term treatment efficacy, cosmesis, and toxicity. Methods and Materials: From January 2000 to April 2006, 80 patients treated with breast-conserving therapy (BCT) received adjuvant radiation using the MammoSite (34 Gy in 3.4-Gy fractions prescribed to 1.0 cm from the balloon surface). Twenty-three patients (29%) had Stage 0 breast cancer, 46 (57%) had Stage I breast cancer, and 11 (14%) had Stage II breast cancer. The median follow-up was 22.1 months. Results: Two ipsilateral breast-tumor recurrences (IBTRs) (2.5%) developed for a 3-year actuarial rate of 2.9% (no regional failures were observed). On molecular-based clonality assay evaluation, both recurrences were clonally related. Younger age at diagnosis was the only variable associated with IBTR (continuous variable, p 0.044; categorical variable [<55 years vs. >55 years], p 0.012). The percentages of patients with good/excellent cosmetic results at 12 and 36 months were 96.9% and 88.2%, respectively (p NS). Patients with applicatorto-skin spacing <7 mm and those who received adjuvant systemic chemotherapy exhibited lower rates of good/excellent cosmetic results, though the association was not statistically significant. The overall incidence of symptomatic seromas and any seromas was 10% and 45%, respectively. The overall incidence of fat necrosis and infections was 8.8% and 11.3%, respectively. Conclusions: Early-stage breast-cancer patients treated with adjuvant APBI using the MammoSite catheter exhibited a 3-year treatment efficacy, cosmesis, and toxicity similar to those observed with other forms of interstitial APBI at this length of follow-up Elsevier Inc. Breast-conserving therapy, Brachytherapy, Partial-breast irradiation. INTRODUCTION Accelerated partial-breast irradiation (APBI) is currently being explored as a further option to deliver adjuvant radiation therapy (RT) after lumpectomy in selected patients with early-stage breast cancer treated with breast-conserving therapy (BCT). Although several different methods can be used to deliver APBI, techniques utilizing interstitial brachytherapy have been the most frequently employed (1). The reported 5-year and 10-year rates of local tumor control using interstitial brachytherapy have been good, but this approach can be difficult to teach and learn (2, 3). In addition, because interstitial brachytherapy requires the utilization of multiple catheters, widespread patient acceptance Reprint requests to: Frank A. Vicini, M.D., F.A.C.R., Department of Radiation Oncology, Beaumont Cancer Institute, William Beaumont Hospital, 3601 W. 13 Mile Rd., Royal Oak, MI Tel: (248) ; Fax: (248) ; fvicini@beaumont.edu has been limited (4). In recognition of these problems, a logistically simpler, technically more reproducible, and patient-friendly device (the MammoSite breast brachytherapy catheter, Cytyc Corp., Marlborough, MA) was developed to deliver APBI (5). This report presents data on treatment efficacy, cosmesis, and toxicity at 3-year follow-up for patients treated with the MammoSite applicator at William Beaumont Hospital (WBH, Royal Oak, MI). METHODS AND MATERIALS Between January 2000 April 2006, 96 patients were treated with adjuvant APBI employing the MammoSite Radiation Ther- Conflict of interest: none. Received Jan 25, 2007, and in revised form Feb 25, Accepted for publication Feb 26,

2 Analysis of MammoSite treatment efficacy K. K. CHAO et al. 33 apy System (Cytyc Corp., Marlborough, MA) breast brachytherapy catheter device. All patients were enrolled in WBH -approved Institutional Review Board protocols. All eligible patients had American Joint Cancer Commission (AJCC, 6th edition) Stage 0 II breast cancer (ductal, lobular, or mixed histology), and underwent local resection (excisional biopsy or partial mastectomy) with a recommended (but not mandatory) minimal clear margin of 2 mm. Patients diagnosed with invasive carcinoma also underwent a sentinel node biopsy and/or axillary lymph node dissection at time of surgery. Additional eligibility criteria included age 40 years, a final tumor size 3.0 cm, and metastatic involvement of 3 axillary lymph nodes. All patients underwent diagnostic mammography and ultrasonography as needed. Breast MRI, bone scan, and additional radiographic studies were performed at the discretion of the treating physician. All abnormal calcifications were completely excised (as verified by postoperative mammography) before starting APBI. Technical eligibility criteria Recommended technical guidelines were established to exclude the treatment of patients with inadequate balloon-to-skin distances, excessive cavity size, or poor balloon-cavity conformance. Patients could be enrolled for treatment before their final lumpectomy, to allow device placement in an open fashion during that procedure. Other patients were enrolled postlumpectomy, and were implanted using a closed technique as previously described (4). The balloon catheter was instilled with sterile, normal saline solution with 10% contrast, to allow for visualization of the device under fluoroscopy. Final determination of suitability for high-dose-rate (HDR) brachytherapy treatment after device placement was performed using computed tomography (CT). The parameters evaluated included the applicator-to-skin distance (recommended minimum of 5 mm, and preferably 7 mm), conformance of the applicator to the lumpectomy cavity, and symmetry of the center catheter shaft. Computed-tomography scans and fluoroscopic simulation were utilized for treatment planning, both to determine dwell positions in the center of the balloon, and for daily confirmation of balloon diameter. Acceptable diameters ranged from 4 6 cm, corresponding to approximately cm 3 fill volumes. The recommended radiation dose fractionation scheme was 34 Gy delivered to a point 1 cm from the surface of the balloon in 3.4-Gy fractions (twice daily, separated by a minimum interfraction time of 6 h) over 5 9 elapsed days with a commercially available Ir-192 remote afterloader. After completing the final treatment fraction, the saline solution was aspirated from the catheter balloon. The deflated applicator was then removed by the radiation oncologist. Sixteen patients received 28 Gy over four fractions given in 2 days. These patients were excluded from this analysis. Patients were seen 1 3 months after treatment, and then followed every 3 months by their radiation oncologist or surgeon for the first 2 years, and every 6 months thereafter. Mammograms were obtained 6 months posttreatment, and then annually, with additional studies ordered at the discretion of the radiologist, radiation oncologist, or surgeon. Local, regional, and distant disease recurrence For the purposes of this analysis, an ipsilateral breast tumor recurrence (IBTR) was defined as the pathologic confirmation of cancer after a disease-free interval in the treated breast (before the development of distant metastasis). All IBTRs were classified clinically by their location in relation to the lumpectomy cavity, according to the criteria described by Recht et al. (6). A true recurrence/marginal miss (TR/MM) was defined as a recurrence of the treated cancer within or immediately adjacent to the primary tumor site. An elsewhere failure (E) was defined as an IBTR several centimeters from the primary site, and was generally felt to be a clinically new primary cancer. A molecular-based clonality assay was used to accurately establish the type of local recurrence (new primary [clonally distinct] vs. recurrence of the index lesion [clonally related]). This technique was previously described (7). Regional failures were classified as an axillary, supraclavicular, or internal mammary node recurrence. For the purposes of this analysis, overall survival reflected all deaths, cancer-related or otherwise. Disease-free survival was based on breast-cancer recurrence of any kind (local or distant). Cosmesis and toxicities Cosmetic results were evaluated at each follow-up visit by the treating radiation oncologist or surgeon, using the Harvard criteria (8). An excellent cosmetic result score was assigned when the treated breast looked essentially the same as the contralateral breast (as related to radiation effects). A good cosmetic score was assigned for minimal but identifiable radiation effects of the treated breast. A fair score meant significant radiation effects were readily observable. A poor score was used for severe sequelae of breast tissue, secondary to radiation effects. Toxicity results were scored based on the Radiation Therapy Oncology Group (RTOG) Common Toxicity Criteria (version 3.0). Any breast infection, mastitis, cellulitis, or abscess that was observed during follow-up was considered an infectious event. Device-related infections were those believed to be secondary to the use of the MammoSite applicator. However, no stringent criteria were established. Fat necrosis was diagnosed either mammographically or clinically. Breast pain was stratified into either no pain or pain with or without the need for analgesics (opioid vs. nonopioid). The presence of a seroma was evaluated at each follow-up visit, and diagnosed clinically or mammographically. Seromas were subcategorized into either symptomatic (associated with pain or requiring intervention by the physician) or asymptomatic. Statistical methods All time intervals were calculated from the date of MammoSite placement. The estimated likelihood of events for IBTR was calculated by the Kaplan-Meier method. Associations between clinical, pathologic, and treatment-related variables and clinical events were analyzed using Cox regression. Associations between factors (cosmesis and toxicity) were analyzed using Pearson s chi-square or Fisher s exact test (two-tailed) and logistic/linear regression. Statistical significance between actuarial outcome curves was calculated with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. All tests were declared statistically significant if calculated p All tests appear as two-sided p values. Descriptive statistics consist of numbers and percentages of responses in each category for discrete measures, and of median, minimum, and maximum values for continuous measures. Version 10.0 or higher of the Systat statistical software package (SSI, Richmond, CA) was used in all statistical analyses.

3 34 I. J. Radiation Oncology Biology Physics Volume 69, Number 1, 2007 Table 1. Patient-related and tumor-related characteristics Characteristic RESULTS Findings Follow-up (months) Median 22.1 Mean 25.8 Range Length of follow-up 1 year 66 (83%) 2 years 36 (45%) 3 years 17 (21%) Age (years) Median 62 Range (13.8%) Stage 0 23 (29%) I 46 (57%) II 11 (14%) DCIS (n 23) Median size (mm) 6 Range (mm) 2 15 Cases 10 mm 18 (78%) Cases 10 mm 5 (22%) Tumor size (n 57)* Median (mm) 9 Range (mm) 1 25 T1 (n, %) 52 (91%) 10 mm 37 (65%) mm 15 (26%) T2 (n, %) 5 (9%) mm 5 (9%) 30 mm 0 Nodes (n 57)* 49 (86%) 8 (14%) One positive node 5 (63%) 2 3 positive nodes 3 (37%) Histologic grade (n 80) Grade I/II 68 (85%) Grade III 10 (12%) Unknown 2 (3%) Receptor status (n 57)* Estrogen receptorpositive 45 (79%) Estrogen receptornegative 8 (14%) Unknown 4 (7%) * Invasive carcinomas. As of April 2006, 96 patients received adjuvant RT using the MammoSite applicator (as the sole RT). Eighty patients were treated with APBI, delivering 34 Gy in 3.4-Gy fractions. These patients constitute the study population. As previously mentioned, an additional 16 patients received a total dose of 28 Gy in four fractions given in 2 days (on a separate protocol), and were excluded from this analysis. Patient-related and treatment-related characteristics of the 80 patients of the study population are presented in Tables 1 and 2. Fifty-seven patients (71%) had invasive carcinoma, while 23 (29%) had ductal carcinoma in situ (DCIS). Eight patients had 3 lymph nodes involved with cancer (14.1%). Forty-four patients (55%) had the Mammosite catheter placed postoperatively (closed-cavity placement). Seventyfive percent of all patients were treated with a small-volume balloon (4 5-cm diameter). The median follow-up time for all patients treated with standard APBI was 22.1 months (range, months). Seven patients (9%) were followed for 5 years, 8 (10%) for 4 years, 17 (21%) for 3 years, 36 (45%) for 2 years, and 66 (83%) for 1 year. Three patients were lost to follow-up. The median follow-up times for patients with an initial diagnosis of invasive or noninvasive cancer were 24.4 and 18.9 months, respectively. Failure patterns and survival outcomes In total, 2 patients (2.5%) developed an IBTR as some component of their initial failure (before distant metastases), for a 3-year actuarial rate of 2.9%. On molecular-based clonality assay evaluation, both were found to be clonally related. The patient who developed a noninvasive cancer recurrence had DCIS as her initial diagnosis. The patient who experienced an invasive cancer recurrence had an invasive ductal carcinoma as her initial diagnosis. The median time to IBTR was 9.6 months (range, months). In one patient (1.3%), the IBTR was clinically felt to be a new primary breast cancer unrelated to the index lesion ( E failure), and in the other patient it was felt to represent a recurrence of the primary cancer (TR/MM failure). However, on molecular-based clonality assay evaluation, both recurrences were clonally related. Table 3 summarizes the 3-year actuarial rates and overall failure patterns Characteristics Table 2. Treatment-related characteristics Findings Margins (n, %) Negative ( 2 mm) 76 (95%) Close (0 1.9 mm) 4 (5%) Systemic treatment Tamoxifen 32 (40%) Unknown 20 (25%) Chemotherapy 14 (17%) Unknown 12 (15%) Time of placement Open 36 (45%) Closed 44 (55%) Median balloon size Spherical Small (4 5 cm) 60 (75%) Large (5 6 cm) 14 (18%) Elliptical 4 5 cm 1 (1%) Unknown 5 (6%) Balloon volume (cm 3 ) Median 60 Range Skin spacing (mm) Median 9 Range 5 28

4 Analysis of MammoSite treatment efficacy K. K. CHAO et al. 35 Table 3. Patterns of failure: 3-year actuarial rates Event All patients IBTR 2.9% Clonally related 2.9% Clonally distinct 0% Nodal failure 0% Distant metastasis 1.3% Disease-free survival 95.8% Overall survival 91.3% Abbreviation: IBTR ipsilateral breast tumor recurrence. Total number of evaluable patients 80. for all patients. No patients developed a regional nodal failure (axillary or otherwise). A number of variables were analyzed for a potential association with the development of an IBTR. These variables included patient age, tumor size, nodal status, overall stage, margin status, estrogen status, histologic grade, use of systemic chemotherapeutic or hormonal therapy, method of device placement (open vs. closed), and applicator-to-skin distance. The only variable associated with the development of an IBTR was younger age at diagnosis (continuous variable, p 0.044; categorical variable [ 55 years vs. 55 years], p 0.012) (Table 4). One patient (1.3%) developed a distant metastasis (DM) to the lumbar spine, for a 3-year actuarial DM-free rate of 98.7%. The time to DM was approximately 4 months after the first day of treatment. This patient did not experience a local recurrence before or after developing a DM. No patient with noninvasive breast cancer developed a DM. At the time of manuscript preparation, 5 patients had expired (6.3%), for a 3-year actuarial overall survival rate of 91.3%. All but one patient (69 years old) had been 75 years of age. All these patients exhibited no evidence of breast-cancer recurrence at time of death. All expired patients had an invasive breast cancer at their initial diagnosis. Thus, in this subgroup of patients diagnosed with invasive carcinoma, the 3-year overall survival rate was 88.1%. The Follow-up visit Table 5. Cosmetic results vs. length of follow-up N Good/excellent cosmesis Percentage (%) 6 months % 12 months % 18 months % 24 months % 30 months % 36 months % 42 months % 48 months % N evaluable patients. 3-year overall survival rate for patients with an initial diagnosis of noninvasive breast cancer was 100%. The 3-year disease-free survival rate for all patients was 95.8% (Table 3). Age as a continuous variable was statistically significant associated with both survival outcomes, with older age being a positive variable for disease-free survival, and a negative factor for overall survival. Cosmetic results The number of patients with good/excellent cosmetic results at 6 months was 64 (10 unrecorded), giving a raw percentage of 98.5%. At 12, 18, 24, 36, and 48 months, the percentages of patients with good/excellent cosmetic results were: 96.9% (62 of 64 evaluable patients, 96.9% (47 of 50 evaluable patients), 97.2% (35 of 36 evaluable patients), 88.2% (15 of 17 evaluable patients), and 100% (8 of 8 evaluable patients). Table 5 summarizes the percentages of patients with good/excellent cosmetic results at 6-month intervals (up to 48 months). No statistically significant change was noted in the percentage of patients with good/ excellent cosmetic results over time. For the 17 patients with both a 12-month and 36-month cosmetic assessment, the rate of good/excellent cosmetic results was 94% at 12 months, and 88% at 36 months (p NS). Table 4. Univariate analysis of factors associated with IBTR, disease-free survival, and overall survival Factors (n evaluable patients) IBTR Disease-free survival Overall survival Age (n 80) (continuous variable) Age ( 55 vs. 55 years old) (categorical variable) DCIS size (n 23) (continuous variable) N/A (no deaths) Invasive tumor size (n 57) (continuous variable) Nodal status (n 57) (negative vs. positive) Overall stage (n 80) (categorical variable) Margin status (n 80) ( 2 mmvs. 2 mm) Estrogen receptor status (n 75) (negative vs. positive) Histological grade (n 78) (categorical variable) Systemic chemotherapy (n 68) (yes vs. no) Adjuvant hormone therapy (n 60) Placement technique (n 80) (open vs. closed) Applicator-to-skin distance (n 78) Abbreviations: IBTR ipsilateral breast-tumor recurrence; DCIS ductal carcinoma in situ.

5 36 I. J. Radiation Oncology Biology Physics Volume 69, Number 1, 2007 Table 6. Factors associated with good/excellent cosmetic results at 24 months Factors N Good/excellent cosmesis (%) p-value (Fisher s exact test) Increased balloon-to-skin distance (numeric variable), logistic * regression* Increased skin spacing (categorical variable) ( 7 mmvs. 7 mm) 36 83% vs. 100% Method of placement (closed cavity vs. open cavity) % vs. 94% Balloon volume ( 50 cm 3 vs. 50 cm 3 ) % vs. 95% Chemotherapy use (yes vs. no) 34 80% vs. 100% Seroma (yes vs. no) 36 89% vs. 100% Infection (yes vs. no) % vs. 97% Age ( 60 years vs. 60 years) % vs. 95% Bra size (A and B vs. C and D) % vs. 100% * Increased balloon-to-skin distance (numeric variable) was analyzed using logistic regression, whereas other variables (other rows) were analyzed by Fisher s exact test. Variables associated with optimal cosmetic results Multiple variables were analyzed for their association with the development of a good/excellent cosmetic result at 24 months (Table 6). All patients with skin spacing 7 mm had good/excellent cosmetic results at 2 years, while 83% of patients with less balloon-to-skin spacing ( 7 mm) had acceptable cosmetic results. Additionally, patients who received chemotherapy had a 2-year rate of good/excellent cosmetic results of 80% vs. 100% in patients who did not receive chemotherapy. However, univariate analysis (Fisher s exact test) did not demonstrate any statistical significance in any of the variables. On multivariate analysis, no factors were found to be independently statistically significant. Toxicities A number of treatment-related toxicities were monitored over time, including seroma formation (total and symptomatic), fat necrosis, infection, and pain. Table 7 summarizes the presence of seroma and fat necrosis overall and at 3, 3 5.9, , , and 24 months after treatment. Although the presence of any seromas (including symptomatic) did not dramatically change over time, the incidence of new seromas appeared to decrease with time (Fig. 1). In addition, total seroma presence was reported more frequently with open vs. closed cavity placements (61% vs. 32%, p 0.013, Fisher s exact test), with the use of larger brachytherapy balloons (5 6 cm vs. 4 5 cm; 79% vs. 36%, p 0.006), and with larger balloon volumes ( 50 cm 3 vs. 50 cm 3 ; 25% vs. 63%, p 0.001). Multiple variables were also evaluated for their association with seroma formation (Table 8). On univariate analysis, open-cavity applicator placement (p 0.013), the use of a larger MammoSite balloon (p 0.006), and larger total balloon volume (p 0.001) were all statistically significant factors associated with an increased risk of seroma formation. The development of a breast infection was associated with the development of a symptomatic seroma (44% vs. 6%, p Table 7. Rates of seroma formation and fat necrosis vs. time Time after implant 3 months 3 6 months 6 12 months months 24 months Overall Evaluable patients (N) Total Open cavity Closed cavity Breast seromas Total 17.5% (14) 25% (20) 25.3% (19) 28.8% (19) 25% (9) 45.0% (36) Open cavity 30.6% (11) 36.1% (13) 44.1% (15) 42.4% (14) 35.3% (6) 61.1% (22) Closed cavity 6.8% (3) 15.9% (7) 9.8% (4) 15.2% (5) 15.8% (3) 31.8% (14) Symptomatic Total 6.3% (5) 8.8% (7) 8.0% (6) 7.6% (5) 5.6% (2) 10.0% (8) Open cavity 11.1% (4) 13.9% (5) 14.7% (5) 12.1% (4) 11.8% (2) 13.9% (5) Closed cavity 2.3% (1) 4.5% (2) 2.4% (1) 3.0% (1) 0% 6.8% (3) Fat necrosis Total 0% 1.3% (1) 0% 4.5% (3) 8.3% (3) 8.8% (7) Open cavity 0% (0) 3.0% (1) 11.8% (2) 8.3% (3) Closed cavity 2.3% (1) 6.1% (2) 5.3% (1) 9.1% (4)

6 Analysis of MammoSite treatment efficacy K. K. CHAO et al. 37 no statistically significant change in cosmetic outcome over this time interval was noted. Our results showed breast seromas in 45% of patients (10% symptomatic rate), fat necrosis in 8.8%, and breast infections in 11.3% of patients overall. These early results on efficacy, cosmesis, and toxicities with APBI using the MammoSite device are similar to other interstitial APBI results with similar follow-up intervals. Fig. 1. Incidence of newly reported seromas, symptomatic (hatched, 8 patients) and total (solid 26 patients), at 6-month intervals. RT radiation therapy ). On multivariate analysis, no factors were found to be independently statistically significant. Nine patients (11.3%) exhibited signs of infection during radiotherapy that required antibiotic treatment. Three patients (3.8%) experienced a late infection that required antibiotics. Fat necrosis was reported in 7 patients (8.8%). Over half (55.7%) of all patients reported experiencing pain that required analgesics during treatment, with 24% requiring temporary opioid analgesics. Fourteen patients (17.5%) continued to report posttreatment pain that required analgesics, but none required opioid analgesics. Four (5%) continued to complain of chronic pain that required nonopioid analgesics for 1-year follow-up. DISCUSSION Data on the William Beaumont Hospital s clinical experience in using the MammoSite breast brachytherapy applicator to deliver APBI were collected to determine 3-year cosmetic results and toxicities and the short-term efficacy associated with its use. With a median follow-up of 22.1 months, 2 patients (2.5%) developed an IBTR, for a 3-year actuarial rate of 2.9%. No patients developed any regional nodal failure. At 2 years, 97% of patients were found to have good/excellent cosmetic results (88% at 3 years), and Ipsilateral breast-tumor recurrence The rationale for the delivery of RT only to the lumpectomy cavity and its immediate adjacent region is based on the observation that the vast majority of all recurrences after standard BCT occur in close proximity to the surgical site (9, 10). Aside from the advantage of reducing the overall treatment duration required for the delivery of RT (compared to standard whole-breast irradiation), APBI decreases the volume of normal tissue exposed to irradiation, theoretically diminishing toxicity to the lung, heart, and surrounding skin. However, for this treatment approach to be considered an acceptable alternative to whole-breast RT, treatment efficacy (local tumor control) must be shown to be equivalent. Although 3-year results are insufficient to establish long-term efficacy, they do provide some indication of the adequacy of this treatment approach in controlling the index lesion in comparison to interstitial APBI with a similar follow-up. The reported 3-year actuarial rate of local failure (2.9%) is comparable to failure rates observed with interstitial brachytherapy to deliver APBI in the RTOG trial and in multiple single-institution experiences from several other centers (with similar follow-ups) (2, 3, 11 15). These trials demonstrate 3 5-year rates of IBTR ranging from 0 6%. Certainly, longer follow-up is needed to confirm the stability of these early control rates. In addition, further follow-up will be useful in helping to establish clinical, pathologic, and technical factors associated with optimal control rates and the patients most suitable for the use of APBI in general, and the MammoSite applicator in particular. In the current analysis, patient age 55 years was associated with an increased risk for IBTR using the Mammo- Site to deliver APBI. All IBTRs (N 2) occurred in this group of patients; their respective ages at treatment were 51 and 42 years. Both recurrences occurred within 12 months after completion of radiotherapy. While it is well-known Table 8. Factors associated with seroma formation Factor Evaluable patients Overall survival (N 36) p value Symptomatic seromas (N 8) p value Method of placement (open vs. closed cavity) 80 61% vs. 32% % vs. 7% Chemotherapy use (yes vs. no) 68 43% vs. 56% % vs. 13% Infection (yes vs. no) 80 67% vs. 42% % vs. 6% Balloon volume ( 50 cm 3 vs. 50 cm 3 ) 80 25% vs. 63% % vs. 12% Catheter size (5 6 cm vs. 4 5 cm) 75 79% vs. 36% % vs. 10% Age ( 60 years vs. 60 years) 80 34% vs. 53% % vs. 11% Bra size (A and B vs. C and D) 33 50% vs. 48% % vs. 0% 0.125

7 38 I. J. Radiation Oncology Biology Physics Volume 69, Number 1, 2007 that younger age at diagnosis is a negative prognostic factor for IBTR and survival in patients who undergo BCT with adjuvant whole-breast RT (16, 17), risk factors for recurrence based on age cutoffs have yet to be defined for patients undergoing APBI. With only a small patient subpopulation 55 years old (N 20) and a low total of IBTR events (N 2) in our study, our current investigation may not be sufficiently mature to accurately report variables that are contraindications for MammoSite APBI. Nonetheless, caution must be exercised in treating younger patients with APBI until further data documenting the efficacy of APBI in this group of patients are available. Regional failure One of the additional concerns expressed with the utilization of APBI is the possibility of higher rates of regional (primarily, axillary) failure. This is based on the observation that the lower axilla is not generally included in the radiotherapy target volume with APBI, as it often is with wholebreast RT. However, no recent APBI study reported a significantly higher rate of regional nodal recurrence. In the current analysis, no axillary failures (AFs) were observed. The low failure rates reported here and in other studies may be attributed to the strict patient-selection process dictated by each protocol. Only additional follow-up and mature Phase III trial data will conclusively establish the impact of APBI or whole-breast RT on the rate of AFs, and to determine if any clinical, pathologic, or treatment-related factors should be avoided for a patient considering APBI. Again, until further data are available documenting the efficacy of APBI in these groups of patients, caution must be exercised. Treatment of ductal carcinoma in situ with APBI Accelerated partial-breast irradiation is now being explored as a possible treatment option for patients with DCIS, with the goal of providing similar local control to wholebreast RT, but with reduced morbidity (and potentially improved quality of life). To our knowledge, the current study represents one of the few (and one of the largest) studies to address the use of MammoSite APBI in patients with DCIS. Benitez et al. (18) reported on a multi-institutional Phase II clinical study in patients with DCIS, with a mean follow-up of 9.5 months. Two breast recurrences were reported in 86 patients, which is similar to our results (one noninvasive local recurrence in the DCIS subgroup, for a 95% local control rate estimate at 3 years) (18). These early outcomes are encouraging, and support the continued investigation of this approach for these low-risk patients. Cosmetic results The results of this trial confirm prior observations by Keisch et al. that early cosmesis is strongly related to applicator-to-skin spacing (5). In addition, our study demonstrates this continued relationship with longer-term follow-up. At 24 months, decreased skin spacing ( 7 mm) was associated with less frequent good/excellent cosmetic results than applicator-to-skin distances 7 mm (83% vs. 100%). However, univariate analysis (Fisher s exact test) did not demonstrate a statistically significant association (p 0.167), which is most likely attributable to the small sample size (N 36). Nonetheless, these data reaffirm the importance of ensuring adequate balloon skin spacing ( 7 mm) to prevent an excessive dose delivered to the skin. Our study also suggests a relationship between the use of chemotherapy and the development of less optimal cosmetic results. At 2 years, 80% (N 4) of patients receiving systemic chemotherapy exhibited good/excellent cosmetic results, compared with 100% (N 29) of patients who did not receive systemic chemotherapy. Univariate analysis (Fisher s exact test), however, did not show a statistically significant relationship (p 0.147). This lack of an association is most likely attributable to the small sample size. Overall, in the 14 patients who received systemic treatment at any follow-up duration, the one individual who demonstrated a less than good/excellent cosmetic result received her first course of chemotherapy 7 days after her last APBI fraction. Except for one other patient, all others (N 12) started chemotherapy at least 2 3 weeks after the completion of APBI. As observed in numerous studies of standard whole-breast irradiation, the concurrent administration of systemic chemotherapy can negatively impact breast cosmesis (19). Camidge and Kunkler studied patients treated with whole-breast irradiation, and postulated that when the interval between the last RT fraction and the start of chemotherapy is 7 days, skin radiosensitization may occur, resulting in less than ideal cosmesis (20). Studies that investigated the use of APBI also reported a relationship between the use of doxorubicin-based chemotherapy with poorer cosmetic outcome (21, 22). Harper and Jenrette (22), in a study of 37 early-stage breast-cancer patients treated with the MammoSite applicator, reported an incidence of radiation recall dermatitis after receiving one cycle of Doxorubicin and cytoxan approximately 3 weeks after completing their APBI regimen. Vicini et al. also reported radiation recall in 15 (3.4%) of 442 evaluable patients in a large multi-institutional trial (4). In our patient, a direct causal relationship between the timing of chemotherapy and radiation could not be inferred with exact confidence, because the applicator-to-skin spacing was approximately 5 mm, which may have contributed to her suboptimal cosmetic result. Although adjuvant chemotherapy is not a contraindication to APBI, we recommend that all patients planning to receive adjuvant chemotherapy be given adequate knowledge of the potential impact on cosmesis, and be advised to start their systemic treatment at least 2 3 weeks after the completion of APBI. Only with further mature follow-up and a larger sample size may definitive statistical relationships be established. Equally crucial, no statistically significant reduction in the number of patients with a good/excellent cosmetic result was observed with longer follow-up. For the 35 patients with both a 12-month and 24-month cosmetic assessment, the rate of good/excellent cosmetic results was 97% and 97% at 12 and 24 months, respectively (p 0.42). Cer-

8 Analysis of MammoSite treatment efficacy K. K. CHAO et al. 39 tainly, additional follow-up will be needed to confirm these observations (further stability of cosmesis over time), because cosmetic results after standard BCT generally stabilize after 3 years. In addition, a recent report indicated that overall cosmetic results can actually improve over time (after 2 years) in patients treated with similar fractionation schedules, using interstitial brachytherapy to deliver APBI (23, 24). However, other late effects (which did not affect overall cosmesis, e.g., telangiectasia) did increase with time, indicating that further analyses are warranted. As these data continue to mature, we will continue to help establish the stability of these observations and the factors associated with optimal long-term cosmetic results. Toxicities The monitoring of specific toxicities (seroma, fat necrosis, infection, and pain) related to the use of this form of APBI is important in assessing overall treatment efficacy. Breast seromas were reported in 45% of patients overall (10% symptomatic rate). Although this rate appears to be high, it should be noted that this is only slightly greater than the overall rates reported in selected studies after standard BCT (range, 10 30%) (25). Unfortunately, specific criteria to define, in a consistent fashion, the presence or severity of seromas after BCT are lacking, making it difficult to objectively compare rates between various types of treatment. Nonetheless, the risk of seroma formation was higher in the subset of patients who underwent an open catheter placement (61% vs. 32%, p 0.013), with a major difference in the acute ( 3 months after implant) period (31% vs. 7%). On univariate analysis, intraoperative placement of the MammoSite (open approach), larger applicator size, and increasing balloon volume were risk factors for seroma formation (p 0.01). Fortunately, the rate of symptomatic seromas was much lower (10%). It will be important to monitor this toxicity over time (and in other studies) to help determine its overall impact on this form of APBI. The overall rates of fat necrosis (8.8%) and infection (11.3%) are similar to those in other series (4, 5, 22 24, 26). There were very few late ( 3 months after implant) infections (3 patients). There was also an increasing incidence of fat necrosis (asymptomatic) over time, which is consistent with other reported APBI results (24). Our study indicates that treatment with the MammoSite catheter is generally well-tolerated. While approximately a quarter of patients reported the need for opioid analgesics, most requested the medication only during removal of the MammoSite applicator. Only 4 patients (5%) reported chronic pain ( 1 year) that required analgesics, and all utilized only nonopioid medications. Unlike seroma formation, the incidence of pain, fat necrosis, and infections did not differ between open or closed placement procedures. All of the above toxicities will continue to be carefully monitored to determine any changes in their incidence over time and the factors associated with their development. Study limitations and future considerations Although these early results utilizing the MammoSite applicator to deliver APBI are encouraging, continued follow-up of these patients and results from other prospective studies and randomized trials will be needed to help validate the long-term efficacy of APBI and the applicability of each APBI technique for certain clinical settings. Fortunately, the device is being studied as 1 of 3 possible APBI techniques in a multi-institutional, prospective, randomized trial: National Surgical Adjuvant Breast and Bowel Project B-39/ RTOG The enrollment of patients (utilizing the MammoSite) in this trial is strongly encouraged, to objectively address the critical endpoints of treatment efficacy, cosmesis, and toxicity. CONCLUSIONS Data on the use of the MammoSite breast brachytherapy catheter to deliver APBI were analyzed to determine the cosmesis and toxicity associated with its use and short-term efficacy. With a median follow-up of 22.1 months, 2 patients (2.5%) developed an IBTR, for a 3-year actuarial rate of 2.9%. No patients developed an AF. At 2 years, 97% of patients were found to have good/excellent cosmetic results (88% at 3 years), and no statistically significant change in cosmetic results was noted over this time interval. Breast seromas developed in 45% of patients overall (10% symptomatic rate). Fat necrosis was observed in 8.8% of all patients. These results demonstrate that treatment efficacy, toxicity, and cosmesis 2 3 years after treatment with APBI using the MammoSite are similar to those reported with other forms of APBI with similar follow-ups. Additional follow-up of these patients is underway, to help establish the long-term efficacy of this specific type of APBI. REFERENCES 1. Arthur DW, Vicini FA. Accelerated partial breast irradiation as a part of breast conservation therapy. J Clin Oncol 2005; 23: King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg 2000;180: Vicini FA, Antonucci JV, Wallace M, et al. Long-term efficacy and patterns of failure after accelerated partial breast irradiation: A molecular assay-based clonality evaluation. Int J Radiat Oncol Biol Phys 2007;68: Vicini FA, Beitsch PD, Quiet CA, et al. 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