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First analysis of patient demographics, technical reproducibility, cosmesis, and early toxicity†
Results of the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial
Version of Record online: 8 AUG 2005
Copyright © 2005 American Cancer Society
Volume 104, Issue 6, pages 1138–1148, 15 September 2005
How to Cite
Vicini, F. A., Beitsch, P. D., Quiet, C. A., Keleher, A., Garcia, D., Snider, H. C., Gittleman, M. A., Zannis, V. J., Kuerer, H., Whitacre, E. B., Whitworth, P. W., Fine, R. E., Haffty, B. G. and Arrambide, L. S. (2005), First analysis of patient demographics, technical reproducibility, cosmesis, and early toxicity. Cancer, 104: 1138–1148. doi: 10.1002/cncr.21289
Presented, in part, at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8–11, 2004.
- Issue online: 31 AUG 2005
- Version of Record online: 8 AUG 2005
- Manuscript Accepted: 17 MAY 2005
- Manuscript Revised: 11 MAY 2005
- Manuscript Received: 25 MAR 2005
- breast-conserving therapy;
- partial breast irradiation;
- radiation therapy;
- breast carcinoma;
Eighty-seven institutions participated in a Registry Trial that was designed to collect data on the clinical use of the MammoSite™ breast brachytherapy catheter for delivering breast irradiation. Patient demographics, technical reproducibility, cosmesis, and early toxicity were evaluated.
From May 4, 2002 through July 30, 2004, 1419 patients with Stage 0, I, or II breast carcinoma who were undergoing breast-conserving therapy were enrolled on the trial. The device was placed in 1403 of these patients. The 1237 patients (87% of enrolled patients) who received accelerated partial breast irradiation (APBI) (34 grays prescribed to 1.0 cm in 10 fractions; 95% of patients who received APBI) constituted the study population; 86% of those patients (1068) had Stages I–II breast carcinoma (median tumor size, 10 mm), and 14% of those patients (169) had Stage 0 breast carcinoma. Ninety-one percent of the patients with invasive carcinoma (977 of 1068 patients) had negative lymph node status, and 99% of all patients had negative margins. The median patient age was 65 years. Systemic chemotherapy alone was administered to 79 patients with invasive carcinoma (7%), hormone therapy was administered to 501 patients (45%), and both were administered to 39 patients (4%). The median follow-up was 5 months.
Five hundred fifty-four catheters (45%) were placed with an open cavity at the time of lumpectomy, and 683 catheters (55%) were placed with a closed cavity after lumpectomy. Skin spacing ranged from 2 mm to 75 mm (median, 10 mm). In 89% of patients, there was a minimum balloon-to-skin distance of 7 mm (2% of patients had distances < 5 mm). In terms of cosmetic assessment, 95% of patients (1030 of 1084 patients) who had a cosmetic assessment had a good/excellent result (last follow-up visit). Cosmetic results at 12 months were good/excellent in 92% of 248 evaluable patients. The median skin spacing (≥ 7 mm vs. < 7 mm) was associated significantly with a good/excellent cosmetic result (96.1% vs. 86.8%; P = 0.0001) overall and at 6 months (P = 0.006). Increasing skin spacing was associated with a good/excellent cosmetic result as a continuous variable (P < 0.0001). In total, 92 of 1140 evaluable patients (8.1%) developed an infection in the breast, which was device-related in 5.3% of patients (60 of 1140 patients). Good/excellent cosmetic results were noted in 86% of these patients (last follow-up visit). Fifteen of 442 evaluable patients (3.4%) developed a radiation recall reaction. Good/excellent cosmetic results were noted in 93% of these patients at their last follow-up visit. One local recurrence (0.1%) was reported (new primary carcinoma).
Clinical evaluation of the ability of the MammoSite™ breast brachytherapy catheter to deliver APBI demonstrated acceptable technical reproducibility between multiple institutions and use in appropriate groups of patients. Cosmetic results at 12 months (92% good/excellent) were comparable to those reported with whole-breast RT. Early toxicity rates (infections, radiation recall) appeared to be acceptable. Cancer 2005. © 2005 American Cancer Society.
The equivalence of conservative surgery (CS) and radiation therapy (RT) to mastectomy in the management of women with early-stage breast carcinoma has been demonstrated in several Phase III trials with long-term follow-up.1, 2 Despite the efficacy of this treatment approach, the precise amount of clinically uninvolved breast tissue surrounding the lumpectomy cavity that requires RT after CS never has been established. Traditionally, standard RT after CS has included elective treatment of the entire breast for presumed occult disease.3 This additional “elective” treatment of clinically uninvolved breast tissue with RT generally is considered responsible for a significant part of the acute and chronic toxicity associated with CS and RT as well as the protracted time commitment required for its completion. In recognition of these problems, limiting the RT field to the region of the surgical bed after CS has been investigated as a possible option for the management of selected patients. If it is proven efficacious, then such an approach theoretically may increase the breast-conservation option to more women and offer the potential advantages of reduced treatment-related toxicities, improvements in the quality of life of patients with cancer and provide a logistically simpler and more practical method for breast-conserving therapy (BCT).
In this report, we present clinical evaluation of the use of a new device (the MammoSite™ breast brachytherapy catheter) for delivering accelerated partial breast irradiation (APBI) in selected patients treated with BCT. These data were collected in a manufacturer-sponsored Registry Trial that was developed to provide information on the optimal use of the device in clinical practice. On November 17, 2003, the American Society of Breast Surgeons (ASBS) assumed management of the trial. The first summary of the data accumulated to date by the ASBS on technical reproducibility, acute toxicity, cosmesis, and patient demographics is presented.
MATERIALS AND METHODS
Between May 4, 2002 and July 30, 2004, 87 institutions participated in a Registry Trial that was designed to collect data on the clinical use of the MammoSite™ device as a modality for the delivery of APBI or as boost irradiation. The trial was initiated concurrently by the manufacturer with the clearance of the brachytherapy device by the United States Food and Drug Administration (FDA) for clinical use in May, 2002. The goals and objectives of the trial were to provide a method to collect data prospectively, objectively, and systematically on the clinical use of the brachytherapy applicator. Data on the technical reproducibility of the device on a large scale, acute toxicity, cosmesis, and adherence to placement in appropriate patients were sought. A previous trial in 43 patients that was used to obtain FDA clearance and to establish the safety of the device as a breast brachytherapy catheter was reported previously.4 On November 17, 2003, the ASBS assumed complete management of the trial. In total, 882 patients had been enrolled on the trial when the ASBS assumed its management. Since assumption of the trial, an additional 537 patients have been enrolled by the ASBS.
Synergos Inc., an independent, full-service Contract Research Organization (CRO) that is not affiliated with the ASBS, the manufacturer, or any of the institutions participating in this trial, was hired to provide services to collect, manage, and analyze data for the ASBS. This CRO provides regulatory, clinical trial management, monitoring, data management, statistical analysis, and report writing services for numerous pharmaceutical and medical device companies. After assuming management of the Registry Trial, the ASBS asked Synergos Inc. to initiate an additional follow-up protocol to verify and collect more complete information about cosmetic results, adjuvant therapy, adverse events, radiation recall reactions, disease recurrence, and patient survival. The additional data collection began in July, 2004, for the 1051 patients who had at least 1 follow-up visit at that time and has been completed for 881 (84%) of these patients.
Registry Trial Design/Patient Enrollment
All centers that had been trained and were using the MammoSite™ device clinically were offered and encouraged to participate in the Registry Trial. The Registry Trial Program was incorporated into the regional training programs for the device. At each MammoSite™ training session, a presentation was given that discussed the procedure for enrollment in the program and the benefits of participating. Each center that attended the training program was given a Registry Trial Program disk and was encouraged to participate. A Registry Trial Program brochure also was produced and distributed by the manufacturer that described the process and the benefits of participating. Finally, a one page “newsletter” that detailed some of the demographic data from the Registry Trial Program was distributed on a monthly basis to all centers. The ASBS has continued to publish the newsletter on a quarterly basis.
The recruitment objectives for the program were to incorporate as many institutions as feasible to provide for a large data base of patients in various clinical settings (i.e., academic, private practice, and hospital based). No site with adequate resources to complete the required data forms was denied participation in the study. It should be noted that patients could be enrolled on the trial at anytime (before, during, and after treatment), although enrollment prior to treatment was encouraged strongly (see Results, below).
Because data entry and processing were continuous processes for this program, a data cut-off date was chosen for the current report to allow for auditing and analysis. The cut-off date for the submission of patient data for analysis was November 11, 2004. In total, 1280 treated patients were submitted for analysis from a total of 87 participating institutions. Follow-up data (≥ 1 mo) were collected on these 1280 patients through November 11, 2004.
Patient Eligibility Criteria
Recommended criteria for patient enrollment in the protocol using the device were based on previous publications on the use of APBI and included by the American Brachytherapy Society (ABS)5: age older than 45 years, tumor ≥ 2 cm in greatest dimension, invasive ductal histology, negative lymph node status, negative marginal status (National Surgical Adjuvant Breast and Bowel Project [NSABP] definition), applicator placement within 10 weeks of final lumpectomy procedure, and a cavity postlumpectomy with 1 dimension of at least 3.0 cm.4, 6 Recommended exclusion criteria included an extensive intraductal component, lobular histology, or collagen vascular disease.
Technical Eligibility Criteria
Recommended technical guidelines were established in the protocol to exclude the treatment of patients with inadequate balloon-to-skin distances, excessive cavity size, or poor balloon-cavity conformance. Patients could be enrolled prior to final lumpectomy to allow device placement in an open fashion during that procedure; other patients were enrolled postlumpectomy and underwent implantation using a closed technique (see below).
Final determination of suitability for high-dose-rate (HDR) brachytherapy treatment was recommended after device placement using computed tomography (CT). The parameters measured included the applicator-skin distance (recommended minimum, 5 mm; preferably, ≥ 7 mm), conformance of the applicator to the target area 1 cm around the lumpectomy cavity, and symmetry of the center catheter shaft. CT and fluoroscopic simulation were advised for treatment planning, both to determine the single dwell position in the center of the balloon and for daily confirmation of balloon diameter. Acceptable diameters ranged from 4 cm to 6 cm, corresponding to 35–125 cc fill volumes. The recommended radiation dose fractionation scheme was 34 grays (Gy) delivered at a point 1.0 cm from the surface of the balloon in 3.4 Gy fractions (twice daily separated by a minimum of 6 hrs) over 5–7 elapsed days with various commercially available, remote HDR after-loaders. For boost patients, the recommended dose was 10 Gy at a point 1 cm form the surface of the balloon in 5-Gy fractions (twice daily), preferably over 1 day (interfraction separation was a minimum of 6 hrs).
Recommended Implantation Techniques
To insure proper implantation of the device, guidelines were provided by the manufacturer. These guidelines were summarized in a previous report.4
Data Collection and Quality Assurance
Information on patient demographics, technical reproducibility, cosmesis, toxicity, and overall efficacy were collected on the Registry Trial data forms that were supplied to investigators. Examples of data requested are presented in Tables 1–5. After the ASBS assumed management of the trial, additional data were collected. These included additional follow-up to verify and collect more complete information about cosmetic results, adjuvant therapy, adverse events, radiation recall reactions, disease recurrence, and patient survival.
|Median age in yrs (range)||65 (35–93)|
|AJCC tumor classification|
|Tis (in situ)||169 (13.7)|
|Invasive carcinoma: No. of patients (%)||1068 (86.3)|
|T1a (< 0.5 cm)||144 (11.6)|
|T1b (> 0.5 cm and < 1.0 cm)||424 (34.3)|
|T1c (> 1.0 cm and < 2.0 cm)||423 (34.2)|
|T2 (> 2.0 cm and < 5.0 cm)||77 (6.2)|
|No. of patients with APBI (%) (n = 1237)|
|Stage 0||169 (13.7)|
|Stage I||991 (80.1)|
|Stage II||77 (6.2)|
|No of patients with invasive carcinoma (%) (n = 1068)|
|Margins: No. of patients (%)|
|EIC: No. of patients (%)|
|Systemic therapy (invasive carcinoma) : No. of patients (%)|
|Hormone therapy||501 (46.9)|
|Time of enrollment: No. of patients (%)|
|Prior to treatment||630 (50.9)|
|After treatment||536 (43.3)|
|Median days (range)||6.5 (1–731)|
|Median mos (range)||5 (1–25)|
|≥24 mos: No. of patients (%)||19 (1.5)|
|≥18 mos: No. of patients (%)||70 (5.7)|
|≥12 mos: No. of patients (%)||248 (20.0)|
|≥9 mos: No. of patients (%)||368 (29.7)|
|≥6 mos: No. of patients (%)||555 (44.9)|
|≥3 mos: No. of patients (%)||755 (61.0)|
|Characteristic||No. of patients (%)|
|Time of catheter placement|
|Open cavity||554 (44.8)|
|Closed cavity||683 (55.2)|
|SET technique||170 (24.9)|
|US guidance||508 (74.4)|
|≥ 10 mm||791 (63.9)|
|≥ 9 mm||875 (70.7)|
|≥ 8 mm||987 (79.8)|
|≥ 7 mm||1099 (88.8)|
|≥ 6 mm||1158 (93.6)|
|≥ 5 mm||1215 (98.2)|
|No. of patients enrolled (n = 1419)|
|Treated with brachytherapy||1280 (90.2)|
|Partial breast irradiation||1237 (87.2)|
|Not implanted||16 (1.1)|
|No. of patients explanted||123 (8.7)|
|Open cavity||69 (56.1)|
|Closed cavity||54 (43.9)|
|Reasons for not implanting|
|Positive lymph nodes||9 (56.2)|
|Patient request||4 (25.0)|
|Lobular histology||3 (18.8)|
|Reason for explantation|
|Skin distance||43 (35.0)|
|Cavity conformance||35 (28.5)|
|Positive margins||13 (10.6)|
|Balloon failure||11 (8.9)|
|Positive lymph nodes||9 (7.3)|
|Partial breast irradiation total dose|
|34 Gy in 10 fractions||1207 (97.6)|
|32 Gy in 8 fractions||10 (0.8)|
|Other fractionation schedules||20 (1.6)|
|APBI dose specification|
|100% at 1.0 cm||1175 (95.5)|
|Median days of catheter implantation (range)||(0–62)|
|Visit||No. of patients||No. of patients (%)|
|Excellent/good cosmesis||Fair/poor cosmesis|
|All visits||1084||1030 (95.0)||54 (5.0)|
|3 mos||755||717 (95.0)||38 (5.0)|
|6 mos||555||526 (94.8)||29 (5.2)|
|9 mos||368||346 (94.0)||22 (6.0)|
|12 mos||248||229 (92.3)||19 (7.7)|
|18 mos||70||63 (90.0)||7 (10.0)|
|24 mos||19||18 (94.7)||1 (5.3)|
|Variable analyzed||Cosmetic result: No of patients (%)||P value|
|No. of patients (% of total)||598 (55.2)||432 (39.9)||45 (4.2)||9 (0.8)|
|Median skin spacing (mm)||10.0||10.0||8.0||8.0||<0.0001a|
|< 7 mm skin spacing (n = 121)||46 (38.0)||59 (48.8)||14 (11.6)||2 (1.6)||0.0001b|
|≥ 7 mm skin spacing (n = 964)||552 (57.3)||373 (38.7)||31 (3.2)||7 (0.7)|
|Open cavity placement (n = 488; 45%)||275 (56.4)||185 (37.9)||22 (4.5)||6 (1.2)||0.3275c|
|Closed cavity placement (n = 586; 55%)||323 (54.2)||247 (41.4)||23 (3.9)||3 (0.5)|
|Mean ± SD balloon fill (cc)||56.6 ± 17.8||55.4 ± 17.8||54.3 ± 14.8||57.0 ± 14.4|
|Balloon fill ≤ 50 cc||262 (52.0)||218 (43.2)||21 (4.2)||3 (0.6)||0.7813d|
|Balloon fill > 50 cc||336 (57.9)||214 (36.9)||24 (4.1)||6 (1.0)|
|Bra sizes A and B||124 (49.6)||105 (42.0)||17 (6.8)||4 (1.6)||0.0074e|
|Bra sizes C and D||474 (56.8)||327 (39.2)||28 (3.4)||5 (0.6)|
|Yesf||55 (48.3)||52 (45.6)||7 (6.1)||0 (0.0)||0.4974g|
|No||543 (56.0)||380 (39.2)||38 (3.9)||9 (0.9)|
|Yesh||30 (34.1)||49 (55.7)||5 (5.7)||4 (4.5)||0.0349i|
|No||566 (57.0)||382 (38.5)||40 (4.0)||5 (0.5)|
|Median follow-up (mos)||6||4||5||13|
|Eventa||No. of patients||%|
|Total no. of evaluable patients with infections (n = 1140)||92||8.1|
|Device related event (evaluable patients = 1140)||60||5.3|
|Cosmesis (at last follow-up)|
All data forms were collected and reviewed for inaccuracies, omissions, and conflicting information by Synergos Inc. On receipt of the data forms, a medical review was performed to ensure that none of the pertinent data were omitted or contained conflicting information. Patients were not included in the Registry Trial until all of the information that was deemed critical was provided. In addition, an audit of 10% of the patients (random) was performed (at the request of the ASBS) to verify the accuracy of the data collected. During the course of the audit, source documents (when available) were used to verify as much of the data as possible.
Institutional review board (IRB) approval was not required for participation in the Registry Trial but was recommended by the sponsor. Eighty-percent of the clinical sites were affiliated with an IRB and obtained IRB approval to participate in the study. All patients enrolled in the study were required to sign an informed consent, and patients who were treated on or after April 14, 2003, were required to sign a Notice of Privacy Practices in accordance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA agreement) allowing the release of their data. All clinical sites were provided with a sample informed consent and HIPAA agreement that contained all of the required elements necessary for informed consent. Prior to November, 2003, the manufacturer reviewed the site's final informed consent and HIPAA agreement for required elements; and, after November, 2003, the ASBS assumed this responsibility. Patient data submitted without an informed consent and/or HIPAA, if applicable, were not part of this analysis.
Cosmesis was evaluated at each follow-up visit by the treating radiation oncologist or surgeon using the Harvard criteria (provided in the Registry Trial data forms).7 An excellent cosmetic result score was assigned when the treated breast looked essentially the same as the contralateral breast (as it relates 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 readily were observable. A poor score was used for severe sequelae of breast tissue secondary to radiation effects.
At the time of this analysis, 1140 patients were evaluable (i.e., had data available on infection scoring) for the development of any infection (device, radiation, or surgically related). Events that were reported as “infectious events” included breast infection, mastitis, cellulitis, or abscess (at any point during follow-up). Device-related infections were those that the investigator believed were secondary to the use of the MammoSite (no stringent criteria were established).
Radiation recall reactions
At the time of this analysis, 442 patients were evaluable for the development of a radiation recall reaction. The definition of a recall reaction was not specified in the original Registry Trial data forms. This information was collected after the ASBS assumed management of the trial. The definition of a radiation recall reaction was not defined strictly by the ASBS and referred to the generalized development of a significant skin reaction (erythema, dry/moist desquamation) approximately 3–7 weeks after the completion of RT. Thus, it may be assumed that a radiation recall reaction is either a delayed effect of RT on the skin or the redevelopment of a skin reaction secondary to the administration of radiosensitizing drugs.
A local recurrence was defined as a reappearance of carcinoma in the treated breast and was confirmed pathologically.
Standard statistical methods were employed to analyze all data. The following techniques were used: descriptive statistics, Fisher exact test, Kurskal–Wallis test, and analysis of variance. All tests were declared statistically significant if the calculated P value was ≤ 0.05. 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 medians, minimum values, and maximum values for continuous measures. Version 8.0 or higher of the SAS® statistical software package was used to provide all statistical analyses.
In total, 1419 patients were enrolled in the trial as of November 10, 2004 (the trial was to be closed to further accrual after 1500 patients had been enrolled), and 1403 of 1419 patients who were enrolled in the study were implanted with the device. Reasons for not implanting the device included positive lymph node status (9 patients; 56% of nonimplanted patients), patient request (4 patients; 25% of nonimplanted patients), and lobular histology (3 patients; 19% of nonimplanted patients). One thousand two hundred eighty of the implanted patients (91%) were treated with brachytherapy. One thousand two hundred thirty-seven patients (87% of all patients) received APBI and constitute the study population. An additional 43 patients were treated with boost therapy.
Reasons for explantation (as reported by investigators) of the device (123 of 1403 patients; 9%) included inadequate balloon-to-skin distance (43 patients; 35% of explanted patients; 3.1% overall), poor cavity-balloon conformance (35 patients; 28% of explanted patients; 2.5% overall), inadequate margins (13 patients), balloon deflation (11 patients), positive lymph node status (9 patients), balloon symmetry problem (4 patients), lobular histology (3 patients), adverse event (2 patients), large tumor size (1 patient), patient request (1 patient), and vascular involvement (1 patient). Of these 123 patients, 69 patients (56.1%) had the device placed using an open cavity technique, and 54 patients (43.9%) had the device placed using a closed cavity technique.
Information on the time of enrollment indicated that 630 of 1237 patients (51%) were registered on the trial before treatment, and 536 patients (43%) were registered after treatment (in 6% of patients, the time of enrollment was not available for this analysis). Of these 536 patients, 376 patients (70%) were enrolled within 1 month of treatment, and 446 patients (83%) were enrolled within 6 months of treatment.
Patient and Tumor Demographics
Demographic and tumor characteristics of the 1237 patients who received APBI are listed in Table 1. The median tumor size was 1.0 cm (range, 0.1–4.5 cm). Eighty-six percent of patients had invasive tumors (Stage I–II), and 14% of patients had pure ductal carcinoma in situ. It was reported that 5% of patients with invasive carcinoma (58 of 1068 patients) had an extensive intraductal component. Margins of excision were negative according to NSABP criteria in 99% of patients. An axillary staging procedure was performed in 1010 patients (95%) with invasive carcinoma. Only 33 patients with invasive disease (3.1%) had positive lymph nodes. Systemic chemotherapy was administered to 118 patients with invasive carcinoma (11.0%), hormone therapy was administered to another 501 patients (46.9%), and both were administered to 39 patients (3.7%).
In total, 223 different investigators at 87 sites placed the device. Five hundred fifty-four patients (45%) had devices placed with an open cavity at the time of lumpectomy, and 683 patients (55%) had devices placed with a closed cavity using ultrasound guidance (508 patients; 74%) or using the scar-entry technique (170 patients; 25%).
The median time from device placement to removal (completion of brachytherapy) was 9 days (range, 1–62 days). Closed cavity implants were placed a median of 3 weeks (range, from 1 day to 21 wks) after lumpectomy. Brachytherapy was initiated a median of 4 days (range, 0–56 days) after surgery in open cavity implants.
The median balloon fill volume was 55 cc (range, 20–126 cc). This inflation volume corresponds to an approximate 4.7-cm diameter. Skin spacing ranged from 2 mm to 75 mm (median, 10 mm). Eighty-nine percent of patients had a minimum balloon-to-skin distance of 7 mm. Twenty-two patients (2%) were treated with skin distances of less than the recommended 5 mm.
In total, 1170 of 1237 patients (95%) who were treated with APBI received 34 Gy in 10 fractions prescribed to 1 cm from the balloon surface. The remaining 67 APBI patients (5%) were treated with various, minimally different fractionation schedules (the treating physicians elected to adjust either the total dose delivered or the depth at which the dose was delivered to compensate for the less than recommended skin distances). In total, 43 patients were treated with boost irradiation, and 21 of those patients (49%) received 10 Gy in 2 fractions.
Ninety-five percent of all patients (1030 of 1084 patients) who had a cosmetic assessment reportedly had a good/excellent result at their last follow-up visit (Table 3). Cosmetic results at 12 months were good/excellent in 92% of all patients (248 evaluable patients). Several factors were analyzed for their association with the cosmetic outcome. Factors that were associated with a good/excellent cosmetic result are listed in Table 4. Skin spacing (≥ 7 mm vs. < 7 mm) was associated significantly with a good/excellent cosmetic result (96.1% vs. 86.8%; P = 0.0001) overall and at the 6-month follow-up visit (n = 555 patients; 95.9% vs. 87.1%; P = 0.006). Skin spacing also was associated with a good/excellent cosmetic result as a continuous variable (P < 0.0001). Larger bra size (C and D cup size vs. A and B cup size) and the absence of an infection also were associated (minimally) with obtaining a good/excellent cosmetic result (96% vs. 91.6%; P = 0.0074; and 95.5% vs. 89.8%; P = 0.0349, respectively). There was no difference in the rate of good/excellent cosmetic results in patients who were enrolled on the trial before treatment versus patients who were enrolled after treatment (95.3% vs. 94.6%, respectively; P = 0.6661).
In total, 92 patients (8.1%) developed an infection (Table 5) in the treated breast (1140 patients were evaluable for the development of any infection [device, radiation, or surgically related]). Events that were reported as “infectious events” included breast infection, mastitis, cellulitis, or abscess (at any point during follow-up). Device-related infections developed in 60 of 1040 patients (5.3%). Good/excellent cosmetic results were noted in 86% of all patients who developed any type of infection (at their last follow-up visit).
A number of factors were analyzed for a correlation with the increased risk of developing an infection. No variable was associated with an increased risk (open cavity placement vs. closed cavity placement, 9.6% vs. 6.8%; P = 0.1005; use of systemic chemotherapy, 12% vs. 7.5%; P = 0.1131; length of implantation in days [< 10 days vs. ≥ 10 days], 7.5% vs. 8.7%; P = 0.5472; and time of enrollment onto the registry trial [before or after treatment], 8.5% vs. 7.8%; P = 0.7337).
Radiation recall reactions.
A radiation recall reaction was reported in 15 of 442 patients (3.4%) who had this information recorded (data collected after the ASBS assumed the trial). The extent of the radiation recall reaction was reported as minimal for one patient, moderate for eight patients, severe for two patients, and unknown in four patients. In the 8 patients for whom the duration was known, the average was 27.2 days. In 4 patients, the catheters were placed with an open cavity; and, in 11 patients, the catheters were placed with a closed cavity. Seven patients were enrolled on the trial before treatment, and eight patients were enrolled after treatment.
Of the 442 evaluable patients, 74 patients had received chemotherapy (Table 6). A recall reaction developed in 10 of 74 patients (13.5%) who received chemotherapy versus 5 of 368 patients (1.4%) who did not receive chemotherapy (P < 0.0001). In addition, a recall reaction developed in 3 of 50 patients (6%) who had skin spacing < 7 mm versus 12 of 392 patients (3%) who had skin spacing ≥ 7 mm (P = 0.2346). Finally, a recall reaction developed in 6 of 34 patients (17.6%) who received chemotherapy within 4 weeks of RT versus 4 of 28 patients (14.3%) who received chemotherapy > 4 weeks after removal of the catheter (P = 1.0). The timing of chemotherapy administration was unknown for 12 patients.
|Characteristic||No. of patients||%|
|Total no. of evaluable patients||442||36.0|
|Total no. of patients reported||15||3.4|
|Chemotherapy given (n = 74)|
|Recall reaction (Yes)||10||13.5|
|Recall reaction (No)||64||87.5|
|No chemotherapy given (n = 367)|
|Recall reaction (Yes)||5||1.4|
|Recall reaction (No)||363||98.6|
|Time to chemotherapya|
|< 14 days||3/19||15.8|
|≥ 14 days||7.43||16.3|
|< 21 days||5/25||20.0|
|≥ 21 days||5/37||13.5|
|< 28 days||6/34||17.6|
|≥ 28 days||4/48||14.3|
|Skin spacing < 7 mm|
|Recall reaction (positive)||3||6.0|
|Recall reaction (negative)||47||94.0|
|Skin spacing ≥ 7 mm|
|Recall reaction (positive)||12||3.1|
|Recall reaction (negative)||380||96.9|
Factors that were analyzed for an association with the development of a radiation recall reaction included the use of systemic chemotherapy, when chemotherapy started after RT (in days), breast bra size (A or B vs. C or D), and decreasing skin spacing (in mm). When factors were examined in a univariate manner, only skin spacing as a continuous variable (P = 0.0441) and the use of systemic chemotherapy (P < 0.0001) were associated with the development a recall reaction. Good/excellent cosmetic results were noted in 93% of patients who reportedly experienced a radiation recall reaction at their last follow-up visit. One local recurrence (0.1%) has been reported to date (new primary carcinoma).
Data on the clinical use of the MammoSite™ breast brachytherapy applicator were collected in a clinical trial to determine the technical reproducibility, patient demographics, acute toxicity, and early cosmesis associated with its use on a large scale. Ninety-five percent of patients (1030 of 1084 patients) who had a cosmetic assessment had a good/excellent result at their last follow-up visit. Cosmetic results at 12 months were good/excellent in 92% of all patients (248 evaluable patients). In total, 92 patients (8.1%) developed an infection in the treated breast. Device-related infections developed in 60 of 1140 patients (5.3%). Good/excellent cosmetic results were noted in 86% of these patients at their last follow-up visit. Ten of 74 evaluable patients (13.5%) who received systemic chemotherapy developed a radiation recall reaction (3.4% of evaluable patients overall). Good/excellent cosmetic results were noted in 93% of these patients at their last follow-up visit. Finally, only 1 local recurrence (0.1%) has been reported to date (new primary carcinoma). Clinical evaluation of the MammoSite™ breast brachytherapy catheter to deliver APBI demonstrates acceptable technical reproducibility between multiple institutions and use in appropriate groups of patients. Cosmetic results at 12 months were comparable to those reported with whole-breast RT. Early toxicity rates (infections, radiation recall) appear to be acceptable.
The rationale for the delivery of RT only to the region of the lumpectomy cavity after CS is the belief that, in selected patients, elective treatment of the entire breast may not be needed.5 Most data from numerous single-institutions employing this treatment approach reflect excellent 5-year results, and the popularity of APBI has increased significantly. Multicatheter-based interstitial brachytherapy implants remain the best studied means of delivering APBI.8 The data on interstitial implantation used in this setting suggest that, in properly selected patients, high rates of local control and cosmesis can be expected.9–19 Despite these encouraging results, acceptance of interstitial brachytherapy has been limited for several reasons, including the complexity of the procedure and treatment planning, the lack of formal training, and the steep learning curve related to the procedure.
To improve the acceptance of APBI for both patients and physicians, several different methods of delivering APBI have been developed recently. These methods include the MammoSite™ breast brachytherapy catheter,4 three-dimensional conformal external beam radiation therapy,20, 21 and single-fraction intraoperative RT.22 Each of these technologies are in various stages of development and testing, and several Phase III trials have been initiated.23
In this report, the results of the initial clinical experience with the MammoSite™ device on a large scale in the community are presented. During the study, 223 different investigators at 87 sites placed the device according to specified guidelines in 1403 patients. Unfortunately, accurately documenting the actual dose delivered in these patients was not possible, because the submission of three-dimensional dose-volume histogram analyses of each treatment was not required. Therefore, additional time will be needed to establish the long-term effects of this method of APBI on local control, toxicity, and cosmetic results. In addition, further experience will be required to help define the most optimal patients suitable for the use of the device and its most optimal application. However, given the novel nature of this technique and its use by numerous investigators in various clinical settings, these early results are encouraging and suggest that use of the device in a multiinstitutional trial is feasible.
The results of this trial confirm prior observations by Keisch et al. that early cosmesis is related strongly to skin spacing.4 At 12 months, 96% of patients had a good/excellent cosmetic result with a skin spacing ≥ 7 mm. However, it also should be noted that, even in patients with < 7 mm of skin spacing, 86% of patients had a good/excellent cosmetic result, suggesting that others factors (area/volume of tissue receiving higher doses) may impact on the ultimate cosmetic result. Additional follow-up will be needed to confirm these observations (stability of cosmesis over time), because cosmetic results after standard BCT stabilize after 3 years. However, data from Benitez et al. show that cosmetic results actually improved over time (after 2 years) in patients who were treated with similar fractionation schedules using interstitial brachytherapy to deliver APBI.24 Nonetheless, as these data continue to mature, further analyses by the ASBS will be conducted to help establish the stability of these observations and the factors associated with long-term cosmetic results.
Infections developed in 8.1% of patients overall. These findings compare favorably with data from previous surgical and RT series with BCT in which the rates of breast infections have ranged from 3.6% to 14.3%.25, 26 In addition, the findings reported in a previous study of patients who received APBI using interstitial brachytherapy also indicated that this rate is in keeping with what has been observed.24 In that analysis, infections developed in 22 of 199 patients (11%), including 7% early infections (≤ 1 mo postimplant removal) and 4% late infections (> 1 mo postimplant removal). Five of the 22 infections (2% of all patients) required surgery, either incision and drainage or debridement. There was a statistically significant difference between infection rates with open cavity placement (8.5%) versus closed cavity placement (2.5%) of the interstitial needles (P = 0.005). A statistically significant difference in the rate of infection between open and closed placement of the MammoSite™ device was not observed in this study. In a recently published study using the MammoSite™ device to deliver APBI, a 16% infection rate was observed in the first group of patients treated at that institution (Table 7).27 This rate decreased with further experience and the use of additional catheter care instructions (including antibiotics) currently recommended by the manufacturer at each training course.
|Institution||No. of patients||Follow-up (mos)||Local recurrence (%)||Good/excellent cosmetic results (%)||Infection (%)|
|Multiinstitutional trial (Keisch et al., 20034)||43||30a||0||86a||4.7|
|MammoSite™ registry trial (Gittleman et al., 200328)||106||NR||0||90||6.0|
|Tufts-New England Medical Center (Shah et al., 200429)||28||19||0||93||NR|
|St. Vincent's Comprehensive Cancer Center (Richards et al., 200427)||32||11||0||86||16.0|
|Breast Care Center of the Southwest (Zannis et al., 200330)||21||NR||NR||NR||NR|
|Rush University Medical Center (Dowlatshahi et al., 200431)||112||NR||0||80||6.0|
Radiation Recall Reactions
The description of a significant radiation skin reaction occurring approximately 3–7 weeks after the completion of RT has been referred to loosely as a “radiation recall reaction.” It is believed that this effect is precipitated or enhanced by the concurrent use of certain systemic chemotherapy agents. The implications of this observation on the use of the MammoSite™ device (or any other form of APBI) are uncertain. The hypofractionated RT schedule that is used with APBI typically can result in delayed skin reactions (3–7 wks). Consequently, it is difficult to ascertain whether these findings are the anticipated outcome of the accelerated RT schedule or of the concurrent use of chemotherapy. In the current trial, patients with smaller skin spacing more frequently experienced a “radiation recall reaction” (without chemotherapy), suggesting that these skin changes more likely are the expected result of hypofractionated RT. Similarly, patients who received concurrent chemotherapy were more likely to experience a recall reaction, suggesting that, in some patients, the early use of systemic chemotherapy agents can exacerbate or precipitate this reaction. Fortunately, only a small percentage of patients overall reportedly experienced this reaction (3.4%), and 86% of these patients had good/excellent cosmetic results at their last follow-up visit. Nonetheless, continued observation of patients who are treated with systemic chemotherapy and APBI are needed to help determine whether special precautions may be required in these patients, such as 1) the delayed start of chemotherapy, 2) avoidance of certain radiosensitizing drugs, or 3) use only in patients with greater skin spacing.
Study Strengths and Limitations
It is important to point out that, although the median follow-up was only 5 months for the entire group of patients in this study, a marked statistical association was identified related to skin spacing and cosmetic outcome (see above). These results underscore the value of data obtained from a very large registry trial that otherwise may not be obtained in much smaller single or multiinstitutional studies.
Despite the encouraging early results of this trial, further improvements in the device implantation procedure (both open and closed cavity), technical development of more anatomically optimal balloon shapes and sizes, and research into the use of multiple dwell positions are needed. In addition, longer follow-up of these patients and results from other prospective, independent studies are needed to confirm these early observations. Because this was not a prospective trial, and patients could be enrolled at various times, the results should be interpreted with some caution. Selection bias in patient enrollment cannot be ruled out; thus, the reported rates of infection, cosmesis, local recurrence, and technical reproducibility must be viewed with this in mind. However, subset analyses of the 51% of patients enrolled prior to treatment demonstrated no statistically significant differences in any of these measures of efficacy (cosmesis, technical reproducibility, infections, radiation recall, etc.). In addition, the growing body of published data on the device confirms the early observations in this trial (see Table 7). Nonetheless, the true long-term efficacy of APBI needs to be confirmed in well designed, prospective, randomized trials comparing partial-breast RT versus whole-breast RT. Such a trial has been approved recently by the National Cancer Institute (NSABP trial B-39 and Radiation Therapy Oncology Group trial 0413) and will include the MammoSite™ catheter as 1 of 3 techniques for delivering APBI. Institutions are encouraged strongly to enter patients onto this important trial to confirm or disprove the excellent 5-year results observed in single-institution experiences with APBI, to help establish the most optimal means of delivering APBI, and to identify the patient population most suitable for its application.
In conclusion, clinical evaluation of the ability of the MammoSite breast brachytherapy catheter to deliver APBI demonstrated acceptable technical reproducibility between multiple institutions and use in appropriate groups of patients. Cosmetic results at 12 months (92% good/excellent) were comparable to those reported with whole-breast RT. Early toxicity rates (infections, radiation recall) appear acceptable.
The authors thank the numerous institutions, physicians, and health care personnel who enrolled patients on this trial.
- 17Exclusive brachytherapy after conservative surgery in cancer of the breast [abstract]. Lyon Chir. 1993; 89: 128., , .
- 28Clinical evaluation of the MammoSite breast brachytherapy catheter: an analysis of technical reproducibility, acute toxicity and patient demographics [abstract]. Int J Radiat Oncol Biol Phys. 2003; 57(Supp): S365., , , et al.