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Comparison of accelerated partial breast irradiation via multicatheter interstitial brachytherapy versus whole breast radiation

Comparison of accelerated partial breast irradiation via multicatheter interstitial brachytherapy... Background: Brachytherapy as adjuvant treatment for early-stage breast cancer has become widely available and offers patients an expedited treatment schedule. Given this, many women are electing to undergo brachytherapy in lieu of standard fractionation radiotherapy. We compare outcomes between patients treated with accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy versus patients who were also eligible for and offered APBI but who chose whole breast radiation (WBI). Methods: Patients treated from December 2002 through May 2007 were reviewed. Selection criteria included patients with pTis-T2N0 disease, ≤ 3 cm unifocal tumors, and negative margins who underwent breast conservation surgery. Local control (LC), cause-specific (CSS) and overall survival (OS) were analyzed. Results: 202 patients were identified in the APBI cohort and 94 patients in the WBI cohort. Median follow-up for both groups exceeded 60 months. LC was 97.0% for the APBI cohort and 96.2% for the WBI cohort at 5 years (ns). Classification by 2010 ASTRO APBI consensus statement categories did not predict worse outcomes. Conclusion: APBI via multicatheter interstitial brachytherapy provides similar local failure rates compared to WBI at 5 years for properly selected patients. Excellent results were seen despite the high fraction of younger patients (< 60 years old) and patients with DCIS. Introduction partial breast irradiation (APBI) techniques have been Prospective randomized controlled trials have estab- developed. Early studies of APBI have described impress- lished breast conservation therapy (BCT), consisting of ively low ipsilateral breast tumor recurrence (IBTR) rates partial mastectomy and adjuvant radiation therapy, [6,7]. We have offered APBI or WBI therapy as treatment offers equivalent disease control in women with Stage I options for early-stage breast cancer in appropriately and II breast cancer as compared to mastectomy and selected patients since December 2002. The purpose of significantly superior disease control when compared to this report is to review the outcomes of our multicatheter partial mastectomy alone [1,2]. In the setting of ductal APBI in comparison to a cohort of patients eligible for carcinoma in situ, adjuvant radiation therapy has been and offered APBI but treated with WBI during the same shown to increase local control [3-5]. time interval. The standard method for administering breast irradia- tion as a part of BCT is whole breast irradiation (WBI) Methods delivered in five daily fractions per week for several weeks. Patient selection and data analysis th In an effort to expedite radiation therapy, accelerated Patients diagnosed with T -T N M (AJCC 6 Edition) is 2 0 0 unifocal breast cancers ≤ 3cminsizefromDecember 2002 through May 2007 who underwent breast conser- * Correspondence: izoberi@radonc.wustl.edu ving therapy with negative margins and received adjuvant Department of Radiation Oncology and Siteman Cancer Center, radiation therapy with either APBI using multicatheter Washington University School of Medicine, Saint Louis, MO 63110, USA Full list of author information is available at the end of the article © 2012 Ferraro et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ferraro et al. Radiation Oncology 2012, 7:53 Page 2 of 10 http://www.ro-journal.com/content/7/1/53 interstitial breast irradiation or WBI via external beam Medicine Human Research Protection Office approved irradiation were identified. Patients who received neoad- this study. juvant systemic therapy were not eligible for APBI and are not included in this review. All patients included in Surgery the study were eligible for and offered the option of APBI All patients underwent partial mastectomy as a part of or WBI at initial radiation oncology consultation. BCT. Negative surgical margins were defined as ≥ 2mm Patients who were not eligible for APBI and/or only of tumor free tissue on all margins or removal of the offered WBI were excluded from this study to limit bias. breast tissue to the pectoralis fascia with no evidence of Three patients with synchronous primaries in bilateral tumor invasion into the fascia. Re-excisions were often breasts were identified in the APBI cohort with each performed if the initial tumor-free margin was < 2 mm. breast cancer considered independently. A small number of patients who did not have either a APBI was generally not recommended to patients sentinel lymph node biopsy or an axillary dissection younger than 40 years. However three patients in the were included if they had no evidence for axillary invol- APBI cohort were in their thirties at diagnosis. Two of vement at the time of diagnosis or treatment, this these patients had prior radiation and APBI was offered to included three patients undergoing APBI for an IBTR minimize the volume of reirradiation. The third patient previously treated with WBI. Axillary assessment was declined WBI but was willing to do APBI. Given the pre- not required in patients with DCIS. sence of these three patients in the APBI cohort, we included patients seen in the study time period who were Systemic therapy in their thirties, who received WBI, and who would have Systemic therapy consisted of some combination of met the other eligibility criteria for APBI. endocrine, cytotoxic chemotherapy, biologic therapy, or Breast cancer subtype for invasive cancers was approxi- no systemic therapy. For patients that received APBI mated using estrogen receptor (ER), progesterone receptor and cytotoxic chemotherapy, APBI occurred prior to (PR), and Human Epidermal growth factor Receptor 2 cytotoxic chemotherapy in all but two cases. For (HER2/neu) status [8]. patients who received WBI and cytotoxic chemotherapy, Patients were classified according to the ASTRO con- WBI occurred after cytotoxic chemotherapy. sensus statement for APBI [9]. Presence or absence of lymphovascular space invasion (LVSI) was reported; how- Interstitial implant technique ever, extent was not specifically addressed. Similarly, Interstitial implants (ISI) were placed using a free hand extensive intraductal component (EIC) was reported as technique encompassing the surgical cavity with a 2 cm present without regards to size in the majority of reports. margin of breast tissue in all directions. All implants were Therefore the presence of LVSI or EIC was considered multiplanar with an intraplane catheter spacing of 12 mm cautionary. No patient was known to be BRCA1/2 and an interplane spacing of 1.5 to 2.0 cm. The use of positive. more than two planes was common. For the first 46 Time to event and length of follow-up was calculated patients, ISI were placed intraoperatively with an open using the date of final surgery as day 0. An IBTR was a surgical cavity. ISI insertion via real-time ultrasound gui- failure for local control (LC). LC was defined as one minus dance (U/S) with a closed surgical cavity was predomi- the local recurrence rate (LR). Further, IBTR were classi- nantly used after this point. fied as “true recurrence” when they occurred in the same The initial eight patients underwent two dimensional quadrant as the initial tumor, or “elsewhere” if they brachytherapy treatment planning using pairs of orthogo- occurred in a separate quadrant. Recurrences in the supra- nal plain films. All subsequent patients underwent three- clavicular, infraclavicular, internal mammary, intrapec- dimensional (3D) treatment planning. Within one day of toral, and axillary nodes were defined as a locoregional completion of ISI placement, patients underwent com- recurrence (LRR). puted tomography (CT) simulation for 3D treatment plan- Continuous variables were compared using two-tailed t- ning. CT compatible markers were placed in each tests and categorical variables were compared using Fish- catheter. CT images were obtained using 2 mm slice thick- er’s exact test with p values ≤ 0.05 considered significant. ness through the ISI volume plus several centimeters of Estimates of LR, LRR, disease-free survival (DFS), cause surrounding tissue. specific survival (CSS), and overall survival (OS) were per- TheCTdataset wastransferred to thebrachytherapy formed using the Kaplan-Meier method using SAS version planning system for selection of HDR dwell positions 9.2 (SAS Institute Inc., Cary, NC). Survival was compared and optimization of their relative weights. The Plato using log-rank tests. Predictive effects were analyzed using Brachytherapy software system (Nucletron B. V., Veenen- a Cox proportional hazards multivariate regression model daal, The Netherlands) was used through November 2006 with two-sided tests. Washington University School of after which treatment planning was done using the Ferraro et al. Radiation Oncology 2012, 7:53 Page 3 of 10 http://www.ro-journal.com/content/7/1/53 Brachyvision system (Varian, Palo Alto, CA). The surgical Table 1 Patient demographics and tumor characteristics cavity was identified on the CT dataset by contouring the All Disease seroma along with any surgical clips and density changes. APBI WBI P value The Planning Target Volume (PTV) was created by adding Patients 202 94 a uniform 2 cm margin to the surgical cavity contour and Months Follow-up 64.3 64.1 0.422 subsequently limited to 5 mm away from the skin surface. (Range) (2.2-96.6) (4.4-98.4) Pectoral muscle, chest wall, and axilla were excluded from Median Age 60.0 56.9 0.087 the PTV. (Range) (34.7-84.3) (33.0-83.2) Dwell positions within each catheter were separated by Race < 0.001* 5-7 mm. The dosimetric goal was to cover at least 95% of Caucasian 169 (83.7%) 52 (55.3%) the PTV with the prescription dose while maintaining a Black 31 (15.4%) 42 (44.7%) ratio of the prescription dose to the mean central dose of Other 2 (1.0%) 0 (0%) ≥ 0.70. Following the report by Arthur et al. that suggested Anatomy dose-volume predictors for fat necrosis [10], our dosi- Side 0.803 metric goals expanded to limit the volume receiving more Right 97 (48.0%) 47 (50.0%) than 150% (V ) of the prescription dose to ≤ 50 mL, Left 105 (52.0%) 47 (50.0%) V ≤ 20 mL, and 1-V /V ≥ 0.70. Planning was 200 150 100 Quadrant accomplished by geometric optimization of the prescrip- UOQ 88 (43.6%) 64 (68.1%) < 0.001* tion dose to the mean central dose and subsequent user UIQ 53 (26.2%) 17 (18.1%) graphical optimization. LIQ 29 (14.4%) 5 (5.3%) The prescription dose was 34 Gy in ten fractions admi- LOQ 32 (15.8%) 8 (8.5%) nistered twice daily with a six hour interfraction separation Grade 0.207 over five to seven days for all but two patients. One patient DCIS 40 (19.8%) 18 (19.1%) received 32 Gy in 8 fractions. The second patient was trea- I 78 (38.6%) 25 (26.6%) ted for a recurrent cancer in a previously irradiated field II 55 (27.2%) 27 (28.7%) and received a dose of 30 Gy in 10 fractions. Treatment III 29 (14.4%) 20 (21.3%) began one to two working days after the simulation. Unknown 0 (0%) 4 (4.3%) Catheters were removed after the last fraction. Stage Quality assurance was accomplished by performing an Tis 40 (19.8%) 18 (19.1%) autoradiograph of the treatment plan and a manual expo- T1 3 (1.5%) 4 (4.3%) mic sure calculation that was compared to the predicted value T1 23 (11.4%) 7 (7.4%) based on the Paterson-Parker tables using the volume T1 67 (33.2%) 29 (30.9%) receiving 340 cGy [11]. T1 54 (26.7%) 31 (33.0%) T1 147 (72.8%) 71 (75.5%) Whole breast irradiation T2 15 (7.4%) 5 (5.3%) Patients in the WBI cohort were treated to the whole Histology 0.092 breast using tangential beams. Patients received a dose of DCIS 40 (19.8%) 18 (19.1%) 42.56-50.4 Gy in 1.8-2.66 Gy fractions. Most patients Invasive Ductal 141 (69.8%) 60 (63.8%) received a boost. 50 Gy in 200 cGy fractions to the whole Invasive Lobular 8 (4.0%) 11 (11.7%) breast followed by a 10 Gy boost to the tumor bed was the Invasive Tubular 7 (3.5%) 1 (1.1%) most frequent WBI dose prescription. Invasive Mucinous 5 (2.5%) 2 (2.1%) Invasive Papillary 1 (0.5%) 2 (2.1%) Results Estrogen Receptor 0.464 Patient characteristics are shown in Table 1. 202 ER + 167 (82.7%) 71 (71.6%) patients were identified in the APBI cohort and 94 in ER - 26 (12.9%) 15 (16.0%) the WBI cohort. Median follow-up exceeded 60 months ER Unknown 9 (4.5%) 8 (8.5%) for both groups. One hundred one APBI patients were Progesterone Receptor 0.489 ≤ 60 years (50.0%), and 37 patients were ≤ 50 years old PR + 134 (66.3%) 56 (59.6%) (18.3%). Fifty-three WBI patients were ≤ 60 years old PR - 59 (29.2%) 30 (31.9%) (56.4%) and 23 patients were ≤ 50 years old (24.5%). PR Unknown 9 (4.5%) 8 (8.5%) Characteristics are given for DCIS and invasive disease Her-2/Neu 0.350 (Invasive Only) patients in Table 2. Overexpressed 14 (6.9%) 9 (4.5%) Seven patients treated with APBI were treated in a Not Overexpressed 147 (72.8%) 62 (66.0%) previously irradiated field. Three of these patients had Ferraro et al. Radiation Oncology 2012, 7:53 Page 4 of 10 http://www.ro-journal.com/content/7/1/53 Table 1 Patient demographics and tumor characteristics covered by the prescription dose. Dose homogeneity as (Continued) assessed by 1-V /V had a median value of 0.80. 150 100 Dosimetric parameter averages for the APBI patients are Unknown 41 (20.3%) 23 (24.5%) given in Table 3. Disease Type Luminal A 128 (63.4%) 51 (54.3%) 0.353 Recurrence rates and survival analysis Luminal B 9 (4.5%) 7 (7.5%) The LR, LRR, and DFS were similar between the groups Her-2/Neu 5 (2.5%) 2 (2.1%) (Table 4). Survival curves demonstrating LC for all dis- Basal 16 (7.9%) 11 (3.7%) ease, DCIS only and invasive disease only stratified by DCIS 40 (19.8%) 18 (6.1%) radiationmethodare giveninFigure 1.There wasno Unable to classify 4 (2.0%) 5 (5.3%) statistical difference in OS or CSS between the groups. LVSI (Invasive Only) 0.591 While OS was not significantly lower, it was trending Present 10 (4.9%) 6 (8.1%) lower in the APBI group compared to the WBI cohort. Absent 152 (74.5%) 70 (91.9%) A number of patients who received APBI had significant LCIS 0.011* medical co-morbidities and chose APBI over WBI. Present 15 (7.4%) 17 (18.1%) These patients were opposed to omitting radiation ther- Absent 187 (92.6%) 77 (81.9%) apy and chose APBI for the convenience of a shorter EIC (Invasive Only) 0.688 time commitment. Seven of these patients died from Present 4 (2.5%) 3 (3.9%) their pre-existing comorbidities (Table 5). Absent 148 (91.4%) 73 (96.1%) Characteristics of patients who experienced disease Unknown 10 (6.2%) 0 (0%) recurrence are described in Table 6. In all cases with an Endocrine Therapy 0.182 (Invasive Only) initial diagnosis of regional or metastatic failure, no evi- Given 127 (78.4%) 50 (65.8%) dence of local failure was present. The patient treated via Not Given 34 (21.0%) 21 (27.6%) APBI who developed a regional failure at 55.0 months was Unknown 1 (0.6%) 5 (6.6%) found to have a nodal recurrence in a portion of the axilla Endocrine Therapy 0.756 that would likely have been covered using tangential beam (DCIS Only) if given WBI. The other patient treated with APBI who Given 29 (72.5%) 14 (77.8%) developed a regional recurrence was diagnosed at 17.1 Not Given 11 (27.5%) 4 (22.2%) months with an axillary nodal recurrence that would have Unknown 0 (0%) 0 (0%) been superior to the upper tangent border if treated by Cytotoxic Chemotherapy 0.102 WBI. Both regional failures were in the APBI group and (Invasive Only) were axillary failures. Both patients had negative sentinel Given 35 (21.6%) 23 (30.3%) lymph node biopsies at initial diagnosis. It was estimated Not Given 127 (78.4%) 49 (64.5%) that one of the site of one of the axillary failures would Unknown 0 (0%) 4 (5.3%) have been treated with standard tangential fields if WBI * Statistically significant had been given and the other would not have been included. All patients who developed regional or distant disease remained free of IBTR at death or last follow up. previously received WBI as a part of BCT for a prior diagnosis of breast cancer and received repeat BCT for Classification by ASTRO consensus guidelines an IBTR diagnosed at least 10 years after the initial Using the criteria to outlined in the 2009 ASTRO con- diagnosis. Four patients received radiation therapy for sensus statement on APBI (Table 7), patients in both tumors treated earlier in life (two had Hodgkin’slym- phoma and two had an upper extremity sarcoma). the WBI and APBI cohorts were categorized into one of Six patients treated via APBI did not have surgical three categories: acceptable, cautionary or unsuitable assessment of the axilla. Of these patients, 4 had pre- (Table 8). viously undergone axillary dissections so reassessment Overall, the APBI and WBI groups were significantly was not technically feasible. For the remaining two different with respect to ASTRO consensus category patients, one had a < 1 mm focus of invasive disease in classification (p = 0.017). None of the ASTRO consen- the setting of LCIS and the other had a 6 mm focus of sus categories predicted LR, LRR or DFS either when invasive tubular disease. analyzed by treatment group or when analyzed in the entire study population. In a multivariate model for LRR APBI dosimetry in which radiation method was force entered, age, stage, 192 patients had ≥ 90% of the PTV covered by the pre- radiation method, biomarker pattern, and ASTRO con- scription dose and 133 patients had ≥ 95% of the PTV sensus category were all non-significant predictors. Ferraro et al. Radiation Oncology 2012, 7:53 Page 5 of 10 http://www.ro-journal.com/content/7/1/53 Table 2 Patient demographics and tumor characteristics for DCIS and invasive disease DCIS Invasive APBI WBI P value APBI WBI P value Patients 40 18 162 76 Months Follow-up 69.4 72.7 0.502 62.9 62.1 0.543 (Range) (13.7-92.6) (24.6-87.6) (2.2-96.6) (4.4-98.4) Median Age 59.2 56.5 0.752 61.4 58.1 0.079 (Range) (40.3-82.4) (41.4-84.2) (34.7-84.3) (33.0-84.7) Race 0.018 < 0.001 Caucasian 31 (77.5%) 10 (55.6%) 138 (85.2%) 44 (57.9%) Black 9 (22.5%) 8 (44.4%) 22 (13.6%) 32 (42.1%) Other 0 (0%) 0 (0%) 2 (1.2%) 0 (0.0%) Anatomy Side 0.776 1.000 Right 17 (42.5%) 9 (50.0%) 80 (49.4%) 38 (50.0%) Left 23 (57.5%) 9 (50.0%) 82 (50.6%) 38 (50.0%) Quadrant 0.049 < 0.001 UOQ 18 (45.0%) 14 (77.8%) 70 (43.2%) 50 (65.8%) UIQ 7 (17.5%) 3 (16.7%) 46 (28.4%) 14 (18.4%) LIQ 6 (15.0%) 1 (5.6%) 23 (14.2%) 4 (5.3%) LOQ 9 (22.5%) 0 (0%) 23 (14.2%) 8 (10.5%) Estrogen Receptor 0.548 0.256 ER + 28 (70.0%) 12 (66.7%) 139 (85.8%) 59 (77.6%) ER - 3 (7.5%) 0 (0%) 23 (14.2%) 15 (19.7%) ER Unknown 9 (22.5%) 6 (33.3%) 0 (0%) 2 (2.6%) Progesterone Receptor 0.727 0.369 PR + 21 (52.5%) 9 (50.0%) 113 (69.8%) 49 (64.5%) PR - 10 (25.0%) 3 (16.7%) 49 (30.2%) 27 (35.5%) PR Unknown 9 (22.5%) 6 (33.3%) 0 (0%) 2 (2.6%) LCIS 0.084 Present 1 (2.5%) 3 (16.7%) 14 (8.6%) 14 (18.4%) 0.050 Absent 39 (97.5%) 15 (83.3%) 148 (91.4%) 62 (81.6%) Discussion Table 4 5-year survival rates and number of failures Multicatheter APBI represents the first form of partial APBI WBI P value breast irradiation offered at Washington University as Overall an alternative to WBI for a select group of early-stage Local Recurrence Rate 3.04% (5) 3.82% (3) 0.721 breast cancer patients. Our experience suggests that Locoregional Recurrence Rate 4.25% (7) 3.82% (3) 0.902 Disease-Free Survival 94.3% (9) 93.4% (8) 0.870 Table 3 Dosimetric parameters for multicatheter APBI Cause Specific Survival 99.4% (1) 98.9% (1) 0.954 treatments Overall Survival 91.9% (15) 96.7% (3) 0.113 Median Minimum Maximum DCIS V 222 97.3 775 Local Recurrence Rate 2.56% (1) 6.25% (1) 0.573 V 43.6 19.1 190 Disease-Free Survival 97.4% (1) 93.8% (1) 0.573 V 15.6 7.01 58.2 Cause Specific Survival 100% (0) 100% (0) - (1-V /V ) 0.8 0.45 0.88 Overall Survival 97.5% (1) 100% (1) 0.843 150 100 DHI 0.83 0.56 1.00 Invasive Disease PTV Volume 154.5 57.6 552 Local Recurrence Rate 3.24% (4) 3.10% (2) 0.939 PTV Coverage 148.5 56.2 520 Locoregional Recurrence Rate 4.80% (6) 3.10% (2) 0.669 % PTV Coverage 95.7% 78.5% 100% Disease-Free Survival 93.8% (8) 94.1% (4) 0.920 Cavity Volume 18.4 cc 1.4 cc 114 cc Cause Specific Survival 99.3% (1) 98.6% (1) 0.968 Number of Catheters 20 10 37 Overall Survival 90.4% (14) 95.6% (3) 0.093 Ferraro et al. Radiation Oncology 2012, 7:53 Page 6 of 10 http://www.ro-journal.com/content/7/1/53 this method offers similar LRR, DFS, CSS, and OS A. All Patients compared to WBI. Our series includes a significant 1.00 number of young patients and patients treated for pure DCIS. Both of these subgroups had no significant dif- 0.80 ference in LRR, DFS, CSS or OS with APBI as com- pared to WBI. 0.60 The most significant limitation of this series is length of follow-up given the long natural history of breast cancer. 0.40 While the low number of events is encouraging, it does limit the statistical analysis of predictors of these events. APBI 0.20 WBI As this patient population matures, occurrences will p = 0.721 inevitably increase, making more complex analyses possi- 0 20 40 60 80 100 ble. Selection bias may also limit the applicability of this Months to Local Recurrence analysis as it is a retrospective study; however, we do APBI 189 180 116 33 WBI 90 83 57 24 0 report a concurrent cohort of patients who were eligible Number at Risk for and offered APBI but who selected WBI whose out- comes were similar. It was practice in our clinic to offer B. DCIS 1.00 each patient both options when it was felt that either option was technically feasible and appropriate for the 0.80 specific patient’s disease. 0.60 Previous APBI experiences Multicatheter APBI has been practiced for over 20 years. 0.40 The Oschner clinic reported one of the first series of patients treated in this fashion. A phase I/II trial of HDR APBI 0.20 or Low Dose Rate (LDR) brachytherapy was initiated in WBI p = 0.573 the early 1990s to evaluate tumor control in wide-field partial breast irradiation. Patients with Tis-T2 disease 020 40 60 80 less than 4 cm in diameter with 0-3 positive axillary Months to Local Recurrence 27 7 APBI 39 38 nodes were treated. One in breast recurrence and three WBI 18 16 14 2 Number at Risk nodal recurrences were reported at 75 months, all three nodal recurrences in patients with extracapsular nodal C. Invasive Disease disease at the time of treatment [12]. Similar early studies 1.00 were also performedatother institutionsandbythe Radiation Therapy Oncology Group 9517 cooperative 0.80 study [6,7,13,14]. An exhaustive list of APBI studies using a variety of techniques is reported in Smith et al [9]. 0.60 Recent reports are congruent with our findings. McHaffee et al. report the Wisconsin experience with 0.40 HDR interstitial brachytherapy using multicatheter or APBI MammoSite balloon techniques. The majority of the 322 0.20 WBI patients reported in the series underwent multicatheter p = 0.939 APBI and were planned using modern 3D-CT methods. 020 40 60 80 Patients received 32 Gy in 8 BID fractions or 34 Gy in 10 Months to Local Recurrence BID fractions. The 5-year LR was 4.8% and the 5-year APBI 89 26 0 150 142 WBI 72 68 43 19 0 DFS was 89.6% [15]. Strnad et al. reports the results from Number at Risk the German-Austrian Phase II trial investigating multi- Figure 1 Survival and time-to-recurrence for patients treated catheter brachytherapy in 274 patients. Inclusion criteria with WBI or APBI. A. Survival curve demonstrating time to local for this study were stricter than our study, requiring recurrence for all patients stratified by type of radiation received. B. Time to local recurrence for patients treated for DCIS stratified by absence of LVSI and a maximum histologic grade of II/ type of radiation received. C. Time to local recurrence for patients III. The 5-year and 8-year actuarial survival was reported treated for invasive disease stratified by type of radiation received. as 97.7% and 95%, respectively for the entire cohort. DFS Survival Probability Survival Probability Survival Probability Ferraro et al. Radiation Oncology 2012, 7:53 Page 7 of 10 http://www.ro-journal.com/content/7/1/53 Table 5 Characteristics of patients who expired and causes of death Age at APBI T Histology Grade Biomarker Adjuvant Radiation Time to Death Cause of Death Diagnosis Class stage Pattern Treatment Modality (months) 77.5 cautionary 2 ductal II +/+/- R + E APBI 43.76 CAD*, Anoxic Brain Injury after V Fib episode 35.6 unsuitable 2 ductal III -/-/+ R APBI 60.35 Recreational Drug Overdose 45.4 unsuitable 2 ductal II +/+/- R + C + E APBI 74.68 Breast Cancer 81.8 acceptable 1a ductal II +/+/- R APBI 2.83 Stroke/Fall 57.4 cautionary 1a ductal I +/+/- R APBI 8.25 Cirrhosis* with Hepatocellular Cancer 51.6 cautionary 1a ductal III +/-/- R + E APBI 35.91 Colon Cancer* 66.5 cautionary 1a ductal III -/-/- R APBI 41.95 Myelodysplastic Syndrome 34.7 unsuitable 1b tubular I +/+/- R APBI 2.96 Urosepsis 79.1 acceptable 1b ductal II +/+/- R + E APBI 16.33 CAD*, MI 80.2 acceptable 1b ductal I +/+/- R APBI 32.20 COPD* 72.3 acceptable 1b ductal I +/+/- R + E APBI 33.71 High Grade Sarcoma* 70.7 cautionary 1b ductal III -/-/- R APBI 46.29 Breast Cancer 50.2 cautionary 1c ductal III -/-/- R + C APBI 5.95 Chemotherapy Toxicity 58.6 cautionary 1c ductal III -/-/- R APBI 13.50 Ovarian Cancer* 66.1 acceptable 1c ductal II +/+/- R + E APBI 56.48 Melanoma 68.8 acceptable 1c ductal II +/+/- R + E APBI 58.48 CHF/COPD* 66.8 acceptable 1c ductal I +/+/- R + E APBI 80.89 Stroke 49.1 unsuitable Is DCIS II +/+/- R APBI 13.70 Polycystic Kidney Disease* 67.1 cautionary Is DCIS III -/-/+ R APBI 74.35 Pneumonia (Restrictive Lung Disease*) 70.93 acceptable 1b ductal I +/+/- R + E WBI 14.78 M. avium infection (Chronic bronchiectasis*) 68.55 cautionary 1b ductal III +/+/- R WBI 22.01 Breast cancer 68.76 acceptable 1c mucinous II +/+/- R + E WBI 23.10 Parkinson’s Disease 48.83 unsuitable is DCIS II +/-/- R + E WBI 67.02 CAD*, MI *condition present prior to diagnosis of breast cancer; abbreviations as Table 3. CAD: coronary artery disease, COPD: chronic obstructive pulmonary disease, MI: myocardial infarction was 96.1% and 88% at 5 and 8 years [16]. Shah et al. DCIS patients are included. Jeruss et al. examined out- reports a retrospective series of 199 patients treated via comes of patients enrolled on the American Society of LDR or HDR interstitial brachytherapy matched to a Breast Surgeons APBI MammoSite registry trial treated cohort of patients treated with WBI. The LDR technique for pure DCIS. Eligibility criteria included size < 4.5 cm as defined mammographically, clinically negative nodes, delivered 50 Gy over 96 hours at 0.52 Gy/h. The HDR and negative margins. One hundred ninety-four patients technique delivered 32 Gy in 8 fractions BID or 34 Gy in 10 fractions BID. The LR rate was 5.0% for the APBI were identified with 36% of the patients having high- cohort and 3.8% for the matched WBI patient cohort at grade disease and 53% of the patients receiving endo- 12 years (ns). DFS was 91% for the APBI cohort and 87% crine therapy. Dose prescription was 34 Gy in 10 BID for the WBI cohort (ns) [17]. Polgár et al. reports the fractions. The 5-year LR was 3.39% and DFS was 93.2% Hungarian experience with APBI, the longest follow-up [19]. In addition, McHaffee et al reports 32 patients intheliteraturefor theHDR multicathetertechnique. treated as described above for DCIS with no recurrences Inclusion criteria included size < 2 cm, negative margins, at 5 years [15]. maximum histologic grade of II/III, pN0-N1mic. Carci- noma in situ or lobular carcinoma were excluded. The 5- APBI consensus statement and 12-year LR was 4.4% and 9.3%, respectively. DFS was In 2009, ASTRO APBI consensus statement task force 75.3% at 12 years [18]. released guidelines for appropriate patient selection for LR rate in 40 patients treated via APBI with pure APBI [9]. After review of the literature, three general DCIS (45% high grade) in our series was less than 3% at categories were developed from a number of patient and five years. While treatment of pure DCIS via APBI his- tumor characteristics with special focus selecting patients torically has been controversial, recent reports have for APBI outside of clinical trial. The GEC-ESTRO group demonstrated good local control, even when high-grade released a similar statement in 2010 [20]. Ferraro et al. Radiation Oncology 2012, 7:53 Page 8 of 10 http://www.ro-journal.com/content/7/1/53 Table 6 Characteristics of patients with failure Age at Menopause ASTRO Size Histology Grade Biomarker Node Adjuvant Radiation Initial Failure Salvage Current Diagnosis Status Category Pattern Biopsy Treatment Modality Failure (months) Treatment Status 61.7 Post cautionary 1.00 DCIS II +/-/? No R + E APBI Local - E 20.3 MRM + C + E NED 62.1 Post acceptable 0.30 IDC I +/+/- Yes R + E APBI Local - T 45.3 MRM + C NED 66.8 Post acceptable 1.00 IDC II +/+/- Yes R + E APBI Local - E 59.6 SM NED 69.3 Post acceptable 2.00 IDC II +/-/- Yes R + E APBI Local - E 38.2 PM + C + WBI NED +E 59.5 Post cautionary 2.00 IDC II +/-/- Yes R + E + C APBI Local - E 47.1 MRM + C + E NED 68.2 Post cautionary 0.90 IDC III -/-/- Yes R WBI Local - E 49.5 MRM NED 57.0 Post cautionary 1.50 IDC III -/-/- Yes R + C WBI Local - T 5.2 SM NED 56.5 Post cautionary 0.90 DCIS III +/+/? No R WBI Local - T 49.3 SM NED 62.3 Post acceptable 0.60 IDC II +/+/- Yes R + E WBI Local - E 97.5 MRM + E NED 45.4 Pre unsuitable 3.00 IDC II +/+/- Yes R + E + C APBI Regional 55.0 SR + C Expired 53.6 Post cautionary 3.00 IDC II +/+/- Yes R + E APBI Regional 17.1 SR + C + R NED 70.7 Post cautionary 0.80 IDC III -/-/- Yes R APBI Metastatic 32.4 C + H Expired 68.6 Post cautionary 1.00 IDC III +/+/- Yes R WBI Metastatic 13.2 - Expired 71.1 Post cautionary 2.10 IDC III -/-/+ Yes R + C APBI Metastatic 45.4 C + R Under Treatment 56.5 Post cautionary 2.90 IDC III +/+/+ Yes R + C + E APBI Metastatic 60.8 R Under Treatment 58.1 Post cautionary 1.50 IDC II +/-/- Yes R WBI Metastatic 46.1 C Under Treatment Abbreviations: SM simple mastectomy, MRM modified radical mastectomy, PM partial mastectomy, R radiotherapy, C chemotherapy, E endocrine therapy, H Herceptin, Local-T - true recurrence, Local-E - elsewhere recurrence. Biomarker pattern shows the status for estrogen receptor, progesterone receptor, and HER2/neu using the following symbolic code: (ER)/(PR)/(HER2/neu). Presence of the biomarker is indicated by ‘+,’ absence by ‘-,’ unknown by ‘?.’ Ferraro et al. Radiation Oncology 2012, 7:53 Page 9 of 10 http://www.ro-journal.com/content/7/1/53 Table 7 ASTRO APBI consensus statement categories and classification criteria Criteria Suitable Cautionary Unsuitable Age ≥ 60 50-59 < 50 Tumor Size ≤ 2 cm 2-3 cm > 3 cm T Stage T1 Tis and T2 T3-T4 Nodal biopsy Yes - No Margins Negative (≥ 2 mm) Close (< 2 mm) Positive Histology Invasive ductal or other favorable subtypes Invasive Lobular - Pure DCIS No ≤ 3cm >3cm ER Receptor Positive Negative - LVSI* No Limited/Focal Extensive EIC* No ≤ 3cm >3cm * Presence of LVSI and EIC were considered cautionary in this study. Multicentricity, multifocality, neoadjuvant chemo/endocrine therapy, and known BRCA1/2 mutations were not present in any patients in this study. Pathologic nodal stage was pN0 for all patients who underwent axillary assessment Recently, Shaitelman and colleagues reviewed patients time to local failure at 4-years between the treatment who received APBI via the MammoSite brachytherapy types for any of the three ASTRO classifications [23]. technique as a part of BCT [21]. 1025 of the 1449 McHaffee et al. analyzed a cohort of 322 patients who patients on the MammoSite Registry could be classified received APBI via multicatheter brachytherapy or Mam- using the ASTRO consensus criteria. Of these patients, moSite balloon brachytherapy and retrospectively classi- 419 were classified as suitable, 430 as cautionary, and fied patients using the ASTRO guidelines. ASTRO 176 as unsuitable. This classification scheme did not classification criteria including margin status, EIC, histol- predict different outcomes with regards to local or ogy and size, but not age did predict decreased IBTR and regional disease recurrence, DFS, CSS, or OS. The only LRR. Overall, the reported 5-year IBTR rate for patients statistically significant difference between the categories classified as suitable was 1.6% compared to 6.6% for was with regards to rate of distant metastases. This sug- patients in the unsuitable cohort [15]. gests that the classification may predict disease that While APBI has been successfully adopted as treatment tends to be more aggressive, regardless of local control modality by many institutions, there is limited phase III modality employed. data available guide patient selection. Two large, multi- Beitsch and colleagues reviewed outcomes for patients institutional phase III trials, NSABP B-39/RTOG 0413 treated on the MammoSite registry trial that were retro- and the GEC-ESTRO APBI trial are underway will likely spectively classified as unsuitable by the ASTRO guidelines be the sources for the identification criteria that will dis- [22]. This analysis identified 176 patients as unsuitable and criminate between patients that will or will not be found that there was no difference in local, regional, or adversely affected with regards to disease control based distant failure between the unsuitable and other classifica- on treatment technique, if any exist. These studies include patients with high-risk disease characteristics and tions. In addition, only ER status was correlated with IBTR also allow for variation in APBI technique. While these on univariate analysis when looking at all patients in the registry, suggesting that the ASTRO criteria lack power to studies will help clarify outcomes and identify sub-popu- identify a cohort of patients that are more likely to recur lations of higher-risk patients not appropriate for APBI, locally fail after APBI compared to WBI. Zauls et al. com- these data will likely not be available for multiple years. pared patients treated with WBI and APBI via Mammo- In the interim this report offers additional evidence Site balloon therapy and did not find a difference in the regarding the safety and efficacy of APBI. Table 8 Distribution of patient factors across ASTRO consensus statement parameters Overall (%) Age at Diagnosis Tumor Size T Stage ER Status Histology DCIS EIC LVSI Nodal Assessment APBI Acceptable 58 (28.7) 101 147 147 167 194 162 158 152 156 Cautionary 104 (51.5) 64 15 55 35 8 40 4 10 0 Unsuitable 40 (19.8) 37 0 0 0 0 0 - - 6 WBI Acceptable 16 (17.0) 41 71 71 71 83 76 73 70 67 Cautionary 47 (50.0) 30 5 23 23 11 18 3 6 0 Unsuitable 31 (33.0) 23 0 0 0 0 0 - - 9 Ferraro et al. Radiation Oncology 2012, 7:53 Page 10 of 10 http://www.ro-journal.com/content/7/1/53 irradiation consensus statement from the American Society for Radiation Acknowledgements Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009, 74:987-1001. We thank the SCC-WUSM and Barnes-Jewish Hospital in St. Louis, Mo., for 10. Arthur DW, Wazer DE, Koo D, Shah N, Berle L, Cuttino L, Yunes M, Rivard M, the use of the Clinical Trials Core, which provided regulatory service. The Todor D, Tong S, et al: The importance of dose volume histogram Siteman Cancer Center is supported in part by NCI Cancer Center Support evaluation in partial breast brachytherapy: a study of dosimetric Grant #P30 CA91842. A portion of the data contained in this manuscript was nd parameters. Int J Radiat Oncol Biol Phys 2003, 57:S361-S362. presented at the ASTRO 52 annual meeting. 11. Williamson JF, Brenner DJ: Physics and Biology of Brachytherapy. In Principles and Practice of Radiation Oncology.. 5 edition. Edited by: Halperin Author details E, Perez CA, Brady LW. Lippincott Williams 2008:. Department of Radiation Oncology and Siteman Cancer Center, 12. King TA, Bolton JS, Kuske RR, Fuhrman GM, Scroggins TG, Jiang XZ: Long- Washington University School of Medicine, Saint Louis, MO 63110, USA. term results of wide-field brachytherapy as the sole method of radiation Department of Surgery and Siteman Cancer Center, Washington University therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J School of Medicine, Saint Louis, MO 63110, USA. Department of Medicine Surg 2000, 180:299-304. and Siteman Cancer Center, Washington University School of, Saint Louis, 13. Wazer DE, Berle L, Graham R, Chung M, Rothschild J, Graves T, Cady B, MO 63110, USA. Department of Surgery, John Cochran Veterans Hospital, Ulin K, Ruthazer R, DiPetrillo TA: Preliminary results of a phase I/II study of Saint Louis, MO 63106, USA. Department of Radiation Oncology, 4921 HDR brachytherapy alone for T1/T2 breast cancer. Int J Radiat Oncol Biol Parkview Place - LL/Campus Box 8224, Saint Louis, MO 63110, USA. Phys 2002, 53:889-897. 14. Vicini FA, Baglan KL, Kestin LL, Mitchell C, Chen PY, Frazier RC, Authors’ contributions Edmundson G, Goldstein NS, Benitez P, Huang RR, Martinez A: Accelerated DF participated in the study design, collected and analyzed patient data, treatment of breast cancer. J Clin Oncol 2001, 19:1993-2001. and drafted the manuscript. AG participated in the study design and helped 15. McHaffie DR, Patel RR, Adkison JB, Das RK, Geye HM, Cannon GM: draft the manuscript. TD performed the statistical analyses for the study. JM Outcomes after accelerated partial breast irradiation in patients with interpreted data and helped draft the manuscript. MN interpreted data and ASTRO consensus statement cautionary features. Int J Radiat Oncol Biol helped draft the manuscript. RA interpreted data and helped draft the Phys 2011, 81:46-51. manuscript. WE interpreted data and helped draft the manuscript. TE 16. Strnad V, Hildebrandt G, Pötter R, Hammer J, Hindemith M, Resch A, interpreted data and helped draft the manuscript. MM helped collect patient Spiegl K, Lotter M, Uter W, Bani M, et al: Accelerated partial breast data and helped draft the manuscript. IZ participated in its design and irradiation: 5-year results of the german-austrian multicenter phase ii coordination. All authors read and approved the final manuscript. trial using interstitial multicatheter brachytherapy alone after breast- Competing interests conserving surgery. Int J Radiat Oncol Biol Phys 2011, 80:17-24. The authors declare that they have no competing interests. 17. Shah C, Antonucci JV, Wilkinson JB, Wallace M, Ghilezan M, Chen P, Lewis K, Mitchell C, Vicini F: Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast Received: 13 December 2011 Accepted: 29 March 2012 irradiation: results of a matched-pair analysis. Radiother Oncol 2011, Published: 29 March 2012 110:210-214. 18. Polgár C, Major T, Fodor J, Sulyok Z, Somogyi A, Lövey K, Németh G, References Kásler M: Accelerated partial-breast irradiation using high-dose-rate 1. Fisher B, Jeong J-H, Anderson S, Bryant J, Fisher ER, Wolmark N: Twenty- interstitial brachytherapy: 12-year update of a prospective clinical study. five-year follow-up of a randomized trial comparing radical mastectomy, Radiother Oncol 2010, 94:274-279. total mastectomy, and total mastectomy followed by irradiation. New 19. Jeruss JS, Kuerer HM, Beitsch PD, Vicini FA, Keisch M: Update on DCIS Engl J Med 2002, 347:567-575. outcomes from the American Society of Breast Surgeons accelerated 2. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, partial breast irradiation registry trial. Ann Surg Oncol 2011, 18:65-71. Marubini E: Twenty-year follow-up of a randomized study comparing 20. Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, breast-conserving surgery with radical mastectomy for early breast Hildebrandt G, Niehoff P, Guinot JL, Guedea F, et al: Patient selection for cancer. New Engl J Med 2002, 347:1227-1232. accelerated partial-breast irradiation (APBI) after breast-conserving 3. Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J, Poller W, surgery: recommendations of the Groupe Europeen de Curietherapie- Fisher ER, Wickerham DL, Deutsch M, Margolese R, et al: Lumpectomy and European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) radiation therapy for the treatment of intraductal breast cancer: findings breast cancer working group based on clinical evidence (2009). Radiother from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 2010, 94:264-273. Oncol 1998, 16:441-452. 21. Shaitelman SF, Vicini FA, Beitsch P, Haffty B, Keisch M, Lyden M: Five-year 4. Julien JP, Bijker N, Fentiman IS, Peterse JL, Delledonne V, Rouanet P, Avril A, outcome of patients classified using the American Society for Radiation Sylvester R, Mignolet F, Bartelink H, Van Dongen JA: Radiotherapy in Oncology consensus statement guidelines for the application of breast-conserving treatment for ductal carcinoma in situ: first results of accelerated partial breast irradiation: an analysis of patients treated on the EORTC randomised phase III trial 10853. Lancet 2000, 355:528-533. the American Society of Breast Surgeons MammoSite Registry Trial. 5. Holmberg L, Garmo H, Granstrand B, Ringberg A, Arnesson L-G, Sandelin K, Cancer 2010, 116:4677-4685. Karlsson P, Anderson H, Emdin S: Absolute risk reductions for local 22. Beitsch P, Vicini F, Keisch M, Haffty B, Shaitelman S, Lyden M: Five-year recurrence after postoperative radiotherapy after sector resection for outcome of patients classified in the “unsuitable” category using the ductal carcinoma in situ of the breast. J Clin Oncol 2008, 26:1247-1252. American Society of Therapeutic Radiology and Oncology (ASTRO) 6. Polgár C, Fodor J, Major T, Németh G, Lövey K, Orosz Z, Sulyok Z, Takácsi- Consensus Panel guidelines for the application of accelerated partial Nagy Z, Kásler M: Breast-conserving treatment with partial or whole breast irradiation: an analysis of patients treated on the American breast irradiation for low-risk invasive breast carcinoma-5-year results of Society of Breast Surgeons MammoSite® Registry trial. Ann Surg Oncol a randomized trial. Int J Radiat Oncol Biol Phys 2007, 69:694-702. 2010, 17(Suppl 3):219-225. 7. Kuske RR, Winter K, Arthur DW, Bolton J, Rabinovitch R, White J, Hanson W, 23. Zauls AJ, Watkins JM, Wahlquist AE, Brackett NC, Aguero EG, Baker MK, Wilenzick RM: Phase II trial of brachytherapy alone after lumpectomy for Jenrette JM, Garrett-Mayer E, Harper JL: Outcomes in Women Treated with select breast cancer: toxicity analysis of RTOG 95-17. Int J Radiat Oncol MammoSite Brachytherapy or Whole Breast Irradiation Stratified by Biol Phys 2006, 65:45-51. ASTRO Accelerated Partial Breast Irradiation Consensus Statement 8. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, Groups. Int J Radiat Oncol Biol Phys 2010. Bellon JR, Wong JS, Smith BL, Harris JR: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 doi:10.1186/1748-717X-7-53 is associated with local and distant recurrence after breast-conserving Cite this article as: Ferraro et al.: Comparison of accelerated partial therapy. J Clin Oncol 2008, 26:2373-2378. breast irradiation via multicatheter interstitial brachytherapy versus 9. Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, whole breast radiation. Radiation Oncology 2012 7:53. Julian TB, Marks LB, Todor DA, Vicini FA, et al: Accelerated partial breast http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Comparison of accelerated partial breast irradiation via multicatheter interstitial brachytherapy versus whole breast radiation

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Copyright © 2012 by Ferraro et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-7-53
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22458887
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Abstract

Background: Brachytherapy as adjuvant treatment for early-stage breast cancer has become widely available and offers patients an expedited treatment schedule. Given this, many women are electing to undergo brachytherapy in lieu of standard fractionation radiotherapy. We compare outcomes between patients treated with accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy versus patients who were also eligible for and offered APBI but who chose whole breast radiation (WBI). Methods: Patients treated from December 2002 through May 2007 were reviewed. Selection criteria included patients with pTis-T2N0 disease, ≤ 3 cm unifocal tumors, and negative margins who underwent breast conservation surgery. Local control (LC), cause-specific (CSS) and overall survival (OS) were analyzed. Results: 202 patients were identified in the APBI cohort and 94 patients in the WBI cohort. Median follow-up for both groups exceeded 60 months. LC was 97.0% for the APBI cohort and 96.2% for the WBI cohort at 5 years (ns). Classification by 2010 ASTRO APBI consensus statement categories did not predict worse outcomes. Conclusion: APBI via multicatheter interstitial brachytherapy provides similar local failure rates compared to WBI at 5 years for properly selected patients. Excellent results were seen despite the high fraction of younger patients (< 60 years old) and patients with DCIS. Introduction partial breast irradiation (APBI) techniques have been Prospective randomized controlled trials have estab- developed. Early studies of APBI have described impress- lished breast conservation therapy (BCT), consisting of ively low ipsilateral breast tumor recurrence (IBTR) rates partial mastectomy and adjuvant radiation therapy, [6,7]. We have offered APBI or WBI therapy as treatment offers equivalent disease control in women with Stage I options for early-stage breast cancer in appropriately and II breast cancer as compared to mastectomy and selected patients since December 2002. The purpose of significantly superior disease control when compared to this report is to review the outcomes of our multicatheter partial mastectomy alone [1,2]. In the setting of ductal APBI in comparison to a cohort of patients eligible for carcinoma in situ, adjuvant radiation therapy has been and offered APBI but treated with WBI during the same shown to increase local control [3-5]. time interval. The standard method for administering breast irradia- tion as a part of BCT is whole breast irradiation (WBI) Methods delivered in five daily fractions per week for several weeks. Patient selection and data analysis th In an effort to expedite radiation therapy, accelerated Patients diagnosed with T -T N M (AJCC 6 Edition) is 2 0 0 unifocal breast cancers ≤ 3cminsizefromDecember 2002 through May 2007 who underwent breast conser- * Correspondence: izoberi@radonc.wustl.edu ving therapy with negative margins and received adjuvant Department of Radiation Oncology and Siteman Cancer Center, radiation therapy with either APBI using multicatheter Washington University School of Medicine, Saint Louis, MO 63110, USA Full list of author information is available at the end of the article © 2012 Ferraro et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ferraro et al. Radiation Oncology 2012, 7:53 Page 2 of 10 http://www.ro-journal.com/content/7/1/53 interstitial breast irradiation or WBI via external beam Medicine Human Research Protection Office approved irradiation were identified. Patients who received neoad- this study. juvant systemic therapy were not eligible for APBI and are not included in this review. All patients included in Surgery the study were eligible for and offered the option of APBI All patients underwent partial mastectomy as a part of or WBI at initial radiation oncology consultation. BCT. Negative surgical margins were defined as ≥ 2mm Patients who were not eligible for APBI and/or only of tumor free tissue on all margins or removal of the offered WBI were excluded from this study to limit bias. breast tissue to the pectoralis fascia with no evidence of Three patients with synchronous primaries in bilateral tumor invasion into the fascia. Re-excisions were often breasts were identified in the APBI cohort with each performed if the initial tumor-free margin was < 2 mm. breast cancer considered independently. A small number of patients who did not have either a APBI was generally not recommended to patients sentinel lymph node biopsy or an axillary dissection younger than 40 years. However three patients in the were included if they had no evidence for axillary invol- APBI cohort were in their thirties at diagnosis. Two of vement at the time of diagnosis or treatment, this these patients had prior radiation and APBI was offered to included three patients undergoing APBI for an IBTR minimize the volume of reirradiation. The third patient previously treated with WBI. Axillary assessment was declined WBI but was willing to do APBI. Given the pre- not required in patients with DCIS. sence of these three patients in the APBI cohort, we included patients seen in the study time period who were Systemic therapy in their thirties, who received WBI, and who would have Systemic therapy consisted of some combination of met the other eligibility criteria for APBI. endocrine, cytotoxic chemotherapy, biologic therapy, or Breast cancer subtype for invasive cancers was approxi- no systemic therapy. For patients that received APBI mated using estrogen receptor (ER), progesterone receptor and cytotoxic chemotherapy, APBI occurred prior to (PR), and Human Epidermal growth factor Receptor 2 cytotoxic chemotherapy in all but two cases. For (HER2/neu) status [8]. patients who received WBI and cytotoxic chemotherapy, Patients were classified according to the ASTRO con- WBI occurred after cytotoxic chemotherapy. sensus statement for APBI [9]. Presence or absence of lymphovascular space invasion (LVSI) was reported; how- Interstitial implant technique ever, extent was not specifically addressed. Similarly, Interstitial implants (ISI) were placed using a free hand extensive intraductal component (EIC) was reported as technique encompassing the surgical cavity with a 2 cm present without regards to size in the majority of reports. margin of breast tissue in all directions. All implants were Therefore the presence of LVSI or EIC was considered multiplanar with an intraplane catheter spacing of 12 mm cautionary. No patient was known to be BRCA1/2 and an interplane spacing of 1.5 to 2.0 cm. The use of positive. more than two planes was common. For the first 46 Time to event and length of follow-up was calculated patients, ISI were placed intraoperatively with an open using the date of final surgery as day 0. An IBTR was a surgical cavity. ISI insertion via real-time ultrasound gui- failure for local control (LC). LC was defined as one minus dance (U/S) with a closed surgical cavity was predomi- the local recurrence rate (LR). Further, IBTR were classi- nantly used after this point. fied as “true recurrence” when they occurred in the same The initial eight patients underwent two dimensional quadrant as the initial tumor, or “elsewhere” if they brachytherapy treatment planning using pairs of orthogo- occurred in a separate quadrant. Recurrences in the supra- nal plain films. All subsequent patients underwent three- clavicular, infraclavicular, internal mammary, intrapec- dimensional (3D) treatment planning. Within one day of toral, and axillary nodes were defined as a locoregional completion of ISI placement, patients underwent com- recurrence (LRR). puted tomography (CT) simulation for 3D treatment plan- Continuous variables were compared using two-tailed t- ning. CT compatible markers were placed in each tests and categorical variables were compared using Fish- catheter. CT images were obtained using 2 mm slice thick- er’s exact test with p values ≤ 0.05 considered significant. ness through the ISI volume plus several centimeters of Estimates of LR, LRR, disease-free survival (DFS), cause surrounding tissue. specific survival (CSS), and overall survival (OS) were per- TheCTdataset wastransferred to thebrachytherapy formed using the Kaplan-Meier method using SAS version planning system for selection of HDR dwell positions 9.2 (SAS Institute Inc., Cary, NC). Survival was compared and optimization of their relative weights. The Plato using log-rank tests. Predictive effects were analyzed using Brachytherapy software system (Nucletron B. V., Veenen- a Cox proportional hazards multivariate regression model daal, The Netherlands) was used through November 2006 with two-sided tests. Washington University School of after which treatment planning was done using the Ferraro et al. Radiation Oncology 2012, 7:53 Page 3 of 10 http://www.ro-journal.com/content/7/1/53 Brachyvision system (Varian, Palo Alto, CA). The surgical Table 1 Patient demographics and tumor characteristics cavity was identified on the CT dataset by contouring the All Disease seroma along with any surgical clips and density changes. APBI WBI P value The Planning Target Volume (PTV) was created by adding Patients 202 94 a uniform 2 cm margin to the surgical cavity contour and Months Follow-up 64.3 64.1 0.422 subsequently limited to 5 mm away from the skin surface. (Range) (2.2-96.6) (4.4-98.4) Pectoral muscle, chest wall, and axilla were excluded from Median Age 60.0 56.9 0.087 the PTV. (Range) (34.7-84.3) (33.0-83.2) Dwell positions within each catheter were separated by Race < 0.001* 5-7 mm. The dosimetric goal was to cover at least 95% of Caucasian 169 (83.7%) 52 (55.3%) the PTV with the prescription dose while maintaining a Black 31 (15.4%) 42 (44.7%) ratio of the prescription dose to the mean central dose of Other 2 (1.0%) 0 (0%) ≥ 0.70. Following the report by Arthur et al. that suggested Anatomy dose-volume predictors for fat necrosis [10], our dosi- Side 0.803 metric goals expanded to limit the volume receiving more Right 97 (48.0%) 47 (50.0%) than 150% (V ) of the prescription dose to ≤ 50 mL, Left 105 (52.0%) 47 (50.0%) V ≤ 20 mL, and 1-V /V ≥ 0.70. Planning was 200 150 100 Quadrant accomplished by geometric optimization of the prescrip- UOQ 88 (43.6%) 64 (68.1%) < 0.001* tion dose to the mean central dose and subsequent user UIQ 53 (26.2%) 17 (18.1%) graphical optimization. LIQ 29 (14.4%) 5 (5.3%) The prescription dose was 34 Gy in ten fractions admi- LOQ 32 (15.8%) 8 (8.5%) nistered twice daily with a six hour interfraction separation Grade 0.207 over five to seven days for all but two patients. One patient DCIS 40 (19.8%) 18 (19.1%) received 32 Gy in 8 fractions. The second patient was trea- I 78 (38.6%) 25 (26.6%) ted for a recurrent cancer in a previously irradiated field II 55 (27.2%) 27 (28.7%) and received a dose of 30 Gy in 10 fractions. Treatment III 29 (14.4%) 20 (21.3%) began one to two working days after the simulation. Unknown 0 (0%) 4 (4.3%) Catheters were removed after the last fraction. Stage Quality assurance was accomplished by performing an Tis 40 (19.8%) 18 (19.1%) autoradiograph of the treatment plan and a manual expo- T1 3 (1.5%) 4 (4.3%) mic sure calculation that was compared to the predicted value T1 23 (11.4%) 7 (7.4%) based on the Paterson-Parker tables using the volume T1 67 (33.2%) 29 (30.9%) receiving 340 cGy [11]. T1 54 (26.7%) 31 (33.0%) T1 147 (72.8%) 71 (75.5%) Whole breast irradiation T2 15 (7.4%) 5 (5.3%) Patients in the WBI cohort were treated to the whole Histology 0.092 breast using tangential beams. Patients received a dose of DCIS 40 (19.8%) 18 (19.1%) 42.56-50.4 Gy in 1.8-2.66 Gy fractions. Most patients Invasive Ductal 141 (69.8%) 60 (63.8%) received a boost. 50 Gy in 200 cGy fractions to the whole Invasive Lobular 8 (4.0%) 11 (11.7%) breast followed by a 10 Gy boost to the tumor bed was the Invasive Tubular 7 (3.5%) 1 (1.1%) most frequent WBI dose prescription. Invasive Mucinous 5 (2.5%) 2 (2.1%) Invasive Papillary 1 (0.5%) 2 (2.1%) Results Estrogen Receptor 0.464 Patient characteristics are shown in Table 1. 202 ER + 167 (82.7%) 71 (71.6%) patients were identified in the APBI cohort and 94 in ER - 26 (12.9%) 15 (16.0%) the WBI cohort. Median follow-up exceeded 60 months ER Unknown 9 (4.5%) 8 (8.5%) for both groups. One hundred one APBI patients were Progesterone Receptor 0.489 ≤ 60 years (50.0%), and 37 patients were ≤ 50 years old PR + 134 (66.3%) 56 (59.6%) (18.3%). Fifty-three WBI patients were ≤ 60 years old PR - 59 (29.2%) 30 (31.9%) (56.4%) and 23 patients were ≤ 50 years old (24.5%). PR Unknown 9 (4.5%) 8 (8.5%) Characteristics are given for DCIS and invasive disease Her-2/Neu 0.350 (Invasive Only) patients in Table 2. Overexpressed 14 (6.9%) 9 (4.5%) Seven patients treated with APBI were treated in a Not Overexpressed 147 (72.8%) 62 (66.0%) previously irradiated field. Three of these patients had Ferraro et al. Radiation Oncology 2012, 7:53 Page 4 of 10 http://www.ro-journal.com/content/7/1/53 Table 1 Patient demographics and tumor characteristics covered by the prescription dose. Dose homogeneity as (Continued) assessed by 1-V /V had a median value of 0.80. 150 100 Dosimetric parameter averages for the APBI patients are Unknown 41 (20.3%) 23 (24.5%) given in Table 3. Disease Type Luminal A 128 (63.4%) 51 (54.3%) 0.353 Recurrence rates and survival analysis Luminal B 9 (4.5%) 7 (7.5%) The LR, LRR, and DFS were similar between the groups Her-2/Neu 5 (2.5%) 2 (2.1%) (Table 4). Survival curves demonstrating LC for all dis- Basal 16 (7.9%) 11 (3.7%) ease, DCIS only and invasive disease only stratified by DCIS 40 (19.8%) 18 (6.1%) radiationmethodare giveninFigure 1.There wasno Unable to classify 4 (2.0%) 5 (5.3%) statistical difference in OS or CSS between the groups. LVSI (Invasive Only) 0.591 While OS was not significantly lower, it was trending Present 10 (4.9%) 6 (8.1%) lower in the APBI group compared to the WBI cohort. Absent 152 (74.5%) 70 (91.9%) A number of patients who received APBI had significant LCIS 0.011* medical co-morbidities and chose APBI over WBI. Present 15 (7.4%) 17 (18.1%) These patients were opposed to omitting radiation ther- Absent 187 (92.6%) 77 (81.9%) apy and chose APBI for the convenience of a shorter EIC (Invasive Only) 0.688 time commitment. Seven of these patients died from Present 4 (2.5%) 3 (3.9%) their pre-existing comorbidities (Table 5). Absent 148 (91.4%) 73 (96.1%) Characteristics of patients who experienced disease Unknown 10 (6.2%) 0 (0%) recurrence are described in Table 6. In all cases with an Endocrine Therapy 0.182 (Invasive Only) initial diagnosis of regional or metastatic failure, no evi- Given 127 (78.4%) 50 (65.8%) dence of local failure was present. The patient treated via Not Given 34 (21.0%) 21 (27.6%) APBI who developed a regional failure at 55.0 months was Unknown 1 (0.6%) 5 (6.6%) found to have a nodal recurrence in a portion of the axilla Endocrine Therapy 0.756 that would likely have been covered using tangential beam (DCIS Only) if given WBI. The other patient treated with APBI who Given 29 (72.5%) 14 (77.8%) developed a regional recurrence was diagnosed at 17.1 Not Given 11 (27.5%) 4 (22.2%) months with an axillary nodal recurrence that would have Unknown 0 (0%) 0 (0%) been superior to the upper tangent border if treated by Cytotoxic Chemotherapy 0.102 WBI. Both regional failures were in the APBI group and (Invasive Only) were axillary failures. Both patients had negative sentinel Given 35 (21.6%) 23 (30.3%) lymph node biopsies at initial diagnosis. It was estimated Not Given 127 (78.4%) 49 (64.5%) that one of the site of one of the axillary failures would Unknown 0 (0%) 4 (5.3%) have been treated with standard tangential fields if WBI * Statistically significant had been given and the other would not have been included. All patients who developed regional or distant disease remained free of IBTR at death or last follow up. previously received WBI as a part of BCT for a prior diagnosis of breast cancer and received repeat BCT for Classification by ASTRO consensus guidelines an IBTR diagnosed at least 10 years after the initial Using the criteria to outlined in the 2009 ASTRO con- diagnosis. Four patients received radiation therapy for sensus statement on APBI (Table 7), patients in both tumors treated earlier in life (two had Hodgkin’slym- phoma and two had an upper extremity sarcoma). the WBI and APBI cohorts were categorized into one of Six patients treated via APBI did not have surgical three categories: acceptable, cautionary or unsuitable assessment of the axilla. Of these patients, 4 had pre- (Table 8). viously undergone axillary dissections so reassessment Overall, the APBI and WBI groups were significantly was not technically feasible. For the remaining two different with respect to ASTRO consensus category patients, one had a < 1 mm focus of invasive disease in classification (p = 0.017). None of the ASTRO consen- the setting of LCIS and the other had a 6 mm focus of sus categories predicted LR, LRR or DFS either when invasive tubular disease. analyzed by treatment group or when analyzed in the entire study population. In a multivariate model for LRR APBI dosimetry in which radiation method was force entered, age, stage, 192 patients had ≥ 90% of the PTV covered by the pre- radiation method, biomarker pattern, and ASTRO con- scription dose and 133 patients had ≥ 95% of the PTV sensus category were all non-significant predictors. Ferraro et al. Radiation Oncology 2012, 7:53 Page 5 of 10 http://www.ro-journal.com/content/7/1/53 Table 2 Patient demographics and tumor characteristics for DCIS and invasive disease DCIS Invasive APBI WBI P value APBI WBI P value Patients 40 18 162 76 Months Follow-up 69.4 72.7 0.502 62.9 62.1 0.543 (Range) (13.7-92.6) (24.6-87.6) (2.2-96.6) (4.4-98.4) Median Age 59.2 56.5 0.752 61.4 58.1 0.079 (Range) (40.3-82.4) (41.4-84.2) (34.7-84.3) (33.0-84.7) Race 0.018 < 0.001 Caucasian 31 (77.5%) 10 (55.6%) 138 (85.2%) 44 (57.9%) Black 9 (22.5%) 8 (44.4%) 22 (13.6%) 32 (42.1%) Other 0 (0%) 0 (0%) 2 (1.2%) 0 (0.0%) Anatomy Side 0.776 1.000 Right 17 (42.5%) 9 (50.0%) 80 (49.4%) 38 (50.0%) Left 23 (57.5%) 9 (50.0%) 82 (50.6%) 38 (50.0%) Quadrant 0.049 < 0.001 UOQ 18 (45.0%) 14 (77.8%) 70 (43.2%) 50 (65.8%) UIQ 7 (17.5%) 3 (16.7%) 46 (28.4%) 14 (18.4%) LIQ 6 (15.0%) 1 (5.6%) 23 (14.2%) 4 (5.3%) LOQ 9 (22.5%) 0 (0%) 23 (14.2%) 8 (10.5%) Estrogen Receptor 0.548 0.256 ER + 28 (70.0%) 12 (66.7%) 139 (85.8%) 59 (77.6%) ER - 3 (7.5%) 0 (0%) 23 (14.2%) 15 (19.7%) ER Unknown 9 (22.5%) 6 (33.3%) 0 (0%) 2 (2.6%) Progesterone Receptor 0.727 0.369 PR + 21 (52.5%) 9 (50.0%) 113 (69.8%) 49 (64.5%) PR - 10 (25.0%) 3 (16.7%) 49 (30.2%) 27 (35.5%) PR Unknown 9 (22.5%) 6 (33.3%) 0 (0%) 2 (2.6%) LCIS 0.084 Present 1 (2.5%) 3 (16.7%) 14 (8.6%) 14 (18.4%) 0.050 Absent 39 (97.5%) 15 (83.3%) 148 (91.4%) 62 (81.6%) Discussion Table 4 5-year survival rates and number of failures Multicatheter APBI represents the first form of partial APBI WBI P value breast irradiation offered at Washington University as Overall an alternative to WBI for a select group of early-stage Local Recurrence Rate 3.04% (5) 3.82% (3) 0.721 breast cancer patients. Our experience suggests that Locoregional Recurrence Rate 4.25% (7) 3.82% (3) 0.902 Disease-Free Survival 94.3% (9) 93.4% (8) 0.870 Table 3 Dosimetric parameters for multicatheter APBI Cause Specific Survival 99.4% (1) 98.9% (1) 0.954 treatments Overall Survival 91.9% (15) 96.7% (3) 0.113 Median Minimum Maximum DCIS V 222 97.3 775 Local Recurrence Rate 2.56% (1) 6.25% (1) 0.573 V 43.6 19.1 190 Disease-Free Survival 97.4% (1) 93.8% (1) 0.573 V 15.6 7.01 58.2 Cause Specific Survival 100% (0) 100% (0) - (1-V /V ) 0.8 0.45 0.88 Overall Survival 97.5% (1) 100% (1) 0.843 150 100 DHI 0.83 0.56 1.00 Invasive Disease PTV Volume 154.5 57.6 552 Local Recurrence Rate 3.24% (4) 3.10% (2) 0.939 PTV Coverage 148.5 56.2 520 Locoregional Recurrence Rate 4.80% (6) 3.10% (2) 0.669 % PTV Coverage 95.7% 78.5% 100% Disease-Free Survival 93.8% (8) 94.1% (4) 0.920 Cavity Volume 18.4 cc 1.4 cc 114 cc Cause Specific Survival 99.3% (1) 98.6% (1) 0.968 Number of Catheters 20 10 37 Overall Survival 90.4% (14) 95.6% (3) 0.093 Ferraro et al. Radiation Oncology 2012, 7:53 Page 6 of 10 http://www.ro-journal.com/content/7/1/53 this method offers similar LRR, DFS, CSS, and OS A. All Patients compared to WBI. Our series includes a significant 1.00 number of young patients and patients treated for pure DCIS. Both of these subgroups had no significant dif- 0.80 ference in LRR, DFS, CSS or OS with APBI as com- pared to WBI. 0.60 The most significant limitation of this series is length of follow-up given the long natural history of breast cancer. 0.40 While the low number of events is encouraging, it does limit the statistical analysis of predictors of these events. APBI 0.20 WBI As this patient population matures, occurrences will p = 0.721 inevitably increase, making more complex analyses possi- 0 20 40 60 80 100 ble. Selection bias may also limit the applicability of this Months to Local Recurrence analysis as it is a retrospective study; however, we do APBI 189 180 116 33 WBI 90 83 57 24 0 report a concurrent cohort of patients who were eligible Number at Risk for and offered APBI but who selected WBI whose out- comes were similar. It was practice in our clinic to offer B. DCIS 1.00 each patient both options when it was felt that either option was technically feasible and appropriate for the 0.80 specific patient’s disease. 0.60 Previous APBI experiences Multicatheter APBI has been practiced for over 20 years. 0.40 The Oschner clinic reported one of the first series of patients treated in this fashion. A phase I/II trial of HDR APBI 0.20 or Low Dose Rate (LDR) brachytherapy was initiated in WBI p = 0.573 the early 1990s to evaluate tumor control in wide-field partial breast irradiation. Patients with Tis-T2 disease 020 40 60 80 less than 4 cm in diameter with 0-3 positive axillary Months to Local Recurrence 27 7 APBI 39 38 nodes were treated. One in breast recurrence and three WBI 18 16 14 2 Number at Risk nodal recurrences were reported at 75 months, all three nodal recurrences in patients with extracapsular nodal C. Invasive Disease disease at the time of treatment [12]. Similar early studies 1.00 were also performedatother institutionsandbythe Radiation Therapy Oncology Group 9517 cooperative 0.80 study [6,7,13,14]. An exhaustive list of APBI studies using a variety of techniques is reported in Smith et al [9]. 0.60 Recent reports are congruent with our findings. McHaffee et al. report the Wisconsin experience with 0.40 HDR interstitial brachytherapy using multicatheter or APBI MammoSite balloon techniques. The majority of the 322 0.20 WBI patients reported in the series underwent multicatheter p = 0.939 APBI and were planned using modern 3D-CT methods. 020 40 60 80 Patients received 32 Gy in 8 BID fractions or 34 Gy in 10 Months to Local Recurrence BID fractions. The 5-year LR was 4.8% and the 5-year APBI 89 26 0 150 142 WBI 72 68 43 19 0 DFS was 89.6% [15]. Strnad et al. reports the results from Number at Risk the German-Austrian Phase II trial investigating multi- Figure 1 Survival and time-to-recurrence for patients treated catheter brachytherapy in 274 patients. Inclusion criteria with WBI or APBI. A. Survival curve demonstrating time to local for this study were stricter than our study, requiring recurrence for all patients stratified by type of radiation received. B. Time to local recurrence for patients treated for DCIS stratified by absence of LVSI and a maximum histologic grade of II/ type of radiation received. C. Time to local recurrence for patients III. The 5-year and 8-year actuarial survival was reported treated for invasive disease stratified by type of radiation received. as 97.7% and 95%, respectively for the entire cohort. DFS Survival Probability Survival Probability Survival Probability Ferraro et al. Radiation Oncology 2012, 7:53 Page 7 of 10 http://www.ro-journal.com/content/7/1/53 Table 5 Characteristics of patients who expired and causes of death Age at APBI T Histology Grade Biomarker Adjuvant Radiation Time to Death Cause of Death Diagnosis Class stage Pattern Treatment Modality (months) 77.5 cautionary 2 ductal II +/+/- R + E APBI 43.76 CAD*, Anoxic Brain Injury after V Fib episode 35.6 unsuitable 2 ductal III -/-/+ R APBI 60.35 Recreational Drug Overdose 45.4 unsuitable 2 ductal II +/+/- R + C + E APBI 74.68 Breast Cancer 81.8 acceptable 1a ductal II +/+/- R APBI 2.83 Stroke/Fall 57.4 cautionary 1a ductal I +/+/- R APBI 8.25 Cirrhosis* with Hepatocellular Cancer 51.6 cautionary 1a ductal III +/-/- R + E APBI 35.91 Colon Cancer* 66.5 cautionary 1a ductal III -/-/- R APBI 41.95 Myelodysplastic Syndrome 34.7 unsuitable 1b tubular I +/+/- R APBI 2.96 Urosepsis 79.1 acceptable 1b ductal II +/+/- R + E APBI 16.33 CAD*, MI 80.2 acceptable 1b ductal I +/+/- R APBI 32.20 COPD* 72.3 acceptable 1b ductal I +/+/- R + E APBI 33.71 High Grade Sarcoma* 70.7 cautionary 1b ductal III -/-/- R APBI 46.29 Breast Cancer 50.2 cautionary 1c ductal III -/-/- R + C APBI 5.95 Chemotherapy Toxicity 58.6 cautionary 1c ductal III -/-/- R APBI 13.50 Ovarian Cancer* 66.1 acceptable 1c ductal II +/+/- R + E APBI 56.48 Melanoma 68.8 acceptable 1c ductal II +/+/- R + E APBI 58.48 CHF/COPD* 66.8 acceptable 1c ductal I +/+/- R + E APBI 80.89 Stroke 49.1 unsuitable Is DCIS II +/+/- R APBI 13.70 Polycystic Kidney Disease* 67.1 cautionary Is DCIS III -/-/+ R APBI 74.35 Pneumonia (Restrictive Lung Disease*) 70.93 acceptable 1b ductal I +/+/- R + E WBI 14.78 M. avium infection (Chronic bronchiectasis*) 68.55 cautionary 1b ductal III +/+/- R WBI 22.01 Breast cancer 68.76 acceptable 1c mucinous II +/+/- R + E WBI 23.10 Parkinson’s Disease 48.83 unsuitable is DCIS II +/-/- R + E WBI 67.02 CAD*, MI *condition present prior to diagnosis of breast cancer; abbreviations as Table 3. CAD: coronary artery disease, COPD: chronic obstructive pulmonary disease, MI: myocardial infarction was 96.1% and 88% at 5 and 8 years [16]. Shah et al. DCIS patients are included. Jeruss et al. examined out- reports a retrospective series of 199 patients treated via comes of patients enrolled on the American Society of LDR or HDR interstitial brachytherapy matched to a Breast Surgeons APBI MammoSite registry trial treated cohort of patients treated with WBI. The LDR technique for pure DCIS. Eligibility criteria included size < 4.5 cm as defined mammographically, clinically negative nodes, delivered 50 Gy over 96 hours at 0.52 Gy/h. The HDR and negative margins. One hundred ninety-four patients technique delivered 32 Gy in 8 fractions BID or 34 Gy in 10 fractions BID. The LR rate was 5.0% for the APBI were identified with 36% of the patients having high- cohort and 3.8% for the matched WBI patient cohort at grade disease and 53% of the patients receiving endo- 12 years (ns). DFS was 91% for the APBI cohort and 87% crine therapy. Dose prescription was 34 Gy in 10 BID for the WBI cohort (ns) [17]. Polgár et al. reports the fractions. The 5-year LR was 3.39% and DFS was 93.2% Hungarian experience with APBI, the longest follow-up [19]. In addition, McHaffee et al reports 32 patients intheliteraturefor theHDR multicathetertechnique. treated as described above for DCIS with no recurrences Inclusion criteria included size < 2 cm, negative margins, at 5 years [15]. maximum histologic grade of II/III, pN0-N1mic. Carci- noma in situ or lobular carcinoma were excluded. The 5- APBI consensus statement and 12-year LR was 4.4% and 9.3%, respectively. DFS was In 2009, ASTRO APBI consensus statement task force 75.3% at 12 years [18]. released guidelines for appropriate patient selection for LR rate in 40 patients treated via APBI with pure APBI [9]. After review of the literature, three general DCIS (45% high grade) in our series was less than 3% at categories were developed from a number of patient and five years. While treatment of pure DCIS via APBI his- tumor characteristics with special focus selecting patients torically has been controversial, recent reports have for APBI outside of clinical trial. The GEC-ESTRO group demonstrated good local control, even when high-grade released a similar statement in 2010 [20]. Ferraro et al. Radiation Oncology 2012, 7:53 Page 8 of 10 http://www.ro-journal.com/content/7/1/53 Table 6 Characteristics of patients with failure Age at Menopause ASTRO Size Histology Grade Biomarker Node Adjuvant Radiation Initial Failure Salvage Current Diagnosis Status Category Pattern Biopsy Treatment Modality Failure (months) Treatment Status 61.7 Post cautionary 1.00 DCIS II +/-/? No R + E APBI Local - E 20.3 MRM + C + E NED 62.1 Post acceptable 0.30 IDC I +/+/- Yes R + E APBI Local - T 45.3 MRM + C NED 66.8 Post acceptable 1.00 IDC II +/+/- Yes R + E APBI Local - E 59.6 SM NED 69.3 Post acceptable 2.00 IDC II +/-/- Yes R + E APBI Local - E 38.2 PM + C + WBI NED +E 59.5 Post cautionary 2.00 IDC II +/-/- Yes R + E + C APBI Local - E 47.1 MRM + C + E NED 68.2 Post cautionary 0.90 IDC III -/-/- Yes R WBI Local - E 49.5 MRM NED 57.0 Post cautionary 1.50 IDC III -/-/- Yes R + C WBI Local - T 5.2 SM NED 56.5 Post cautionary 0.90 DCIS III +/+/? No R WBI Local - T 49.3 SM NED 62.3 Post acceptable 0.60 IDC II +/+/- Yes R + E WBI Local - E 97.5 MRM + E NED 45.4 Pre unsuitable 3.00 IDC II +/+/- Yes R + E + C APBI Regional 55.0 SR + C Expired 53.6 Post cautionary 3.00 IDC II +/+/- Yes R + E APBI Regional 17.1 SR + C + R NED 70.7 Post cautionary 0.80 IDC III -/-/- Yes R APBI Metastatic 32.4 C + H Expired 68.6 Post cautionary 1.00 IDC III +/+/- Yes R WBI Metastatic 13.2 - Expired 71.1 Post cautionary 2.10 IDC III -/-/+ Yes R + C APBI Metastatic 45.4 C + R Under Treatment 56.5 Post cautionary 2.90 IDC III +/+/+ Yes R + C + E APBI Metastatic 60.8 R Under Treatment 58.1 Post cautionary 1.50 IDC II +/-/- Yes R WBI Metastatic 46.1 C Under Treatment Abbreviations: SM simple mastectomy, MRM modified radical mastectomy, PM partial mastectomy, R radiotherapy, C chemotherapy, E endocrine therapy, H Herceptin, Local-T - true recurrence, Local-E - elsewhere recurrence. Biomarker pattern shows the status for estrogen receptor, progesterone receptor, and HER2/neu using the following symbolic code: (ER)/(PR)/(HER2/neu). Presence of the biomarker is indicated by ‘+,’ absence by ‘-,’ unknown by ‘?.’ Ferraro et al. Radiation Oncology 2012, 7:53 Page 9 of 10 http://www.ro-journal.com/content/7/1/53 Table 7 ASTRO APBI consensus statement categories and classification criteria Criteria Suitable Cautionary Unsuitable Age ≥ 60 50-59 < 50 Tumor Size ≤ 2 cm 2-3 cm > 3 cm T Stage T1 Tis and T2 T3-T4 Nodal biopsy Yes - No Margins Negative (≥ 2 mm) Close (< 2 mm) Positive Histology Invasive ductal or other favorable subtypes Invasive Lobular - Pure DCIS No ≤ 3cm >3cm ER Receptor Positive Negative - LVSI* No Limited/Focal Extensive EIC* No ≤ 3cm >3cm * Presence of LVSI and EIC were considered cautionary in this study. Multicentricity, multifocality, neoadjuvant chemo/endocrine therapy, and known BRCA1/2 mutations were not present in any patients in this study. Pathologic nodal stage was pN0 for all patients who underwent axillary assessment Recently, Shaitelman and colleagues reviewed patients time to local failure at 4-years between the treatment who received APBI via the MammoSite brachytherapy types for any of the three ASTRO classifications [23]. technique as a part of BCT [21]. 1025 of the 1449 McHaffee et al. analyzed a cohort of 322 patients who patients on the MammoSite Registry could be classified received APBI via multicatheter brachytherapy or Mam- using the ASTRO consensus criteria. Of these patients, moSite balloon brachytherapy and retrospectively classi- 419 were classified as suitable, 430 as cautionary, and fied patients using the ASTRO guidelines. ASTRO 176 as unsuitable. This classification scheme did not classification criteria including margin status, EIC, histol- predict different outcomes with regards to local or ogy and size, but not age did predict decreased IBTR and regional disease recurrence, DFS, CSS, or OS. The only LRR. Overall, the reported 5-year IBTR rate for patients statistically significant difference between the categories classified as suitable was 1.6% compared to 6.6% for was with regards to rate of distant metastases. This sug- patients in the unsuitable cohort [15]. gests that the classification may predict disease that While APBI has been successfully adopted as treatment tends to be more aggressive, regardless of local control modality by many institutions, there is limited phase III modality employed. data available guide patient selection. Two large, multi- Beitsch and colleagues reviewed outcomes for patients institutional phase III trials, NSABP B-39/RTOG 0413 treated on the MammoSite registry trial that were retro- and the GEC-ESTRO APBI trial are underway will likely spectively classified as unsuitable by the ASTRO guidelines be the sources for the identification criteria that will dis- [22]. This analysis identified 176 patients as unsuitable and criminate between patients that will or will not be found that there was no difference in local, regional, or adversely affected with regards to disease control based distant failure between the unsuitable and other classifica- on treatment technique, if any exist. These studies include patients with high-risk disease characteristics and tions. In addition, only ER status was correlated with IBTR also allow for variation in APBI technique. While these on univariate analysis when looking at all patients in the registry, suggesting that the ASTRO criteria lack power to studies will help clarify outcomes and identify sub-popu- identify a cohort of patients that are more likely to recur lations of higher-risk patients not appropriate for APBI, locally fail after APBI compared to WBI. Zauls et al. com- these data will likely not be available for multiple years. pared patients treated with WBI and APBI via Mammo- In the interim this report offers additional evidence Site balloon therapy and did not find a difference in the regarding the safety and efficacy of APBI. Table 8 Distribution of patient factors across ASTRO consensus statement parameters Overall (%) Age at Diagnosis Tumor Size T Stage ER Status Histology DCIS EIC LVSI Nodal Assessment APBI Acceptable 58 (28.7) 101 147 147 167 194 162 158 152 156 Cautionary 104 (51.5) 64 15 55 35 8 40 4 10 0 Unsuitable 40 (19.8) 37 0 0 0 0 0 - - 6 WBI Acceptable 16 (17.0) 41 71 71 71 83 76 73 70 67 Cautionary 47 (50.0) 30 5 23 23 11 18 3 6 0 Unsuitable 31 (33.0) 23 0 0 0 0 0 - - 9 Ferraro et al. Radiation Oncology 2012, 7:53 Page 10 of 10 http://www.ro-journal.com/content/7/1/53 irradiation consensus statement from the American Society for Radiation Acknowledgements Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009, 74:987-1001. We thank the SCC-WUSM and Barnes-Jewish Hospital in St. Louis, Mo., for 10. Arthur DW, Wazer DE, Koo D, Shah N, Berle L, Cuttino L, Yunes M, Rivard M, the use of the Clinical Trials Core, which provided regulatory service. The Todor D, Tong S, et al: The importance of dose volume histogram Siteman Cancer Center is supported in part by NCI Cancer Center Support evaluation in partial breast brachytherapy: a study of dosimetric Grant #P30 CA91842. A portion of the data contained in this manuscript was nd parameters. Int J Radiat Oncol Biol Phys 2003, 57:S361-S362. presented at the ASTRO 52 annual meeting. 11. Williamson JF, Brenner DJ: Physics and Biology of Brachytherapy. In Principles and Practice of Radiation Oncology.. 5 edition. Edited by: Halperin Author details E, Perez CA, Brady LW. Lippincott Williams 2008:. Department of Radiation Oncology and Siteman Cancer Center, 12. King TA, Bolton JS, Kuske RR, Fuhrman GM, Scroggins TG, Jiang XZ: Long- Washington University School of Medicine, Saint Louis, MO 63110, USA. term results of wide-field brachytherapy as the sole method of radiation Department of Surgery and Siteman Cancer Center, Washington University therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J School of Medicine, Saint Louis, MO 63110, USA. Department of Medicine Surg 2000, 180:299-304. and Siteman Cancer Center, Washington University School of, Saint Louis, 13. Wazer DE, Berle L, Graham R, Chung M, Rothschild J, Graves T, Cady B, MO 63110, USA. Department of Surgery, John Cochran Veterans Hospital, Ulin K, Ruthazer R, DiPetrillo TA: Preliminary results of a phase I/II study of Saint Louis, MO 63106, USA. Department of Radiation Oncology, 4921 HDR brachytherapy alone for T1/T2 breast cancer. Int J Radiat Oncol Biol Parkview Place - LL/Campus Box 8224, Saint Louis, MO 63110, USA. Phys 2002, 53:889-897. 14. Vicini FA, Baglan KL, Kestin LL, Mitchell C, Chen PY, Frazier RC, Authors’ contributions Edmundson G, Goldstein NS, Benitez P, Huang RR, Martinez A: Accelerated DF participated in the study design, collected and analyzed patient data, treatment of breast cancer. J Clin Oncol 2001, 19:1993-2001. and drafted the manuscript. AG participated in the study design and helped 15. McHaffie DR, Patel RR, Adkison JB, Das RK, Geye HM, Cannon GM: draft the manuscript. TD performed the statistical analyses for the study. JM Outcomes after accelerated partial breast irradiation in patients with interpreted data and helped draft the manuscript. MN interpreted data and ASTRO consensus statement cautionary features. Int J Radiat Oncol Biol helped draft the manuscript. RA interpreted data and helped draft the Phys 2011, 81:46-51. manuscript. WE interpreted data and helped draft the manuscript. TE 16. Strnad V, Hildebrandt G, Pötter R, Hammer J, Hindemith M, Resch A, interpreted data and helped draft the manuscript. MM helped collect patient Spiegl K, Lotter M, Uter W, Bani M, et al: Accelerated partial breast data and helped draft the manuscript. IZ participated in its design and irradiation: 5-year results of the german-austrian multicenter phase ii coordination. All authors read and approved the final manuscript. trial using interstitial multicatheter brachytherapy alone after breast- Competing interests conserving surgery. Int J Radiat Oncol Biol Phys 2011, 80:17-24. The authors declare that they have no competing interests. 17. Shah C, Antonucci JV, Wilkinson JB, Wallace M, Ghilezan M, Chen P, Lewis K, Mitchell C, Vicini F: Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast Received: 13 December 2011 Accepted: 29 March 2012 irradiation: results of a matched-pair analysis. 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Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, whole breast radiation. Radiation Oncology 2012 7:53. Julian TB, Marks LB, Todor DA, Vicini FA, et al: Accelerated partial breast

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Radiation OncologySpringer Journals

Published: Mar 29, 2012

References