Cardiac pacing devices (PD) become more prevalent each year but present major impediments to the breast preservation therapy preferred by the vast majority of women with early stage breast cancer. PDs and their complementary metal-oxide semi-conductor (CMOS) technologies may be damaged by radiation, so traditional guidelines have recommended surgical PD relocation prior to breast preservation therapy or mastectomy. The aim of this study was to evaluate whether accelerated partial breast irradiation (APBI) and sub-total whole breast radiation could be administered without inducing PD failure. Twenty consecutive patients with early stage breast cancer and PD were evaluated under the auspices of an institutional review board-approved protocol. All patients had been considered for mastectomy due to concerns of treatment-related device failure. Patients were offered breast conservation radiation therapy following lumpectomy using whole breast radiation therapy (WBRT), modified WBRT (mWBRT), intracavitary high dose rate brachytherapy (HBR), or 3-dimensional conformal accelerated external beam radiation therapy (3D-CRT). Nine patients were treated with WBRT or mWBRT (4 right and 5 left), six with 3D-CRT, and five with HDR. All patients with left-sided lesions were treated with mWBRT which exempted the breast in the peri-device region from excessive radiation. Pre-treatment predictive planning was used to estimate dose to the device, and intrafractional electronic dosimetric measurements were taken of exposure of the device at the suspected maximal dose points. A pacemaker protocol was used to monitor function of the device prior to irradiation, during treatment, and post-therapy. No PD received a cumulative dose in excess of 200 cGy. One patient treated with a linear accelerator had an asymptomatic acute recalibration of her pacemaker likely from CMOS interference by electromagnetic waves. The device representative on site immediately reset her device to specification and she has developed no issues to date. There have been no other device failures, or local recurrences to date at a mean follow up of 3 years. APBI and total/sub-total breast irradiation are safe and offer an alternative to device-mandated mastectomy or pacemaker relocation.

Purpose/Objective(s)Xerostomia can be a devastating side effect of ionizing radiation. Gene therapy using Adenoviral gene transfer of Aquaporin-1 (AQP1) to the salivary gland has been successful; however, elicits strong and progressive host immune response in humans, and the therapeutic response is transient. We evaluated and compared the potential of ultrasound-assisted non-viral gene transfer (UAGT) as a means of delivering AQP1 gene therapy in the mini-swine model.Materials/MethodsA treatment plan with immobilization was devised using a single mini-pig of similar size and weight to others in the study. Irradiation (IR) of the right parotid gland was performed with an electron beam, delivering 10 Gy in a single fraction. Nanometer-scale localized detectors were placed on the skin overlying the treated and control parotid glands during the application of the electron beam, which confirmed no significant dose to the contralateral gland. Isolated parotid saliva was collected in all animals and volume determined by weight, assuming a specific gravity of 1.0. Saliva was collected at pre-IR baseline, and 4, 6, 8, 10, and 12 weeks post-IR; thereafter, gene therapy was delivered at 12 weeks or 14 weeks post-IR. Gene transfer to the salivary gland was performed by a catheter inserted into the opening of Stensen's duct, and gene transfer vector was infused. For Adenoviral gene delivery (n = 4), 1x1010viral particles of AdhAQP1 were diluted in the infusate. For UAGT, a plasmid vector expressing porcine AQP1 was mixed with activated microbubbles and infused. Immediately, a 1MHz acoustic field was applied to the parotid gland in four 30 second treatments (n = 4). Following sacrifice of the animals, blinded slides of the parotids were reviewed by an oral pathologist.ResultsAll animals developed profound, bilateral hyposalivation that began 4 weeks post-IR and stabilized at approximately 38% of pre-IR baseline. The hyposalivation on the uninjured side was notable, as we ruled out radiation dose to the contralateral gland; AQP1 gene therapy with UAGT restored salivary flow to baseline levels in a manner comparable to Adenoviral gene therapy. These novel results suggest a functional neurological coupling of left and right parotid glands. At sacrifice, periductal inflammation was found to be restricted to glands treated with the Adenoviral vector only.ConclusionThese results demonstrate, for the first time, ultrasound-assisted, non-viral gene transfer to the parotid glands of swine; UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy, increasing both safety and the possibility of retreatment for salivary enhancement. Ultrasound-assisted, non-viral gene transfer was successful in the irradiated swine and is a candidate for advancement to a Phase 1 human clinical trial. Purpose/Objective(s)Xerostomia can be a devastating side effect of ionizing radiation. Gene therapy using Adenoviral gene transfer of Aquaporin-1 (AQP1) to the salivary gland has been successful; however, elicits strong and progressive host immune response in humans, and the therapeutic response is transient. We evaluated and compared the potential of ultrasound-assisted non-viral gene transfer (UAGT) as a means of delivering AQP1 gene therapy in the mini-swine model. Xerostomia can be a devastating side effect of ionizing radiation. Gene therapy using Adenoviral gene transfer of Aquaporin-1 (AQP1) to the salivary gland has been successful; however, elicits strong and progressive host immune response in humans, and the therapeutic response is transient. We evaluated and compared the potential of ultrasound-assisted non-viral gene transfer (UAGT) as a means of delivering AQP1 gene therapy in the mini-swine model. Materials/MethodsA treatment plan with immobilization was devised using a single mini-pig of similar size and weight to others in the study. Irradiation (IR) of the right parotid gland was performed with an electron beam, delivering 10 Gy in a single fraction. Nanometer-scale localized detectors were placed on the skin overlying the treated and control parotid glands during the application of the electron beam, which confirmed no significant dose to the contralateral gland. Isolated parotid saliva was collected in all animals and volume determined by weight, assuming a specific gravity of 1.0. Saliva was collected at pre-IR baseline, and 4, 6, 8, 10, and 12 weeks post-IR; thereafter, gene therapy was delivered at 12 weeks or 14 weeks post-IR. Gene transfer to the salivary gland was performed by a catheter inserted into the opening of Stensen's duct, and gene transfer vector was infused. For Adenoviral gene delivery (n = 4), 1x1010viral particles of AdhAQP1 were diluted in the infusate. For UAGT, a plasmid vector expressing porcine AQP1 was mixed with activated microbubbles and infused. Immediately, a 1MHz acoustic field was applied to the parotid gland in four 30 second treatments (n = 4). Following sacrifice of the animals, blinded slides of the parotids were reviewed by an oral pathologist. A treatment plan with immobilization was devised using a single mini-pig of similar size and weight to others in the study. Irradiation (IR) of the right parotid gland was performed with an electron beam, delivering 10 Gy in a single fraction. Nanometer-scale localized detectors were placed on the skin overlying the treated and control parotid glands during the application of the electron beam, which confirmed no significant dose to the contralateral gland. Isolated parotid saliva was collected in all animals and volume determined by weight, assuming a specific gravity of 1.0. Saliva was collected at pre-IR baseline, and 4, 6, 8, 10, and 12 weeks post-IR; thereafter, gene therapy was delivered at 12 weeks or 14 weeks post-IR. Gene transfer to the salivary gland was performed by a catheter inserted into the opening of Stensen's duct, and gene transfer vector was infused. For Adenoviral gene delivery (n = 4), 1x1010viral particles of AdhAQP1 were diluted in the infusate. For UAGT, a plasmid vector expressing porcine AQP1 was mixed with activated microbubbles and infused. Immediately, a 1MHz acoustic field was applied to the parotid gland in four 30 second treatments (n = 4). Following sacrifice of the animals, blinded slides of the parotids were reviewed by an oral pathologist. ResultsAll animals developed profound, bilateral hyposalivation that began 4 weeks post-IR and stabilized at approximately 38% of pre-IR baseline. The hyposalivation on the uninjured side was notable, as we ruled out radiation dose to the contralateral gland; AQP1 gene therapy with UAGT restored salivary flow to baseline levels in a manner comparable to Adenoviral gene therapy. These novel results suggest a functional neurological coupling of left and right parotid glands. At sacrifice, periductal inflammation was found to be restricted to glands treated with the Adenoviral vector only. All animals developed profound, bilateral hyposalivation that began 4 weeks post-IR and stabilized at approximately 38% of pre-IR baseline. The hyposalivation on the uninjured side was notable, as we ruled out radiation dose to the contralateral gland; AQP1 gene therapy with UAGT restored salivary flow to baseline levels in a manner comparable to Adenoviral gene therapy. These novel results suggest a functional neurological coupling of left and right parotid glands. At sacrifice, periductal inflammation was found to be restricted to glands treated with the Adenoviral vector only. ConclusionThese results demonstrate, for the first time, ultrasound-assisted, non-viral gene transfer to the parotid glands of swine; UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy, increasing both safety and the possibility of retreatment for salivary enhancement. Ultrasound-assisted, non-viral gene transfer was successful in the irradiated swine and is a candidate for advancement to a Phase 1 human clinical trial. These results demonstrate, for the first time, ultrasound-assisted, non-viral gene transfer to the parotid glands of swine; UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy, increasing both safety and the possibility of retreatment for salivary enhancement. Ultrasound-assisted, non-viral gene transfer was successful in the irradiated swine and is a candidate for advancement to a Phase 1 human clinical trial.

MammoSite multi-lumen (ML) applicator has fewer outer-lumens (3 vs. 4) with shorter offset (3 mm vs. 5 mm) from the central lumen compared with Contura applicator. This study evaluates dosimetric parameters of MammoSite ML plan and investigates its clinical comparability with Contura applicator. Contura applicator resulted in a highly asymmetrical dose distribution for 14 breast patients whose balloon was located in proximity to both skin and rib (both balloon-skin/-rib distances ≤ 5 mm). For each patient, MammoSite ML applicator was virtually identified on the planning CT images in a commercial treatment planning system (BrachyVision V8.9) and a treatment plan was optimized using the same parameters as for Contura planning. In MammoSite ML planning, catheter 1 was manually positioned along the 3 mm offset line parallel to the central lumen in a two-dimensional (2D) CT image plane which contains catheter 1 identified with a dummy wire in Contura applicator. The position of catheters 2 and 3 was determined by applying a 3D rotation matrix to position coordinates of the applicator 1 with a rotation angle of 120 and 240 degrees, respectively. The 3D rotation matrix was mathematically calculated by the rotation of a point around the central lumen. The same position coordinate of the central lumen in Contura was used for catheter 4 in MammoSite ML. The following dosimetric parameters were evaluated for MammoSite ML plan compared with Contura plan: PTV_EVAL coverage (D95) and maximal dose (Dmax) of skin and rib relative to prescribed dose (PD); breast tissue volume receiving 200% of PD (V200). Wilcoxon matched-pairs signed rank test was used for statistical analysis of plan comparison. Contura plan was better in PTV_EVAL coverage by 0.3%, skin Dmax by 2.7% and rib Dmax by 2.6% of PD, on average, while breast tissue V200 was smaller in MammoSite ML plan by 0.4 cc (Table). The difference was statistically significant (p-value < 0.05) for skin Dmax and breast tissue V200 while insignificant (p-value > 0.05) for PTV_EVAL coverage and rib Dmax. However, the differences in skin Dmax (2.7%) and breast tissue V200 (0.4 cc) were not clinically significant. MammoSite ML applicator can produce a clinically comparable plan with Contura applicator even though it has fewer outer-lumens with shorter offset.Tabled 1Dosimetric comparison between MammoSite ML and Contura plansMeanStandard DeviationMinimumMaximump-valuePTV_EVALD95Contura96.52.793.7100.70.6257MammoSite ML96.22.990.7100.3SkinDmaxContura121.24.7110.3126.10.0134MammoSite ML123.97.1110.5134.3RibDmaxContura148.416.1123.3187.30.104MammoSite ML151.017.1116.1188.6Breast tissueV200Contura5.31.82.08.00.009MammoSite ML4.91.72.27.5 Open table in a new tab

258 Background: Brain metastases account for 100,000 to 170,000 cases per year in the U.S, the bulk being from breast and lung primaries. About 10-15% of breast cancer patients develop brain metastases and historically, their survival has been poor. Introduction of novel chemotherapeutic and biologic agents and newer radiation techniques in the past decade has led to better control of systemic disease raising the possibility of increasing incidence of brain metastases as well as better control of CNS disease. The aim of this study was to determine the survival of breast cancer patients with brain metastases in our practice in the last 10 years. Methods: This study was a retrospective chart analysis and we analyzed the charts of 18 patients with breast cancer who had developed brain metastases. The parameters analyzed included patient age at diagnosis of breast cancer and at development of brain metastases, receptor status and various treatment modalities used to control local as well as Metastatic disease. Results: The median survival time after adjusting for age at diagnosis of breast cancer, age at diagnosis of brain metastases and the number of brain metastases was 55 months. The time to death was analyzed using Cox proportional hazard model, adjusting for age and number of brain metastases. Age at diagnosis of breast cancer was significant with a p-value of 0.007 and the number of brain metastases was not significant with a p-value of 0.55. Using the Log Rank test, median survival for Her2neu positive patients was 71 months and for Her2neu negative patients was 58 months with a non-significant p value of 0.86. Review of treatment modalities revealed that six patients underwent surgical removal of metastases and 12 patients received WBRT. Average number of systemic treatments used was 6.7 including chemotherapeutic, biological and hormonal agents. Conclusions: In our practice, the overall survival of breast cancer patients with brain metastases was found to be 55 months after adjusting for age at diagnosis of breast cancer, age at diagnosis of brain metastases and number of brain metastases. Overall survival did not vary significantly with the number of brain metastases and Her2neu receptor status.

To evaluate our mature follow-up data in women who have developed IBTR following conservation surgery and post-operative external radiotherapy retreated by lumpectomy followed by LDR in lieu of salvage mastectomy. Between 1/1998 and 10/2006, twenty-two patients with TIS or T1 IBTR were offered interstitial LDR following tumor re-excision as an alternative to salvage mastectomy. All patients had an initial lumpectomy followed by standard postoperative external beam radiotherapy [range 5000-6480cGy including boost]. Six recurred as ductal carcinoma in situ, two as infiltrating lobular carcinoma (one with a DCIS component), and fourteen as recurrent invasive carcinoma (four with a DCIS component). The recurrent tumors were excised with final margins of resection free of residual disease per National Surgical Adjuvant Breast and Bowel Project (NSABP) definition. Tumor bed implantation was then carried out with an interstitial technique utilizing 192Iridium with the target volume consisting of the tumor bed plus a minimum 1.0 centimeter clinical margin. With a mean follow up of 67.5 months (range 17-115 months) Twenty-one of twenty-two patients maintained local control at the time of last follow-up or at the time of their death. The single patient who developed a second local recurrence was treated successfully with simple mastectomy. Three patients succumbed to systemic disease at 17 and 24 months after salvage implant therapy. Three patients died from unrelated causes. One patient was lost to follow-up after three years. One patient developed a contralateral breast cancer. Long-term cosmetic results as defined by the Harvard cosmesis scale (13 grade I, 6 grade II, 3 grade III) and the Allegheny General modification (which accounts for the initial cosmetic appearance) the score worsened in only 4 patients. These long-term data suggest that lumpectomy followed by LDR is feasible and may be an acceptable alternative to salvage mastectomy in patients for whom initial breast conservative therapy has failed. The Allegheny General Modification score better represents the long-term cosmetic effects of retreatment.

Purpose/Objective(s)To evaluate cosmesis and toxicity for early stage breast cancer patients treated with adjuvant 3D-CRT to deliver accelerated partial breast irradiation (APBI).Materials/MethodsFrom 2003-June 2006, 61 breasts on 60 patients were treated with 3D-CRT APBI at Virginia Commonwealth University and Allegheny General Hospital. Patients with Stage 0, I, or II breast cancer were eligible if a <3cm tumor was resected with negative surgical margins and axillary evaluation documented 0-3 positive nodes. Target volume and critical structure definitions, as well as dose delivery guidelines, were consistent across both institutions. Patients were treated twice a day, for five days, with 3.85 Gy per fraction and a total dose of 38.5 Gy. Clinical follow-up was conducted at regular intervals that included history, physical exam, and mammography. The overall cosmesis was a physician-graded assessment using the Harvard scale and toxicity was graded according to the Common Toxicity Criteria (v3.0) including hyperpigmentation, edema, telangectasia, pain, surgical defect, fibrosis and fat necrosis. Dose-volume histogram and treatment parameters were collected and analyzed.ResultsMedian follow-up was 18.4 months (range, 2.0-70.2). The median age was 58.7 years (range, 31.4-88.2). Median tumor size was 1.0 cm (range, 0.2-2.5) with the following tumor characteristics: invasive histology 82%; non-invasive histology 18%; ER positive 80%; Her2 positive 8%. Median PTV-Eval size was 206.9cc's (range, 89.2-1052.0. Median PTV-Eval to whole breast volume ratio was 14% (range, 5-30%). Eight (13%) of patients received chemotherapy, 41 (68%) received hormonal therapy. There were no local regional failures and three patients failed distantly (5%). Overall cosmetic outcome was good/excellent in 58 breasts (95%) and fair/poor in three (5%). There were four cases (7%) of grade 3-4 toxicity: one patient with pain; one patient with pain and fat necrosis; one patient with telangectasias; and one patient with fibrosis. No statistical correlation between dosimetric parameters and cosmetic outcome were identified.ConclusionsThe size of treatment cohort and length of follow-up of this experience of 3D-CRT APBI are consistent with data reported by other series. This experience supports the continued on-protocol use of this technique with acceptably low toxicity rates and good/excellent cosmetic outcome in the majority of patients. Purpose/Objective(s)To evaluate cosmesis and toxicity for early stage breast cancer patients treated with adjuvant 3D-CRT to deliver accelerated partial breast irradiation (APBI). To evaluate cosmesis and toxicity for early stage breast cancer patients treated with adjuvant 3D-CRT to deliver accelerated partial breast irradiation (APBI). Materials/MethodsFrom 2003-June 2006, 61 breasts on 60 patients were treated with 3D-CRT APBI at Virginia Commonwealth University and Allegheny General Hospital. Patients with Stage 0, I, or II breast cancer were eligible if a <3cm tumor was resected with negative surgical margins and axillary evaluation documented 0-3 positive nodes. Target volume and critical structure definitions, as well as dose delivery guidelines, were consistent across both institutions. Patients were treated twice a day, for five days, with 3.85 Gy per fraction and a total dose of 38.5 Gy. Clinical follow-up was conducted at regular intervals that included history, physical exam, and mammography. The overall cosmesis was a physician-graded assessment using the Harvard scale and toxicity was graded according to the Common Toxicity Criteria (v3.0) including hyperpigmentation, edema, telangectasia, pain, surgical defect, fibrosis and fat necrosis. Dose-volume histogram and treatment parameters were collected and analyzed. From 2003-June 2006, 61 breasts on 60 patients were treated with 3D-CRT APBI at Virginia Commonwealth University and Allegheny General Hospital. Patients with Stage 0, I, or II breast cancer were eligible if a <3cm tumor was resected with negative surgical margins and axillary evaluation documented 0-3 positive nodes. Target volume and critical structure definitions, as well as dose delivery guidelines, were consistent across both institutions. Patients were treated twice a day, for five days, with 3.85 Gy per fraction and a total dose of 38.5 Gy. Clinical follow-up was conducted at regular intervals that included history, physical exam, and mammography. The overall cosmesis was a physician-graded assessment using the Harvard scale and toxicity was graded according to the Common Toxicity Criteria (v3.0) including hyperpigmentation, edema, telangectasia, pain, surgical defect, fibrosis and fat necrosis. Dose-volume histogram and treatment parameters were collected and analyzed. ResultsMedian follow-up was 18.4 months (range, 2.0-70.2). The median age was 58.7 years (range, 31.4-88.2). Median tumor size was 1.0 cm (range, 0.2-2.5) with the following tumor characteristics: invasive histology 82%; non-invasive histology 18%; ER positive 80%; Her2 positive 8%. Median PTV-Eval size was 206.9cc's (range, 89.2-1052.0. Median PTV-Eval to whole breast volume ratio was 14% (range, 5-30%). Eight (13%) of patients received chemotherapy, 41 (68%) received hormonal therapy. There were no local regional failures and three patients failed distantly (5%). Overall cosmetic outcome was good/excellent in 58 breasts (95%) and fair/poor in three (5%). There were four cases (7%) of grade 3-4 toxicity: one patient with pain; one patient with pain and fat necrosis; one patient with telangectasias; and one patient with fibrosis. No statistical correlation between dosimetric parameters and cosmetic outcome were identified. Median follow-up was 18.4 months (range, 2.0-70.2). The median age was 58.7 years (range, 31.4-88.2). Median tumor size was 1.0 cm (range, 0.2-2.5) with the following tumor characteristics: invasive histology 82%; non-invasive histology 18%; ER positive 80%; Her2 positive 8%. Median PTV-Eval size was 206.9cc's (range, 89.2-1052.0. Median PTV-Eval to whole breast volume ratio was 14% (range, 5-30%). Eight (13%) of patients received chemotherapy, 41 (68%) received hormonal therapy. There were no local regional failures and three patients failed distantly (5%). Overall cosmetic outcome was good/excellent in 58 breasts (95%) and fair/poor in three (5%). There were four cases (7%) of grade 3-4 toxicity: one patient with pain; one patient with pain and fat necrosis; one patient with telangectasias; and one patient with fibrosis. No statistical correlation between dosimetric parameters and cosmetic outcome were identified. ConclusionsThe size of treatment cohort and length of follow-up of this experience of 3D-CRT APBI are consistent with data reported by other series. This experience supports the continued on-protocol use of this technique with acceptably low toxicity rates and good/excellent cosmetic outcome in the majority of patients. The size of treatment cohort and length of follow-up of this experience of 3D-CRT APBI are consistent with data reported by other series. This experience supports the continued on-protocol use of this technique with acceptably low toxicity rates and good/excellent cosmetic outcome in the majority of patients.

Purpose: To demonstrate an objective approach to determine planner-independent skin and rib distance and maximal dose in Contura® high dose rate brachytherapy planning. Method and Materials: A virtual skin volume was produced by expanding the skin surface in three dimensions (3D) external to breast with a certain thickness. Therefore, the maximum dose to this volume occurs on the skin surface as with manual selection method. A 3D rib volume was reconstructed from rib contours on axial CT images. The maximal dose to skin and rib was extracted from their dose volume histograms. Minimum skin and rib distance from the balloon surface was objectively calculated using the inverse square law assuming that the balloon was a sphere and the prescribed dose was located on the surface of a 1-cm expansion from the balloon. For the calculation, three different plans were ubli single dwell position with single lumen (MDSL)and multiple dwell position with single lumen (MDSL) and multiple dwell position with multi-lumen (MDML) plans. Those estimated minimum distance of skin and rib were compared for 24 patients with 48 manual measurements taken by a comprehensive review of 3D planning CT images. Results: The average ± standard deviation (maximum) of estimated skin and rib distance in comparison with manual measurement was 0.4 mm ± 0.4 (1.8) for SDSL, 0.6 mm ± 0.5 (2.5) for MDSL and, 1.3 mm ± 1.2 (5.5) for MDML plans. Agreement within ± 1 mm difference was observed in 46/48 cases for SDSL, 40/48 cases for MDSL, and 25/48 cases for MDML plans. Conclusion: Volumetric information of skin and rib was used to objectively determine their maximal dose. The SDSL plan is better for skin and rib distance measurement because of its spherically symmetric dose distribution. However, asymmetric dose distribution in the MDML plan should be used for treatment.

To retrospectively analyze cardiac dose in women with left breast cancer treated using Contura HDR breast brachytherapy. Twenty-three women with small (<3 cm) carcinoma of the left breast were treated using the Contura applicator. Thirty-four Gy in 10 BID fractions was prescribed with optimization to reduce skin and rib dose. For each patient, the planning CT included the whole heart outlined along with the combined cardiac ventricles. We report maximal and mean dose (Dmax, Dmean), volume receiving 5 Gy (V5), dose to 1 cc of volume (D1cc), biologically effective dose (BED) and generalized equivalent uniform dose (gEUD). For comparison, plans were created using the central lumen only simulating MammoSite treatments. Mean whole heart volume was 677 cc (range, 485-1387) while the mean volume of the ventricles was 354 cc (263-603). Mean minimal distance from balloon surface to the whole heart and ventricles was the same; 33 mm (range, 13-97). Mean distance to the underlying rib from the balloon was on average 14 mm (3-65). Dmean for whole heart was on average 2.63 Gy (range, 0.56-4.68) and 3.56 Gy for ventricles (0.77-6.35). Average V5 was 12.1% for the whole heart and 20.4% for the ventricles. Mean D1cc was 11.9 Gy for whole heart and 11.6 Gy for ventricles. Dmax for each structure was >20 Gy in 4/23 patients. As expected, Dmean for whole heart and ventricles decreased with greater distance from balloon. Similarly, Dmean was lower in patients with greater distance between the balloon surface and the rib. For patients with a rib to balloon surface distance ≤ 10 mm (n = 13), the whole heart Dmean was 3.26 Gy vs. 1.81 Gy in women with a distance of > 10 mm (n = 10), p = 0.00024. Ventricular Dmean was 4.41 Gy in patients with a rib to balloon distance ≤ 10 mm vs. 2.45 Gy with a distance of > 10 mm (p = 0.00017). Average BED3 was 2.35 Gy for the whole heart and 3.37 Gy for the ventricles. Average gEUD (a = 4) was 4.56 Gy for the whole heart and 5.16 Gy for the ventricles. Whole heart Dmean was 2.63 Gy vs. 2.70 Gy for the Contura vs. simulated MammoSite plans (p = < 0.0001). Average whole heart V5 was 12.1% for Contura patients vs. 12.8% in single lumen plans (p = 0.0005). V5 was reduced by the use of Contura in 19/23 (82.6%) women. Mean absolute reduction of V5 was 5.5 cc (<1% of mean heart volume). Dmean, V5, BED and gEUD were higher for the ventricles than for the whole heart, while the average D1cc was slightly higher for whole heart. Dmean for both structures depended on the distance to the balloon but also on rib distance. Therefore, the distance between the balloon surface and rib may be used as an effective surrogate to predict higher heart dose. Although use of Contura resulted in a statistically significant reduction of heart dose compared to single lumen, the absolute difference is probably clinically insignificant.

To compare low dose rate interstitial brachytherapy to high dose rate intracavitary brachytherapy for IBTR re-treated by lumpectomy. Between 1/1998 and 11/2008, 32 patients with TIS to T2 (< 3 cm) breast carcinoma were offered brachytherapy following failed BCT and WBI (range 4500 - 6600 cGy) as an alternative to salvage mastectomy. One additional patient developed an in-field breast cancer following full mantle irradiation (4500 cGy) for Hodgkin's Lymphoma 27 years prior. All tumors were re-excised with negative margins per National Surgical Adjuvant Breast and Bowel Project (NSABP) definition. Following repeat lumpectomy, tumor bed implantation was carried out utilizing a low dose rate (LDR) interstitial technique (4500 -5530 cGy at 35 - 50 cGy per hour to the tumor bed plus a 1.0 cm margin) in 23 patients. Five patients were treated with high dose rate (HDR) brachytherapy (3400 cGy twice daily at 340 cGy/fx according to NSABP B-39/ RTOG 0413 protocol) using the MammoSite system and five were treated using the Contura multi-lumen system. Maximum skin and rib dosages in the patients treated with the Contura system were additionally compared using the central lumen of the catheter in a multi-dwell idealized delivery against a multi-lumen delivery. Two patients (LDR group) developed grade III acute complications by the Common Terminology Criteria for Adverse Events (v. 3.0). Four patients (HDR group) developed grade I acute complications. With the Contura® system, the mean reduction in maximum skin and rib doses was 12.2% and 13.9% respectively (range: 0- 43.7%) compared to MammoSite. With skin and rib distances of less than 1 cm, the mean dose reductions were 18% and 33.6% respectively. NSABP cosmesis grading scores were: Grade I in 25 patients (including the 10 MammoSite and Contura patients), Grade II in 2 patients, Grade III in 3 patients, and was unavailable for 3 patients. 32 of 33 patients remain free of local failure with a mean follow-up of 24.9 months (range 1 - 90.6 months). Repeat BCT and brachytherapy radiation for IBTR is a feasible process. HDR intracavitary brachytherapy has decreased acute toxicities compared to LDR interstitial brachytherapy. The Contura device provides noticeable skin and rib dose reductions. The long term cosmetic effect of HDR intracavitary compared to LDR interstitial brachytherapy following repeat lumpectomy for IBTR is superior. HDR intracavitary brachytherapy and repeat lumpectomy is a reasonable alternative for the treatment of IBTR.

Purpose: To evaluate target dose inhomogeneity for four different breast cancer treatment techniques. Method and Materials: External beam radiotherapy (EBRT) was performed for 12 patients each using either whole or 3D conformal partial breast irradiation (WBI or PBI), 19 patients with high dose rate (HDR) MammoSite® brachytherapy and 13 patients with Contura® multi‐lumen applicator. The PTV_EVAL volume was defined by following NSABP B‐39/RTOG 0413 for PBI, MammoSite® and Contura® while retrospectively delineated for WBI. The differential dose volume histogram was evaluated using mean dose (Dm) and most probable dose (Dmp) relative to prescribed dose (Dpr) and root mean square deviation (RMSD). The biologically effective dose (BED) accounting for non‐uniform dose distribution was computed. Generalized equivalent uniform dose (gEUD) was calculated together with dose homogeneity index (DHI) and conformal index (COIN). Results: Compared to EBRT, the target received higher dose with HDR (Dm: 143% vs. 101%, Dmp: 111% vs. 101%) which increased BED values (77 Gy vs. 73 Gy for fibrosis, 56 Gy vs.47 Gy for erythema, and 63 Gy vs. 57 Gy for breast carcinoma, respectively) and dose inhomogeneity (RMSD: 12.1 vs. 1.8). Due to steeper dose fall‐off, HDR plans were more conformal than EBRT (COIN: 0.84 vs. 0.45). Compared to MammoSite®, Contura® yielded slightly higher dose (BED difference < 0.5 Gy and 0.3 Gy higher in gEUD) which increased DHI by 5% and COIN by 1%. The PBI had large inter‐patient variability of BED values (2–8 times > others) and the smallest BED and gEUD values. The WBI had large inter‐patient variability of gEUD values (14 times > others) due to cold spots. Conclusion: Despite greater inhomogeneity, HDR plans have higher target dose conformality and are less patient‐specific than EBRT plans. However, based on the biological and dosimetric data, the four different techniques are clinically comparable.

Adjuvant radiation and hormonal therapy are administered following surgery in patients with hormone receptor positive breast cancer managed by breast conserving therapy. There are limited data about combined morbidity of aromatase inhibitors and concurrent whole breast radiation therapy (WBRT). In this retrospective analysis, we compared radiation toxicity in patients treated with concurrent anastrozole (ANZ) and WBRT (Group 1), women treated sequentially with WBRT followed by hormonal therapy (Group 2) and those who received concurrent tamoxifen (TAM) and WBRT (Group 3). Records of 253 consecutive hormone receptor positive breast cancer patients (clinical stage 0 - IIIA) were reviewed. Both estrogen (ER) and progesterone (PR) receptors were positive in 83% of women; ER only in 13.4%, and PR only in 3.6%. All received conservation breast surgery followed by WBRT at our institution. Fifty-nine patients (Group 1) received concurrent ANZ prior to and during radiotherapy. In 128 patients (Group 2) adjuvant hormonal therapy (ANZ or TAM) was administered after completion of breast irradiation and, 63 women (Group 3), received concurrent TAM and radiation therapy. Sequence of radiation and hormonal therapy was unknown in three patients excluded from this study. Groups were balanced with respect to tumor characteristics. Women who received concurrent ANZ were older than those treated sequentially with hormonal therapy and than those who received concurrent TAM (average age for Group 1, 65 years; Group 2, 57; Group 3, 52; p = < .0001). More patients with concurrent ANZ or TAM received preceding systemic chemotherapy compared to the sequential group (Group 1, 39.0%; Group 2, 23.4%; Group 3, 50.1%; p = .0006). Despite less frequent use of chemotherapy in the sequential group (Group 2), the frequencies of grade 2 radiation dermatitis (23.7%, 20.3%, 28.6% p =.44), grade 3 radiation dermatitis (8.5%, 7.8%, 1.6% p =.19) and, treatment interruptions due to skin reactions (13.6%, 11.7%, 11.1% p = .90) did not differ significantly between treatment groups. Development of skin hyperpigmentation of any grade was similar in each group, and the rates of excellent cosmetic outcome (as scored by the Harvard criteria) were the same. With a median follow up of 21.5 months, no local failures occurred in the concurrent ANZ group, five occurred in the sequential group (median follow up 20 months), and three in the concurrent TAM group (median follow up 33 months). Anastrozole, administered concurrently with WBRT, did not increase acute morbidity when compared to either sequential administration of radiation and hormonal therapy or concurrent tamoxifen and radiation.

To evaluate clinical outcomes of Choroidal Melanoma (CM) patients treated with 125I episcleral plaque brachytherapy and compare our single surgeon results to the multi-institutional Collaborative Ocular Melanoma Study (COMS). Retrospective review was performed of all CM patients treated with 125I episcleral plaque brachytherapy at Allegheny General Hospital from 6/1996 to 10/2008. All plaques were applied by a single ophthalmologist in accordance with established COMS guidelines. The records of 35 patients (17 male, 18 female; median age 68 years) were available. The median lesion diameter and elevation was 13mm (range 7 - 16 mm) and 7.5 mm (range 3 - 13.5 mm) respectively, while median plaque size was 17 mm (range 14 - 20 mm). Median dose to the apex was 8609 cGy (range 7500-10500 cGy) at a median dose rate of 92 cGy/hr (range 77 to 140 cGy/hr). The median implant duration was 96 hours (range 71.5-105 hrs.). At a median follow-up of 5 years, 33 patients achieved local control and successful organ preservation, while twenty-three retained useful vision in the treated eye. One patient developed a second ipsilateral CM, which was effectively controlled by repeat 125I episcleral plaque application. Two patients required enucleation at 24 and 30 months post-implant for pain and neovascular glaucoma, respectively. Two patients developed hepatic metastasis at 19 and 21 months post-implant, and are the only mortalities to date. Our 5-year local control rate (94.3%), distant metastatic rate (5.7%) and mortality with metastatic disease (5.7%) compare favorably to COMS respective 5-year values of 89.7 %, 25%, and 10%. Application of the 125I episcleral plaque by an experienced ophthalmologist cannot be undervalued and may optimize dose delivery.

Sarcomas arising in the equine species are rare tumours, and treatment generally surgical. Radiotherapy has been used in the management of malignancies of large animals; however, conventional external radiotherapy delivery is difficult. Interstitial brachytherapy has been used in the management of human sarcomas with reasonable success, although equine experience is minimal. We report a case of equine haemangiosarcoma treated with brachytherapy demonstrating the feasibility of the procedure and the highly malignant natural history of haemangiosarcoma. An 8-year-old American Saddlebred gelding presented for evaluation of a soft tissue mass on the forehead which had been present for at least 6 months. Initial surgical attempts at management were unsuccessful; therefore a radiation oncologist specialising in brachytherapy was consulted. The radiation oncologist and veterinary surgeon performed an interstitial implant of the tumour mass on the rostrum of the horse under general anaesthesia. The procedure was well tolerated by the horse. The tumour demonstrated immediate response and was noted to have completely regressed within 6 weeks of the implant removal. Unfortunately, the horse developed widespread metastatic disease and required euthanasia. At the time of necropsy, no visible tumour was identified at the implant site. Interstitial brachytherapy is feasible in soft tissue sarcomas of the horse; however, supportive demands are great with this procedure and we recommend it only be done at large speciality centres.

Purpose: To evaluate the interfraction dose variations due to changes of balloon shape and location in MammoSite HDR brachytherapy using the concept of biological effective dose (BED). Method and Materials: A method was developed to account for non‐uniform dose distribution in the BED calculation. A prescription dose of 34 Gy was delivered twice daily in 10 fractions to 19 patients. The BED value was computed by two different Method: one using the same dose distribution of fraction 1 over fraction 2–10 (constant case) and one using the actual delivered dose distribution for each fraction 1–10 (interfraction variation case — Fx case). The α/β values were adopted from literature and ranged from 2 to 11 based on specific clinical endpoints: acute effects (erythema, desquamation), late effects (fibrosis, telangiectasia) and tumor control. The α value of 0.3 Gy−1 and Tpot value of 13 days were used for cell proliferation. Results: The average difference in BED values between the constant and Fx cases was less than 0.1 Gy over the range of α/β ratios. The maximum difference was larger for late effects (fibrosis, telangiectasia) than acute effects (erythema, desquamation): −3.3 Gy and −2 Gy versus −1.5 Gy and −1.4 Gy corresponding to α/β ratio of 2 and 4 versus 8 and 11, respectively. The negative value means the BED value of Fx case is smaller than that of constant case. By disregarding high inhomogeneity in HDR brachytherapy, the simple calculation assuming uniform dose distribution tends to overestimate BED for fibrosis while underestimating BED for erythema and desquamation. Conclusion: The BED calculation accounting for non‐uniform dose distribution is more clinically relevant compared to the BED calculation which assumes uniform dose distribution across the target volume. Because the mean interfraction variation in dose was within 0.1 Gy across the target volume, the biological effect was clinically insignificant.

Purpose: To evaluate the inter-fractional dose variations due to changes in balloon shape and location in MammoSite partial breast HDR irradiation. Method and Materials: Eleven MammoSite HDR patients were treated with a dose of 34 Gy delivered in 10 fractions twice a day at our institution. For each of these patients, a plan was generated for the first fraction based on the CT scan acquired before treatment. The plan was then used for the remaining 9 fractions without any modification unless a significant change in balloon shape and/or location was observed on the CT scan acquired prior to each treatment fraction. To assess the inter-fractional dose variations, we retrospectively contoured the target (including PTV_EVAL for planning evaluation) as well as critical structures and positioned the catheter on the CT datasets of fraction 2 – 10. Then, we generated two plans utilizing a multiple and single dwell position approaches while using the same dwell time distribution as for the clinical plan of the first fraction. A total of 220 plans generated on 110 CT datasets were evaluated using the following dosimetric metrics: PTV_EVAL coverage, target dose homogeneity index (DHI), target dose conformal index (COIN) as well as maximum dose to ipsilateral lung and skin. Results: For the multiple dwell position approach, the average (maximum) percent inter-fractional variation relative to the first fraction was 1.5% (6.2%) for PTV_EVAL coverage, 1.1% (12.5%) for DHI, 3.4% (11.8%) for COIN, 10.2% (42.6%) for maximum ipsilateral dose, and 6.9% (29.4%) for maximum skin dose. No difference in the dosimetric values was observed using either a multiple or single dwell position approach. Conclusion: The inter-fractional dose variation was patient-specific and dependent upon the balloon deformity and location. While the average variation may not significantly impact the treatment, the maximum variation may be clinically significant.

In MammoSite partial breast HDR irradiation, a CT-based plan of the first fraction is used for subsequent fractions without modification unless significant change in the central balloon diameter is observed on the axial CT image. However, balloon deformity can be noticeable if three-dimensional CT data are rotated and their image intensity is modified to visualize the catheter inside the balloon. Dose deviations from the first-fraction plan over the full course of treatment can occur due to the change in balloon deformity, volume of trapped air gap, and the relative location of balloon to the skin and ipsilateral lung. In this study, the inter-fractional variation in balloon shape and location was evaluated on 200 plans (200 CT data sets for 20 patients treated with 10 fractions) using several dosimetric parameters. Patients were treated to a dose of 34 Gy delivered in 10 fractions twice a day with minimum of 6 hours between fractions. For the first fraction plan, the fractional dose of 3.4 Gy was prescribed to the surface of balloon + 1 cm with multiple dwell position technique. For each patient, additional 9 CT scans were obtained for fractions 2–10 and utilized to generate 9 plans, retrospectively. On those CT data sets, PTV_EVAL and all critical structures were contoured and a catheter was positioned inside the balloon. Furthermore, dwell times were determined from the first fraction plan and held constant through all remaining fractions. The PTV_EVAL volume was used for plan evaluation purposes and obtained by subtracting the balloon volume from a balloon + 1 cm volume. This excluded the volume of lung/pectoralis muscle and the volume of skin + 5 mm. For each patient, the 9 plans were compared to the first fraction plan using dosimetric parameters such as percentage of PTV_EVAL coverage and maximum dose to the skin and ipsilateral lung. The trapped air gap volume shown in Fig. 1 for all patients was gradually decreased from a mean value of 0.74 cc (fraction 1) to 0.18 cc (fraction 10) while it was increased at a certain fraction in some patients. The average (maximum) inter-fractional variation from the first fraction plan was 1.8% (7.3%) for the PTV_EVAL coverage (Fig. 2), 32.3 cGy (176.2 cGy) for the skin maximum dose (Fig. 3), and 26.9 cGy (94.5 cGy) for the ipsilateral lung maximum dose (Fig. 4). The inter-fractional dose variation due to the change in balloon shape and location was patient-specific and dependent upon the balloon deformity and location. The average deviation from the first fraction plan may not be clinically significant. However, the maximum deviation may be clinically significant.

Purpose: Tolerance levels for dosimetric verification of IMRT plans are usually set at constant values. This QA process is not patient specific. It ignores the potential role of fraction size and treatment site in determining the clinical consequences of an error in dose calculation and/or delivery. The objective of this work is to develop dose tolerance levels for IMRT based on radiobiological parameters. Method and Materials: The linear quadratic cell survival model which accounts for the effects of both total dose and fraction size was used. A technique was developed to convert dosimetric tolerance levels between treatment schedules while maintaining a constant uncertainty in a radiobiological parameter. Specifically, a constant tolerance level in a radiobiological parameter is set, rather than in calculated/delivered dose. Calculations were performed for different treatment fractionations and α/β ratios mimicking a wide range of clinical situations. Results: Tumors with low α/β ratio (melanoma, prostate) are more sensitive to errors in total dose. Dosimetric tolerance for such tumors should be approximately 65% of those of other tumors. For such malignances, if a 3% error in calculated/delivered dose is acceptable for treatment of most tumors, this should be reduced to 2% for treatment of these more radiosensitive tumors. In addition, results show that in field late and early responding normal tissues are more sensitive to errors in dose than out of field tissues. Conclusion: Invariant tolerance levels are appropriate for a wide range of clinical IMRT schemes, especially given current uncertainties in clinical α/β values. Assuming that current dosimetric levels are appropriate for some clinical applications, the appropriate values are for all other applications are between 0.5–2 times the currently used values for IMRT QA. In conclusion, tolerance levels for dosimetric QA based on radiobiological parameters provide useful information and may be more appropriate for verifying calculated/delivered dose.