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Background: The value of postmastectomy radiotherapy (PMRT) for pathological node-positive triple-negative breast cancers (TNBC) remains debatable. The aim of this population-based retrospective study was to evaluate the effect of PMRT on survival outcomes in this population., Methods: Patients diagnosed with stage T1-4N1-N3M0 TNBC between 2010 and 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. We used univariate and multivariate Cox regression hazards method to determine the independent prognostic factors associated with 3-year breast cancer-specific survival (BCSS). The effect of PMRT on 3-year BCSS was analyzed after stratification by pathological staging of groups., Results: Of the 4398 patients included in this study, 2649 (60.2%) received PMRT. Younger age, black ethnicity, and advanced tumor (T) and nodal (N) stage were the independent predictors associated with PMRT receipt (all P < 0.05). Patients who received PMRT showed better 3-year BCSS (OR = 0.720, 95% CI = 0.642-0.808, P < 0.001) than those that did not. The effect of PMRT on 3-year BCSS was analyzed after stratification by pathological staging of groups. The results showed that PMRT was associated with better 3-year BCSS in patients with stage T3-4N1 (P = 0.042), T1-4N2 (P < 0.001), and T1-4N3 (P < 0.001), while comparable 3-year BCSS was found between the PMRT and non-PMRT cohorts with T1-2N1 disease (P = 0.191)., Conclusions: Radiotherapy achieved better 3-year BCSS in TNBC patients with stage T3-4N1 and T1-4N2-3 disease. However, no survival benefit was found with the addition of PMRT in patients with T1-2N1 TNBC.

Background: To update the clinical outcome of an elderly women cohort with early breast cancer who underwent accelerated partial breast irradiation (APBI) based on a post-operative single fraction of multicatheter interstitial high dose-rate brachytherapy (MIB)., Material and Methods: A single institution retrospective cohort study was performed focusing on elderly patients (≥ 65 years old) presenting a low-risk breast carcinoma treated by lumpectomy plus axillary evaluation followed by MIB APBI. A single fraction of 16 Gy was prescribed on the 100% isodose. Clinical outcome at 5 years was reported based on local relapse free survival (LRFS), specific survival (SS) and overall survival (OS). Late toxicity was evaluated. Cosmetic results were evaluated clinically by the physician., Results: Between January 2012 and August 2015, 48 women (51 lesions) were treated. Median age was 77.7 years (range: 65-92) with a median tumor size of 12 mm (range: 3-32). Five patients (pts) presented an axillary lymph node involvement (4 Nmic, 1 N1). Invasive ductal carcinoma was the most frequent histology type (86.3%). With a median follow-up of 64 months (range: 56-71), no local relapse occurred while 1 pt. developed an axillary relapse (2.1%). No Grade 3 or higher late toxicity was observed while 16 late toxicities occurred (G1: 14 events [87.5%) mainly G1 breast fibrosis). The rate of excellent cosmetic outcome was 76.4%., Conclusion: We confirmed the safety of the process and remained encouraging clinical outcome of a post-operative single fraction of MIB ABPI in the elderly. This approach leads to consider a very APBI as an attractive alternative to intra-operative radiation therapy while all the patients will be good candidates for APBI in regards to the post-operative pathological report.

Background: The boost irradiation to the tumor bed following whole-breast irradiation (WBI) reduced the risk of ipsilateral breast tumor recurrence (IBTR). However, in Japan, almost all patients with a margin ≤5 mm receive boost irradiation to the tumor bed, but the decision to perform boost irradiation for those with a margin > 5 mm is dependent on the institution. Thus, institutional guidelines on utilizing boost irradiation for patients aged ≤40 or ≤ 50 years vary. We investigated the IBTR rate to assess the appropriate age for boost irradiation to the tumor bed with a margin > 5 mm., Methods: From January 1993 to December 2010, 419 patients with early-stage breast cancer and negative margins (> 5 mm) after breast-conserving surgery received WBI without boost irradiation. The Gray test was used to compare the cumulative incidence of IBTR among patients aged ≤40, 41-50, and ≥ 51 years. Hazard ratios were estimated using the Fine and Gray models. Furthermore, as a subgroup analysis, we investigated whether IBTR depended on the use of systemic therapy, such as anthracycline or taxane regimens., Results: The median follow-up time was 9.3 years. In multivariate analysis, only age predicted IBTR (p = 0.047). The 10-year IBTR rate was 15.7% in patients aged ≤40, 3.8% in those aged 41-50, and 2.0% in patients aged ≥51 years. The difference between patients aged ≤40 and 41-50 years was statistically significant (p = 0.045), whereas the difference between patients aged 41-50 and ≥ 51 years was not significant (p = 0.21)., Conclusions: In our institutional surgical setting, when boost irradiation is performed only for patients with a margin ≤5 mm, the IBTR rate after WBI without boost irradiation was significantly higher in patients aged ≤40 years, suggesting that boost irradiation should be used for patients in this age group.

Background: Our previous studies showed that vasoconstrictor applied topically to rat skin minutes before irradiation completely prevented radiodermatitis. Here we report on a Phase IIa study of topically applied NG12-1 vasoconstrictor to prevent radiodermatitis in post-lumpectomy breast cancer patients who received at least 40 Gray to the whole breast using standard regimens., Methods: Patients had undergone surgery for Stage Ia, Ib, or IIa infiltrating ductal or lobular carcinoma of the breast or ductal carcinoma in situ. NG12-1 formulation was applied topically to the same 50-cm 2 treatment site within the radiation field 20 min before each daily radiotherapy fraction., Results: Scores indicated significant reductions in radiodermatitis at the NG12-1 treatment site versus control areas in the same radiotherapy field. The mean dermatitis score for all subjects was 0.47 (SD 0.24) in the NG12-1-treated area versus 0.72 (SD 0.22) in the control area (P = 0.022). Analysis by two independent investigators indicated radiodermatitis reductions in 9 of the 9 patients with scorable radiodermatitis severity, and one patient with insufficient radiodermatitis to enable scoring. There were no serious adverse events from NG12-1 treatment., Conclusions: Thirty, daily, NG12-1 treatments, topically applied minutes before radiotherapy, were well tolerated and conferred statistically significant reductions in radiodermatitis severity (P = 0.022)., Trial Registration: NCT01263366 ; clinicaltrials.gov.

Purpose: To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction)., Materials and Methods: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old or over and treated with breast conservative surgery for early stage invasive carcinoma., Results: Seventy-three patients were analyzed. Median follow-up was 40 months. The proposed schedule was well tolerated. No Grade 3 toxicity was documented. Late toxicity was assessable for all the treated patients. Two patients (2.7%) developed Grade 2 pain 6 months after PBI. Four patients (5%) developed asymptomatic fat necrosis. Grade 2 fibrosis was observed in 5 patients (6.7%). No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). No statistical correlation between dosimetric parameters and toxicity was found. Patients who developed Grade 2 radiation fibrosis had not higher radiation volumes to the untreated normal breast than those without fibrosis. Cosmesis was judged good/excellent in the majority of the cases (93%). One patient relapsed locally, and one developed distant metastases, corresponding to a 5-year local control and distant metastases-free survival of 98% and 96.7%, respectively., Conclusions: 35 Gy in 7 daily fractions is an effective and well-tolerated regimen to deliver PBI.

Background: The purpose of the study was to evaluate the impact of multiple prognostic factors on the acute skin reaction in adjuvant breast cancer radiotherapy, in particular the impact of hypofractionation (HF) compared to conventional fractionation (CF) and tangential beam (TB) IMRT compared to three-dimensional conformal radiotherapy (3DCRT)., Methods: Two-hundred and sixty-six breast cancer patients with postoperative radiotherapy after breast conserving surgery or mastectomy were retrospectively evaluated. Patients were treated with HF (15 fractions of 2.67 Gy; n = 121) or CF (28 fractions of 1.8 Gy or 25 fractions of 2.0 Gy; n = 145) and TB-IMRT (n = 151) or 3DCRT (n = 115). The acute skin reactions were prospectively assessed using the CTCAE v4 grading scale. Ordinal regression analysis was used to assess the impact of possible prognostic factors on the maximal acute skin reaction., Results: Grade 2 skin reactions were observed in 19 % of the patients treated with CF compared to 2 % treated with HF. On univariate analysis, the fractionation regimen, the PTV (breast versus chest wall), the volume of the PTV and the body mass index were significant prognostic factors for the maximum acute skin reaction. On multivariate analysis, the fractionation regimen (p < 0.00001) and the volume of the PTV (p = 0.0002) remained as independent significant factors., Conclusions: Our data suggest that HF is associated with a significantly reduced maximal acute skin reaction compared to CF.

Background: We designed this study to quantify the effects of radiotherapy (RT) on bone density as a local response in spinal bone metastases of women with breast cancer and, secondly, to establish bone density as an accurate and reproducible marker for assessment of local response to RT in spinal bone metastases., Methods: We retrospectively assessed 135 osteolytic spinal metastases in 115 women with metastatic breast cancer treated at our department between January 2000 and January 2012. Primary endpoint was to compare bone density in the bone metastases before, 3 months after and 6 months after RT. Bone density was measured in Hounsfield units (HU) in computed tomography scans. We calculated mean values in HU and the standard deviation (SD) as a measurement of bone density before, 3 months and 6 months after RT. T-test was used for statistical analysis of difference in bone density as well as for univariate analysis of prognostic factors for difference in bone density 3 and 6 months after RT., Results: Mean bone density was 194.8 HU ± SD 123.0 at baseline. Bone density increased significantly by a mean of 145.8 HU ± SD 139.4 after 3 months (p = .0001) and by 250.3 HU ± SD 147.1 after 6 months (p < .0001). Women receiving bisphosphonates showed a tendency towards higher increase in bone density in the metastases after 3 months (152.6 HU ± SD 141.9 vs. 76.0 HU ± SD 86.1; p = .069) and pathological fractures before RT were associated with a significantly higher increase in bone density after 3 months (202.3 HU ± SD 161.9 vs. 130.3 HU ± SD 129.2; p = .013). Concomitant chemotherapy (ChT) or endocrine therapy (ET), hormone receptor status, performance score, applied overall RT dose and prescription of a surgical corset did not correlate with a difference in bone density after RT., Conclusions: Bone density measurement in HU is a practicable and reproducible method for assessment of local RT response in osteolytic metastases in breast cancer. Our analysis demonstrated an excellent local response within metastases after palliative RT.

Objective: To evaluate clinical outcome after accelerated partial breast irradiation (APBI) in the elderly after high-dose-rate interstitial multi-catheter brachytherapy (HIBT)., Methods and Materials: Between 2005 and 2013, 70 patients underwent APBI using HIBT. Catheter implant was performed intra or post-operatively (referred patients) after lumpectomy and axillary sentinel lymph node dissection. Once the pathological results confirmed the indication of APBI, planification CT-scan was performed to deliver 34 Gy/10f/5d or 32 Gy/8f/4d. Dose-volume adaptation was manually achieved (graphical optimization). Dosimetric results and clinical outcome were retrospectively analyzed. Physician cosmetic evaluation was reported., Results: With a median follow-up of 60.9 months [4.6 - 90.1], median age was 80.7 years [62 - 93.1]. Regarding APBI ASTRO criteria, 61.4%, 18.6% and 20% were classified as suitable, cautionary and non-suitable respectively. Axillary sentinel lymph node dissection was performed in 94.3%; 8 pts (11.5%) presented an axillary involvement. A median dose of 34 Gy [32 - 35] in 8 to 10 fractions was delivered. Median CTV was 75.2 cc [16.9 - 210], median D90 EQD2 was 43.3 Gy [35 - 72.6] and median DHI was 0.54 [0.19 - 0.74]. One patient experienced ipsilateral recurrence (5-year local free recurrence rate: 97.6%. Five-year specific and overall survival rates were 97.9% and 93.2% respectively. Thirty-four patients (48%) presented 47 late complications classified grade 1 (80.8%) and grade 2 (19.2%) with no grade ≥ 3. Cosmetic results were considered excellent/good for 67 pts (95.7%)., Conclusion: APBI using HIBT and respecting strict rules of implantation and planification, represents a smart alternative between no post-operative irradiation and whole breast irradiation delivered over 6 consecutive weeks.

Purpose: The objective of this study is to evaluate toxicity and cosmetic outcome in breast cancer patients treated with adjuvant hypo fractionated radiotherapy to the whole breast, and to identify the risk factors for toxicity., Methods and Materials: Two hundred twelve women with early breast cancer underwent conserving surgery were enrolled in the study. The patients received 40.05 Gy in 15 daily fractions, 2.67 Gy per fraction. The boost to the tumor bed was administered with a total dose of 9 Gy in 3 consecutive fractions in 55 women. Physician-rated acute and late toxicity and cosmetic outcome (both subjective and objective) were prospectively assessed during and after radiotherapy., Results: In our population study the mean age was 63 with the 17% (36 pts) of the women younger than 50 years.The median follow-up was 34 months. By the end of RT, 35 patients out of 212 (16%) no acute toxicity, according to the RTOG criteria, while 145 (68%) and 31 patients (15%) developed grade 1 and grade 2 acute skin toxicity, respectively.Late skin toxicity evaluation was available for all 212 patients with a minimum follow up of 8 months. The distribution of toxicity was: 39 pts (18%) with grade 1 and 2 pts (1%) with grade 2. No worse late skin toxicity was observed.Late subcutaneous grade 0-1 toxicity was recorded in 208 patients (98%) and grade 2 toxicity in 3 patients (2%), while grade 3 was observed in 1 patient only. At last follow up, a subjective and objective good or excellent cosmetic outcome was reported in 93% and 92% of the women, respectively. At univariate and multivariate analysis, the late skin toxicity was correlated with the additional boost delivery (p=0.007 and p=0.023). Regarding the late subcutaneous tissue, a correlation with diabetes was found (p=0.0283)., Conclusion: These results confirm the feasibility and safety of the hypofractionated radiotherapy in patients with early breast cancer. In our population the boost administration was resulted to be a significant adverse prognostic factor for acute and late toxicity. Long-term follow up is need to confirm this finding.

Purpose/objectives: Standard 3D-CRT after BCS may cause skin toxicity with a wide range of intensity including acute effects like erythema or late effects. In order to reduce these side effects it is mandatory to identify potential factors of influence in breast cancer patients undergoing standard three-dimensional conformal radiation therapy (3D-CRT) of the breast and modern systemic therapy., Materials/methods: Between 2006 and 2010 a total of 211 breast cancer patients (median age 52,4 years, range 24-77) after BCS consecutively treated in our institution with 3D-CRT (50 Gy whole breast photon radiotherapy followed by 16 Gy electron boost to the tumorbed) were evaluated with special focus on documented skin toxicity at the end of the 50 Gy-course. Standardized photodocumentation of the treated breast was done in each patient lying on the linac table with arms elevated. Skin toxicity was documented according to the common toxicity criteria (CTC)-score. Potential influencing factors were classified in three groups: patient-specific (smoking, age, breast size, body mass index = BMI, allergies), tumor-specific (tumorsize) and treatment-specific factors (antihormonal therapy with tamoxifen or aromatase inhibitors, chemotherapy). Uni- and multivariate statistical analyses were done using IBM SPSS version 19., Results: After 50 Gy 3D-CRT to the whole breast 28.9% of all 211 patients had no erythema, 62.2% showed erythema grade 1 (G1) and 8.5% erythema grade 2. None of the patients had grade 3/4 (G3/4) erythema.In univariate analyses a significant influence or trend on the development of acute skin toxicities (erythema G0 versus G1 versus G2) was observed for larger breast volumes (p=0,004), smoking during radiation therapy (p=0,064) and absence of allergies (p=0,014) as well as larger tumorsize (p=0,009) and antihormonal therapy (p=0.005).Neither patient age, BMI nor choice of chemotherapy showed any significant effect on higher grade toxicity. In the multivariate analysis, factors associated with higher grade skin toxicity were larger breast target volume (p=0,003), smoking (p=0,034) and absence of allergies (p=0,002)., Conclusion: Patients treated in this study showed less objectively documented skin toxicity after 50 Gy 3D-CRT compared to similar patient cohorts. Factors associated with higher grade skin toxicity were smoking during 3D-CRT, absence of allergies and larger breast volumes.

Background: To report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery., Methods: Between September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8-16). Cosmetic outcomes were assessed as excellent/good or fair/poor., Results: The median age of the population was 68 years (range 36-88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up., Conclusions: The 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

Background: There are limited data on accelerated partial breast irradiation (APBI) using external beam techniques. Moreover, there are recent reports of increased fibrosis and unacceptable cosmesis with APBI using external beam with BID fractionation. We adopted a once daily regimen of APBI with fractionation similar to that shown to be effective in a Canadian randomized trial of whole breast irradiation. It is unclear whether patients with DCIS or invasive lobular carcinoma (ILC) are suitable for APBI., Methods: The retrospective cohort included 310 patients with 312 tumors of T1-T2N0-N1micM0 invasive ductal carcinoma (IDC), ILC, or Tis (DCIS) treated with APBI via external beam. Most patients were treated using IMRT with 16 daily fractions of 270 cGy to a dose of 4320 cGy. The target volume included the lumpectomy cavity plus 1.0 cm to account for microscopic disease and an additional 0.5 to 1.0 cm for setup uncertainty and breathing motion. Ipsilateral breast failure (IBF) was pathologically confirmed as a local failure (LF) or an elsewhere failure (EF)., Results: Median follow-up was 49 months. Among the 312 cases, 213 were IDC, 31 ILC, and 68 DCIS. Median tumor size was 1.0 cm. There were 9 IBFs (2.9%) including 5 LFs and 4 EFs. The IBF rates among patients with IDC, ILC, and DCIS were 2.4%, 3.2%, and 4.4%, respectively, with no significant difference between histologies. When patients were analyzed by the ASTRO APBI consensus statement risk groups, 32% of treated cases were considered suitable, 50% cautionary, and 18% unsuitable. The IBF rates among suitable, cautionary, and unsuitable patients were 4.0%, 2.6%, and 1.8%, respectively, with no significant difference between risk groups. Acute skin reactions were rare and long-term cosmetic outcome was very good to excellent., Conclusions: External beam APBI with once daily fractionation has a low rate of IBF consistent with other published APBI studies. The ASTRO risk stratification did not differentiate a subset of patients with a higher rate of IBF. APBI may be an appropriate treatment for women with DCIS and ILC.

Background and Objective: The role of postmastectomy radiotherapy (PMRT) in breast cancer patients with T1-T2 tumors and 1-3 positive axillary nodes is still uncertain. This study investigated the value of PMRT for these patients., Methods: In the retrospective data of 488 eligible patients, survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using a log-rank test and the Cox proportional hazards model, respectively., Results: The median observation time was 54 months. The 5- and 10-year locoregional recurrence-free survival (LRFS) rates were 90.8% and 86.9%, respectively. The 5- and 10-year disease-free survival (DFS) rates were 82.0% and 74.3%, respectively. The 5- and 10-year overall survival (OS) rates were 90.7% and 82.7%, respectively. For the 412 patients without PMRT, T2 classification, 2-3 positive nodes, and hormone (estrogen and progesterone) receptor-negative were risk factors for locoregional recurrence in the multivariate analysis. On the basis of these 3 risk factors, the group with 2-3 factors had a 10-year LRFS rate of 63.1% compared with 96.1% for the group with 0-1 factors (P < 0.001). For the group with 2-3 risk factors, LRFS and DFS were significantly improved by PMRT, with the 5- and 10-year LRFS rates without PMRT of 82.4% and 63.1%, respectively, and, with PMRT, of 98.1% at both 5 years and 10 years (P = 0.002). The 5- and 10-year DFS rates without PMRT were 72.0% and 57.6%, respectively, and, with PMRT, the 5- and 10-year DFS rates were 89.4% and 81.7%, respectively (P = 0.007). There was no significant difference in the 10-year OS rates between patients with and without PMRT. However, there is the potential benefit of 15.3% (87.1% vs. 71.8%, P = 0.072). Conversely, the group with 0-1 factors of PMRT had no effect on prognosis., Conclusions: In patients receiving mastectomy with T1-T2 breast cancer with 1-3 positive nodes, for the group with 2-3 risk factors, PMRT significantly improved LRFS and DFS and has potential benefit in OS.

Background and Objective: The role of adjuvant radiotherapy to the regional nodes in women with T1 to T2 breast cancer and one to three positive nodes is controversial. This study compared and analyzed the prognosis of patients with T1-T2 breast cancer with one to three positive nodes after modified radical mastectomy with or without postoperative radiotherapy., Methods: The cases of 434 women patients with T1 to T2 breast cancer with one to three positive lymph nodes after modified radical mastectomy were reviewed, of which 196 patients received postoperative radiotherapy and 238 patients did not. The ipsilateral chest wall and supraclavicular fossa were irradiated with doses of 46-50 Gy in 23-25 fractions., Results: For all patients, the 3- and 5-year rates of overall survival (OS) were 94.7% and 85.7% respectively, local control (LC) 96.5% and 95.6%;, and disease-free survival (DFS) 89.3% and 82.3% respectively. The 3- and 5-year OS rates for patients without radiotherapy were 92.7% and 97.1% and for those with radiotherapy were 82.4% and 89.2%, both with significant differences (P = 0.039). The 3- and 5-year LC rates for patients without radiotherapy were 94.8% and 98.4% and for those with radiotherapy were 93.6% and 97.7%, again with significant differences (P = 0.041). The 3- and 5-year DFS rates for patients without radiotherapy were 87.8% and 91.3% and for patients with radiotherapy were 78.5% vs 86.1% (P = 0.047)., Conclusions: Postoperative radiotherapy confers better rates of OS, LC, and DFS in patients with T1 to T2 breast cancer with one to three positive nodes after modified radical mastectomy.