Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial.

BACKGROUND: Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS: We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS: Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION: Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING: German Cancer Aid, Germany.

Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial.

BACKGROUND: Previous results from the GEC-ESTRO trial showed that accelerated partial breast irradiation (APBI) using multicatheter brachytherapy in the treatment of early breast cancer after breast-conserving surgery was non-inferior to whole-breast irradiation in terms of local control and overall survival. Here, we present 5-year results of patient-reported quality of life. METHODS: We did this randomised controlled phase 3 trial at 16 hospitals and medical centres in seven European countries. Patients aged 40 years or older with 0-IIA breast cancer were randomly assigned (1:1) after breast-conserving surgery (resection margins ≥2 mm) to receive either whole-breast irradiation of 50 Gy with a boost of 10 Gy or APBI using multicatheter brachytherapy. Randomisation was stratified by study centre, tumour type, and menopausal status, with a block size of ten and an automated dynamic algorithm. There was no masking of patients or investigators. The primary endpoint of the trial was ipsilateral local recurrence. Here, we present 5-year results of quality of life (a prespecified secondary endpoint). Quality-of-life questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30, breast cancer module QLQ-BR23) were completed before radiotherapy (baseline 1), immediately after radiotherapy (baseline 2), and during follow-up. We analysed the data according to treatment received (as-treated population). Recruitment was completed in 2009, and long-term follow-up is continuing. The trial is registered at ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 633 patients had accelerated partial breast irradiation and 551 patients had whole-breast irradiation. Quality-of-life questionnaires at baseline 1 were available for 334 (53%) of 663 patients in the APBI group and 314 (57%) of 551 patients in the whole-breast irradiation group; the response rate was similar during follow-up. Global health status (range 0-100) was stable in both groups: at baseline 1, APBI group mean score 65·5 (SD 20·6) versus whole-breast irradiation group 64·6 (19·6), p=0·37; at 5 years, APBI group 66·2 (22·2) versus whole-breast irradiation group 66·0 (21·8), p=0·94. The only moderate, significant difference (difference of 10-20 points) between the groups was found in the breast symptoms scale. Breast symptom scores were significantly higher (ie, worse) after whole-breast irradiation than after APBI at baseline 2 (difference of means 13·6, 95% CI 9·7-17·5; p<0·0001) and at 3-month follow-up (difference of means 12·7, 95% CI 9·8-15·6; p<0·0001). INTERPRETATION: APBI with multicatheter brachytherapy was not associated with worse quality of life compared with whole-breast irradiation. This finding supports APBI as an alternative treatment option after breast-conserving surgery for patients with early breast cancer. FUNDING: German Cancer Aid.

Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.

BACKGROUND: We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS: We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. INTERPRETATION: 5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. FUNDING: German Cancer Aid.

GEC-ESTRO multicenter phase 3-trial: Accelerated partial breast irradiation with interstitial multicatheter brachytherapy versus external beam whole breast irradiation: Early toxicity and patient compliance.

BACKGROUND AND PURPOSE: To compare early side effects and patient compliance of accelerated partial breast irradiation (APBI) with multicatheter brachytherapy to external beam whole breast irradiation (WBI) in a low-risk group of patients with breast cancer. MATERIAL AND METHODS: Between April 2004 and July 2009, 1328 patients with UICC stage 0-IIA breast cancer were randomized to receive WBI with 50Gy and a boost of 10Gy or APBI with either 32.0Gy/8 fractions, or 30.1Gy/7 fractions (HDR-brachytherapy), or 50Gy/0.60-0.80Gy per pulse (PDR-brachytherapy). This report focuses on early side-effects and patient compliance observed in 1186 analyzable patients. ClinicalTrials.gov identifier: NCT00402519. RESULTS: Patient compliance was excellent in both arms. Both WBI and APBI were well tolerated with moderate early side-effects. No grade 4 toxicity had been observed. Grade 3 side effects were exclusively seen for early skin toxicity (radiation dermatitis) with 7% vs. 0.2% (p<0.0001), and breast infection with 0% vs. 0.2% (p=n.s.) for patients treated with WBI and APBI. The incidence of grades 1-2 early side effects for WBI and APBI was 86% vs. 21% (p<0.0001) for skin toxicity, 2% vs. 20% (p<0.0001) for mild hematoma, and 2% vs. 5% (p=0.01) for mild breast infection rates, respectively. No differences had been found regarding grades 1-2 early breast pain (26% vs. 29%, p=0.23). CONCLUSIONS: APBI with interstitial multicatheter brachytherapy was tolerated very well and dramatically reduced early skin toxicity in comparison to standard WBI.

Impact of heterogeneity-corrected dose calculation using a grid-based Boltzmann solver on breast and cervix cancer brachytherapy.

PURPOSE: To analyze the impact of heterogeneity-corrected dose calculation on dosimetric quality parameters in gynecological and breast brachytherapy using Acuros, a grid-based Boltzmann equation solver (GBBS), and to evaluate the shielding effects of different cervix brachytherapy applicators. MATERIAL AND METHODS: Calculations with TG-43 and Acuros were based on computed tomography (CT) retrospectively, for 10 cases of accelerated partial breast irradiation and 9 cervix cancer cases treated with tandem-ring applicators. Phantom CT-scans of different applicators (plastic and titanium) were acquired. For breast cases the V20Gyαß3 to lung, the D0.1cm(3) , D1cm(3) , D2cm(3) to rib, the D0.1cm(3) , D1cm(3) , D10cm(3) to skin, and Dmax for all structures were reported. For cervix cases, the D0.1cm(3) , D2cm(3) to bladder, rectum and sigmoid, and the D50, D90, D98, V100 for the CTVHR were reported. For the phantom study, surrogates for target and organ at risk were created for a similar dose volume histogram (DVH) analysis. Absorbed dose and equivalent dose to 2 Gy fractionation (EQD2) were used for comparison. RESULTS: Calculations with TG-43 overestimated the dose for all dosimetric indices investigated. For breast, a decrease of ~8% was found for D10cm(3) to the skin and 5% for D2cm(3) to rib, resulting in a difference ~ -1.5 Gy EQD2 for overall treatment. Smaller effects were found for cervix cases with the plastic applicator, with up to -2% (-0.2 Gy EQD2) per fraction for organs at risk and -0.5% (-0.3 Gy EQD2) per fraction for CTVHR. The shielding effect of the titanium applicator resulted in a decrease of 2% for D2cm(3) to the organ at risk versus 0.7% for plastic. CONCLUSIONS: Lower doses were reported when calculating with Acuros compared to TG-43. Differences in dose parameters were larger in breast cases. A lower impact on clinical dose parameters was found for the cervix cases. Applicator material causes systematic shielding effects that can be taken into account.

5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.

BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING: German Cancer Aid.

Interobserver variations of target volume delineation in multicatheter partial breast brachytherapy after open cavity surgery.

PURPOSE: To investigate interobserver variations of target volume delineations in accelerated partial breast irradiation with multicatheter brachytherapy (BT) and to assess the impact of guidelines on consistency of contouring. METHODS AND MATERIALS: A contouring study with two phases in interstitial accelerated partial breast irradiation after open cavity surgery was conducted by the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology Breast Cancer Working Group. Contours of cavity and planning target volume (PTV) on preimplant and postimplant CT images were delineated. In Phase 1, nine radiation oncologists defined the target volumes of 5 patients, whereas in Phase 2, four observers draw the contours of 4 patients applying guidelines. In Phase 1, experience in breast BT after open cavity surgery was assessed. The delineations were compared between Phase 1 and Phase 2, the impact of guidelines was assessed, and cavity visualization score was related to consistency of delineations. RESULTS: Significant interobserver variability in delineations of lumpectomy cavity and PTV was observed among the participants. Observers with BT experience after open cavity surgery outlined the cavity and PTV more consistently (conformity indexgen: 0.52 vs. 0.48 and 0.59 vs. 0.55 for preimplant and postimplant cavities). For all volumes, the mean Vmax/Vmin was 2.2 vs. 2.8. Having used guidelines all conformity indices increased significantly. For cavity, the increase was 14% and 11%, whereas for the PTV, 28% and 17% on the preimplant and postimplant CT images, respectively. A strong correlation was found between consistency of contours and cavity visualization score. CONCLUSIONS: Simple guidelines on defining the lumpectomy cavity significantly increased the consistency of contouring. Reliable consistency of target volume definition can be expected only for good cavity visibility.

Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery.

OBJECTIVE: The aim was to develop a delineation guideline for target definition for APBI or boost by consensus of the Breast Working Group of GEC-ESTRO. PROPOSED RECOMMENDATIONS: Appropriate delineation of CTV (PTV) with low inter- and intra-observer variability in clinical practice is complex and needs various steps as: (1) Detailed knowledge of primary surgical procedure, of all details of pathology, as well as of preoperative imaging. (2) Definition of tumour localization before breast conserving surgery inside the breast and translation of this information in the postoperative CT imaging data set. (3) Calculation of the size of total safety margins. The size should be at least 2 cm. (4) Definition of the target. (5) Delineation of the target according to defined rules. CONCLUSION: Providing guidelines based on the consensus of a group of experts should make it possible to achieve a reproducible and consistent definition of CTV (PTV) for Accelerated Partial Breast Irradiation (APBI) or boost irradiation after breast conserving closed cavity surgery, and helps to define it after selected cases of oncoplastic surgery.

Is oncoplastic surgery a contraindication for accelerated partial breast radiation using the interstitial multicatheter brachytherapy method?

PURPOSE: To evaluate accelerated partial breast irradiation (APBI) in patients after oncoplastic surgery for early breast cancer. METHODS AND MATERIALS: A retrospective analysis of 136 breasts of 134 patients, who received breast-conserving oncoplastic surgery for low-risk breast cancer between 2002 and 2010 in the Universities of Vienna and Luebeck followed by adjuvant APBI applying total doses of pulse dose rate of 50.4 Gy or high-dose rate (HDR) of 32 Gy over 4 days. Target volume definition was performed by the use of surgical-free margin data, related to intraoperatively fixed clip positions, pre- and postoperative imaging, and palpation. RESULTS: At the time of data acquisition, 131 of 134 patients were alive. The median follow-up time was 39 months (range, 4-106 months). After high-dose rate treatment, 3 of 89 patients showed systemic progress after a mean follow-up of 47 months (range, 19-75 months) and 2 patients had a different quadrant in-breast tumor after 27 and 35 months. One patient died 7 months after treatment of unknown causes. After pulse dose rate treatment, 1 of 45 patients had a local recurrence after 42 months and 1 patient died because of another cause after 13 months. We observed mild fibrosis in 27 breasts, telangiectasia in 6, hyperpigmentation in 14 cases, and keloid formation in 1. CONCLUSIONS: These preliminary results suggest the feasibility of multicatheter APBI after oncoplastic breast-conserving surgery in selected low-risk breast cancer patients; however, special attention to target volume definition is needed. Further prospective investigations with long follow-up are needed to define the real value of the procedure.

Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group.

PURPOSE: To analyse the clinical outcome after salvage lumpectomy and multi-catheter brachytherapy (MCB) for ipsilateral breast tumour recurrence (IBTR). MATERIAL AND METHODS: Between 09/00 and 09/10, 217 patients presenting an IBTR underwent lumpectomy and MCB (low, pulsed, or high-dose rate). Survival rates without second local recurrence (2nd LR), distant metastasis (DM), and overall survival (OS) were analysed as well as late effects and cosmetic results. Univariate and multivariate analyses (MVA) based on IBTR data were performed to find prognostic factors for 2nd LR, DM, and OS. RESULTS: Median follow-up after the IBTR was 3.9 years [range: 1.1-10.3]. Five and 10-year actuarial 2nd LR rates were 5.6% [range: 1.5-9.5] and 7.2% [range: 2.1-12.1], respectively. Five and 10-year actuarial DM rates were 9.6% [range: 5.7-15.2] and 19.1% [range: 7.8-28.3], respectively. Five and 10-year actuarial OS rates were 88.7% [range: 83.1-94.8] and 76.4% [range: 66.9-87.3], respectively. In MVA, histological grade was prognostic factor for 2nd LR (p=0.008) and OS (p=0.02); while tumour size was prognostic factor for DM (p=0.03). G3-4 complication rate was 11%. Excellent/good cosmetic result was achieved in 85%. CONCLUSION: This study suggests that in case of IBTR, lumpectomy plus MCB is feasible and effective in preventing 2nd LR with an OS rate at least equivalent to those achieved with salvage mastectomy.

German, Austrian and Swiss consensus conference on the diagnosis and local treatment of the axilla in breast cancer.

The German, Austrian and Swiss (D.A.CH) Societies of Senology gathered together in 2012 to address dwelling questions regarding axillary clearance in breast cancer patients. The Consensus Panel consisted of 14 members of these societies and included surgical oncologists, gynaecologists, pathologists and radiotherapists. With regard to omitting axillary lymph node dissection in sentinel lymph node macrometastases, the Panel consensually accepted this option for low-risk patients only. A simple majority voted against extending radiotherapy to the axilla after omitting axillary dissection in N1 disease. Consensus was yielded for the use of axillary ultrasound and prospective registers for such patients in the course of follow-up. The questions regarding neoadjuvant therapy and the timing of sentinel lymph node biopsy failed to yield consensus, yet both options (before or after) are possible in clinically node-negative disease.

Partial breast irradiation for locally recurrent breast cancer within a second breast conserving treatment: alternative to mastectomy? Results from a prospective trial.

PURPOSE: To assess the outcome of multi-catheter pulse dose rate (PDR) brachytherapy of re-irradiation for local ipsilateral breast tumour recurrence (IBTR) in regard to local control, survival, morbidity and quality of life (QoL). PATIENTS AND METHODS: Between 1999 and 2006, 39 patients were included with histologically confirmed IBTR, Karnofsky index ≥80% and refusal of mastectomy. Exclusion criteria were multicentric invasive growth pattern, unclear surgical margins, distant metastasis and a postoperative breast not suitable for interstitial brachytherapy. Primary endpoint was local tumour control. Morbidity, cosmetic outcome and QoL were assessed in 24/39 patients. RESULTS: The five year actuarial local control rate was 93% after a mean follow up of 57 (±30) months with two second local relapses. Overall survival and disease free survival, both at 5 years, were 87% and 77%, respectively. Late side effects Grade 1-2 were observed in 20/24 patients after a mean follow-up of 30 (±18) months. Late side effects ≥Grade 3 occurred in 4/24 patients. Cosmetic outcome was excellent to fair in 76% of women. Overall QoL was comparable to a healthy control group. Mean scores of scales and items of QLQ-BR23 were comparable to primary breast conserving therapy. CONCLUSIONS: Accelerated PDR-brachytherapy following breast conserving surgery (BCS) for local IBTR results in local tumour control comparable to mastectomy. Morbidity is moderate; the cosmetic outcome is good and hardly any impairment on QoL is observed.

Accelerated partial breast irradiation with interstitial implants: risk factors associated with increased local recurrence.

PURPOSE: To analyze patient, disease, and treatment-related factors regarding their impact on local control after interstitial multicatheter accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Between November 2000 and April 2005, 274 patients with early breast cancer were recruited for the German-Austrian APBI Phase II trial (ClinicalTrials.gov identifier: NCT00392184). In all, 64% (175/274) of the patients received pulsed-dose-rate (PDR) brachytherapy and 36% (99/274) received high-dose-rate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 3 to 4 days. RESULTS: The median follow-up time was 64 months (range, 9-110). The actuarial 5-year local recurrence free survival rate (5-year LRFS) was 97.7%. Comparing patients with an age <50 years (49/274) vs. ≥50 years (225/274), the 5-year LRFS resulted in 92.5% and 98.9% (exact p = 0.030; 99% confidence interval, 0.029-0.032), respectively. Antihormonal treatment (AHT) was not applied in 9% (24/274) of the study population. The 5-year LRFS was 99% and 84.9% (exact p = 0.0087; 99% confidence interval, 0.0079-0.0094) in favor of the patients who received AHT. Lobular histology (45/274) was not associated with worse local control compared with all other histologies (229/274). The 5-year LRFS rates were 97.6% and 97.8%, respectively. CONCLUSIONS: Local control at 5 years is excellent and comparable to therapeutic successes reported from corresponding whole-breast irradiation trials. Our data indicate that patients <50 years of age ought to be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology need not be an exclusion criterion for future APBI trials.

Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breast-conserving surgery.

PURPOSE: To evaluate the impact of accelerated partial breast irradiation on local control, side effects, and cosmesis using multicatheter interstitial brachytherapy as the sole method for the adjuvant local treatment of patients with low-risk breast cancer. METHODS AND MATERIALS: 274 patients with low-risk breast cancer were treated on protocol. Patients were eligible for the study if the tumor size was < 3 cm, resection margins were clear by at least 2 mm, no lymph node metastases existed, age was >35 years, hormone receptors were positive, and histologic grades were 1 or 2. Of the 274 patients, 175 (64%) received pulse-dose-rate brachytherapy (D(ref) = 50 Gy). and 99 (36%) received high-dose-rate brachytherapy (D(ref) = 32.0 Gy). RESULTS: Median follow-up was 63 months (range, 9-103). Only 8 of 274 (2.9%) patients developed an ipsilateral in-breast tumor recurrence at the time of analysis. The 5-year actuarial local recurrence-free survival probability was 98%. The 5- year overall and disease-free survival probabilities of all patients were 97% and 96%, respectively. Contralateral in-breast malignancies were detected in 2 of 274 (0.7%) patients, and distant metastases occurred in 6 of 274 (2.2%). Late side effects ≥ Grade 3 (i.e., breast tissue fibrosis and telangiectasia) occurred in 1 patient (0.4%, 95%CI:0.0-2.0%) and 6 patients (2.2%, 95%CI:0.8-4.7%), respectively. Cosmetic results were good to excellent in 245 of 274 patients (90%). CONCLUSIONS: The long-term results of this prospective Phase II trial confirm that the efficacy of accelerated partial breast irradiation using multicatheter brachytherapy is comparable with that of whole breast irradiation and that late side effects are negligible.

Accelerated partial breast irradiation with multi-catheter brachytherapy: Local control, side effects and cosmetic outcome for 274 patients. Results of the German-Austrian multi-centre trial.

BACKGROUND AND PURPOSE: To evaluate the safety and effectiveness of accelerated partial breast irradiation (APBI) with multi-catheter brachytherapy. PATIENTS AND METHODS: Between 11/2000 and 04/2005, 274 patients participated. Patients were eligible for APBI if they had histologically confirmed breast cancer, a tumour diameter 3cm, complete resection with clear margins 2mm, negative axillary lymph nodes or singular nodal micro-metastasis, no distant metastases, hormone receptor-positive tumours, and were >/= 35 years. Patients were excluded if mammographically they showed a multicentric invasive growth pattern, poorly differentiated tumours, residual diffuse micro-calcifications, extensive intraductal component, or vessel invasion. Median follow-up was 32 months (range; 8-68). RESULTS: The local control rate was 99.3% (272/274), the 3 year-local-recurrence-free survival probability, 99.6%. Peri-operative complications occurred in 5.5% (15/274): 9 (3.3%) experienced implant infection and 6 (2.2%) hematoma. Acute toxicity (Grade 1/2 radio-dermatitis) was seen in 6.6% (18/274). Late side effects >/= Grade 3 (fibrosis, telangiectasia) occurred in 1.8% (4/274). Cosmetic results were excellent/good in 94% (253/274). CONCLUSIONS: This analysis underlined the safety and effectiveness of APBI in a carefully selected subgroup with favourable disease characteristics. Of course, longer follow-up and randomised trials are necessary to conclusively assess the potential of APBI.

Interstitial brachytherapy alone after breast conserving surgery: interim results of a German-Austrian multicenter phase II trial.

PURPOSE: To evaluate the value of interstitial brachytherapy (iBT) alone in the treatment of low-risk breast cancer patients with regard to local control, side effects, and cosmesis. METHODS AND MATERIALS: From November 2000 to January 2004, 176 patients with low-risk breast cancer were treated with iBT only. Patients were eligible for entering the study if: the tumor size was <3 cm; resection margins were clear by at least 2 mm; there were no lymph node metastases or only one micrometastasis (pNo, pNmi); age was >35 years; steroid hormone receptor was positive; and histologic grade was 1 or 2. Seventy-five percent of patients received pulsed-dose-rate brachytherapy (D(ref) = 50 Gy); 25% of patients received high-dose-rate brachytherapy (D(ref) = 32.0 Gy). An interim analysis is presented for all patients after an interim follow-up of 12 months, and for half the patient population with an interim follow-up of 21 months. RESULTS: All patients remained disease-free on the date of analysis. A perioperative complication breast infection was recorded for 1/176 (0.6%) patients. Late toxicity i.e., hypersensation, hyperpigmentation, fibrosis, or teleangiectasia was observed in 1-12% of all patients. Grade I Fibrosis was registered in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Similarly, grade I teleangiectasia was observed in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92-95% of patients. CONCLUSIONS: Brachytherapy as monotherapy in low-risk breast cancer patients after breast-conserving surgery is an effective, precise treatment modality without perioperative morbidity, low acute, mild late toxicity, and yields good to excellent cosmetic results.

Accelerated partial breast irradiation with iridium-192 multicatheter PDR/HDR brachytherapy. Preliminary results of the German-Austrian multicenter trial.

PURPOSE: To evaluate perioperative morbidity, toxicity, and cosmetic outcome in patients treated with interstitial brachytherapy to the tumor bed as the sole irradiation modality after breast-conserving surgery. PATIENTS AND METHODS: From November 1, 2000 to January 31, 2004, 176 women with early-stage breast cancer became partakers in a protocol of tumor bed irradiation alone using pulsed-dose-rate (PDR) or high-dose-rate (HDR) interstitial multicatheter implants. Patients became eligible, if their tumor was an infiltrating carcinoma < or = 3 cm in diameter, the surgical margins were clear by at least 2 mm, the axilla was surgically staged node-negative, the tumor was estrogen and/or progesterone receptor-positive, well or moderately differentiated (G1/2), the tumor did not contain an extensive intraductal component (EIC) and the patient's age was > 35 years. Implants were positioned using a template guide, delivering either 49.8 Gy in 83 consecutive hours (PDR) or 32.0 Gy in two daily fractions over 4 days (HDR). Perioperative morbidity, toxicity, and cosmetic outcome were assessed. Interim findings of the first 69 patients, who were treated in this multicenter trial, after a median follow-up of 24 months (range, 15-39 months) are presented. RESULTS: One of the 69 patients (1.4%) developed a bacterial infection of the implant. No other perioperative complications, for example bleeding or hematoma, were observed. Acute toxicity was low: 2.9% of the patients (2/69) experienced mild radiodermatitis. Late toxicity: hypersensation/mild pain 7.2% (5/69), intermittent but tolerable pain 1.4% (1/69), mild dyspigmentation 10.1% (7/69), mild fibrosis 11.6% (8/69), moderate fibrosis 1.4% (1/69), mild telangiectasia (< 1 cm(2)) 11.6% (8/69), and moderate teleangiectasia (1-4 cm(2)) 1.4% (1/69). Good to excellent cosmetic results were observed in 92.4% of the patients evaluated. All patients (n = 176) remained disease-free to the date of evaluation. CONCLUSION: This analysis indicates that accelerated partial breast irradiation with iridium-192 interstitial multicatheter PDR/HDR implants is feasible with low perioperative morbidity, low acute and mild late toxicity, and does not significantly affect cosmetic results at a median follow-up of 24 months.

Locally recurrent breast cancer: pulse dose rate brachytherapy for repeat irradiation following lumpectomy-- a second chance to preserve the breast.

PURPOSE: To perform and assess the effectiveness of local excision of recurrent tumor followed by postoperative pulse dose rate (PDR) brachytherapy. MATERIALS AND METHODS: From 1994 to 2000, 17 patients who had small recurrent breast carcinomas after initially undergoing breast-conserving therapy (BCT), which included postoperative radiation therapy, were treated with local tumor excision and PDR brachytherapy. Recurrences occurred at a median time of 50 months (range, 11-208 months) after primary treatment. Eight patients underwent a combination of PDR brachytherapy (total dose range, 12.5-28.0 Gy) and external-beam radiation therapy (EBT) (total dose range, 12-30 Gy). Nine patients underwent radiation therapy with 40.2-50.0-Gy PDR brachytherapy only. The prescribed radiation dose was 0.5-1.0 Gy per pulse. Patients were examined for local tumor control and treatment-related side effects. RESULTS: Twelve of 17 patients had no local tumor at a median follow-up time of 59 months (range, 20-84 months); two of these patients showed signs of having distant disease. One patient died after a cerebral stroke without evidence of tumor. Four women treated with combined EBT and brachytherapy had secondary local tumor recurrences 4, 8, 8, and 11 months after therapy and had to undergo mastectomy. Despite having undergone radiation therapy previously, patients had side effects limited to moderate (grade 1-2) fibrosis. CONCLUSION: Local tumor excision combined with PDR brachytherapy for small local-regional tumor recurrences after primary BCT is feasible and well tolerated and might obviate mastectomy. Preliminary experiences are encouraging. Further studies are required for appropriate patient selection.

Oligodendroglial cells in culture effectively dispose of exogenous hydrogen peroxide: comparison with cultured neurones, astroglial and microglial cells.

To investigate the antioxidative capacities of oligodendrocytes, rat brain cultures enriched for oligodendroglial cells were prepared and characterized. These cultures contained predominantly oligodendroglial cells as determined by immunocytochemical staining for the markers galactocerebroside and myelin basic protein. If oligodendroglial cultures were exposed to exogenous hydrogen peroxide (100 micro m), the peroxide disappeared from the incubation medium following first order kinetics with a half-time of approximately 18 min. Normalization of the disposal rate to the protein content of the cultures by calculation of the specific hydrogen peroxide detoxification rate constant revealed that the cells in oligodendroglial cultures have a 60% to 120% higher specific capacity to dispose of hydrogen peroxide than cultures enriched for astroglial cells, microglial cells or neurones. Oligodendroglial cultures contained specific activities of 133.5 +/- 30.4 nmol x min(-1) x mg protein(-1) and 27.5 +/- 5.4 nmol x min(-1) x mg protein(-1) of glutathione peroxidase and glutathione reductase, respectively. The specific rate constant of catalase in these cultures was 1.61 +/- 0.54 min(-1) x mg protein(-1). Comparison with data obtained by identical methods for cultures of astroglial cells, microglial cells and neurones revealed that all three of the enzymes which are involved in hydrogen peroxide disposal were present in oligodendroglial cultures in the highest specific activities. These results demonstrate that oligodendroglial cells in culture have a prominent machinery for the disposal of hydrogen peroxide, which is likely to support the protection of these cells in brain against peroxides when produced by these or by surrounding brain cells.

Long-term results (10 years) of intensive breast conserving therapy including a high-dose and large-volume interstitial brachytherapy boost (LDR/HDR) for T1/T2 breast cancer.

BACKGROUND AND PURPOSE: During the past 15 years many retrospective studies and prospective randomized trials have been published supporting the use of breast conserving treatment (BCT) including surgery and radiotherapy. However, there are still many controversies on the necessary amount of resection, the width of the resection margins and the optimal radiation technique, dose and volume, in particular of the boost. In this retrospective study a large cohort of 410 women with early breast cancer treated with BCT including an interstitial brachytherapy (BT) boost is evaluated after a long follow-up period. MATERIAL AND METHODS: In order to clarify the impact of the different treatment-related factors on local control, these were carefully discriminated, based on widely accepted classification and reporting systems for surgery as well as for radiotherapy. The surgical approach was classified according to EORTC criteria and a high rate of quadrantectomies (60%) was found. Dose and volume of interstitial BT is reported according to recommendations of ICRU 58, and reveals a significant radiation dose and volume: minimum target dose, mean central dose (MCD) and '85% of MCD' for low-dose rate (LDR) BT was mean 20, 28 and 24 Gy, for high-dose rate (HDR) BT it was mean '10, 15 and 13 Gy, respectively; the treated volume was 104 cc for LDR BT and 83 cc for HDR BT. RESULTS: The actuarial rates for overall survival, disease-free survival and disease-specific survival were 97, 90 and 98% at 5 years and 85, 79 and 92% at 10 years. There have been only 16 breast recurrences in 410 treated patients resulting in a 5- and 10-year actuarial local recurrence rate of 2 and 3.9%, respectively; six recurrences (1.5%) were in the original quadrant. Except age and menopausal status, all tumour- and patient-related risk factors had no significant impact on local control. CONCLUSIONS: Our data confirm that intensive BCT leads to excellent long-term results in terms of local control, masking classical risk factors. This high-dose and large-volume interstitial BT seems to be superior to classical BCT without BT.