Investigating the impact of breast positioning control on physical treatment parameters in multi-catheter breast brachytherapy.

PURPOSE: To assess the effects of a workflow for reproducible patient and breast positioning on implant stability during high-dose-rate multi-catheter breast brachytherapy. METHODS: Thirty patients were treated with our new positioning control workflow. Implant stability was evaluated based on a comparison of planning-CTs to control-CTs acquired halfway through the treatment. To assess geometric stability, button-button distance variations as well as Euclidean dwell position deviations were evaluated. The latter were also quantified within various separated regions within the breast to investigate the location-dependency of implant alterations. Furthermore, dosimetric variations to target volume and organs at risk (ribs, skin) as well as isodose volume changes were analyzed. Results were compared to a previously treated cohort of 100 patients. RESULTS: With the introduced workflow, the patient fraction affected by button-button distance variations > 5 mm and by dwell position deviations > 7 mm were reduced from 37% to 10% and from 30% to 6.6%, respectively. Implant stability improved the most in the lateral to medial breast regions. Only small stability enhancements were observed regarding target volume dosimetry, but the stability of organ at risk exposure became substantially higher. D0.2ccm skin dose variations > 12.4% and D0.1ccm rib dose variations > 6.7% were reduced from 11% to 0% and from 16% to 3.3% of all patients, respectively. CONCLUSION: Breast positioning control improved geometric and dosimetric implant stability for individual patients, and thus enhanced physical plan validity in these cases.

Initial needle tracking with the first standalone combined infrared camera - CT system for brachytherapy-analysis of tracking accuracy and uncertainties.

PURPOSE: A prototype infrared camera - cone-beam computed tomography (CBCT) system for tracking in brachytherapy has recently been developed. We evaluated for the first time the corresponding tracking accuracy and uncertainties, and implemented a tracking-based prediction of needles on CBCT scans. METHODS: A marker tool rigidly attached to needles was 3D printed. The precision and accuracy of tool tracking was then evaluated for both static and dynamic scenarios. Euclidean distances between the tracked and CBCT-derived markers were assessed as well. To implement needle tracking, ground truth models of the tool attached to 200 mm and 160 mm needles were matched to the tracked positions in order to project the needles into CBCT scans. Deviations between projected and actual needle tips were measured. Finally, we put our results into perspective with simulations of the system's tracking uncertainties. RESULTS: For the stationary scenario and dynamic movements, we achieved tool-tracking precision and accuracy of 0.04 ± 0.06 mm and 0.16 ± 0.18 mm, respectively. The tracked marker positions differed by 0.52 ± 0.18 mm from the positions determined via CBCT. In addition, the predicted needle tips in air deviated from the actual tip positions by only 1.62 ± 0.68 mm (200 mm needle) and 1.49 ± 0.62 mm (160 mm needle). The simulated tracking uncertainties resulted in tip variations of 1.58 ± 0.91 mm and 1.31 ± 0.69 mm for the 200 mm and 160 mm needles, respectively. CONCLUSION: With the innovative system it was possible to achieve a high tracking and prediction accuracy of marker tool and needles. The system shows high potential for applicator tracking in brachytherapy.

DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.

PURPOSE: The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. MATERIALS AND METHODS: For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). CONCLUSION AND RECOMMENDATIONS: Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

First implementation of an innovative infra-red camera system integrated into a mobile CBCT scanner for applicator tracking in brachytherapy-Initial performance characterization.

PURPOSE: To enable a real-time applicator guidance for brachytherapy, we used for the first time infra-red tracking cameras (OptiTrack, USA) integrated into a mobile cone-beam computed tomography (CBCT) scanner (medPhoton, Austria). We provide the first description of this prototype and its performance evaluation. METHODS: We performed assessments of camera calibration and camera-CBCT registration using a geometric calibration phantom. For this purpose, we first evaluated the effects of intrinsic parameters such as camera temperature or gantry rotations on the tracked marker positions. Afterward, calibrations with various settings (sample number, field of view coverage, calibration directions, calibration distances, and lighting conditions) were performed to identify the requirements for achieving maximum tracking accuracy based on an in-house phantom. The corresponding effects on camera-CBCT registration were determined as well by comparing tracked marker positions to the positions determined via CBCT. Long-term stability was assessed by comparing tracking and a ground-truth on a weekly basis for 6 weeks. RESULTS: Robust tracking with positional drifts of 0.02 ± 0.01 mm was feasible using the system after a warm-up period of 90 min. However, gantry rotations affected the tracking and led to inaccuracies of up to 0.70 mm. We identified that 4000 samples and full coverage were required to ensure a robust determination of marker positions and camera-CBCT registration with geometric deviations of 0.18 ± 0.03 mm and 0.42 ± 0.07 mm, respectively. Long-term stability showed deviations of more than two standard deviations from the initial calibration after 3 weeks. CONCLUSION: We implemented for the first time a standalone combined camera-CBCT system for tracking in brachytherapy. The system showed high potential for establishing corresponding workflows.

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.

Survey on brachytherapy training among radiation oncology residents in the German-speaking regions of Europe.

PURPOSE: This survey aimed to determine the perception of brachytherapy training among residents in the DACH region, consisting of Austria, Germany and Switzerland. MATERIAL & METHODS: An online questionnaire containing 22 questions related to trainee demographics (n = 5) and to brachytherapy training (n = 17) was sent in two iterations in 11/2019 and 02/2020. The following topics were evaluated: institutional support, barriers to training, extent of training, site-specific training (prostate, gynaecology, breast, gastrointestinal and skin), preferences for further training and outlook on overall development of brachytherapy. The responses were mostly based on a Likert scale of 1 to 5, thereby reflecting strength of opinion. Descriptive statistics were used to describe frequencies. RESULTS: Among the 108 respondents, approximately 69% of residents considered the ability to perform brachytherapy independently to be important or somewhat important. However, only 31% of respondents reported to have a dedicated brachytherapy training during residency. The major limitation to achieve independence in performing brachytherapy was seen in a low case load in Austria, in the lack of training in Switzerland and in both of them in Germany. CONCLUSION: The interest in brachytherapy training among residents in German-speaking countries was generally high, but there is a perceived lack of sufficient case volumes and partially also in formal training opportunities. Fellowships at departments with a high case load as part of a formalised curriculum and dedicated hands-on workshops at national or international conferences might help to overcome these issues.

First clinical experience with a novel, mobile cone-beam CT system for treatment quality assurance in brachytherapy.

BACKGROUND AND PURPOSE: On-site cone-beam computed tomography (CBCT) has gained in importance in adaptive brachytherapy during recent years. Besides treatment planning, there is increased need particularly for image-guidance during interventional procedures and for image-guided treatment quality assurance (QA). For this purpose, an innovative CBCT device was rolled out at our hospital as the first site worldwide. We present the first clinical images and experiences. MATERIALS AND METHODS: The novel CBCT system is constructed of a 121 cm diameter ring gantry, and features a 43.2â€¯× 43.2 cm2 flat-panel detector, wireless remote-control via tablet-PC, and battery-powered maneuverability. Within the first months of clinical operation, we performed CBCT-based treatment QA for a total of 26 patients (8 with breast, 16 with cervix, and 2 with vaginal cancer). CBCT scans were analyzed regarding potential movements of implanted applicators in-situ during the brachytherapy course. RESULTS: With the presented device, treatment QA was feasible for the majority of patients. The CBCT scans of breast patients showed sufficient contrast between implanted catheters and tissue. For gynecologic patients, a distinct visualization of applicators was achieved in general. However, reasonable differentiations of organic soft tissues were not feasible. CONCLUSION: The CBCT system allowed basic treatment QA measures for breast and gynecologic patients. For image-guidance during interventional brachytherapy procedures, the current image quality is not adequate. Substantial performance enhancements are required for intraoperative image-guidance.

Technical evaluation of the cone-beam computed tomography imaging performance of a novel, mobile, gantry-based X-ray system for brachytherapy.

PURPOSE: A novel, mobile cone-beam computed tomography (CBCT) system for image-guided adaptive brachytherapy was recently deployed at our hospital as worldwide first site. Prior to the device's clinical operation, a profound characterization of its imaging performance was conducted. This was essential to optimize both the imaging workflow and image quality for achieving the best possible clinical outcomes. We present the results of our investigations. METHODS: The novel CBCT-system features a ring gantry with 121 cm clearance as well as a 43.2 × 43.2 cm2 flat-panel detector, and is controlled via a tablet-personal computer (PC). For evaluating its imaging performance, the geometric reproducibility as well as imaging fidelity, computed tomography (CT)-number accuracy, uniformity, contrast-noise-ratio (CNR), noise characteristics, and spatial resolution as fundamental image quality parameters were assessed. As dose metric the weighted cone-beam dose index (CBDIw ) was measured. Image quality was evaluated using standard quality assurance (QA) as well as anthropomorphic upper torso and breast phantoms. Both in-house and manufacturer protocols for abdomen, pelvis, and breast imaging were examined. RESULTS: Using the in-house protocols, the QA phantom scans showed altogether a high image quality, with high CT-number accuracy (R2  > 0.97) and uniformity (<12 Hounsfield Unit (HU) cupping), reasonable noise and imaging fidelity, and good CNR at bone-tissue transitions of up to 28:1. Spatial resolution was strongly limited by geometric instabilities of the device. The breast phantom scans fulfilled clinical requirements, whereas the abdomen and pelvis scans showed severe artifacts, particularly at air/bone-tissue transitions. CONCLUSION: With the novel CBCT-system, achieving a high image quality appears possible in principle. However, adaptations of the standard protocols, performance enhancements in image reconstruction referring to artifact reductions, as well as the extinction of geometric instabilities are imperative.

Post-neoadjuvant treatment with capecitabine and trastuzumab emtansine in breast cancer patients-sequentially, or better simultaneously?

PURPOSE: Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk settings. We reviewed the evidence for sequencing of postoperative radiation and chemotherapy, with a focus on a capecitabine and trastuzumab emtansine (T-DM1)-based regimen. METHODS: A systematic literature search using the PubMed/MEDLINE/Web of Science database was performed. We included prospective and retrospective reports published since 2015 and provided clinical data on toxicity and effectiveness. RESULTS: Six studies were included, five of which investigated capecitabine-containing regimens. Of these, four were prospective investigations and one a retrospective matched comparative analysis. One randomized prospective trial was found for T­DM1 and radiotherapy. In the majority of these reports, radiation-associated toxicities were not specifically addressed. CONCLUSION: Regarding oncologic outcome, the influence of sequencing radiation therapy with maintenance capecitabine chemotherapy in the post-neoadjuvant setting is unclear. Synchronous administration of capecitabine is feasible, but reports on possible excess toxicities are partially conflicting. Dose reduction of capecitabine should be considered, especially if normofractionated radiotherapy is used. In terms of tolerance, hypofractionated schedules seem to be superior in terms of toxicity in concurrent settings. T­DM1 can safely be administered concurrently with radiotherapy.

Moderate hypofractionation remains the standard of care for whole-breast radiotherapy in breast cancer: Considerations regarding FAST and FAST-Forward.

Moderate hypofractionation is the standard of care for adjuvant whole-breast radiotherapy after breast-conserving surgery for breast cancer. Recently, 10-year results from the FAST and 5­year results from the FAST-Forward trial evaluating adjuvant whole-breast radiotherapy in 5 fractions over 5 weeks or 1 week have been published. This article summarizes recent data for moderate hypofractionation and results from the FAST and FAST-Forward trial on ultra-hypofractionation. While the FAST trial was not powered for comparison of local recurrence rates, FAST-Forward demonstrated non-inferiority for two ultra-hypofractionated regimens in terms of local control. In both trials, the higher-dose experimental arms resulted in elevated rates of late toxicity. For the lower dose experimental arms of 28.5 Gy over 5 weeks and 26 Gy over 1 week, moderate or marked late effects were similar in the majority of documented items compared to the respective standard arms, but significantly worse in some subdomains. The difference between the standard arm and the 26 Gy of the FAST-Forward trial concerning moderate or marked late effects increased with longer follow-up in disadvantage of the experimental arm for most items. For now, moderate hypofractionation with 40-42.5 Gy over 15-16 fractions remains the standard of care for the majority of patients with breast cancer who undergo whole-breast radiotherapy without regional nodal irradiation after breast-conserving surgery.

Tumour-Infiltrating Inflammatory Cells in Early Breast Cancer: An Underrated Prognostic and Predictive Factor?

The role of tumour-infiltrating inflammatory cells (TIICs) in the disease progression of hormone-receptor-positive breast cancer (HR+ BC) is largely unclear since it is generally regarded as the least immunogenic BC subtype. This study investigated the prognostic significance of CD1a+ dendritic cells, CD20+ B cells, CD45RO+ memory T cells and CD4+ T-helper cells in HR+ BC. One hundred and forty-six patients were treated for early stage, distant-metastases-free HR+ BC in an accelerated partial breast irradiation (APBI) phase II trial. Immunohistochemistry was used to double-stain two adjoining sets of tissue microarrays from pre-RT (radiotherapy) tumour resection samples for CD1a/CD20 and CD45RO/CD4. Cell densities of CD1a+, CD20+, CD45RO+ and CD4+ TIICs in the stromal and intraepithelial compartment were registered semiautomatically. High densities of CD20+ and CD4+ TIICs were strongly associated with reduced disease-free survival (DFS), while high stromal CD45RO+ TIIC densities were indicators of subsequent successful treatment. An immunoscore based on CD20+ and CD45RO+ TIIC densities identified three different risk groups (p < 0.001). Thus, contrary to current assumptions, intratumoural immune cell composition might be an important prognostic indicator and a possible contributing factor in the outcome of HR+ BC and should be the subject of further research. Specifically, B-cell infiltration entailed an increased relapse rate and could play an important role in disease progression.

Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.

PURPOSE: To compare results after chemoradiotherapy with and without deep regional hyperthermia in patients with anal cancer. METHODS: Between 2000 and 2015, a total of 112 consecutive patients with UICC stage I-IV anal cancer received chemoradiotherapy with 5­fluororuracil and mitomycin C (CRT). In case of insufficient tumor response 4-6 weeks after chemoradiotherapy, patients received an interstitial pulsed-dose-rate brachytherapy boost. Additionally, 50/112 patients received hyperthermia treatments (HCRT). RESULTS: Median follow-up was 41 (2-165) months. After 5 years follow-up, overall (95.8 vs. 74.5%, P = 0.045), disease-free (89.1 vs. 70.4%, P = 0.027), local recurrence-free (97.7 vs. 78.7%, P = 0.006), and colostomy-free survival rates (87.7 vs. 69.0%, P = 0.016) were better for the HCRT group. Disease-specific, regional failure-free, and distant metastasis-free survival rates showed no significant differences. The adjusted hazard ratios for death were 0.25 (95% CI, 0.07 to 0.92; P = 0.036) and for local recurrence 0.14 (95% CI, 0.02 to 1.09; P = 0.06), respectively. Grades 3-4 early toxicities were comparable with the exception of hematotoxicity, which was higher in the HCRT group (66 vs. 43%, P = 0.032). Incidences of late side effects were similar with the exception of a higher telangiectasia rate in the HCRT group (38.0 vs. 16.1%, P = 0.009). CONCLUSION: Additional regional hyperthermia improved overall survival, local control, and colostomy rates. Its potential beneficial role has to be confirmed in a prospective randomized setting. Therefore, the HyCAN trial has already been established by our group and is currently recruiting patients (Clinicaltrials.gov identifier: NCT02369939).

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.

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.

Accelerated partial breast irradiation with external beam radiotherapy : First results of the German phase 2 trial.

BACKGROUND AND PURPOSE: To evaluate the feasibility and efficacy of external beam three-dimensional (3D) conformal accelerated partial breast irradiation (APBI) for selected patients with early breast cancer. PATIENTS AND METHODS: Between 2011 and 2016, 72 patients were recruited for this prospective phase 2 trial. Patients were eligible for APBI if they had histologically confirmed breast cancer or pure ductal carcinoma in situ (DCIS), a tumor diameter ≤3 cm, clear resection margins ≥2 mm, no axillary lymph node involvement, no distant metastases, tumor bed clips, and were aged ≥50 years. Patients were excluded if mammography showed a multicentric invasive growth pattern, or if they had residual diffuse microcalcifications postoperatively, an extensive intraductal component, or vessel invasion. Patients received 3D conformal external beam APBI with a total dose of 38 Gy in 10 fractions in 1-2 weeks. The trial had been registered at the German Clinical Trials Register, DRKS-ID: DRKS00004417. RESULTS: Median follow-up was 25.5 months (range 1-61 months). Local control was maintained in 71 of 72 patients. The 3­year local recurrence rate was 2.1% (95% confidence interval, CI: 0-6.1%). Early toxicity (grade 1 radiodermatitis) was seen in 34.7% (25/72). Late side effects ≥ grade 3 did not occur. Cosmetic results were rated as excellent/good in 96.7% (59/61). CONCLUSION: APBI with external beam radiotherapy techniques is feasible with low toxicity and, according to the results of the present and other studies, on the way to becoming a standard treatment option for a selected subgroup of patients.

Electromagnetic tracking (EMT) technology for improved treatment quality assurance in interstitial brachytherapy.

Electromagnetic Tracking (EMT) is a novel technique for error detection and quality assurance (QA) in interstitial high dose rate brachytherapy (HDR-iBT). The purpose of this study is to provide a concept for data acquisition developed as part of a clinical evaluation study on the use of EMT during interstitial treatment of breast cancer patients. The stability, accuracy, and precision of EMT-determined dwell positions were quantified. Dwell position reconstruction based on EMT was investigated on CT table, HDR table and PDR bed to examine the influence on precision and accuracy in a typical clinical workflow. All investigations were performed using a precise PMMA phantom. The track of catheters inserted in that phantom was measured by manually inserting a 5 degree of freedom (DoF) sensor while recording the position of three 6DoF fiducial sensors on the phantom surface to correct motion influences. From the corrected data, dwell positions were reconstructed along the catheter's track. The accuracy of the EMT-determined dwell positions was quantified by the residual distances to reference dwell positions after using a rigid registration. Precision and accuracy were investigated for different phantom-table and sensor-field generator (FG) distances. The measured precision of the EMT-determined dwell positions was ≤ 0.28 mm (95th percentile). Stability tests showed a drift of 0.03 mm in the first 20 min of use. Sudden shaking of the FG or (large) metallic objects close to the FG degrade the precision. The accuracy with respect to the reference dwell positions was on all clinical tables < 1 mm at 200 mm FG distance and 120 mm phantom-table distance. Phantom measurements showed that EMT-determined localization of dwell positions in HDR-iBT is stable, precise, and sufficiently accurate for clinical assessment. The presented method may be viable for clinical applications in HDR-iBT, like implant definition, error detection or quantification of uncertainties. Further clinical investigations are needed.

Organ-sparing treatment of penile cancer with interstitial pulsed-dose-rate brachytherapy.

AIM: To assess the efficacy and toxicity profile of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy for penile carcinoma. PATIENTS AND METHODS: From August 2002 to February 2014, 13 men with penile cancer were treated by interstitial brachytherapy. The tumor stage was T1 for eight patients, T2 for four patients, and T3 for one patient. The tumor grade was well differentiated for five patients and moderately differentiated for seven patients, while it was unknown for one patient. Lymph node staging was positive for three of 13 patients. All patients were treated using interstitial PDR brachytherapy with dose specifications according to the Paris system. For data collection of erectile dysfunction, the International Index of Erectile Function questionnaire was used, supplemented by the follow-up data. RESULTS: The median follow-up was 54.0 months (range, 13-155 months). Only one patient (1/13, 7.7 %) with local failure was documented. At 5 and 10 years, the local cumulative recurrence rate, disease-free survival, and the cancer-specific survival rates were 12.5 % (95 % CI, 80.4-119.6), 80.8 % (95 % CI, 75.2-124.8), and 77.9 % (95 % CI, 74.3-125.7), respectively. At the time of analysis, nine of 13 men were alive; two of 13 men died of distant metastases from the tumor and two for other reasons with no sign of cancer disease. Serious late side effects such as soft tissue necrosis occurred in four of 13 patients (30 %) and all were successfully treated with medication. Mutilating salvage surgery was not necessary in any of the cases. Urethral stenosis was documented for two of 13 (15.4 %) and dysuria occurred in four of 13 patients (30.8 %). Eight of 11 men (72.7 %) never or only sometimes had erectile dysfunction. CONCLUSION: In selected patients, interstitial PDR brachytherapy of penile cancer is effective as an organ-sparing treatment. It yields satisfactory results for the conservation of sexual function.

The role of brachytherapy in the treatment of squamous cell carcinoma of the head and neck.

Brachytherapy is a form of intensive local irradiation, allowing effective protection of surrounding structures with preservation of organ function and results in a favorable therapeutic ratio. It can be used alone, adjuvantly after surgery, and as a local boost in combination with external-beam radiation therapy. This paper is a literature review on the role of brachytherapy in the management of head and neck cancers with a special emphasis on papers published in the last 5 years. Technical details, effectiveness and potential toxicities of brachytherapy when used in different combinations with other therapeutic modalities and tumor sites are presented. Brachytherapy is an attractive treatment option in the management of primary malignancies and recurrent tumors in previously irradiated areas of the head and neck. It is effective and safe, and results in good functional and oncological outcomes.