Cost-benefit ratio of modern medical education using micro-costing: a model calculation using the example of an innovative breast brachytherapy workshop.

BACKGROUND AND PURPOSE: Radiation oncology is an essential component of therapeutic oncology and necessitates well-trained personnel. Multicatheter brachytherapy (MCBT) is one radiotherapeutic option for early-stage breast cancer treatment. However, specialized hands-on training for MCBT is not currently included in the curriculum for residents. A recently developed hands-on brachytherapy workshop has demonstrated promising results in enhancing knowledge and practical skills. Nevertheless, these simulation-based teaching formats necessitate more time and financial resources. Our analyses include computational models for the implementation and delivery of this workshop and can serve as a basis for similar educational initiatives. METHODS: This study aimed to assess the cost-effectiveness of a previously developed and evaluated breast brachytherapy simulation workshop. Using a micro-costing approach, we estimated costs at a detailed level by considering supplies, soft- and hardware, and personnel time for each task. This method also allows for a comprehensive evaluation of the costs associated with implementing new medical techniques. The workshop costs were divided into two categories: development and workshop execution. The cost analysis was conducted on a per-participant basis, and the impact on knowledge improvement was measured using a questionnaire. RESULTS: The total workshop costs were determined by considering the initial workshop setup expenses including the development and conceptualization of the course with all involved collaborators, as well as the costs incurred for each individual course. The workshop was found to be financially efficient, with a per-participant cost of €â€¯39, considering the industrial sponsorship provided for brachytherapy equipment. In addition, we assessed the workshop's efficacy by analyzing participant feedback using Likert scale evaluations. The findings indicated a notable enhancement in both theoretical and practical skills among the participants. Moreover, the cost-to-benefit ratio (CBFR) analysis demonstrated a CBFR of €â€¯13.53 for each Likert point increment. CONCLUSION: The hands-on brachytherapy workshop proved to be a valuable and approximately cost-effective educational program, leading to a significant enhancement in the knowledge and skills of the participants. Without the support of industrial sponsorship, the costs would have been unattainable.

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.

Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells.

To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, it should be compared whether one combination therapy is more effective than the other. Colorectal cancer cells (HT-29) were treated with irinotecan or oxaliplatin, both alone and in combination with 5-FU, and subsequently irradiated. The cell growth, metabolic activity and proliferation of cells were investigated, and the clonogenic survival was determined. Furthermore, the assessment of radiation-induced DNA damage and the influence of the drugs and their combinations on DNA damage repair was investigated. Treatment with irinotecan or oxaliplatin in combination with 5-FU inhibited proliferation and metabolic activity as well as clonogenic survival and the DNA damage repair capacity of the tumor cells. The comparison of oxaliplatin and irinotecan with simultaneous irradiation showed the same effect of both drugs. When oxaliplatin or irinotecan was combined with 5-FU, tumor cell survival was significantly lower than with monotherapy; however, there was no superiority of either combination regimen. Our results have shown that the combination of 5-FU and irinotecan is as effective as the combination of 5-FU with oxaliplatin. Therefore, our data support the use of FOLFIRI as a radiosensitizer.

Modification of the Langendorff system of the isolated beating heart for experimental radiotherapy at a synchrotron: 4000†Gy in a heart beat.

Microbeam radiotherapy could help to cure malignant tumours which are currently still considered therapy-resistant. With an irradiation target in the thoracic cavity, the heart would be one of the most important organs at risk. To assess the acute adverse effects of microbeam irradiation in the heart, a powerful ex vivo tool was created by combining the Langendorff model of the isolated beating mammalian heart with X-Tream dosimetry. In a first pilot experiment conducted at the Biomedical and Imaging Beamline of the Australian Synchrotron, the system was tested at a microbeam peak dose approximately ten times higher than the anticipated future microbeam irradiation treatment doses. The entire heart was irradiated with a dose of 4000 Gy at a dose rate of >6000 Gy s-1, using an array of 50 µm-wide microbeams spaced at a centre-to-centre distance of 400 µm. Although temporary arrhythmias were seen, they reverted spontaneously to a stable rhythm and no cardiac arrest occurred. This amazing preservation of cardiac function is promising for future therapeutic approaches.

Induction of Radiodermatitis in Nude Mouse Model Using Gamma Irradiator IBL 637.

INTRODUCTION: Acute radiodermatitis is a common, though severe, side effect of radiotherapy against cancer that may lead to an interruption or even abortion of the radiotherapy. Mouse models provide an excellent tool to study pathomechanisms of a radiation-induced dermatitis as well as to test and develop novel innovative treatment strategies. OBJECTIVE: The aim of this study was to provide an overview of different mouse models and irradiation devices that have been used so far and to describe the process of the induction of a radiation dermatitis in an immune proficient nude mouse model (SKH1-Hrhr) using a IBL 637 cesium-137γ-ray machine. METHODS: This process includes the construction of a radiation shielding chamber, restricting the radiation to the right hind leg of the mouse, a dosimetry, and a dose finding study to identify the appropriate irradiation dose to induce a moderate radiation dermatitis. RESULTS: A radiation shielding chamber was successfully constructed allowing selective irradiation of the right hind leg. A moderate radiodermatitis is induced with irradiation doses in the range of 60-70 Gy under the here described conditions. Symptoms peak about 8 days after irradiation and decrease relatively quickly thereafter. Histological analyses confirmed typical signs of inflammation. CONCLUSION: This study describes for the first time a protocol to induce a moderate radiodermatitis in the nude mouse model SKH1-Hrhr using a IBL 637 gamma irradiator. This protocol will allow researchers to study novel treatment strategies to alleviate the burden of a radiodermatitis as a side effect of cancer treatment.

Pepper Alkaloid Piperine Increases Radiation Sensitivity of Cancer Cells from Glioblastoma and Hypopharynx In Vitro.

In our study, our aim was to examine the cytotoxic and radio-sensitizing effect of the alkaloid piperine, a major pungent of black pepper, on two different human epithelial tumor cell lines in vitro. The growth of the human cell lines T98G (glioblastoma) and FaDu (hypopharyngeal carcinoma) was examined under the influence of piperine in different concentrations. In addition, after combined treatment with ionizing radiation, long-term survival was investigated with a colony formation assay. The proliferation was analyzed using the BrdU-assay, while the DNA repair capacity was examined via the γH2AX assay. Piperine reduced the growth of both cell lines in a concentration-dependent manner as well as a time-dependent one. After combined treatment with piperine and ionizing radiation, an inhibition of clonogenic survival could be proven. A reduced proliferation capacity and an additive effect on DNA damage 24 h after irradiation are possible causal mechanisms, which were also demonstrated for both cell lines. Based on the results presented in this study, piperine was shown to have cytotoxic antitumor activity and a radio-sensitizing effect in micromolar concentrations in the human tumor cells that were tested. Based on these results piperine represents a potential therapeutic option in radio-oncological treatment.

Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol.

Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible.

Evaluating the Suitability of 3D Bioprinted Samples for Experimental Radiotherapy: A Pilot Study.

Radiotherapy is an important component in the treatment of lung cancer, one of the most common cancers worldwide, frequently resulting in death within only a few years of diagnosis. In order to evaluate new therapeutic approaches and compare their efficiency with regard to tumour control at a pre-clinical stage, it is important to develop standardized samples which can serve as inter-institutional outcome controls, independent of differences in local technical parameters or specific techniques. Recent developments in 3D bioprinting techniques could provide a sophisticated solution to this challenge. We have conducted a pilot project to evaluate the suitability of standardized samples generated from 3D printed human lung cancer cells in radiotherapy studies. The samples were irradiated at high dose rates using both broad beam and microbeam techniques. We found the 3D printed constructs to be sufficiently mechanically stable for use in microbeam studies with peak doses up to 400 Gy to test for cytotoxicity, DNA damage, and cancer cell death in vitro. The results of this study show how 3D structures generated from human lung cancer cells in an additive printing process can be used to study the effects of radiotherapy in a standardized manner.

Perspectives for microbeam irradiation at the SYRMEP beamline.

It has been shown previously both in vitro and in vivo that microbeam irradiation (MBI) can control malignant tumour cells more effectively than the clinically established concepts of broad beam irradiation. With the aim to extend the international capacity for microbeam research, the first MBI experiment at the biomedical beamline SYRMEP of the Italian synchrotron facility ELETTRA has been conducted. Using a multislit collimator produced by the company TECOMET, arrays of quasi-parallel microbeams were successfully generated with a beam width of 50 µm and a centre-to-centre distance of 400 µm. Murine melanoma cell cultures were irradiated with a target dose of approximately 65 Gy at a mean photon energy of ∼30 keV with a dose rate of 70 Gy s-1 and a peak-to-valley dose of ∼123. This work demonstrated a melanoma cell reduction of approximately 80% after MBI. It is suggested that, while a high energy is essential to achieve high dose rates in order to deposit high treatment doses in a short time in a deep-seated target, for in vitro studies and for the treatment of superficial tumours a spectrum in the lower energy range might be equally suitable or even advantageous.

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture.

Background Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA's influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 µM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.

Tumor-dose-rate variations during robotic radiosurgery of oligo and multiple brain metastases.

PURPOSE: For step-and-shoot robotic stereotactic radiosurgery (SRS) the dose delivered over time, called local tumor-dose-rate (TDR), may strongly vary during treatment of multiple lesions. The authors sought to evaluate technical parameters influencing TDR and correlate TDR to clinical outcome. MATERIAL AND METHODS: A total of 23 patients with 162 oligo (1-3) and multiple (>3) brain metastases (OBM/MBM) treated in 33 SRS sessions were retrospectively analyzed. Median PTV were 0.11 cc (0.01-6.36 cc) and 0.50 cc (0.12-3.68 cc) for OBM and MBM, respectively. Prescription dose ranged from 16 to 20 Gy prescribed to the median 70% isodose line. The maximum dose-rate for planning target volume (PTV) percentage p in time span s during treatment (TDRs,p) was calculated for various p and s based on treatment log files and in-house software. RESULTS: TDR60min,98% was 0.30 Gy/min (0.23-0.87 Gy/min) for OBM and 0.22 Gy/min (0.12-0.63 Gy/min) for MBM, respectively, and increased by 0.03 Gy/min per prescribed Gy. TDR60min,98% strongly correlated with treatment time (ρ = -0.717, p < 0.001), monitor units (MU) (ρ = -0.767, p < 0.001), number of beams (ρ = -0.755, p < 0.001) and beam directions (ρ = -0.685, p < 0.001) as well as lesions treated per collimator (ρ = -0.708, P < 0.001). Median overall survival (OS) was 20 months and 1­ and 2­year local control (LC) was 98.8% and 90.3%, respectively. LC did not correlate with any TDR, but tumor response (partial response [PR] or complete response [CR]) correlated with all TDR in univariate analysis (e.g., TDR60min,98%: hazard ration [HR] = 0.974, confidence interval [CI] = 0.952-0.996, p = 0.019). In multivariate analysis only concomitant targeted therapy or immunotherapy and breast cancer tumor histology remained a significant factor for tumor response. Local grade ≥2 radiation-induced tissue reactions were noted in 26.3% (OBM) and 5.2% (MBM), respectively, mainly influenced by tumor volume (p < 0.001). CONCLUSIONS: Large TDR variations are noted during MBM-SRS which mainly arise from prolonged treatment times. Clinically, low TDR corresponded with decreased local tumor responses, although the main influencing factor was concomitant medication.

Evaluation of Choroidal Melanoma Vascularization by Color Doppler Flow Imaging: An Option for Follow-Up Tumor Control Assessment after CyberKnife®?

Background and Objectives: Thus far, tumor control for choroidal melanoma after teletherapeutic radiation is clinically difficult. In contrast to brachytherapy, the tumor height does not necessarily have to shrink as a result of teletherapy. Therefore, the objective of this study was to evaluate tumor vascularization determined by color Doppler flow imaging (CDFI) as a possible approach for monitoring the therapy response after teletherapy of choroidal melanoma. Materials and Methods: A single-center retrospective pilot study of 24 patients was conducted, all of whom had been diagnosed with choroidal neoplasm, treated and followed up. Besides tumor vascularization, the following parameters were collected: age, gender, tumor entity, location, radiation dose, knowledge of relapse, tumor height, radiation-related complications, occurrence of metastases, visual acuity in logMAR. Results: The level of choroidal melanoma vascularization markedly decreased in all included subjects after treatment with the CyberKnife® technology. Initially, the level of vascularization was 2.1 (SD: 0.76 for n = 10); post-therapeutically, it averaged 0.14 (SD: 0.4). Regarding the tumor apex, CDFI sonography also demonstrated a significant tumor regression (mean value pre-therapeutically: 8.35 mm-SD: 3.92 for n = 10; mean value post-therapeutically: 4.86 mm-SD: 3.21). The level of choroidal melanoma vascularization declined in the patient collective treated with ruthenium-106 brachytherapy. The pre-therapeutic level of vascularization of 2 (SD: 0 for n = 2) decreased significantly to a level of 0 (mean: 0-SD: 0). The tumor height determined by CDFI did not allow any valid statement regarding local tumor control. In contrast to these findings, the patient population of the control group without any radiation therapy did not show any alterations in vascularization. Conclusions: Our data suggest that the determination of the tumor vascularization level using CDFI might be a useful and supplementary course parameter in the follow-up care of choroidal melanoma to monitor the success of treatment. This especially applies to robot-assisted radiotherapy using CyberKnife®. Further studies are necessary to validate the first results of this assessment.

Radiosensitizing effects of trabectedin on human A549 lung cancer cells and HT-29 colon cancer cells.

Background and Purpose Trabectedin is a unique alkylating agent with promising effects against a range of solid tumors. In this study, we aimed to examine the cytotoxic and radiosensitizing effects of trabectedin on two human epithelial tumor cell lines in vitro, and its effects on DNA repair capacity. Methods Cancer cells (A549: human lung cancer cells, HT-29: colon cancer cells) were treated with either trabectedin alone for the determination of their growth, or in combination with radiation for the determination of their metabolic activity, proliferation, and clonogenic survival. Besides, the γH2AX foci assay was performed for the assessment of ionizing radiation-induced DNA damage and to evaluate the influence of trabectedin on DNA damage repair. Results Treatment with trabectedin resulted in a growth-inhibiting effect on both cell lines, with the IC50 values remaining within a low nanomolar range. Analyses of metabolic activity confirmed a cytotoxic influence of trabectedin and a BrdU assay demonstrated an antiproliferative effect. When combined with radiation, incubation with trabectedin was found to enhance the radiosensitivity of the tumor cells. The γH2AX foci assay resulted in an increased number of DNA double-strand breaks (DSBs) in cells treated with trabectedin. Conclusion The results of this study underline the antitumor activity of trabectedin at low nanomolar concentrations. We demonstrated that trabectedin enhanced radiation response in human lung (A549) cancer cells and colon (HT-29) cancer cells. Further studies are necessary to examine trabectedin as a potential candidate for future applications in radiotherapy.

First Insights into the Effect of Low-Dose X-Ray Irradiation in Adipose-Derived Stem Cells.

(1) Background: Emerging interest of physicians to use adipose-derived stem cells (ADSCs) for regenerative therapies and the fact that low-dose irradiation (LD-IR ≤ 0.1 Gy) has been reported to enhance the proliferation of several human normal and bone-marrow stem cells, but not that of tumor cells, lead to the idea of improving stem cell therapies via low-dose radiation. Therefore, the aim of this study was to investigate unwanted side effects, as well as proliferation-stimulating mechanisms of LD-IR on ADSCs. (2) Methods: To avoid donor specific effects, ADSCs isolated from mamma reductions of 10 donors were pooled and used for the radiobiological analysis. The clonogenic survival assay was used to classify the long-term effects of low-dose radiation in ADSCs. Afterwards, cytotoxicity and genotoxicity, as well as the effect of irradiation on proliferation of ADSCs were investigated. (3) Results: LD (≤ 0.1 Gy) of ionizing radiation promoted the proliferation and survival of ADSCs. Within this dose range neither geno- nor cytotoxic effects were detectable. In contrast, greater doses within the dose range of >0.1-2.0 Gy induced residual double-strand breaks and reduced the long-term survival, as well as the proliferation rate of ADSCs. (4) Conclusions: Our data suggest that ADSCs are resistant to LD-IR. Furthermore, LD-IR could be a possible mediator to improve approaches of stem cells in the field of regenerative medicine.

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.

Breathing-motion-compensated robotic guided stereotactic body radiation therapy : Patterns of failure analysis.

PURPOSE: We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs. PATIENTS AND METHODS: Between 2011 and 2016, a total of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1-372.0 cc). Medians of mean GTV BEDα/ß =10 Gy (BED = biological effective dose) was 148.5 Gy10 (31.5-233.3 Gy10) and prescribed planning target volume (PTV) BEDα/ß =10 Gy was 89.7 Gy10 (28.8-151.2 Gy10), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with α/ß ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases). RESULTS: Median follow-up was 10.4 months (2.0-59.0 months). The 2­year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2­year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3 × 12-13 Gy) and higher average GTV dose (equivalence of 3 × 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade 3 side effects were rare (0.5%). CONCLUSIONS: Robotic guided BMC-SBRT can be considered a safe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points.

Direct dose correlation of MRI morphologic alterations of healthy liver tissue after robotic liver SBRT.

PURPOSE: For assessing healthy liver reactions after robotic SBRT (stereotactic body radiotherapy), we investigated early morphologic alterations on MRI (magnetic resonance imaging) with respect to patient and treatment plan parameters. PATIENTS AND METHODS: MRI data at 6-17 weeks post-treatment from 22 patients with 42 liver metastases were analyzed retrospectively. Median prescription dose was 40 Gy delivered in 3-5 fractions. T2- and T1-weighted MRI were registered to the treatment plan. Absolute doses were converted to EQD2 (Equivalent dose in 2Gy fractions) with α/ß-ratios of 2 and 3 Gy for healthy, and 8 Gy for modelling pre-damaged liver tissue. RESULTS: Sharply defined, centroid-shaped morphologic alterations were observed outside the high-dose volume surrounding the GTV. On T2-w MRI, hyperintensity at EQD2 isodoses of 113.3 ± 66.1 Gy2, 97.5 ± 54.7 Gy3, and 66.5 ± 32.0 Gy8 significantly depended on PTV dimension (p = 0.02) and healthy liver EQD2 (p = 0.05). On T1-w non-contrast MRI, hypointensity at EQD2 isodoses of 113.3 ± 49.3 Gy2, 97.4 ± 41.0 Gy3, and 65.7 ± 24.2 Gy8 significantly depended on prior chemotherapy (p = 0.01) and total liver volume (p = 0.05). On T1-w gadolinium-contrast delayed MRI, hypointensity at EQD2 isodoses of 90.6 ± 42.5 Gy2, 79.3 ± 35.3 Gy3, and 56.6 ± 20.9 Gy8 significantly depended on total (p = 0.04) and healthy (p = 0.01) liver EQD2. CONCLUSIONS: Early post-treatment changes in healthy liver tissue after robotic SBRT could spatially be correlated to respective isodoses. Median nominal doses of 10.1-11.3 Gy per fraction (EQD2 79-97 Gy3) induce characteristic morphologic alterations surrounding the lesions, potentially allowing for dosimetric in-vivo accuracy assessments. Comparison to other techniques and investigations of the short- and long-term clinical impact require further research.

Treatment planning for spinal radiosurgery : A competitive multiplatform benchmark challenge.

PURPOSE: To investigate the quality of treatment plans of spinal radiosurgery derived from different planning and delivery systems. The comparisons include robotic delivery and intensity modulated arc therapy (IMAT) approaches. Multiple centers with equal systems were used to reduce a bias based on individual's planning abilities. The study used a series of three complex spine lesions to maximize the difference in plan quality among the various approaches. METHODS: Internationally recognized experts in the field of treatment planning and spinal radiosurgery from 12 centers with various treatment planning systems participated. For a complex spinal lesion, the results were compared against a previously published benchmark plan derived for CyberKnife radiosurgery (CKRS) using circular cones only. For two additional cases, one with multiple small lesions infiltrating three vertebrae and a single vertebra lesion treated with integrated boost, the results were compared against a benchmark plan generated using a best practice guideline for CKRS. All plans were rated based on a previously established ranking system. RESULTS: All 12 centers could reach equality (n = 4) or outperform (n = 8) the benchmark plan. For the multiple lesions and the single vertebra lesion plan only 5 and 3 of the 12 centers, respectively, reached equality or outperformed the best practice benchmark plan. However, the absolute differences in target and critical structure dosimetry were small and strongly planner-dependent rather than system-dependent. Overall, gantry-based IMAT with simple planning techniques (two coplanar arcs) produced faster treatments and significantly outperformed static gantry intensity modulated radiation therapy (IMRT) and multileaf collimator (MLC) or non-MLC CKRS treatment plan quality regardless of the system (mean rank out of 4 was 1.2 vs. 3.1, p = 0.002). CONCLUSIONS: High plan quality for complex spinal radiosurgery was achieved among all systems and all participating centers in this planning challenge. This study concludes that simple IMAT techniques can generate significantly better plan quality compared to previous established CKRS benchmarks.

Radiation Sensitivity of Adipose-Derived Stem Cells Isolated from Breast Tissue.

Within their niche, adipose-derived stem cells (ADSCs) are essential for homeostasis as well as for regeneration. Therefore, the interest of physicians is to use ADSCs as a tool for radiation oncology and regenerative medicine. To investigate related risks, this study analyses the radiation response of adult stem cells isolated from the adipose tissue of the female breast. To avoid donor-specific effects, ADSCs isolated from breast reduction mammoplasties of 10 donors were pooled and used for the radiobiological analysis. The clonogenic survival fraction assay was used to classify the radiation sensitivity in comparison to a more radiation-sensitive (ZR-75-1), moderately sensitive (MCF-7), and resistant (MCF10A) cell lines. Afterwards, cytotoxicity and genotoxicity of irradiation on ADSCs were investigated. On the basis of clonogenic cell survival rates of ADSCs after irradiation, we assign ADSCs an intermediate radiation sensitivity. Furthermore, a high repair capacity of double-strand breaks is related to an altered cell cycle arrest and increased expression of cyclin-dependent kinase (CDK) inhibitor p21. ADSCs isolated from breast tissue exhibit intermediate radiation sensitivity, caused by functional repair mechanisms. Therefore, we propose ADSCs to be a promising tool in radiation oncology.

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.