SAFESTEREO: phase II randomized trial to compare stereotactic radiosurgery with fractionated stereotactic radiosurgery for brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Effect of breathing motion on robustness of proton therapy plans for left-sided breast cancer patients with indication for locoregional irradiation.

PURPOSE: To investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation. MATERIALS AND METHODS: Clinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the Dmean of the heart. RESULTS: Correlations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans. CONCLUSION: The effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Acute toxicity of intraoperative radiotherapy and external beam-accelerated partial breast irradiation in elderly breast cancer patients.

BACKGROUND AND PURPOSE: We investigated the acute toxicity of accelerated partial breast irradiation using external beam (EB-APBI) or intraoperative radiotherapy (IORT) techniques in elderly breast cancer patients. MATERIALS AND METHODS: Women ≥ 60 years with unifocal breast tumors of ≤ 30 mm were eligible for this prospective multi-center cohort study. IORT was applied with electrons following lumpectomy (23.3 Gy). EB-APBI was delivered using 3D-CRT or IMRT in 10 daily fractions of 3.85 Gy within 6 weeks after surgery. Acute toxicity was scored using the CTCAE v3.0 at 3 months after treatment. Patient-reported symptoms were analyzed using visual analogue scales (VAS) for pain and fatigue (scale 0-10), and single items from the EORTC QLQ-C30 and Breast Cancer questionnaires. RESULTS: In total, 267 (IORT) and 206 (EB-APBI) patients were available for toxicity analysis. More patients experienced ≥ grade 2 CTCAE acute toxicity in the IORT group (10.4% IORT and 4.9% EB-APBI; p = 0.03); grade 3 toxicity was low (3.3% IORT and 1.5% EB-APBI; ns); and no grade 4 toxicity occurred. EB-APBI patients experienced less fatigue direct postoperatively (EORTC p < 0.00, VAS p < 0.00). After 3 months only pain, according to the VAS scale, was significantly worse in the EB-APBI group (p < 0.00). CONCLUSION: Acute toxicity after IORT and EB-APBI treatment is acceptable.

Less increase of CT-based calcium scores of the coronary arteries : Effect three years after breast-conserving radiotherapy using breath-hold.

PURPOSE: The aim of this prospective longitudinal study was to compare coronary artery calcium (CAC) scores determined before the start of whole breast irradiation with those determined 3 years afterwards. PATIENTS AND METHODS: Changes in CAC scores were analysed in 99 breast cancer patients. Three groups were compared: patients receiving left- and right-sided radiotherapy, and those receiving left-sided radiotherapy with breath-hold. We analysed overall CAC scores and left anterior descending (LAD) and right coronary artery (RCA) CAC scores. Between the three groups, changes of the value of the LAD minus the RCA CAC scores of each individual patient were also compared. RESULTS: Three years after breath-hold-based whole breast irradiation, a less pronounced increase of CAC scores was noted. Furthermore, LAD minus RCA scores in patients treated for left-sided breast cancer without breath-hold were higher when compared to LAD minus RCA scores of patients with right-sided breast cancers and those with left-sided breast cancer treated with breath-hold. CONCLUSION: Breath-hold in breast-conserving radiotherapy leads to a less pronounced increase of CT-based CAC scores. Therefore, breath-hold probably prevents the development of radiation-induced coronary artery disease. However, the sample size of this study is limited and the follow-up period relatively short.

Target Volume Coverage and Organ at Risk Doses for Left-sided Whole-breast Irradiation With or Without Internal Mammary Chain Irradiation: A Comparison Between Three Techniques Representing the Past and the Present.

AIMS: The 15-year results of the EORTC 229922-10925 phase III trial showed a significant reduction in breast cancer mortality and breast cancer recurrences after internal mammary chain (IMC) and medio-supraclavicular irradiation. Unexpectedly, cardiac death was not increased, and the incidence of cardiac events did not differ between left- and right-sided cases, although target volume coverages and organ at risk doses were unknown. Therefore, a planning study was carried out comparing the past and the present, to eventually enable, thereafter, an increased therapeutic ratio of IMC irradiation. MATERIALS AND METHODS: A planning study was carried out on target volume coverage and organ at risk doses for whole-breast irradiation (WBI) ± IMC comparing the results between two-dimensional radiotherapy (free-breathing), hybrid intensity-modulated radiotherapy (IMRT; breath-hold) and robust intensity-modulated proton therapy (IMPT; free-breathing) for 10 left-sided breast cancer cases. Two-dimensional radiotherapy consisted of two tangential wedged photon breast fields and mixed electron/photon beams for the IMC. Hybrid IMRT included two tangential photon breast fields (70%) complemented with IMRT (30%). IMPT plans were created using multi-field robust optimisation (5 mm set-up and 3% range uncertainties) with two (WBI) or three (WBI + IMC) beams. RESULTS: Target volume dose objectives were met for hybrid IMRT and IMPT. For two-dimensional radiotherapy, target coverage was 97% and 83% for breast and IMC, respectively. The mean heart dose for WBI only was <2 Gy for all techniques. For WBI + IMC, heart doses (mean heart dose, mean left anterior descending region, volume of the heart receiving 5 Gy (V5) were significantly higher for two-dimensional radiotherapy when compared with contemporary techniques. The V5 left anterior descending region reduced from 100% (two-dimensional radiotherapy) to 70% and 20% for hybrid IMRT and IMPT, respectively. CONCLUSION: Contemporary radiotherapy techniques result in improved target volume coverage and significantly decreased heart doses for WBI + IMC radiotherapy. Hence, nowadays an increased therapeutic ratio of elective IMC irradiation may be anticipated.

Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences.

AIMS: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. MATERIALS AND METHODS: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. RESULTS: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. CONCLUSION: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.

Reduced increase of calcium scores using breath-hold in left-sided whole breast irradiation.

PURPOSE: In this prospective longitudinal study, Coronary Artery Calcium (CAC) scores determined before the start of whole breast irradiation were compared with those determined 7 years afterwards. The aim was to examine whether the use of a breath-hold (BH) technique is associated with less increase of CAC scores. METHODS AND MATERIALS: Changes in CAC scores were analysed in 87 breast cancer patients. The results of the following groups were compared: patients receiving right (R) or left-sided radiotherapy using free breathing (L-FB) with those receiving left-sided radiotherapy with BH (L-BH). We compared the changes of CAC scores between these groups over time, testing the hypothesis that a significantly reduced increase of calcium scores is observed when using BH. RESULTS: For L-BH cases, when compared with L-FB cases, for overall as well as for Left Anterior Descending coronary artery (LAD) CAC scores, we noted significantly less increased CAC scores (p < 0.01). This effect of BH was even more striking in the group with CAC scores >0 at baseline. The attenuated increase over time of CAC scores in the L-BH group was robust to correction for age and statin use (p < 0.05). CONCLUSION: After a median follow-up of 7.4 years, we found significantly less increased CAC scores when using BH. This is a relevant finding since higher levels of CAC scores are associated with higher probabilities of coronary artery events. Moreover, it underlines the rationale for the use of BH in left-sided whole breast irradiation.

Health-related quality of life of breast cancer patients after accelerated partial breast irradiation using intraoperative or external beam radiotherapy technique.

PURPOSE: To compare health-related quality of life (HRQL) in elderly breast cancer patients between two types of Accelerated Partial Breast Irradiation: intraoperative radiotherapy (IORT) and external beam APBI (EB-APBI). METHODS: Between 2011 and 2016 women ≥60 years undergoing breast conserving therapy for early stage breast cancer were included in a prospective multi-centre cohort study. Patients were treated with electron IORT (1 × 23.3 Gy) or photon EB-APBI (10 × 3.85 Gy daily). HRQL was measured by the EORTC-QLQ C30 and BR23 questionnaires before surgery and at several time points until 1 year. RESULTS: HRQoL data was available of 204 IORT and 158 EB-APBI patients. In longitudinal analyses emotional functioning and future perspective were significantly, but not clinically relevantly, worse in IORT-treated patients, and improved significantly during follow-up in both groups. All other aspects of HRQL slightly worsened after treatment and recovered within 3 months with an improvement until 1 year. Cross-sectional analysis showed that postoperatively fatigue and role functioning were significantly worse in IORT patients compared to EB-APBI patients who were not yet irradiated, but the difference was not clinically relevant. At other timepoints there were no significant differences. Multivariable analysis at 1 year identified comorbidity and systemic therapy as risk factors for a worse global health score (GHS). CONCLUSIONS: EB-APBI and IORT were well tolerated. Despite a temporary deterioration after treatment, all HRQL scales recovered within 3 months resulting in no clinically relevant differences until 1 year between groups nor compared to baseline levels.

The ArcCHECK diode array for dosimetric verification of HybridArc.

The aim of this work is to evaluate dosimetric accuracy of a new treatment modality, HybridArc, in iPlan RT Dose 4.5 (BrainLAB, Feldkirchen, Germany) using a four-dimensional diode array (ArcCHECK, Sun Nuclear Corporation, Melbourne, USA). HybridArc is able to enhance dynamic conformal arcs with inversely planned elements. HybridArc plans for various sites (intracranial and extracranial) were constructed and after that these plans were recalculated for the ArcCHECK diode array with Monte Carlo (MC) and Pencil Beam (PB) dose algorithms in iPlan RT Dose. All measurements of these HybridArc plans were performed with 6 MV photon beams of a Novalis accelerator (BrainLAB, Feldkirchen, Germany) using the ArcCHECK device without and with an insert containing an ionization chamber. Comparison of the absolute dose distributions measured and calculated in iPlan RT Dose with the MC algorithm at the cylinder of the ArcCHECK diode array for HybridArc plans gives good agreement, even for the 2% dose difference and 2 mm distance-to-agreement criteria. The PB calculations significantly differ from the ArcCHECK measurements so that the MC algorithm is found to be superior to the PB algorithm in the calculation of the HybridArc plans. One of the drawbacks of the PB calculations in iPlan RT Dose is the too large arc step size of 10°. Use of a finer angular resolution may improve the PB results significantly.

Verification measurements and clinical evaluation of the iPlan RT Monte Carlo dose algorithm for 6 MV photon energy.

This study presents data for verification of the iPlan RT Monte Carlo (MC) dose algorithm (BrainLAB, Feldkirchen, Germany). MC calculations were compared with pencil beam (PB) calculations and verification measurements in phantoms with lung-equivalent material, air cavities or bone-equivalent material to mimic head and neck and thorax and in an Alderson anthropomorphic phantom. Dosimetric accuracy of MC for the micro-multileaf collimator (MLC) simulation was tested in a homogeneous phantom. All measurements were performed using an ionization chamber and Kodak EDR2 films with Novalis 6 MV photon beams. Dose distributions measured with film and calculated with MC in the homogeneous phantom are in excellent agreement for oval, C and squiggle-shaped fields and for a clinical IMRT plan. For a field with completely closed MLC, MC is much closer to the experimental result than the PB calculations. For fields larger than the dimensions of the inhomogeneities the MC calculations show excellent agreement (within 3%/1 mm) with the experimental data. MC calculations in the anthropomorphic phantom show good agreement with measurements for conformal beam plans and reasonable agreement for dynamic conformal arc and IMRT plans. For 6 head and neck and 15 lung patients a comparison of the MC plan with the PB plan was performed. Our results demonstrate that MC is able to accurately predict the dose in the presence of inhomogeneities typical for head and neck and thorax regions with reasonable calculation times (5-20 min). Lateral electron transport was well reproduced in MC calculations. We are planning to implement MC calculations for head and neck and lung cancer patients.

Path-length distribution and path-length-resolved Doppler measurements of multiply scattered photons by use of low-coherence interferometry.

We report first results of measurements by low-coherence Doppler interferometry of the path-length distribution of photons undergoing multiple scattering in a highly turbid medium. We use a Mach-Zehnder interferometer with multimode graded-index fibers and a superluminescent diode as the light source. The path-length distribution is obtained by recording of the heterodyne fluctuations that arise from the Brownian motion of particles in an Intralipid suspension as a function of the optical path length. The experimental path-length distribution is in good agreement with predictions of Monte Carlo simulations. In the heterodyne spectrum, an increase of the mean Doppler frequency with path length is observed.

Instrument-independent flux units for laser Doppler perfusion monitoring assessed in a multi-device study on the renal cortex.

To investigate the feasibility of instrument-independent perfusion units for laser Doppler flowmetry, a comparison was performed of two commercial fiberoptic laser Doppler perfusion monitors measuring the same flux situation for two different types of probes. In vivo measurements were performed on the cortex of pig's kidney, with an ultrasonic arterial flow meter as reference. The flow was mainly varied by internal arterial constriction using a balloon catheter. For each probe, instruments are compared in terms of the ratio of laser Doppler flux and arterial flow. For a given probe, the flux-to-flow ratios of the two instruments show a linear mutual relationship for a wide variety of arterial flows and laser Doppler fluxes. In vitro measurements were performed on an aqueous suspension of polystyrene microspheres. For the probe with interfiber distance 500 microm the ratio of the in vivo fluxes appears to agree within 16% to the value found in vitro, while for the 250-microm probe a difference of 28% was found. For a wide range of fluxes, the in vivo flux values of one instrument can be translated into flux values for the other instrument, in spite of the instrumental differences. This enables the user to render experimental results independent of the specific instrument, thus facilitating multi-center studies.