Integrating cine EPID, dynamic delivery, and the off-axis Winston-Lutz test to enhance quality control in multiple brain metastasis stereotactic radiotherapy.

PURPOSE: Stereotactic radiotherapy (SRT) has transformed cancer treatment, especially for brain metastases. Ensuring accurate SRT delivery is crucial, with the Winston-Lutz test being an important quality control tool. Off-axis Winston-Lutz (OAWL) tests are designed for accuracy assessment, but most are limited to fixed angles and hampered by local-field shifts caused by suboptimal Multi-Leaf Collimator (MLC) positioning. This study introduces a new OAWL approach for quality control in multi-brain-metastasis SRT. Utilizing cine Electronic Portal Imaging Device (EPID) images, it can be used with dynamic conformal arc (DCA) therapy. However, dynamic OAWL (DOAWL) is prone to more local-field shifts due to dynamic MLC movements. A two-step DOAWL is proposed: step 1 calculates local-field shifts using dynamic MLC movements in the beam-eye view data from the Treatment Planning System (TPS), while step 2 processes cine EPID images with an OAWL algorithm to isolate true deviations. METHODS: Validation involved an anthropomorphic head phantom with metallic ball-bearings, Varian TrueBeam STx accelerator delivering six coplanar/non-coplanar DCA beams, cine EPID, and ImageJ's OAWL analysis algorithm. RESULTS: Inherent local-field shifts ranged from 0.11 to 0.49 mm; corrected mean/max EPID-measured displacement was 0.34/1.03 mm. Few points exceeded 0.75/1.0-mm thresholds. CONCLUSIONS: This two-step DOAWL test merges cine-EPID acquisitions, DCA, OAWL, and advanced analysis and offers effective quality control for multi-brain-metastasis SRT. Its routine implementation may also improve physicist knowledge of the treatment precision of their machines.

Evaluation of a Scintillating Plastic Optical Fiber Device for Measuring kV-Cone Beam Computed Tomography Dose.

BACKGROUND: Justification of imaging procedures such as cone beam computed tomography (CBCT) in radiotherapy makes no doubt. However, the CBCT composite dose is rarely reported or optimized, even though the repeated CBCT cumulative dose can be up to 3% of the prescription dose. This study aimed to evaluate the performance and utility of a new plastic scintillating optical fiber dosimeter for CBCT dosimetric quality assurance (QA) applications before a potential application in patient composite CBCT dosimetry. METHODS: The dosimeter, made of 1 mm diameter plastic fiber, was installed under a linear accelerator treatment table and linked to photodetectors. The fiber impact on the fluence and dose delivered was respectively assessed with an electronic portal imaging device (EPID) and EBT3 Gafchromic® film. The presence of artifacts was visually evaluated on kV images. The dosimeter performances were determined for various acquisition parameters by comparison with ionization chamber values. RESULTS: The maximum impact of the fiber on the fluence measured by the EPID was -1.2% for the 6 MV flattening filter-free beam. However, the fiber did not alter the film dose profile when measured for all the beams tested. The fiber was not visible at energies ≥ 80 kV and was merely visible on the CBCT images. When the rate of images per second or mA was changed, the maximum relative difference between the device and the ionization chamber CTDIs was <5%. Changing collimation led to a -7.2% maximum relative difference with an absolute dose difference that was insignificant (-0.3 mGy). Changing kV was associated with a -8.7% maximum relative difference, as published in the literature. CONCLUSIONS: The dosimeter may be a promising device for CBCT recurrent dosimetry quality control or dose optimization. According to these results, further developments are in progress in order to adapt the solution to the measurement of patient composite CBCT doses.

Evaluation of the ability of the Brainlab Elements Cranial Distortion Correction algorithm to correct clinically relevant MRI distortions for cranial SRT.

PURPOSE: Cranial stereotactic radiotherapy (SRT) requires highly accurate lesion delineation. However, MRI can have significant inherent geometric distortions. We investigated how well the Elements Cranial Distortion Correction algorithm of Brainlab (Munich, Germany) corrects the distortions in MR image-sets of a phantom and patients. METHODS: A non-distorted reference computed tomography image-set of a CIRS Model 603-GS (CIRS, Norfolk, VA, USA) phantom was acquired. Three-dimensional T1-weighted images were acquired with five MRI scanners and reconstructed with vendor-derived distortion correction. Some were reconstructed without correction to generate heavily distorted image-sets. All MR image-sets were corrected with the Brainlab algorithm relative to the computed tomography acquisition. CIRS Distortion Check software measured the distortion in each image-set. For all uncorrected and corrected image-sets, the control points that exceeded the 0.5-mm clinically relevant distortion threshold and the distortion maximum, mean, and standard deviation were recorded. Empirical cumulative distribution functions (eCDF) were plotted. Intraclass correlation coefficient (ICC) was calculated. The algorithm was evaluated with 10 brain metastases using Dice similarity coefficients (DSC). RESULTS: The algorithm significantly reduced mean and standard deviation distortion in all image-sets. It reduced the maximum distortion in the heavily distorted image-sets from 2.072 to 1.059 mm and the control points with > 0.5-mm distortion fell from 50.2% to 4.0%. Before and especially after correction, the eCDFs of the four repeats were visually similar. ICC was 0.812 (excellent-good agreement). The algorithm increased the DSCs for all patients and image-sets. CONCLUSION: The Brainlab algorithm significantly and reproducibly ameliorated MRI distortion, even with heavily distorted images. Thus, it increases the accuracy of cranial SRT lesion delineation. After further testing, this tool may be suitable for SRT of small lesions.

Prospective validation of stringent dose constraints for prostatic stereotactic radiation monotherapy: results of a single-arm phase II toxicity-oriented trial.

PURPOSE: There are no safety-focused trials on stereotactic body radiotherapy (SBRT) for localized prostate cancer. This prospective 3­year phase II trial used binomial law to validate the safety and efficacy of SBRT with stringent organ at risk dose constraints that nevertheless permitted high planning target volume doses. METHODS: All consecutive ≥ 70-year-old patients with localized prostate adenocarcinoma who underwent SBRT between 2014 and 2018 at the National Radiotherapy Center in Luxembourg were included. Patients with low Cancer of Prostate Risk Assessment (CAPRA) scores (0-2) and intermediate scores (3-5) received 36.25 Gy. High-risk (6-10) patients received 37.5 Gy. Radiation was delivered in 5 fractions over 9 days with Cyberknife-M6™ (Accuray, Sunnyvale, CA, USA). Primary study outcome was Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) genitourinary and rectal toxicity scores at last follow-up. Based on binomial law, SRBT was considered safe in this cohort of 110 patients if there were ≤ 2 severe toxicity (CTCAEv4 grade ≥ 3) cases. Secondary outcomes were biochemical progression-free survival (bPFS) and patient quality of life (QOL), as determined by the IPPS and the Urinary Incontinence QOL questionnaire. RESULTS: The first 110 patients who were accrued in a total cohort of 150 patients were included in this study and had a median follow-up of 36 months. Acute grade ≥ 3 toxicity never occurred. One transient late grade 3 case was observed. Thus, our SBRT program had an estimated severe toxicity rate of < 5% and was safe at the p < 0.05 level. Overall bPFS was 90%. QOL did not change relative to baseline. CONCLUSION: The trial validated our SBRT regimen since it was both safe and effective.

Proof of Concept of a Binary Blood Assay for Predicting Radiosensitivity.

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Technical Note: A 3D-printed phantom for radiochromic film evaluation of moving lung tumor SBRT without dose convolution.

PURPOSE: A common dosimetric quality assurance (QA) method in stereotactic body radiation therapy (SBRT) of lung tumors is to use lung phantoms with radiochromic film. However, in most phantoms, the film moves with the tumor, leading to the blurring effect. This technical note presents the QA performance of a novel phantom in which the film is fixed; this phantom can be used for both patient-specific QA and end-to-end testing. METHODS: Lung tumor motion was simulated with the CIRS Model 008A phantom. A lung-equivalent insert that consisted of a fixed radiochromic film around which a 2-cm tumor moved in the inferior/superior direction (i.e., mimicking respiration-induced tumor motion) was generated by 3D printing. Two common SBRT plans [dynamic conformal arc (DCA) and volumetric-modulated arc therapy (VMAT)] were calculated on the average intensity projection (AIP) image set in Varian Eclipse using the dose calculation algorithm Acuros XB. The plans were delivered by a Varian TrueBeam STx accelerator using 6-MV flattening filter-free energy. EBT3 films were used for treatment-dose verification. The measured and planned dose distributions were compared by using the local gamma index at 3% and 2 mm. RESULTS: Mean gamma pass rates of film and planned dose distributions were all ≥95%. DCA and VMAT plans did not differ in gamma pass rates. Planned and measured dose distributions agreed well, as did planned and measured gamma maps. CONCLUSIONS: With this new insert, measured and planned dose distributions were very similar, which supports the current view in the field that dose calculations on AIP image sets account sufficiently for tumor motion during treatment. The phantom also performed well despite challenging breathing parameters (large tumor amplitude and slow breathing rate) and the application of a complex treatment technique (VMAT). This phantom could facilitate clinical and end-to-end film-based dosimetric QA for lung SBRT. TAXONOMY: Twenty-seven TH- Radiation dose measurement devices. Eleven Phantoms for dosimetric measurement.

Cranial organs at risk delineation: heterogenous practices in radiotherapy planning.

BACKGROUND: Segmentation is a crucial step in treatment planning that directly impacts dose distribution and optimization. The aim of this study was to evaluate the inter-individual variability of common cranial organs at risk (OAR) delineation in neurooncology practice. METHODS: Anonymized simulation contrast-enhanced CT and MR scans of one patient with a solitary brain metastasis was used for delineation and analysis. Expert professionals from 16 radiotherapy centers involved in brain structures delineation were asked to segment 9 OAR on their own treatment planning system. As reference, two experts in neurooncology, produced a unique consensual contour set according to guidelines. Overlap ratio, Kappa index (KI), volumetric ratio, Commonly Contoured Volume, Supplementary Contoured Volume were evaluated using Artiview™ v 2.8.2-according to occupation, seniority and level of expertise of all participants. RESULTS: For the most frequently delineated and largest OAR, the mean KI are often good (0.8 for the parotid and the brainstem); however, for the smaller OAR, KI degrade (0.3 for the optic chiasm, 0.5% for the cochlea), with a significant discrimination (p < 0.01). The radiation oncologists, members of Association des Neuro-Oncologue d'Expression Française society performed better in all indicators compared to non-members (p < 0.01). Our exercise was effective in separating the different participating centers with 3 of the reported indicators (p < 0.01). CONCLUSION: Our study illustrates the heterogeneity in normal structures contouring between professionals. We emphasize the need for cerebral OAR delineation harmonization-that is a major determinant of therapeutic ratio and clinical trials evaluation.

Radiation-Induced Mitotic Catastrophe Enhanced by Gold Nanoparticles: Assessment with a Specific Automated Image Processing Workflow.

In recent years, the use of gold-based nanoparticles in radiotherapy has been extensively studied, and the associated radiosensitization mechanism has been evaluated in a variety of in vitro studies. Given that mitotic catastrophe is widely involved in radiation-induced cell death, we evaluated the effect of gold nanoparticles on this key event. Most of the methods currently used to visualize and quantify morphological changes and multinucleation are manual. To circumvent this time-consuming step, we developed and optimized an image processing workflow (based on freely accessible software and plugins) for the automated quantification of mitotic catastrophes. We validated this approach in three cell lines by comparing the number of radiation-induced mitotic catastrophes detected using the automated and manual methods in the presence and absence of nanoparticles. With the Bland-Altman analysis, the automated and manual counting methods were found to be fully interchangeable. The ultimate goal of this work was to determine whether mitotic catastrophe was critically involved in radiationinduced cell death after prior exposure to gold nanoparticles. In the radioresistant U87 cell line, exposure to gold nanoparticles was associated with a shorter time course for the events related to mitotic catastrophe, which peaked at 96 h postirradiation. Mitotic catastrophe was dose-dependent in both the presence and absence of gold nanoparticles. These results demonstrate that cell exposure to gold nanoparticles led to an increase in mitotic catastrophe events, and confirm the marked radiosensitizing effect observed in clonogenic assays.

Monte Carlo simulations guided by imaging to predict the in vitro ranking of radiosensitizing nanoparticles.

This article addresses the in silico-in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.

Robustness Analysis of a Geant4-GATE Simulator for Nanoradiosensitizers Characterization.

The increase of computational environments dedicated to the simulation of nanoparticles (NP)-X-Rays interactions has opened new perspectives in computer-aided-design of nanostructured materials for biomedical applications. Several published studies have shown a crucial need of standardization of these numerical simulations. That is why, a robustness multivariate analysis was performed in this paper. A gold nanoparticle (GNP) of 100 nm diameter was selected as a standard nanosystem activated by a X-ray source placed just below the NP. Two response variables were examined: the dose enhancement in seven different spatial regions of interest around the NP and the duration of the experiments. Nine factors were pre-identified as potentially critical. A Plackett-Burman design of numerical experiments was applied to estimate and test the effects of each simulation factors on the examined responses. Four factors-the working volume, the spatial resolution, the spatial cutoff, and the computational mode (parallelization)-do not significantly affect the dose deposition results and none except the last one may reduce the computational duration. The energy cutoff may cause significant variations of the dose enhancement in some specific regions of interest: the higher the cutoff, the closer the secondary particles will stop from the GNP. By contrast, the Auger effect as well as the choice of the physical medium and the fluence level clearly appear as critical simulation parameters. Consequently, these four factors may be compulsory examined before comparing and interpreting any simulation results coming from different simulation sessions.

Nanoparticles for Radiation Therapy Enhancement: the Key Parameters.

This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.

Quality assessment of fluorodeoxyglucose positron emission tomography imaging in clinical setting: definition of standard quality control parameters for patients treated for lymphoma.

PURPOSE: We designed standard parameters for quality controls (QCs) of F-fluorodeoxyglucose positron emission tomography (FDG PET) images in the clinical setting, and validated them in both cross-sectional and longitudinal cohorts of patients with lymphoma under treatment. METHODS: The procedure is based on the measurement of mean standardized uptake value (SUV mean) in three specific regions of interest drawn within pulmonary, liver, and bone tissues [reference (Ref)]. Intraobserver and interobserver reproducibility [percentage of coefficient of variation (CV%)] were calculated using PET scans of healthy participants. Cross-sectional interpatient QCs were defined as the 95% ranges of normal values of Ref-SUV mean. Transversal QCs were applied on PET scans of patients treated for lymphoma (n=378) looking at Ref-SUV mean out of range. Longitudinal intrapatient QCs were defined as the 95% limits of the SUV mean variation between two consecutive scans (ΔSUV limits). Longitudinal QCs were applied in a group of 94 pairs of consecutive PET scans under treatment for lymphoma looking at patients having Ref-ΔSUV limits out of range. RESULTS: Intraobserver CV% remained below 3%, whereas interobserver CV% was a maximum of 5.3%. Both in transversal and longitudinal cohorts of patients treated for lymphoma, none of the PET scans simultaneously showed the three Ref-SUV mean out of range. Similar results were obtained with ΔSUV limits. Situations in which these limits were exeeded were associated with a recent history of acute infectious pulmonary disease (lung tissues) and granulocytes colony-stimulating factors concomitant treatment and stimulation of bone marrow (bone tissues). CONCLUSION: A standardized and reproducible FDG PET QC protocol using SUV mean measurements using three tissues of Ref was validated, and may be applied in the clinical setting or in a clinical trial.