Repeatability and reproducibility of prostate apparent diffusion coefficient values on a 1.5 T magnetic resonance linear accelerator.

Background and Purpose: Integrated magnetic resonance linear accelerator (MR-Linac) systems offer potential for biologically based adaptive radiation therapy using apparent diffusion coefficient (ADC). Accurate tracking of longitudinal ADC changes is key to establishing ADC-driven dose adaptation. Here, we report repeatability and reproducibility of intraprostatic ADC using deformable image registration (DIR) to correct for inter-fraction prostate changes. Materials and Methods: The study included within-fraction repeat ADC measurements for three consecutive fractions for 20 patients with prostate cancer treated on a 1.5 T MR-Linac. We deformably registered successive fraction T2-weighted images and applied the deformation vector field to corresponding ADC maps to align to fraction 2. We delineated gross tumour volume (GTV), peripheral zone (PZ) and prostate clinical target volume (CTV) regions-of-interest (ROIs) on T2-weighted MRI and copied to ADC maps. We computed intraclass correlation coefficients (ICC) and percent repeatability coefficient (%RC) to determine within-fraction repeatability and between-fraction reproducibility for individual voxels, mean and 10th percentile ADC values per ROI. Results: The ICC between repeats and fractions was excellent for mean and 10th percentile ADC in all ROIs (ICC > 0.86), and moderate repeatability and reproducibility existed for individual voxels (ICC > 0.542). Similarly, low %RC within-fraction (4.2-17.9 %) mean and 10th percentile ADC existed, with greater %RC between fractions (10.2-36.8 %). Higher %RC existed for individual voxel within-fraction (21.7-30.6 %) and between-fraction (32.1-34.5 %) ADC. Conclusions: Results suggest excellent ADC repeatability and reproducibility in clinically relevant ROIs using DIR to correct between-fraction anatomical changes. We established the precision of voxel-level ADC tracking for future biologically based adaptation implementation.

Physical dose validation of dynamic treatment for Gamma Knife radiosurgery.

BACKGROUND: Dynamic treatment in Gamma Knife (GK) radiosurgery systems delivers radiation continuously with couch movement, as opposed to stationary step-and-shoot treatment where radiation is paused when moving between isocenters. Previous studies have shown the potential for dynamic GK treatment to give faster treatment times and improved dose conformity and homogeneity. However, these studies focused only on computational simulations and lack physical validation. PURPOSE: This study aims conduct dynamic treatment dosimetric validation with physical experimental measurements. The experiments aim to (1) address assumptions made with computational studies, such as the validity of treating a continuous path as discretised points, (2) investigate uncertainties in translating computed plans to actual treatment, and (3) determine ideal treatment planning parameters, such as interval distance for the path discretization, collimator change limitations, and minimum isocenter treatment times. METHODS: This study uses a GK ICON treatment delivery machine, and a motion phantom custom-made to attach to the machine's mask adapter and move in 1D superior-inferior motion. Phantom positioning is first verified through comparisons against couch motion and computed doses. For dynamic treatment experiments, the phantom is moved through a program that first reads the desired treatment plan isocenters' position, time, and collimator sizes, then carries out the motion continuously while the treatment machine delivers radiation. Measurements are done with increasing levels of complexity: varying speed, varying collimator sizes, varying both speed and collimator sizes, then extends the same measurements to simulated 2D motion by combining phantom and couch motion. Dose comparisons between phantom motion radiation measurements and either couch motion measurements or dose calculations are analyzed with 2 mm/2% and 1 mm/2% gamma indices, using both local and global gamma index calculations. RESULTS: Phantom positional experiments show a high accuracy, with global gamma indices for all dose comparisons ≥ $\ge $ 99%. Discretization level to approximate continuous path as discrete points show the good dose matches with dose calculations when using 1 and 2-mm gaps. Complex 1D motion, including varying speed, collimator sizes, or both, as well as 2D motion with the same complexities, all show good dose matches with dose calculations: the scores are ≥ $\ge $ 92.0% for the strictest 1 mm/2% local gamma index calculation, ≥ $\ge $ 99.8% for 2 mm/2% local gamma index, and ≥ $\ge $ 97.0% for all global gamma indices. Five simulated 2D treatments with optimized plans scored highly as well, with all gamma index scores ≥ $\ge $ 95.3% when compared to stationary treatment, and scores ≥ $\ge $ 97.9% when compared to plan calculated dose. CONCLUSIONS: Dynamic treatment computational studies are validated, with dynamic treatment shown to be physically feasible and deliverable with high accuracy. A 2-mm discretization level in treatment planning is proposed as the best option for shorter dose calculation times while maintaining dose accuracy. Our experimental method enables dynamic treatment measurements using the existing clinical workflow, which may be replicated in other centers, and future studies may include 2D or 3D motion experiments, or planning studies to further quantify potential indication-specific benefits.

Recommendations for improved reproducibility of ADC derivation on behalf of the Elekta MRI-linac consortium image analysis working group.

BACKGROUND AND PURPOSE: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it. MATERIALS AND METHODS: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm2, region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CVD) and calculation methods (CVC). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group. RESULTS: The median (range) CVD and CVC were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CVC to 0.04 (0.01-0.16). CVD was comparable between ROI types. CONCLUSION: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations.

Plan Assessment Metrics for Dose Painting in Stereotactic Radiosurgery.

Purpose: As radiation therapy treatment precision increases with advancements in imaging and radiation delivery, dose painting treatment becomes increasingly feasible, where targets receive a nonuniform radiation dose. The high precision of stereotactic radiosurgery (SRS) makes it a good candidate for dose painting treatments, but no suitable metrics to assess dose painting SRS plans exist. Existing dose painting assessment metrics weigh target overdose and underdose equally but are unsuited for SRS plans, which typically avoid target underdose more. Current SRS metrics also prioritize reducing healthy tissue dose through selectivity and dose fall-off, and these metrics assume single prescriptions. We propose a set of metrics for dose painting SRS that would meet clinical needs and are calculated with nonuniform dose painting prescriptions. Methods and Materials: Sample dose painting SRS prescriptions are first created from Gamma Knife SRS cases, apparent diffusion coefficient magnetic resonance images, and various image-to-prescription functions. Treatment plans are found through semi-infinite linear programming optimization and using clinically determined isocenters, then assessed with existing and proposed metrics. Modified versions of SRS metrics are proposed, including coverage, selectivity, conformity, efficiency, and gradient indices. Quality factor, a current dose painting metric, is applied both without changes and with modifications. A new metric, integral dose ratio, is proposed as a measure of target overdose. Results: The merits of existing and modified metrics are demonstrated and discussed. A modified conformity index using mean or minimum prescription dose would be suitable for dose painting SRS with integral or maximum boost methods, respectively. Either modified efficiency index is a suitable replacement for the existing gradient index. Conclusions: The proposed modified SRS metrics are appropriate measures of plan quality for dose painting SRS plans and have the advantage of giving equal values as the original SRS metrics when applied to single-prescription plans.

Using a Nominal Group Technique to Develop a Science Communication Curriculum for Health Professionals and Clinical Researchers.

Effective science communication is fundamental to closing the gap from research and innovation to clinical implementation. Existing paradigms of science communication are often challenged by a lack of skill and engagement, particularly from those who progress the science. Currently, a standardized curriculum on science communication, with global applicability, does not exist. The purpose of this project is to address the gap in training by health professionals and clinical researchers through the development of a globally relevant curriculum for science communication. The nominal group technique (NGT) was used whereby a convenience sample of eleven science communication experts from across the globe generated, discussed, and arrived at a consensus on topics that should be included in a standardized science communication curriculum. Experts represented diverse backgrounds within the health sciences. Due to the COVID-19 pandemic and geographical constraints, the NGT was conducted virtually. The consensus-building methodology allowed for each expert to equally present ideas and collaborate with one another to create a robust and comprehensive curriculum for effective science communication. Expert panelists reached a consensus on 10 essential components of a standardized global science communication curriculum. Following the refinement of the curriculum topic areas, a virtual meeting with project co-investigators was held to review the topics and discuss relevance, applicability, and appeal to the local contexts. A standardized science communication curriculum is needed for health professionals and clinical researchers. The NGT achieved expert consensus on the core topics. The next steps are to develop the course ensuring optimal participation from learners across the globe.

Assessment of intra-fraction motion during frameless image guided Gamma Knife stereotactic radiosurgery.

As frameless stereotactic radiosurgery increase in use, the aim of this study was to evaluate intra-fraction motion through cone-beam CT (CBCT) and high-definition motion management (HDMM) systems. Intra-fraction motion measured between localization, repeat localization and post-treatment CBCTs were correlated to intra-faction motion indicated by the HDMM files using the Pearson coefficient (r). A total of 302 plans were reviewed from 263 patients (114 male, 149 female); 216 pairs of localization-repeat localization, and 260 localization-post-treatment CBCTs were analyzed against HDMM logs. We found the magnitude of intra-fraction motion detected by the HDMM system were larger than the corresponding CBCT results.

Incorporating cross-voxel exchange for the analysis of dynamic contrast-enhanced imaging data: pre-clinical results.

Tumours exhibit abnormal interstitial structures and vasculature function often leading to impaired and heterogeneous drug delivery. The disproportionate spatial accumulation of a drug in the interstitium is determined by several microenvironmental properties (blood vessel distribution and permeability, gradients in the interstitial fluid pressure). Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the quantification of tracer perfusion based on contrast enhancement measured with non-invasive imaging techniques. An advanced cross-voxel exchange model (CVXM) was recently developed to provide a comprehensive description of tracer extravasation as well as advection and diffusion based on cross-voxel tracer kinetics (Sinnoet al2021). Transport parameters were derived from DCE-MRI of twenty TS-415 human cervical carcinoma xenografts by using CVXM. Tracer velocity flows were measured at the tumour periphery (mean 1.78-5.82µm.s-1) pushing the contrast outward towards normal tissue. These elevated velocity measures and extravasation rates explain the heterogeneous distribution of tracer across the tumour and its accumulation at the periphery. Significant values for diffusivity were deduced across the tumours (mean 152-499µm2.s-1). CVXM resulted in generally smaller values for the extravasation parameterKext(mean 0.01-0.04 min-1) and extravascular extracellular volume fractionve(mean 0.05-0.17) compared to the standard Tofts parameters, suggesting that Toft model underestimates the effects of inter-voxel exchange. The ratio of Tofts' extravasation parameters over CVXM's was significantly positively correlated to the cross-voxel diffusivity (P< 0.0001) and velocity (P= 0.0005). Tofts' increasedvemeasurements were explained using Sinnoet al(2021)'s theoretical work. Finally, a scan time of 15 min renders informative estimations of the transport parameters. However, a duration as low as 7.5 min is acceptable to recognize the spatial variation of transport parameters. The results demonstrate the potential of utilizing CVXM for determining metrics characterizing the exchange of tracer between the vasculature and the tumour tissue. Like for many earlier models, additional work is strongly recommended, in terms of validation, to develop more confidence in the results, motivating future laboratory work in this regard.

Pattern of Recurrence of Glioblastoma Versus Grade 4 IDH-Mutant Astrocytoma Following Chemoradiation: A Retrospective Matched-Cohort Analysis.

Background and Purpose: To quantitatively compare the recurrence patterns of glioblastoma (isocitrate dehydrogenase-wild type) versus grade 4 isocitrate dehydrogenase-mutant astrocytoma (wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase, respectively) following primary chemoradiation. Materials and Methods: A retrospective matched cohort of 22 wild type isocitrate dehydrogenase and 22 mutant isocitrate dehydrogenase patients were matched by sex, extent of resection, and corpus callosum involvement. The recurrent gross tumor volume was compared to the original gross tumor volume and clinical target volume contours from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the recurrent gross tumor volume outside the gross tumor volume and clinical target volume, and positional differences of the recurrent gross tumor volume centroid from the gross tumor volume and clinical target volume. Results: The gross tumor volume was smaller for wild type isocitrate dehydrogenase patients compared to the mutant isocitrate dehydrogenase cohort (mean ± SD: 46.5 ± 26.0 cm3 vs 72.2 ± 45.4 cm3, P = .026). The recurrent gross tumor volume was 10.7 ± 26.9 cm3 and 46.9 ± 55.0 cm3 smaller than the gross tumor volume for the same groups (P = .018). The recurrent gross tumor volume extended outside the gross tumor volume in 22 (100%) and 15 (68%) (P= .009) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively; however, the volume of recurrent gross tumor volume outside the gross tumor volume was not significantly different (12.4 ± 16.1 cm3 vs 8.4 ± 14.2 cm3, P = .443). The recurrent gross tumor volume centroid was within 5.7 mm of the closest gross tumor volume edge for 21 (95%) and 22 (100%) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively. Conclusion: The recurrent gross tumor volume extended beyond the gross tumor volume less often in mutant isocitrate dehydrogenase patients possibly implying a differential response to chemoradiotherapy and suggesting isocitrate dehydrogenase status might be used to personalize radiotherapy. The results require validation in prospective randomized trials.

Incorporating cross-voxel exchange into the analysis of dynamic contrast-enhanced imaging data: theory, simulations and experimental results.

Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the estimation of perfusion properties of tumour tissues but many assume no dispersion associated with tracer transport away from the capillaries and through the tissue. At the level of a voxel, this translates to assuming no cross-voxel tracer exchange, often leading to the misinterpretation of derived perfusion parameters. Tofts model (TM), a compartmental model widely used in oncology, also makes this assumption. A more realistic description is required to quantify kinetic properties of tracers, such as convection and diffusion. We propose a Cross-Voxel Exchange Model (CVXM) for analysing cross-voxel tracer kinetics.In silicodatasets quantifying the roles of convection and diffusion in tracer transport (which TM ignores) were employed to investigate the interpretation of Tofts' perfusion parameters compared to CVXM. TM returned inaccurate values ofKtransandvewhere diffusive and convective mechanisms are pronounced (up to 20% and 300% error respectively). A mathematical equation, developed in this work, predicts and gives the correct physiological interpretation of Tofts've.Finally, transport parameters were derived from dynamic contrast enhanced-magnetic resonance imaging of a TS-415 human cervical carcinoma xenograft by using TM and CVXM. The latter deduced lower values ofKtransandvecompared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155µm2s-1) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3µm s-1detected). The results serve as a proof of concept establishing the feasibility of using CVXM for accurately determining transport metrics that characterize the exchange of tracer between voxels. CVXM needs to be investigated further as its parameters can be linked to the tumour microenvironment properties (permeability, pressure…), potentially leading to enhanced personalized treatment planning.

Integration of quantitative imaging biomarkers in clinical trials for MR-guided radiotherapy: Conceptual guidance for multicentre studies from the MR-Linac Consortium Imaging Biomarker Working Group.

Quantitative imaging biomarkers (QIBs) derived from MRI techniques have the potential to be used for the personalised treatment of cancer patients. However, large-scale data are missing to validate their added value in clinical practice. Integrated MRI-guided radiotherapy (MRIgRT) systems, such as hybrid MRI-linear accelerators, have the unique advantage that MR images can be acquired during every treatment session. This means that high-frequency imaging of QIBs becomes feasible with reduced patient burden, logistical challenges, and costs compared to extra scan sessions. A wealth of valuable data will be collected before and during treatment, creating new opportunities to advance QIB research at large. The aim of this paper is to present a roadmap towards the clinical use of QIBs on MRIgRT systems. The most important need is to gather and understand how the QIBs collected during MRIgRT correlate with clinical outcomes. As the integrated MRI scanner differs from traditional MRI scanners, technical validation is an important aspect of this roadmap. We propose to integrate technical validation with clinical trials by the addition of a quality assurance procedure at the start of a trial, the acquisition of in vivo test-retest data to assess the repeatability, as well as a comparison between QIBs from MRIgRT systems and diagnostic MRI systems to assess the reproducibility. These data can be collected with limited extra time for the patient. With integration of technical validation in clinical trials, the results of these trials derived on MRIgRT systems will also be applicable for measurements on other MRI systems.

Transformational Role of Medical Imaging in (Radiation) Oncology.

Onboard, real-time, imaging techniques, from the original megavoltage planar imaging devices, to the emerging combined MRI-Linear Accelerators, have brought a huge transformation in the ability to deliver targeted radiation therapies. Each generation of these technologies enables lethal doses of radiation to be delivered to target volumes with progressively more accuracy and thus allows shrinking of necessary geometric margins, leading to reduced toxicities. Alongside these improvements in treatment delivery, advances in medical imaging, e.g., PET, and MRI, have also allowed target volumes themselves to be better defined. The development of functional and molecular imaging is now driving a conceptually larger step transformation to both better understand the cancer target and disease to be treated, as well as how tumors respond to treatment. A biological description of the tumor microenvironment is now accepted as an essential component of how to personalize and adapt treatment. This applies not only to radiation oncology but extends widely in cancer management from surgical oncology planning and interventional radiology, to evaluation of targeted drug delivery efficacy in medical oncology/immunotherapy. Here, we will discuss the role and requirements of functional and metabolic imaging techniques in the context of brain tumors and metastases to reliably provide multi-parametric imaging biomarkers of the tumor microenvironment.

Implementation of Cardiac Stereotactic Radiotherapy: From Literature to the Linac.

Stereotactic radiotherapy (SBRT) has been applied to treat cardiac arrhythmias, but our institution had not yet implemented this technique. Here, we explain how we used implementation science and knowledge translation to provide cardiac SBRT to a critically ill patient with malignancy-associated refractory ventricular tachycardia. We reviewed the critical factors that enabled the implementation of this urgent treatment, such as the context of the implementation, the characteristics of the intervention, and the stakeholders. These principles can be used by other radiation programs to implement novel treatments in urgent settings, where the gold standard process of planning and developing policies and protocols is not possible.

Impact of EGFR mutation on outcomes following SRS for brain metastases in non-small cell lung cancer.

INTRODUCTION: Patients with EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) are at particularly high risk of developing brain metastases (BrM). In addition to EGFR targeting tyrosine kinase inhibitors (TKI), radiosurgery (SRS) has an important role in the management of EGFRm BrM. However, data specific to the response and toxicity of EGFRm BrM to SRS are sparse. We evaluated the incidence of local failure (LF) and toxicity of EGFRm and EGFR-wild-type (EGFRwt) BrM treated with SRS. METHODS: We analyzed a prospective registry of BrM patients treated at our centre between 2008 and 2017 and identified EGFRm and EGFRwt NSCLC patients treated with SRS ±â€¯systemic therapy for BrM. Incidences of local failure (LF) and radionecrosis (RN) were determined, and Cox regression was performed for univariate and multivariate analyses (MVAs). RESULTS: We analyzed data from 218 patients (615 lesions - 225 EGFRm and 390 EGFRwt). Median imaging follow-up per patient was 14.5 months (0.5-96.3). Prior to or concomitant with SRS, 62 % of EGFRm patients received TKI and 93 % received TKI post SRS. The 24-month incidence of LF was 6% and 16 % for EGFRm BrM and EGFRwt, respectively (0.43(0.19-0.95); p = 0.037). The 24-month incidence of RN was 4% and 6% for EGFRm and EGFRwt BrM, respectively (0.8(0.32-1.98) p = 0.63). On MVA, BrM size and prescription dose (PD) significantly correlated with a higher risk of LF and BrM size correlated with a higher risk of RN. CONCLUSION: We observed excellent rates of response and toxicity following SRS in EGFRm compared to EGFRwt NSCLC, suggesting that EGFRm BrM have a favourable risk benefit ratio compared to EGFRwt NSCLC.

Clinicopathologic and Treatment Features of Long-Term Surviving Brain Metastasis Patients.

BACKGROUND: The purpose of our study was to characterize clinical features among brain metastasis (BM) patients who were long term survivors (LTS). METHODS: We reviewed a registry of BM patients referred to our multidisciplinary BM clinic between 2006 and 2014 and identified 97 who lived ≥ 3 years following BM diagnosis. The clinical and treatment characteristics were obtained from a prospectively maintained database, and additional information was obtained through review of electronic medical records and radiologic images. Survival analyses were performed using the Kaplan-Meier method. RESULTS: Median follow up for LTS was 67 months (range 36-181). Median age was 54 years, 65% had single BM, 39% had stable extracranial disease at the time of BM treatment, and brain was the first site of metastasis in 76%. Targetable mutations were present in 39% of patients and 66% received treatment with targeted-, hormonal-, or immuno-therapy. Brain surgery at the time of diagnosis was performed in 40% and stereotactic radiosurgery (SRS) or whole brain radiotherapy (alone or combination) in 52% and 56%, respectively. Following initial BM treatment, 5-year intracranial disease-free survival was 39%, and the cumulative incidence of symptomatic radio-necrosis was 16%. Five and ten-year overall survival was 72% and 26%, respectively. CONCLUSION: Most LTS were younger than 60 years old and had a single BM. Many received treatment with surgery or targeted, immune, or hormonal therapy.

Patient perspectives on frame versus mask immobilization for gamma knife stereotactic radiosurgery.

PURPOSE: To assess patient experiences and perspectives following Gamma Knife (GK) stereotactic radiosurgery (SRS) using frame versus mask immobilization. METHODS: Patients who received GK-SRS using both frame and mask immobilization were included in this study. One-on-one semi-structured interviews, led by a third-party expert, were used to gain insight into the patient experience. To reduce memory bias of either immobilization device, patients underwent the interview at their follow-up appointment. Initial assessment of patient transcriptions was completed by one study staff; a second member reviewed transcripts for thematic saturation. All interviews were independently coded for themes to minimize interpretation bias. RESULTS: Fifteen patients were consented; 12 were successfully interviewed (3 lost due to deteriorating health status). Interviews ranged from 30 to 60 min in duration. The most common patient concern regarding the frame was pain (9 patients), while the primary concerns with the mask system were the ability to remain still (6 patients) and claustrophobia (4 patients). Eleven patients chose the mask as their preferred choice in terms of their overall experience. Two themes emerged during the interviews that spoke to patient satisfaction with each process: unexpected pain with frame placement; and tightness experienced while wearing the mask during treatment. CONCLUSIONS: From the patient perspective there was overwhelming agreement that the mask was the preferred choice for GK-SRS. The patient experience could be improved by enhanced education to better prepare patients on what to expect during the frame placement and mask treatment processes.

Neurological Death is Common in Patients With EGFR Mutant Non-Small Cell Lung Cancer Diagnosed With Brain Metastases.

PURPOSE: Brain metastases (BrM) are common in patients with epidermal growth factor receptor (EGFRm) mutant non-small cell lung cancer (NSCLC). We sought to determine the rate of neurologic death (ND) in this population. METHODS AND MATERIALS: We analyzed data from 198 patients who received a diagnosis of BrM from EGFRm NSCLC between 2004 and 2016, comparing patients whose initial treatment for BrM was stereotactic radiosurgery with or without tyrosine kinase inhibitors (TKI), whole brain radiation therapy (WBRT) with or without TKI, or TKI alone. The incidence of ND was determined using a competing risks analysis. Univariate and multivariate analyses were used to identify clinical variables associated with this outcome. RESULTS: The percentage of patients who initially received stereotactic radiosurgery, whole brain radiation therapy, or TKI alone was 22%, 61%, and 17%, respectively. Median overall survival in these subgroups was 31.1, 14.6, and 24.6 months, respectively (P = .0016). The 5-year incidence of ND among all patients was 40% and did not significantly vary according to treatment group. In a multivariable model, only leptomeningeal disease at any point in a patient's disease course significantly correlated with ND (hazard ratio 4.75, P <.001). CONCLUSIONS: Among our cohort of patients with BrM from EGFRm NSCLC, the incidence of ND was significantly higher than suggested by previous reports. BrM should be considered a driver of mortality in many patients with EGFRm NSCLC, and treatments providing better control of BrM, lower neurocognitive side effects, and maintenance of quality of life are needed.

Efficacy of stereotactic radiosurgery for radiation-induced meningiomas.

PURPOSE: Stereotactic radiosurgery is an established treatment option for sporadic meningiomas, though limited data exists for radiation-induced lesions. METHODS: Patients treated with cobalt-60 radiosurgery between October 2005 and December 2018 in an institutional registry were reviewed. Single fraction treatments were prescribed to the 50% isodose line. Lesions were deemed to be radiation-induced according to standard criteria previously established by Cahan et al. RESULTS: A total of 37 patients with 72 lesions were analysed. Median follow up per patient was 44 months (range, 1.4-150.7 months). Median age at initial radiotherapy was 5 years (4 months-48 years), and at radiosurgery was 38 years. Of the 72 lesions, 62 were grade 1 (n = 4) or radiologically-diagnosed (n = 58), six were grade 2 and four were grade 3. Median lesion volume was 2.13 cc (0.04-13.8 cc), while the median radiosurgery margin dose was 13 Gy. Local control, on a per lesion basis, was 88.6% at 5 years (95% confidence interval [CI] 72.3-95.6). For grade 1 or radiologically-diagnosed lesions, local control was 96.6% at 5 years (95% CI 77.9-99.5), whereas those with grade 2 or higher lesions had a local control of 40% at 5 years (95% CI 5.2-75.3, p = 0.005). Radiologic oedema developed in 17 lesions (23.6%) and was symptomatic in 12 patients (16.7%). Doses above 12 Gy were not associated with local control probability (p = 0.292). CONCLUSION: Radiosurgery is an effective treatment option for grade 1 or radiologically-diagnosed radiation-induced meningiomas, with 12 Gy appearing to be a sufficient dose.

A Multidisciplinary Approach to Implement Image-Guided Craniospinal Irradiation.

PURPOSE: Practical considerations dictated a change in the craniospinal irradiation (CSI) technique. We report our experience in developing and refining CSI planning and treatment parameters, using a 3-isocenter image-guided intensity-modulated radiation therapy (IG-IMRT) technique. METHODS AND MATERIALS: Two institutional values guided development: multidisciplinary decision-making and coordinated considerations throughout simulation, planning, and delivery. Patient immobilization and simulation parameters were selected based on treatment delivery system limitations. Commissioning fluence verification maps were acquired to verify dose in regions of overlapping fields. Robustness analysis was performed to assess impact of potential setup errors measured through IGRT verification. Treatment considerations included order of isocenter imaging and treatment and respective IGRT frequency, modality, and image registration thresholds. RESULTS: Overall film measurements were within 3% of planned dose, confirmed by phantom composite measurements showing all points were within 97% of planned dose. Setup sensitivity analysis suggested a 3-mm setup tolerance was sufficient to ensure confidence in the delivered plan. As the most critical organs at risk were in the superior isocenter, the daily isocenter treatment order was confirmed as superior, middle, and inferior. Daily cone beam computed tomography guidance was chosen for all isocenters (3° rotational threshold). Except for the superior/inferior direction of the middle and inferior isocenters, which were adjusted to 3 mm based on sensitivity analysis, a 1-mm translational threshold was used. CONCLUSIONS: An IG-IMRT CSI technique has been developed and implemented in our institution through a multidisciplinary approach. This process highlights the collaborative, iterative approach used to successfully integrate a new treatment technique in an image-guidance era.

A prospective, multi-centre trial of multi-parametric MRI as a biomarker in anal carcinoma.

BACKGROUND AND PURPOSE: To investigate the role of multi-parametric magnetic resonance imaging (MP-MRI) as a biomarker for squamous cell carcinoma of the anal canal (SCCAC). MATERIALS AND METHODS: From January 2013 to January 2017, 25 patients with non-metastatic SCCAC were enrolled in a multi-centre prospective clinical trial, of whom 20 completed protocol treatment. MP-MRIs, incorporating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) sequences, were performed before (baseline), during the second and fourth weeks of chemo-radiotherapy (CRT), and 8 weeks following treatment completion. Histogram analysis of multi-parametric maps generated maximum, mean, median, minimum, skewness, kurtosis, and standard deviation metrics. Exact logistic regression and ROC AUC analyses were performed for each metric at every timepoint. An elastic net LASSO logistic regression was also performed using all measures at each timepoint. RESULTS: With a median follow up of 17.1 months, 3/20 patients had a local recurrence, and 5/20 had any recurrence. Several apparent diffusion coefficient (ADC) metrics extracted from DW-MRIs correlated with local recurrence and demonstrated excellent discrimination: baseline skewness (p = 0.04, ROC AUC 0.90) and standard deviation (SD) (p = 0.02, ROC AUC 0.90), week 2 skewness (p = 0.02, ROC AUC 0.91) and SD (p = 0.01, ROC AUC 0.94), week 4 kurtosis (p = 0.01, AUC 0.92) and SD (p = 0.01, ROC AUC 0.96). Changes in minimum ADC between baseline and week 2 (p = 0.02, ROC AUC 0.94) and baseline and week 4 (p = 0.02, ROC AUC 0.94) were prognostic for local recurrence. For prediction of any recurrence, ADC minimum (p = 0.02, ROC AUC 0.87) and SD (p = 0.01, ROC AUC 0.85) at baseline, and ADC maximum (p = 0.03, ROC AUC 0.77) and SD (p = 0.02, ROC AUC 0.81) at week 4 were significant. On LASSO logistic regression, ADC minimum and SD at baseline were retained for any recurrence. The only significant finding for DCE-MRI was a correlation of k-trans min at the second follow-up with local recurrence (p = 0.05, AUC 0.84). CONCLUSION: Several ADC parameters at various time points correlate with recurrence suggesting DW-MRI is a potential biomarker for SCCAC.

A Nanoemulsion with A Porphyrin Shell for Cancer Theranostics.

A nanoemulsion with a porphyrin shell (NewPS) was created by the self-assembly of porphyrin salt around an oil core. The NewPS system has excellent colloidal stability, is amenable to different porphyrin salts and oils, and is capable of co-loading with chemotherapeutics. The porphyrin salt shell enables porphyrin-dependent optical tunability. The NewPS consisting of pyropheophorbide a mono-salt has a porphyrin shell of ordered J-aggregates, which produced a narrow, red-shifted Q-band with increased absorbance. Upon nanostructure dissociation, the fluorescence and photodynamic reactivity of the porphyrin monomers are restored. The spectrally distinct photoacoustic imaging (at 715 nm by intact NewPS) and fluorescence increase (at 671 nm by disrupted NewPS) allow the monitoring of NewPS accumulation and disruption in mice bearing KB tumors to guide effective photodynamic therapy. Substituting the oil core with Lipiodol affords additional CT contrast, whereas loading paclitaxel into NewPS facilitates drug delivery.