High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Stereotactic body radiotherapy of central lung tumours using a 1.5 T MR-linac: First clinical experiences.

Background: MRI-guidance may aid better discrimination between Organs at Risk (OARs) and target volumes in proximity of the mediastinum. We report the first clinical experiences with Stereotactic Body Radiotherapy (SBRT) of (ultra)central lung tumours on a 1.5 T MR-linac. Materials and Methods: Patients with an (ultra)central lung tumour were selected for MR-linac based SBRT treatment. A T2-weighted 3D sequence MRI acquired during free breathing was used for daily plan adaption. Prior to each fraction, contours of Internal Target Volume (ITV) and OARs were deformably propagated and amended by a radiation oncologist. Inter-fractional changes in volumes and coverage of target volumes as well as doses in OARs were evaluated in offline and online treatment plans. Results: Ten patients were treated and completed 60 Gy in 8 or 12 fractions. In total 104 fractions were delivered. The median time in the treatment room was 41 min with a median beam-on time of 8.9 min. No grade ≥3 acute toxicity was observed. In two patients, the ITV significantly decreased during treatment (58 % and 37 %, respectively) due to tumour shrinkage. In the other patients, 81 % of online ITVs were within ±15 % of the volume of fraction 1. Comparison with the pre-treatment plan showed that ITV coverage of the online plan was similar in 52 % and improved in 34 % of cases. Adaptation to meet OAR constraints, led to decreased ITV coverage in 14 %. Conclusions: We describe the workflow for MR-guided Radiotherapy and the feasibility of using 1.5 T MR-linac for SBRT of (ultra) central lung tumours.

The impact of etiology in lesion-symptom mapping - A direct comparison between tumor and stroke.

INTRODUCTION: Lesion-symptom mapping is a key tool in understanding the relationship between brain structures and behavior. However, the behavioral consequences of lesions from different etiologies may vary because of how they affect brain tissue and how they are distributed. The inclusion of different etiologies would increase the statistical power but has been critically debated. Meanwhile, findings from lesion studies are a valuable resource for clinicians and used across different etiologies. Therefore, the main objective of the present study was to directly compare lesion-symptom maps for memory and language functions from two populations, a tumor versus a stroke population. METHODS: Data from two different studies were combined. Both the brain tumor (N = 196) and stroke (N = 147) patient populations underwent neuropsychological testing and an MRI, pre-operatively for the tumor population and within three months after stroke. For this study, we selected two internationally widely used standardized cognitive tasks, the Rey Auditory Verbal Learning Test and the Verbal Fluency Test. We used a state-of-the-art machine learning-based, multivariate voxel-wise approach to produce lesion-symptom maps for these cognitive tasks for both populations separately and combined. RESULTS: Our lesion-symptom mapping results for the separate patient populations largely followed the expected neuroanatomical pattern based on previous literature. Substantial differences in lesion distribution hindered direct comparison. Still, in brain areas with adequate coverage in both groups, considerable LSM differences between the two populations were present for both memory and fluency tasks. Post-hoc analyses of these locations confirmed that the cognitive consequences of focal brain damage varied between etiologies. CONCLUSION: The differences in the lesion-symptom maps between the stroke and tumor population could partly be explained by differences in lesion volume and topography. Despite these methodological limitations, both the lesion-symptom mapping results and the post-hoc analyses confirmed that etiology matters when investigating the cognitive consequences of lesions with lesion-symptom mapping. Therefore, caution is advised with generalizing lesion-symptom results across etiologies.

First experimental exploration of real-time cardiorespiratory motion management for future stereotactic arrhythmia radioablation treatments on the MR-linac.

Objective.Stereotactic arrhythmia radioablation (STAR) is a novel, non-invasive treatment for refractory ventricular tachycardia (VT). The VT isthmus is subject to both respiratory and cardiac motion. Rapid cardiac motion presents a unique challenge. In this study, we provide first experimental evidence for real-time cardiorespiratory motion-mitigated MRI-guided STAR on the 1.5 T Unity MR-linac (Elekta AB, Stockholm, Sweden) aimed at simultaneously compensating cardiac and respiratory motions.Approach.A real-time cardiorespiratory motion-mitigated radiotherapy workflow was developed on the Unity MR-linac in research mode. A 15-beam intensity-modulated radiation therapy treatment plan (1 × 25 Gy) was created in Monaco v.5.40.01 (Elekta AB) for the Quasar MRI4Dphantom (ModusQA, London, ON). A film dosimetry insert was moved by combining either artificial (cos4, 70 bpm, 10 mm peak-to-peak) or subject-derived (59 average bpm, 15.3 mm peak-to-peak) cardiac motion with respiratory (sin, 12 bpm, 20 mm peak-to-peak) motion. A balanced 2D cine MRI sequence (13 Hz, field-of-view = 400 × 207 mm2, resolution = 3 × 3 × 15 mm3) was developed to estimate cardiorespiratory motion. Cardiorespiratory motion was estimated by rigid registration and then deconvoluted into cardiac and respiratory components. For beam gating, the cardiac component was used, whereas the respiratory component was used for MLC-tracking. In-silico dose accumulation experiments were performed on three patient data sets to simulate the dosimetric effect of cardiac motion on VT targets.Main results.Experimentally, a duty cycle of 57% was achieved when simultaneously applying respiratory MLC-tracking and cardiac gating. Using film, excellent agreement was observed compared to a static reference delivery, resulting in a 1%/1 mm gamma pass rate of 99%. The end-to-end gating latency was 126 ms on the Unity MR-linac. Simulations showed that cardiac motion decreased the target's D98% dose between 0.1 and 1.3 Gy, with gating providing effective mitigation.Significance.Real-time MRI-guided cardiorespiratory motion management greatly reduces motion-induced dosimetric uncertainty and warrants further research and development for potential future use in STAR.

Morphological changes after cranial fractionated photon radiotherapy: Localized loss of white matter and grey matter volume with increasing dose.

PURPOSE: Numerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). METHODS AND MATERIALS: From our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. RESULTS: Performing DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. CONCLUSIONS: Radiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

Simultaneous multi-slice accelerated 4D-MRI for radiotherapy guidance.

4D-MRI is becoming increasingly important for daily guidance of thoracic and abdominal radiotherapy. This study exploits the simultaneous multi-slice (SMS) technique to accelerate the acquisition of a balanced turbo field echo (bTFE) and a turbo spin echo (TSE) coronal 4D-MRI sequence performed on 1.5 T MRI scanners. SMS single-shot bTFE and TSE sequences were developed to acquire a stack of 52 coronal 2D images over 30 dynamics. Simultaneously excited slices were separated by half the field of view. Slices intersecting with the liver-lung interface were used as navigator slices. For each navigator slice location, an end-exhale dynamic was automatically identified, and used to derive the self-sorting signal by rigidly registering the remaining dynamics. Navigator slices were sorted into 10 amplitude bins, and the temporal relationship of simultaneously excited slices was used to generate sorted 4D-MRIs for 12 healthy volunteers. The self-sorting signal was validated using anin vivopeak-to-peak motion analysis. The smoothness of the liver-lung interface was quantified by comparing to sagittal cine images acquired directly after the SMS-4D-MRI sequence. To ensure compatibility with the MR-linac radiotherapy workflow, the 4D-MRIs were transformed into 3D mid-position (MidP) images using deformable image registration. Consistency of the deformable vector fields was quantified in terms of the distance discordance metric (DDM) in the body. The SMS-4D-TSE sequence was additionally acquired for 3 lung cancer patients to investigate tumor visibility. SMS-4D-MRI acquisition and processing took approximately 7 min. 4D-MRI reconstruction was possible for 26 out of 27 acquired datasets. Missing data in the sorted 4D-MRIs varied from 4%-26% for the volunteers and varied from 8%-24% for the patients. Peak-to-peak (SD) amplitudes analysis agreed within 1.8 (1.1) mm and 0.9 (0.4) mm between the sorted 4D-MRIs and the self-sorting signals of the volunteers and patients, respectively. Liver-lung interface smoothness was found to be in the range of 0.6-3.1 mm for volunteers. The percentage of DDM values smaller than 2 mm was in the range of 85%-89% and 86%-92% for the volunteers and patients, respectively. Lung tumors were clearly visibility in the SMS-4D-TSE images and MidP images. Two fast SMS-accelerated 4D-MRI sequences were developed resulting in T2/T1or T2weighted contrast. The SMS-4D-MRIs and derived 3D MidP-MRIs yielded anatomically plausible images and good tumor visibility. SMS-4D-MRI is therefore a strong candidate to be used for treatment simulation and daily guidance of thoracic and abdominal MR-guided radiotherapy.

Impact of the COVID-19 pandemic on quality of life and emotional wellbeing in patients with bone metastases treated with radiotherapy: a prospective cohort study.

Implementation of COVID-19 measures may have induced concerns about access and quality of health care for cancer patients with bone metastases, and it may have affected their quality of life. In this study, we evaluated the effect of the first COVID-19 lockdown on quality of life and emotional functioning of patients with stage IV cancer treated for painful bone metastases in the UMC Utrecht, the Netherlands. A COVID-19 specific questionnaire was sent to active participants in the Prospective Evaluation of interventional StudiEs on boNe meTastases (PRESENT) cohort, consisting of patients irradiated for metastatic bone disease. Patient reported outcomes (PROs) were compared with the last two PROs collected within the PRESENT cohort before the COVID-19 lockdown in the Netherlands on the 16th of March. For the 169 (53%) responders, median age at start of lockdown was 68 years (range 38-92) and 62% were male. Patients reported a statistically significant decrease in emotional functioning (83.6 to 79.2, P = 0.004) and in general quality of life score during the COVID-19 lockdown (72.4 to 68.7, P = 0.007). A steep increase in feeling isolated was reported (18% before and 67% during lockdown). This study has shown a strong increase in the experience of isolation and a decrease of emotional functioning and general quality of life during the COVID-19 lockdown in cancer patients with bone metastases. Due to the nature of the treatment of this patient population, efforts should be made to minimize these changes during future lockdowns.

Age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours.

BACKGROUND AND PURPOSE: Brain metastases originating from gynaecological tumours are a rare phenomenon, but have an increasing incidence due to better targeted therapies. This study aimed to identify factors that predict survival in these patients, which can be used in creating a robust prognostic tool for shared decision making. MATERIALS AND METHODS: We identified a consecutive cohort of 73 patients treated for gynaecological brain metastases in two tertiary institutions. Baseline demographics, pathology and serum CA-125 were included in a multivariable Cox proportional hazards model. RESULTS: Median overall survival in our cohort was 14.4 months, with a one-year survival of 56.4% and a two-year survival of 39.1%. Thirty-eight patients (52.1%) had ovarian carcinoma as the primary malignancy. The following factors were significantly associated with survival: age (HR 1.05 per year), CA-125 (HR 1.02 par 50 U/ml), and uterine and vulvar primary tumours (when compared to ovarian carcinoma, with HRs 3.07 and 8.70). A post-hoc analysis with primary tumour site reclassified into ovary versus non-ovary showed a HR of 0.50 for ovarian primary tumour type. CONCLUSION: We have found that age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours. Our findings may provide a foundation for future development of prediction models, for the benefit of both patients and physicians.

Impact of body fat distribution and sarcopenia on the overall survival in patients with spinal metastases receiving radiotherapy treatment: a prospective cohort study.

Introduction: An increasing number of patients is diagnosed with spinal metastases due to elevated cancer incidence and improved overall survival. Patients with symptomatic spinal bone metastases often receive radiotherapy with or without surgical stabilisation. Patients with a life expectancy of less than 3 months are generally deemed unfit for surgery, therefore adequate pre-treatment assessment of life expectancy is necessary. The aim of this study was to assess new factors associated with overall survival for this category of patients.Patients and methods: Patients who received radiotherapy for thoracic or lumbar spinal metastases from June 2013 to December 2016 were included in this study. The pre-treatment planning CT for radiotherapy treatment was used to assess the patient's visceral fat area, subcutaneous fat area, total muscle area and skeletal muscle density on a single transverse slice at the L3 level. The total muscle area was used to assess sarcopenia. Furthermore, data were collected on age, sex, primary tumour, Karnofsky performance score, medical history, number of bone metastases, non-bone metastases and neurological symptoms. Univariable and multivariable cox regressions were performed to determine the association between our variables of interest and the survival at 90 and 365 days.Results: A total of 310 patients was included. The median age was 67 years. Overall survival rates for 90 and 365 days were 71% and 36% respectively. For 90- and 365-day survival, the Karnofsky performance score, muscle density and primary tumour were independently significantly associated. The visceral or subcutaneous fat area and their ratio and sarcopenia were not independently associated with overall survival.Conclusions: Of the body morphology, only muscle density was statistically significant associated with overall survival after 90 and 365 days in patients with spinal bone metastases. Body fat distribution was not significantly associated with overall survival.

Eliminating biasing signals in lung cancer images for prognosis predictions with deep learning.

Deep learning has shown remarkable results for image analysis and is expected to aid individual treatment decisions in health care. Treatment recommendations are predictions with an inherently causal interpretation. To use deep learning for these applications in the setting of observational data, deep learning methods must be made compatible with the required causal assumptions. We present a scenario with real-world medical images (CT-scans of lung cancer) and simulated outcome data. Through the data simulation scheme, the images contain two distinct factors of variation that are associated with survival, but represent a collider (tumor size) and a prognostic factor (tumor heterogeneity), respectively. When a deep network would use all the information available in the image to predict survival, it would condition on the collider and thereby introduce bias in the estimation of the treatment effect. We show that when this collider can be quantified, unbiased individual prognosis predictions are attainable with deep learning. This is achieved by (1) setting a dual task for the network to predict both the outcome and the collider and (2) enforcing a form of linear independence of the activation distributions of the last layer. Our method provides an example of combining deep learning and structural causal models to achieve unbiased individual prognosis predictions. Extensions of machine learning methods for applications to causal questions are required to attain the long-standing goal of personalized medicine supported by artificial intelligence.

Ischemic stroke after radiation therapy for pituitary adenomas: a systematic review.

Radiation therapy is widely used for the treatment of residual and recurrent pituitary adenomas and proved to effectively control tumor growth. However, it is suggested that this treatment might result in an increased risk of ischemic stroke. This review aims to evaluate the radiotherapy-related risk of stroke in pituitary adenoma patients. PubMed and Embase databases were systematically searched for current literature on ischemic stroke risk after radiotherapy in pituitary adenoma, in accordance with the PRISMA statement. Two authors independently selected eligible studies and extracted data. The New Castle Ottawa-scale was used for quality assessment. Out of 264 publications, 11 studies were selected, including 4394 irradiated patients. Incidence of ischemic stroke ranged from 0 to 11.6% (mean 6.7%). While one large, long term follow-up study showed a threefold increased risk of stroke after radiation therapy, another nationwide study of high quality found no significant difference in stroke risk after irradiation. Four studies, which applied stereotactic radiosurgery (SRS) or Gamma-knife surgery (GKS), found no ischemic strokes. Included studies described different radiation techniques and regimens and different lengths of follow-up. In conclusion, complications of cerebral ischemia after radiotherapy for pituitary adenoma are infrequently reported. Moreover, after correction for several confounders, no significant difference in ischemic stroke rate between irradiated and non-irradiated patients could be identified.

Therapy-resistant tumor microvascular endothelial cells contribute to treatment failure in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a devastating disease with high mortality and poor prognosis. Cancer stem cells (CSCs) have recently been defined as a fraction of tumor cells highly resistant to therapy and subsequently considered to be responsible for tumor recurrence. These cells have been characterized in GBM and suggested to reside in and be supported by the tumor microvascular niche. Here we evaluated the response of tumor microvascular endothelial cells (tMVECs) to radio- and chemotherapy, and analyzed how this affects their interaction with CSCs. Our data demonstrate that tMVECs exhibit extreme resistance to both therapies, with the main response to irradiation being senescence. Importantly, senescent tMVECs can be detected in human GBM samples as well as in mice upon irradiation. Even though permanently arrested, they are still viable and able to support CSC growth with the same efficacy as non-senescent tMVECs. Intriguingly, GBM CSCs themselves are capable of differentiating into cells with similar features as tMVECs that subsequently undergo senescence when exposed to radiation. This indicates that endothelial-like cells are therapy resistant and, more importantly, support expansion of GBM cells.

Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma.

BACKGROUND: Angiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I-II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment. PATIENTS AND METHODS: Twenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m(2)), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression. RESULTS: Overall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images. CONCLUSION: Treatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.

Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines--a clue to radioresistance?

OBJECTIVE: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. METHODS: Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of gamma-rays from a (137)Cs source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. RESULTS: Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). CONCLUSION: Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance.