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.

Assessment of minimum target dose as a predictor of local failure after spine SBRT.

OBJECTIVES: Metastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. METHODS: Spine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20-24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27-36 Gy and 21-24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. RESULTS: 522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3-54.4). The cumulative incidence of local failure was 10.5 % (7.4-13.4) at 1 year and 16.3 % (12.6-19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 - 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6-9.4) vs. 14.2 % (8.3-19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). CONCLUSIONS: Spine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14-15.3 Gy with single fraction SBRT is recommended whenever possible.

Assessment of Radiation Dosage to the Hippocampi during Treatment of Multiple Brain Metastases Using Gamma Knife Therapy.

Background and Objectives: Brain metastases (BMs) pose significant clinical challenges in systemic cancer patients. They often cause symptoms related to brain compression and are typically managed with multimodal therapies, such as surgery, chemotherapy, whole brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS). With modern oncology treatments prolonging survival, concerns about the neurocognitive side effects of BM treatments are growing. WBRT, though widely used for multiple BMs, has recognized neurocognitive toxicity. SRS, particularly Gamma Knife (GK) therapy, offers a minimally invasive alternative with fewer side effects, suitable for patients with a quantifiable number of metastases and better prognoses. Materials and Methods: A retrospective analysis was conducted on 94 patients with multiple BMs treated exclusively with GK at an academic medical center. Patients with prior WBRT were excluded. This study focused on the mean radiation dose received by the hippocampal area, estimated according to the 'Hippocampal Contouring: A Contouring Atlas for RTOG 0933' guidelines. Results: The precision of GK equipment results in mean doses of radiation that are lower than those suggested by RTOG 0933 and observed in other studies. This precision may help mitigate cognitive dysfunction and other side effects of hippocampal irradiation. Conclusions: GK therapy facilitates the administration of smaller, safer radiation doses to the hippocampi, which is advantageous even for lesions in the temporal lobe. It is feasible to treat multiple metastases, including cases with more than 10, but it is typically reserved for patients with fewer metastases, with an average of 3 in this study. This underlines GK's potential for reducing adverse effects while managing BMs effectively.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Socio-economic disparities influence likelihood of post-operative radiation to resection cavities of metastatic brain tumors.

PURPOSE: Irradiating the surgical bed of resected brain metastases improves local and distant disease control. Over time, stereotactic radiosurgery (SRS) has replaced whole brain radiotherapy (WBRT) as the treatment standard of care because it minimizes long-term damage to neuro-cognition. Despite this data and growing adoption, socio-economic disparities in clinical access can result in sub-standard care for some patient populations. We aimed to analyze the clinical and socio-economic characteristics of patients who did not receive radiation after surgical resection of brain metastasis. METHODS: Our sample was obtained from Clinformatics® Data Mart Database and included all patients from 2004 to 2021 who did or did not receive radiation treatment within sixty days after resection of tumors metastatic to the brain. Regression analysis was done to identify factors responsible for loss to adjuvant radiation treatment. RESULTS: Of 8362 patients identified who had undergone craniotomy for resection of metastatic brain tumors, 3430 (41%) patients did not receive any radiation treatment. Compared to patients who did receive some form of radiation treatment (SRS or WBRT), patients who did not get any form of radiation were more likely to be older (p = 0.0189) and non-white (p = 0.008). Patients with Elixhauser Comorbidity Index ≥3 were less likely to receive radiation treatment (p < 0.01). Fewer patients with household income ≥ $75,000 did not receive radiation treatment (p < 0.01). CONCLUSION: Age, race, household income, and comorbidity status were associated with differential likelihood to receive post-operative radiation treatment.

Hypofractionation and SABR: 25 years of evolution in medical physics and a glimpse of the future.

As we were invited to write an article for celebrating the 50th Anniversary of Medical Physics journal, on something historically significant, commemorative, and exciting happening in the past decades, the first idea came to our mind is the fascinating radiotherapy paradigm shift from conventional fractionation to hypofractionation and stereotactic ablative radiotherapy (SABR). It is historically and clinically significant since as we all know this RT treatment revolution not only reduces treatment duration for patients, but also improves tumor control and cancer treatment outcomes. It is also commemorative and exciting for us medical physicists since the technology development in medical physics has been the main driver for the success of this treatment regimen which requires high precision and accuracy throughout the entire treatment planning and delivery. This article provides an overview of the technological development and clinical trials evolvement in the past 25 years for hypofractionation and SABR, with an outlook to the future improvement.

Assessment of gamma knife radiosurgery for unruptured cerebral arterioveneus malformations based on multi-parameter radiomics of MRI.

OBJECTIVE: The treatment of Gamma knife radiosurgery (GKS) for unruptured Arteriovenous Malformations (AVM) remains controversial. A safe, effective and non-invasive method to predict outcome seems attractive for GKS. The purpose of this study was to develop and validate a MRI based multi-parameter radiomics model predicting the outcome of GKS for unruptured AVM. METHODS: Eighty-eight unruptured AVM patients who initial underwent GKS between January 2011 and December 2016 in our hospital were included in this retrospective study. Patients were divided into two groups named as favourable and unfavourable outcome, according to the clinical outcome. Favourable outcome was defined as obliteration without post-SRS hemorrhage or permanent radiation-induced changes (RIC). Multivariate logistic regression analysis was used to select appropriate clinical features and construct a clinical predicting model. In terms of radiomic model, manually segmentation and radiomics extracted were performed on each AVM lesions. Finally, 1684 radiomics features were extracted and Recursive Feature Elimination (RFE) method combined with Random forest classifier were used for feature selection and model construction. The performance of the radiomics model was evaluated by the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, the favourable group was further divided into early and late respond subgroup according to the time of obliteration evaluated by 2 years. The selected features were further compared according the respond time. RESULTS: The median duration of neuroimaging follow-up was 65 months, 56 patients showed favourable outcome and 17 patients were observed obliteration within 2 years. The radiomics model constructed by 12 selected features achieved significant higher AUC of 0.88 (95% confidence interval 0.87-0.90) than traditional scoring system for predicting AVM outcome. Two selected radiomics features named "Dependence Variance" and "firstorder-Skewness" were found significant difference between the patients with early or late-respond. CONCLUSIONS: The results suggest that the radiomics features could be successfully used for the pretreatment prediction of outcome for GKS in unruptured AVMs, which is helpful for decision-making process on unruptured AVM patients.

On the effect of dose delivery temporal domain on the biological effectiveness of central nervous system CyberKnife radiosurgery applications: theoretical assessment using the concept of biologically effective dose.

OBJECTIVE: The diversity in technical configuration between clinically available radiosurgery systems, results in accordingly diverse treatment times for the same physical dose prescription, spanning from several min to more than 1 h. This, combined with evidence supporting the impact of dose delivery temporal pattern on the bio-effectiveness of low-LET radiation treatments, challenges the 'acute exposure' assumption adopted clinically to estimate the biological outcome of a given treatment scheme under the concept of biologically effective dose (BED).Approach: In this work, the treatment plans of 30 patients underwent CyberKnife radiosurgery for vestibular schwannoma (VS), prescribing a marginal dose of 13 Gy to the tumor, were retrospectively reviewed and the corresponding dose distributions were resolved in the temporal domain. For this purpose, the dose delivery timeline for each treatment was calculated based on relevant treatment plan data and technical specifications of the CyberKnife system, while dosimetry data were independently acquired on a CT-based digital model of each patient using an in-house developed dose calculation algorithm.Main results: Results showed that CyberKnife delivers highly inhomogeneous dose rate distributions in the temporo-spatial domain. This influences the delivered BED levels due to alterations in the sublethal damage repair (SLR) occurring within the treatment session. Using a BED framework involving SLR effects, it was shown that each physical dose iso-surface is associated with a BEDslrrange. For the patient cohort studied, a typical range of 2%, with respect to the mean BEDslrvalue was found at 1σ.Significance: The marginal BEDslrdelivered to the tumor by the prescription dose iso-surface deteriorates with treatment time, involving both beam-on time and beam-off gaps. For treatment time,T, between 21 and 50 min, this can be expressed byBEDslr(Gy2.47)=-0.35±2.8%∙Tmin+(76.74±0.4%).Compared to the acute exposure approach, a BED 'loss' of 21% is associated with the delivery of 13 Gy to the VS-tumor in 35 min.

Microwave Ablation versus Stereotactic Body Radiotherapy for Stage I Non-Small Cell Lung Cancer: A Cost-Effectiveness Analysis.

PURPOSE: To assess the cost effectiveness of microwave ablation (MWA) and stereotactic body radiotherapy (SBRT) for patients with inoperable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A literature search was performed in MEDLINE with broad search clusters. A decision-analytic model was constructed over a 5-year period. The model incorporated treatment-related complications and long-term recurrence. All clinical parameters were derived from the literature with preference to long-term prospective trials. A healthcare payers' perspective was adopted. Outcomes were measured in quality-adjusted life years (QALYs) extracted from prior studies and U.S. dollars from Medicare reimbursements and prior studies. Base case calculations, probabilistic sensitivity analysis with 10,000 Monte Carlo simulations, and multiple 1- and 2-way sensitivity analyses were performed. RESULTS: MWA yielded a health benefit of 2.31 QALYs at a cost of $195,331, whereas SBRT yielded a health benefit of 2.33 QALYs at a cost of $225,271. The incremental cost-effectiveness ratio was $1,480,597/QALY, indicating that MWA is the more cost-effective strategy. The conclusion remains unchanged in probabilistic sensitivity analysis with MWA being the optimal cost strategy in 99.84% simulations. One-way sensitivity analyses revealed that MWA remains cost effective when its annual recurrence risk is <18.4% averaged over 5 years, when the SBRT annual recurrence risk is >1.44% averaged over 5 years, or when MWA is at least $7,500 cheaper than SBRT. CONCLUSIONS: MWA appears to be more cost effective than SBRT for patients with inoperable stage I NSCLC.

Patterns of Pretreatment Diagnostic Assessment in Patients Treated with Stereotactic Body Radiation Therapy (SBRT) for Non-Small Cell Lung Cancer (NSCLC): Special Characteristics in the COVID Pandemic and Influence on Outcomes.

The pandemic raised a discussion about the postponement of medical interventions for non-small cell lung cancer (NSCLC). We analyzed the characteristics of pretreatment diagnostic assessment in the pandemic and the influence of diagnostic assessment on outcomes. A total of 96 patients with stereotactic body radiation therapy (SBRT) for NSCLC were included. The number of patients increased from mean 0.9 (2012-2019) to 1.45 per month in the COVID era (p < 0.05). Pandemic-related factors (contact reduction, limited intensive care unit resources) might have influenced clinical decision making towards SBRT. The time from pretreatment assessment (multidisciplinary tumor board decision, bronchoscopy, planning CT) to SBRT was longer during the COVID period (p < 0.05). Reduced services, staff shortage, or appointment management to mitigate infection risks might explain this finding. Overall survival, progression-free survival, locoregional progression-free survival, and distant progression-free survival were superior in patients who received a PET/CT scan prior to SBRT (p < 0.05). This supports that SBRT guidelines advocate the acquisition of a PET/CT scan. A longer time from PET/CT scan/conventional staging to SBRT (<10 vs. ≥10 weeks) was associated with worse locoregional control (p < 0.05). The postponement of diagnostic or therapeutic measures in the pandemic should be discussed cautiously. Patient- and tumor-related features should be evaluated in detail.

Is the CyberKnife© radiosurgery system effective and safe for patients? An umbrella review of the evidence.

Background: The CyberKnife© system combines real-time image guidance and a dynamic tracking system to implement frameless radiotherapy. This umbrella review is aimed to evaluate the effectiveness and safety of CyberKnife. Methods: A comprehensive search of health technology assessments and systematic reviews was performed among the Embase, PubMed and other grey databases until July 2020. Treatment outcomes were extracted, and the quality of included studies were assessed using AMSTAR-2. Results: Nineteen studies were eligible. CyberKnife not only had a wide range of applications, long overall survival and great local control, but also had a limited toxicity and good cost-effectiveness compared with other radiotherapy equipment. Conclusion: Despite the relatively low quality of the evidence, our findings can still provide a decision reference for policymakers.

An umbrella review on the effectiveness and safety of the CyberKnife^© system was performed by comprehensively searching for all related publications. The CyberKnife system had excellent effect on treatment of cancer and some noncancer diseases, with limited toxicity. Additionally, it was a cost-effective treatment compared with other types of radiotherapy. Despite the relatively low quality of the included evidence, our findings can still provide a comprehensive decision reference for policymakers of patients, government and hospitals.

Risk of Cardiovascular Toxicity According to Tumor Laterality Among Older Patients With Early Stage Non-small Cell Lung Cancer Treated With Radiation Therapy.

BACKGROUND: The long-term risk of cardiovascular outcomes from either stereotactic body radiation therapy (SBRT) or three-dimensional conformal radiation therapy (3DCRT) plus intensity-modulated radiation therapy (IMRT) to treat early stage non-small cell lung cancer (NSCLC) is largely unknown. As continued adoption of SBRT accelerates, it is important to delineate unforeseen cardiovascular risks associated with treatment. RESEARCH QUESTION: Does the long-term risk of cardiovascular outcomes for patients with early stage NSCLC treated with either SBRT or 3DCRT plus IMRT differ by tumor laterality? STUDY DESIGN AND METHODS: Data from the Surveillance, Epidemiology, and End Results registry linked to Medicare was analyzed to identify a sample of 3,256 patients (1,506 treated with SBRT and 1,750 treated with 3DCRT plus IMRT) with node-negative stage I or IIA NSCLC. Cardiovascular events were identified using diagnosis codes, and outcomes were compared between left- and right-sided tumors. We assumed that tumor laterality was random and that the radiation field for left-sided tumors likely would result in greater dose to cardiac tissues. Cox regression models were fit to quantify the association of laterality on outcomes. RESULTS: Patients were followed up for a median of 2 years. Those treated with SBRT showed no difference in hazard of any cardiovascular outcomes by tumor laterality, including the cardiovascular composite (hazard ratio [HR] comparing left- vs right-sided tumors, 0.98; 95% CI, 0.84-1.15). In contrast, patients treated with 3DCRT plus IMRT showed a greater risk of congestive heart failure (HR, 1.23; 95% CI, 1.01-1.48) and percutaneous coronary artery intervention (HR, 2.24; 95% CI, 1.12-4.47). INTERPRETATION: Patients with left- vs right-sided early stage NSCLC showed similar rates of cardiovascular events when treated with SBRT. However, these patients also showed higher rates of select cardiac events when they were treated with 3DCRT plus IMRT. This study provides evidence that SBRT may provide a safer option over 3DCRT plus IMRT for patients with left-sided early stage NSCLC and underscores the need for long-term follow-up for patients treated with radiation therapy.

Development and Assessment of a Predictive Score for Vertebral Compression Fracture After Stereotactic Body Radiation Therapy for Spinal Metastases.

IMPORTANCE: Vertebral compression fracture (VCF) is a potential adverse effect following treatment with stereotactic body radiation therapy (SBRT) for spinal metastases. OBJECTIVE: To develop and assess a risk stratification model for VCF after SBRT. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted at a high-volume referral center included 331 patients who had undergone 464 spine SBRT treatments from December 2007 through October 2019. Data analysis was conducted from November 1, 2020, to August 17, 2021. Exclusions included proton therapy, prior surgical intervention, vertebroplasty, or missing data. EXPOSURES: One and 3 fraction spine SBRT treatments were most commonly delivered. Single-fraction treatments generally involved prescribed doses of 16 to 24 Gy (median, 20 Gy; range, 16-30 Gy) to gross disease compared with multifraction treatment that delivered a median of 30 Gy (range, 21-50 Gy). MAIN OUTCOMES AND MEASURES: The VCF and radiography components of the spinal instability neoplastic score were determined by a radiologist. Recursive partitioning analysis was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was the criterion for node splitting. RESULTS: Of the 331 participants, 88 were women (27%), and the mean (IQR) age was 63 (59-72) years. With a median follow-up of 21 months (IQR, 11-39 months), we identified 84 VCFs (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median of 9 months (IQR, 3-21 months) to developing a VCF. From 15 candidate variables, 6 were identified using the backward selection method, feature importance testing, and a correlation heatmap. Four were selected via recursive partitioning analysis: epidural tumor extension, lumbar location, gross tumor volume of more than 10 cc, and a spinal instability neoplastic score of more than 6. One point was assigned to each variable, and the resulting multivariable Cox model had a concordance of 0.760. The hazard ratio per 1-point increase for VCF was 1.93 (95% CI, 1.62-2.30; P < .001). The cumulative incidence of VCF at 2 years (with death as a competing risk) was 6.7% (95% CI, 4.2%-10.7%) for low-risk (score, 0-1; 273 [58.3%]), 17.0% (95% CI, 10.8%-26.7%) for intermediate-risk (score, 2; 99 [21.3%]), and 35.4% (95% CI, 26.7%-46.9%) for high-risk cases (score, 3-4; 92 [19.8%]) (P < .001). Similar results were observed for freedom from VCF using stratification. CONCLUSIONS AND RELEVANCE: The results of this cohort study identify a subgroup of patients with high risk for VCF following treatment with SBRT who may potentially benefit from undergoing prophylactic spinal stabilization or vertebroplasty.

Re-irradiation of canine non-lymphomatous nasal tumours using stereotactic radiation therapy (10 Gy x 3) for both courses: Assessment of outcome and toxicity in 11 dogs.

No uniformly beneficial treatments exist for dogs with non-lymphomatous nasal tumours (NLNT) that relapse after radiotherapy (RT). Reirradiation may prolong survival and improve quality of life. In this retrospective study, we describe outcomes for 11 dogs that had CT-confirmed locoregional progression of NLNT after an initial course of stereotactic RT (SRT#1; 10 Gy × 3) and were then re-treated with the same type of protocol (SRT#2, also 10 Gy × 3). The median time between SRT #1 and SRT #2 was 243 days (95% CI: 78-385 days). Ten dogs (91%) had a clinical benefit after SRT#1; five dogs (45%) had clinical benefit after SRT#2. Adverse events after SRT#2 included nasocutaneous or oronasal fistula formation (N = 3 at 180, 270, and 468 days), seizures (N = 2 at 78 and 330 days), bacterial or fungal rhinitis (N = 2 at 240 and 385 days), and facial swelling (N = 1 at 90 days). All 11 dogs have died, due to disease progression, presumed radiotoxicity, or declining quality of life; in most cases, it was difficult to discern between these conditions. The median overall survival time (OST) from SRT#1 was 745 days (95% CI: 360-1132). The median overall survival time (OST) from SRT #2 was 448 days (95% CI: 112-626). For these dogs, survival was prolonged, but adverse events after SRT#2 were common (8/11; 73%). Therefore, before consenting to re-irradiation with this protocol, pet owners should be counselled about survivorship challenges, including risk for severe toxicities, and persistence of clinical signs.

The centrally restricted diffusion sign on MRI for assessment of radiation necrosis in metastases treated with stereotactic radiosurgery.

PURPOSE: Differentiation of radiation necrosis from tumor progression in brain metastases treated with stereotactic radiosurgery (SRS) is challenging. For this, we assessed the performance of the centrally restricted diffusion sign. METHODS: Patients with brain metastases treated with SRS who underwent a subsequent intervention (biopsy/resection) for a ring-enhancing lesion on preoperative MRI between 2000 and 2020 were included. Excluded were lesions containing increased susceptibility limiting assessment of DWI. Two neuroradiologists classified the location of the diffusion restriction with respect to the post-contrast T1 images as centrally within the ring-enhancement (the centrally restricted diffusion sign), peripherally correlating to the rim of contrast enhancement, both locations, or none. Measures of diagnostic accuracy and 95% CI were calculated for the centrally restricted diffusion sign. Cohen's kappa was calculated to identify the interobserver agreement. RESULTS: Fifty-nine patients (36 female; mean age 59, range 40 to 80) were included, 36 with tumor progression and 23 with radiation necrosis based on histopathology. Primary tumors included 34 lung, 12 breast, 5 melanoma, 3 colorectal, 2 esophagus, 1 head and neck, 1 endometrium, and 1 thyroid. The centrally restricted diffusion sign was seen in 19/23 radiation necrosis cases (sensitivity 83% (95% CI 63 to 93%), specificity 64% (95% CI 48 to 78%), PPV 59% (95% CI 42 to 74%), NPV 85% (95% CI 68 to 94%)) and 13/36 tumor progression cases (difference p < 0.001). Interobserver agreement was substantial, at 0.61 (95% CI 0.45 to 70.8). CONCLUSION: We found a low probability of radiation necrosis in the absence of the centrally restricted diffusion sign.

Outcome of intracerebral cavernoma treated by Gamma Knife radiosurgery based on a double-blind assessment of treatment indication.

BACKGROUND: The benefit and the risk profile of Gamma Knife radiosurgery (GKRS) for intracerebral cavernoma remains incompletely defined in part due to the natural history of low incidence of bleeding and spontaneous regression of this vascular malformation. In this study, we retrieved cases from a prospectively collected database to assess the outcome of intracerebral cavernoma treated with GKRS using a double blinded review process for treatment. METHODS: From 2003 to 2018, there were 94 cases of cavernoma treated by GKRS in the doubly blinded assessments by two experienced neurological and approved for GKRS treatment. All the patients received GKRS with margin dose of 11-12 (Gray) Gy and afterwards were assessed for neurological outcome, radiologic response, and quality of life. RESULTS: The median age of the patients was 48 (15-85) years with median follow up of 77 (26-180) months post SRS. The mean target volume was 1.93 ± 3.45 cc. In those who has pre-SRS epilepsy, 7 of 16 (43.7%) achieved seizure freedom (Engel I/II) and 9 of 16 (56.3%) achieved decreased seizures (Engel III) after SRS. Rebleeding occurred in 2 cases (2.1%) at 13 and 52 months post SRS. The radiologic assessment demonstrated 20 (21.3%) cases of decreased cavernoma volume, 69 (73.4%) were stable, and 5 (7.3%) increased size. Eighty-seven of 94 (92.5%) cases at the last follow up achieve improvement in their quality of life, but 7 cases (7.4%) showed a deterioration. In statistical analysis, the effective seizure control class (Engel I/II) was highly correlated with patient harboring a single lesion (p < 0.05) and deep seated location of the cavernoma (p < 0.01). New neurological deficits were highly correlated with decreased mental (p < 0.001) and physical (p < 0.05) components of quality of life testing, KPS (p < 0.001), deep seated location (p < 0.01), and increased nidus volume (p < 0.05). Quality of life deterioration either in physical component (p < 0.01), mental component (p < 0.01), and KPS (p < 0.05) was highly correlated with increased cavernoma volume. CONCLUSION: Low margin dose GKRS for intracerebral cavernoma offers reasonable seizure control and improved quality of life while conferring a low risk of treatment complications including adverse radiation effect.

Clinical assessment of a biophysical model for distinguishing tumor progression from radiation necrosis.

PURPOSE: The efficacy of an imaging-driven mechanistic biophysical model of tumor growth for distinguishing radiation necrosis from tumor progression in patients with enhancing lesions following stereotactic radiosurgery (SRS) for brain metastasis is validated. METHODS: We retrospectively assessed the model using 73 patients with 78 lesions and histologically confirmed radiation necrosis or tumor progression. Postcontrast T1-weighted MRI images were used to extract parameters for a mechanistic reaction-diffusion logistic growth model mechanically coupled to the surrounding tissue. The resulting model was then used to estimate mechanical stress fields, which were then compared with edema visualized on FLAIR imaging using DICE similarity coefficients. DICE, model, and standard radiographic morphometric analysis parameters were evaluated using a receiver operating characteristic (ROC) curve for prediction of radiation necrosis or tumor progression. Multivariate logistic regression models were then constructed using mechanistic model parameters or advanced radiomic features. An independent validation was performed to evaluate predictive performance. RESULTS: Tumor cell proliferation rate resulted in ROC AUC = 0.86, 95% CI: 0.76-0.95, P < 0.0001, 74% sensitivity and 95% specificity) and DICE similarity coefficient associated with high stresses demonstrated an ROC AUC = 0.93, 95% CI: 0.86-0.99, P < 0.0001, 81% sensitivity and 95% specificity. In a multivariate logistic regression model using an independent validation dataset, mechanistic modeling parameters had an ROC AUC of 0.95, with 94% sensitivity and 96% specificity. CONCLUSIONS: Imaging-driven biophysical modeling of tumor growth represents a novel method for accurately predicting clinically significant tumor behavior.

Long-term metabolic evolution of brain metastases with suspected radiation necrosis following stereotactic radiosurgery: longitudinal assessment by F-DOPA PET.

BACKGROUND: The evolution of radiation necrosis (RN) varies depending on the combination of radionecrotic tissue and active tumor cells. In this study, we characterized the long-term metabolic evolution of RN by sequential PET/CT imaging with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (F-DOPA) in patients with brain metastases following stereotactic radiosurgery (SRS). METHODS: Thirty consecutive patients with 34 suspected radionecrotic brain metastases following SRS repeated F-DOPA PET/CT every 6 months or yearly in addition to standard MRI monitoring. Diagnoses of local progression (LP) or RN were confirmed histologically or by clinical follow-up. Semi-quantitative parameters of F-DOPA uptake were extracted at different time points, and their diagnostic performances were compared with those of corresponding contrast-enhanced MRI. RESULTS: Ninety-nine F-DOPA PET scans were acquired over a median period of 18 (range: 12-66) months. Median follow-up from the baseline F-DOPA PET/CT was 48 (range 21-95) months. Overall, 24 (70.6%) and 10 (29.4%) lesions were classified as RN and LP, respectively. LP occurred after a median of 18 (range: 12-30) months from baseline PET. F-DOPA tumor-to-brain ratio (TBR) and relative standardized uptake value (rSUV) increased significantly over time in LP lesions, while remaining stable in RN lesions. The parameter showing the best diagnostic performance was rSUV (accuracy = 94.1% for the optimal threshold of 1.92). In contrast, variations of the longest tumor dimension measured on contrast-enhancing MRI did not distinguish between RN and LP. CONCLUSION: F-DOPA PET has a high diagnostic accuracy for assessing the long-term evolution of brain metastases following SRS.

Cost-Effectiveness Analysis of Stereotactic Ablative Radiation Therapy in Patients With Oligometastatic Cancer.

PURPOSE: The Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors phase 2 randomized clinical trial found that stereotactic ablative radiation therapy (SABR) improved outcomes among cancer patients with oligometastatic disease. Yet, the cost of SABR along with the large number of patients with oligometastatic disease raises the important question of value. This study sought to evaluate the cost-effectiveness of the addition of SABR compared with standard therapy alone among cancer patients with oligometastatic disease. METHODS AND MATERIALS: We constructed a Markov model to simulate treatment with stereotactic ablative radiation therapy or standard therapy among patients with oligometastatic cancers. The model derived transition probabilities from Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors clinical trial data to estimate risks of toxicity, disease progression and survival. Health care costs and health utilities were estimated from the literature. Probabilistic and one-way sensitivity analyses evaluate model uncertainty. Cost-effectiveness was estimated from both the health care sector and societal perspectives with an incremental cost-effectiveness ratio (ICER) defined as dollars per quality-adjusted life year (QALY). An ICER less than $100,000/QALY was considered cost-effective. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. RESULTS: The addition of SABR increased total costs by $54,260 (health care sector perspective) or $72,799 (societal perspective) and improved effectiveness by 1.88 QALYs compared with standard therapy, leading to an ICER of $28,906/QALY (health care sector perspective) or $38,783/QALY (societal perspective). The model was modestly sensitive to assumptions about tumor progression, although the model was not sensitive to assumptions about survival or cost of treatment. Probabilistic sensitivity analyses demonstrated that SABR was the cost-effective treatment option 99.8% (health care sector perspective) or 98.7% (societal perspective) of the time. CONCLUSIONS: The addition of SABR increased costs and improved quality adjusted survival, overall leading to a cost-effective treatment strategy for patients with oligometastatic cancer.

Is SABR Cost-Effective in Oligometastatic Cancer? An Economic Analysis of the SABR-COMET Randomized Trial.

PURPOSE: The phase 2 randomized study SABR-COMET demonstrated that in patients with controlled primary tumors and 1 to 5 oligometastatic lesions, SABR was associated with improved progression-free survival (PFS) compared with standard of care (SoC), but with higher costs and treatment-related toxicities. The aim of this study was to assess the cost-effectiveness of SABR versus SoC in this setting. METHODS AND MATERIALS: A Markov model was constructed to perform a cost-utility analysis from the Canadian health care system perspective. Utility values and transition probabilities were derived from individual-level data from the SABR-COMET trial. One-way, 2-way, and probabilistic sensitivity analyses were performed. Costs were expressed in 2018 CAD. A separate analysis based on US payer's perspective was performed. An incremental cost-effectiveness ratio (ICER) at a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) was used. RESULTS: In the base case scenario, SABR was cost-effective at an ICER of $37,157 per QALY gained. This finding was most sensitive to the number of metastatic lesions treated with SABR (ICER: $28,066 per QALY for 2, increasing to $64,429 per QALY for 5), difference in chemotherapy use (ICER: $27,173-$53,738 per QALY), and PFS hazard ratio (HR) between strategies (ICER: $31,548-$53,273 per QALY). Probabilistic sensitivity analysis revealed that SABR was cost-effective in 97% of all iterations. Two-way sensitivity analysis demonstrated a nonlinear relationship between the number of lesions and the PFS HR. To maintain cost-effectiveness for each additional metastasis, the HR must decrease by approximately 0.047. The US cost analysis yielded similar results, with an ICER of $54,564 (2018 USD per QALY) for SABR. CONCLUSIONS: SABR is cost-effective for patients with 1 to 5 oligometastatic lesions compared with SoC.