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Purpose: Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial.Methods and Materials: One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance-based local control and reirradiation rates for each treated spine segment.Results: The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval [CI], 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P < .001). cEBRT (hazard ratio [HR], 3.48; 95% CI, 1.94-6.25; P < .001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12).Conclusions: Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort. [ABSTRACT FROM AUTHOR]

Purpose: Multileaf collimator (MLC) linear accelerator (Linac)-based hypofractionated stereotactic radiation therapy (HSRT) is increasingly used not only for large brain metastases or those adjacent to critical structures but also for those metastases that would otherwise be considered for single-fraction radiosurgery (SRS). However, data on outcomes in general are limited, and there is a lack of understanding regarding optimal dosing. Our aim was to report mature image-based outcomes for MLC-Linac HSRT with a focus on clinical and dosimetric factors associated with local failure (LF).Methods and Materials: A total of 220 patients with 334 brain metastases treated with HSRT were identified. All patients were treated using a 5-fraction daily regimen and were followed with clinical evaluation and volumetric magnetic resonance imaging every 2 to 3 months. Overall survival and progression-free survival were calculated using the Kaplan-Meier method, with LF determined using Fine and Gray's competing risk method. Predictive factors were identified using Cox regression multivariate analysis.Results: Median follow-up was 10.8 months. Median size of treated metastasis was 1.9 cm; 60% of metastases were <2 cm in size. The median total dose was 30 Gy in 5 fractions; 36% of the cohort received <30 Gy. The median time to LF and 12-month cumulative incidence of LF was 8.5 months and 23.8%, respectively. Median time to death and 12-month overall survival rates were 11.8 months and 48.2%, respectively. Fifty-two metastases (15.6%) had an adverse radiation effect, of which 32 (9.5%) were symptomatic necrosis. Multivariable analysis identified worse LF in patients who received a total dose of <30 Gy (hazard ratio, 1.62; P = .03), with LF at 6 and 12 months of 13% and 33% for patients treated with <30 Gy versus 5% and 19% for patients treated with >30 Gy. Exploratory analysis demonstrated a dose-response effect observed in all histologic types, including among breast cancer subtypes.Conclusion: Optimal local control is achieved with HSRT of ≥30 Gy in 5 daily fractions, independent of tumor volume and histology, with an acceptable risk of radiation necrosis. [ABSTRACT FROM AUTHOR]

Liver metastases are common in patients with neuroendocrine tumours. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined everolimus and radiation for neuroendocrine liver metastases. This single-arm, single-centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. O verall survival, progression-free survival and freedom from a change in systemic therapy were estimated by the Kaplan-Meier method. Forty metastases were treated in 14 patients. No grade 3 or higher toxicities were identified in the concurrent treatment phase; one patient developed grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One- and 2-year local control were 97% and 71%. Median progress ion-free survival was 12 months. One- and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation are well-tolerated for neuroendocrine liver metastases and are associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population. [ABSTRACT FROM AUTHOR]

Background: Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10-20%. Stereotactic body radiotherapy delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis.Methods: This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0-2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov, NCT02512965.Findings: Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3-6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14-1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77-6·80; p=0·0003). The most common grade 3-4 adverse event was grade 3 pain (five [4%] of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed.Interpretation: Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed.Funding: Canadian Cancer Society and the Australian National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

• Simplified IVIM metrics from MRIs taken during chemoradiation have prognostic value. • Nonenhancing T2-FLAIR regions have important prognostic value. Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome. 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC T1C , ADC T2-FLAIR) and perfusion fraction (f T1C , f T2-FLAIR) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated. Higher ADC T2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01–1.15, p = 0.025], lower f T2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04–4.27, p = 0.018), and lack of increase in ADC T2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02–1.22, p = 0.02) were associated with early progression. Combining ADC T2-FLAIR at baseline, f T2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f T2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56–0.95, p = 0.018) was associated with longer PFS. ADC T2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or f T2-FLAIR at fraction 10 significantly predicted early progression. f T2-FLAIR at fraction 10 was associated with PFS. [ABSTRACT FROM AUTHOR]

Dysregulated hormonal production remains a challenge in the management of neuroendocrine neoplasms (NEN). We report 4 cases of patients with functional NEN treated with stereotactic body radiation therapy (SBRT) to either the primary/dominant metastatic site of disease or the end organ of hormonal release. No significant toxicities were observed during or after treatment. Each patient has had biochemical, clinical and radiographic response to therapy, providing proof of concept that SBRT is an effective therapeutic strategy for functional neuroendocrine neoplasms. [ABSTRACT FROM AUTHOR]

The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/β = 10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P <.001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P =.030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P =.042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P =.035) and older age (HR, 1.035; P <.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P =.016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P =.019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P =.008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P <.1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis. [ABSTRACT FROM AUTHOR]

Purpose: To monitor cellular and metabolic characteristics of glioblastoma (GBM) over the course of standard 6-week chemoradiation treatment with chemical exchange saturation transfer (CEST)-MRI; and to identify the earliest time point CEST could determine subsequent therapeutic response.Methods and Materials: Nineteen patients with newly diagnosed GBM were recruited, and CEST-MRI was acquired immediately before (Day0), 2 weeks (Day14) and 4 weeks (Day28) into treatment, and 1 month after the end of treatment (Day70). Several CEST metrics, including magnetization transfer ratio and area under the curve of CEST peaks corresponding to nuclear Overhauser effect (NOE) and amide protons (MTRNOE, MTRAmide, CESTNOE, and CESTAmide respectively), magnetization transfer (MT), and direct water effect were investigated. Lack of early progression was determined as no increase in tumor size or worsening of clinical symptoms according to routine post-chemoradiation serial structural MRI.Results: Changes in MTRNOE (nonprogressors = 1.35 ± 0.18, progressors = 0.97 ± 0.22, P = .006) and MTRAmide (nonprogressors = 1.25 ± 0.17, progressors = 0.99 ± 0.10, P = .017) between baseline (Day0) and Day14 resulted in the best separation of nonprogressors from progressors. Moreover, the baseline (Day0) MTRNOE (nonprogressors = 6.5% ± 1.6%, progressors = 9.1% ± 2.1%, P = .015), MTRAmide (nonprogressors = 6.7% ± 1.7%, progressors = 8.9% ± 1.9%, P = .028), MT (nonprogressors = 3.8% ± 0.9%, progressors = 5.4% ± 1.4%, P = .019), and CESTNOE (nonprogressors = 4.1%ċHz ± 1.7%ċHz, progressors = 6.1%ċHz ± 1.9%ċHz, P = .044) were able to identify progressors even before the start of the treatment.Conclusions: Chemical exchange saturation transfer (CEST) provides imaging-based biomarkers of GBM response as early as 2 weeks into the treatment. Certain CEST metrics can characterize tumor aggressiveness and identify early progressors even before beginning the treatment. Such an early biomarker of response may allow for adjusting the GBM treatment plan for adaptive radiation therapy in early progressors and more confidently continuing standard adjuvant treatment for nonprogressors. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiotherapy (SBRT) improves complete pain response for painful spinal metastases compared to conventional external beam radiotherapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT vs. cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control (SC).24 phase II/III trial. Methods/materials: 137/229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT, and 71 patients (169 segments) treated with cEBRT. The primary outcomes were MR-based local control and reirradiation rates for each treated spine segment. Results: The median follow-up was 11.3 months (IQR:5.3-27.7 months), and median OS in the SBRT and cEBRT cohorts were 21.6 and 18.9 months (p=0.428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of “Mass” (paraspinal and/or epidural disease extension). Risk of local failure after SBRT vs. cEBRT at 6, 12 and 24 months were 2.8% vs. 11.2%, 6.1% vs. 28.4% and 14.8% vs. 35.6%, respectively (p<0.001). cEBRT (HR:3.48, 95%CI:1.94-6.25, p<0.001) and presence of “Mass” (HR:2.07, 95%CI:1.29-3.31, p=0.002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT vs. cEBRT, were 2.2% vs 15.8% (p=0.002) and 22.9 months vs. 9.5 months respectively. Radioresistant histology (HR:2.66, 95%CI:1.43-4.94, p=0.002) and cEBRT (HR:2.34, 95%CI:1.14-4.78, p=0.002) independently predicted for reirradiation. 8/12 iatrogenic vertebral compression fractures (VCFs) were after SBRT and 4/12 after cEBRT; Grade 3 toxicities were isolated to the SBRT cohort (5/12). Conclusions: Risk of local failure and reirradiation is lower with SBRT compared to cEBRT for spinal metastases. Although the iatrogenic VCF rates were within expectations, Grade 3 VCF were isolated to the SBRT cohort. [ABSTRACT FROM AUTHOR]

Purpose Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The presence of hip prostheses results in significant image artifacts making delineation of anatomy for planning difficult with traditional kilovoltage CT images. This report presents the use of megavoltage computed tomography (MVCT) imaging acquired with a helical tomotherapy unit to plan a high-dose-rate (HDR) prostate brachytherapy treatment for a patient with bilateral hip prostheses. Methods and Materials: A 77-year-old man presented with a localized clinical Stage T3a, Gleason 7 prostate cancer. Past history was also significant for bilateral hip prostheses. Staging workup included a negative bone scan and CT of abdomen and pelvis. The pelvic CT exhibited significant streak artifacts obscuring the prostate. HDR monotherapy with adjuvant androgen deprivation therapy was proposed. On the day of the implant and after catheter insertion, MVCT imaging of the pelvic area of the patient was obtained using a commercial helical tomotherapy unit. The MVCT images were transferred to Nucletron PLATO (v14.3.2) for planning with optimization of catheter dwell positions and times. Results: MVCT images acquired with the helical tomotherapy unit allow good visualization of bony anatomy and of the hip prosthesis. No reconstruction streak artifacts are visible in the images as seen in the diagnostic kilovoltage CT images. Sufficient soft tissue contrast exists to allow delineation of the bladder and rectum. The absence of streak artifacts provides good quantification of Hounsfield number in the region surrounding the hip prosthesis and allows for good dose quantification. Conclusions: MVCT images obtained using the commercial helical tomotherapy unit have been shown to provide good soft tissue contrast and no streak artifacts when planning a patient for prostate HDR brachytherapy having bilateral prosthetic hip replacements. The rectum and bladder can be clearly seen in the MVCT images and contoured independently. Prostate delineation is assumed from the position of the brachytherapy catheters. [Copyright &y& Elsevier]

Age- and sex-specific estimates of the rate of cardiac morbidity among Hodgkin lymphoma (HL) patients treated with doxorubicin-based chemotherapy and radiation therapy (RT) are scarce. We evaluated the risk of hospital admission for cardiac disease in 615 HL patients, adjusting for age, sex, treatment, cardiac risk factors and competing causes of death. Compared with the general population, the risk of cardiac morbidity was highest among patients treated with both doxorubicin and mediastinal RT (HR = 2.77, p < 0.0001). Mediastinal RT without chemotherapy also significantly increased the risk (HR = 1.82, p = 0.038). For females and males treated with doxorubicin plus mediastinal RT at age 40, the estimated 15-year incidence rate of cardiac hospitalisation were 7.3% and 16.5%, respectively, rates 5-15% higher than expected. These results suggest that the risk of clinically important cardiac toxicity following HL treatment that includes both doxorubicin and mediastinal RT may be greater than that reported in prior studies of patients treated with RT alone. [ABSTRACT FROM AUTHOR]

Although spine stereotactic body radiation therapy (SBRT) is considered a standard of care in the mobile spine, mature evidence reporting outcomes specific to sacral metastases is lacking. Furthermore, there is a need to validate the existing sacral SBRT international consensus contouring guidelines to define the optimal contouring approach. We report mature rates of local failure (LF), adverse events, and the effect of contouring deviations in the largest experience to date specific to sacrum SBRT. Consecutive patients who underwent sacral SBRT from 2010 to 2021 were retrospectively reviewed. The primary endpoint was magnetic resonance imaging–based LF with a focus on adherence to target volume contouring recommendations. Secondary endpoints included vertebral compression fracture and neural toxicity. Of the 215 sacrum segments treated in 112 patients, most received 30 Gy/4 fractions (51%), 24 Gy/2 fractions (31%), or 30 Gy/5 fractions (10%). Sixteen percent of segments were nonadherent to the consensus guideline with a more restricted target volume (undercontoured). The median follow-up was 21.4 months (range, 1.5-116.9 months). The cumulative incidence of LF at 1 and 2 years was 18.4% and 23.1%, respectively. In those with guideline adherent versus nonadherent contours, the LF rate at 1 year was 15.1% versus 31.4% and at 2 years 18.8% versus 40.0% (hazard ratio [HR], 2.5; 95% CI, 1.4-4.6; P =.003), respectively. On multivariable analysis, guideline nonadherence (HR, 2.4; 95% CI, 1.3-4.7; P =.008), radioresistant histology (HR, 2.4; 95% CI, 1.4-4.1; P <.001), and extraosseous extension (HR, 2.5; 95% CI, 1.3-4.7; P =.005) predicted for an increased risk of LF. The cumulative incidence of vertebral compression fracture was 7.1% at 1 year and 12.3% at 2 years. Seven patients (6.3%) developed peripheral nerve toxicity, of whom 4 had been previously radiated. Sacral SBRT is associated with high efficacy rates and an acceptable toxicity profile. Adhering to consensus guidelines for target volume delineation is recommended to reduce the risk of LF. [ABSTRACT FROM AUTHOR]

The Canadian Cancer Trials Group (CCTG) Symptom Control 24 protocol (SC.24) was a multicenter randomized controlled phase 2/3 trial conducted in Canada and Australia. Patients with painful spinal metastases were randomized to either 24 Gy/2 stereotactic body radiation therapy (SBRT) or 20 Gy/5 conventional external beam radiation therapy (CRT). The study met its primary endpoint and demonstrated superior complete pain response rates at 3 months following SBRT (35%) versus CRT (14%). SBRT planning and delivery is resource intensive. Given its benefits in SC.24, we performed an economic analysis to determine the incremental cost-effectiveness of SBRT compared with CRT. The trial recruited 229 patients. Cost-effectiveness was assessed using a Markov model taking into account observed survival, treatments costs, retreatment, and quality of life over the lifetime of the patient. The EORTC-QLU-C10D was used to determine quality of life values. Transition probabilities for outcomes were from available patient data. Health system costs were from the Canadian health care perspective and were based on 2021 Canadian dollars (CAD). The incremental cost-effectiveness ratio (ICER) was expressed as the ratio of incremental cost to quality-adjusted life years (QALY). The impact of parameter uncertainty was investigated using deterministic and probabilistic sensitivity analyses. The base case for SBRT compared with CRT had an ICER of $9,040CAD per QALY gained. Sensitivity analyses demonstrated that the ICER was most sensitive to variations in the utility assigned to "No local failure" ($5,457CAD to $241,051CAD per QALY), adopting low and high estimates of utility and the cost of the SBRT (ICERs ranging from $7345-$123,361CAD per QALY). It was more robust to variations in assumptions around survival and response rate. SBRT is associated with higher upfront costs than CRT. The ICER shows that, within the Canadian health care system, SBRT with 2 fractions is likely to be more cost-effective than CRT. [ABSTRACT FROM AUTHOR]

Background: The radiotherapy process relies on several metrics in determining a notion of "distance" from one three‐dimensional region‐of‐interest (ROI) to another. The majority are symmetric (or commutative) and do not contain information pertaining to directionality. Growth versus regression, for example, is not inherently distinguished by these metrics. Purpose: The purpose of this work was to formalize a unidirectional distance metric, motivated by radiotherapy margin concepts, which we term the migration distance. Informally, the migration distance from ROI X$X$ to Y$Y$ is the minimum isotropic expansion of X$X$ such that Y$Y$ is completely encompassed by the expansion. If Y$Y$ is contained within X$X$, the migration distance is negative with magnitude equal to the maximum isotropic contraction of X$X$ such that Y$Y$ remains contained within contraction. The metric is demonstrated by quantifying glioblastoma interfraction target changes. Methods: An explicit mathematical formulation of the migration distance is presented and contrasted with the related Hausdorff distance. The results are demonstrated for the gross tumor volume (GTV) dynamics of a glioblastoma cohort consisting of 111 patients that underwent standard chemoradiotherapy with offline MR imaging at planning, fraction 10, fraction 20, and 1‐month post radiotherapy. Results: The mean ± SD of the GTV migration distance relative to planning was 5.9 ± 3.9 mm at fraction 10, 6.2 ± 4.4 mm at fraction 20, and 7.9 ± 7.1 mm at 1‐month post radiotherapy. The maximum GTV migration distance across all patients at the same timepoints was 20.4, 20.7, and 45.5 mm, respectively. Conclusions: We have proposed and demonstrated a unidirectional distance metric. The migration distance may have applications in the quantification of anatomical changes, planning target volume designs, and dosimetric radiotherapy plan assessment. [ABSTRACT FROM AUTHOR]

Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT. [ABSTRACT FROM AUTHOR]

There is an increased risk of second primary cancers (SPCs) after neuroendocrine tumor (NET) diagnosis. The clinical significance of SPCs in this population is unknown. The purpose of this study was to evaluate the association between SPCs after NET diagnosis and survival. We performed a population-based, retrospective cohort study of NET patients (gastrointestinal, pancreatic, or lung primary) from 2000 to 2016 using the Surveillance, Epidemiology, and End Results database. Cox regression models assessed the association between SPCs and NET-specific (NET-SS), cancer-specific (CSS), and overall survival (OS). Of 58,553 NET patients, 7.9% experienced an SPC. SPCs were associated with worse OS (hazard ratio (HR) 2.14, 95% CI 1.94-2.36) and CSS (HR 2.31, 95% CI 2.06-2.59) with no difference in NET-SS (HR 1.04, 95% CI 0.87-1.23). Stratified analyses by histologic grade showed similar results for well and moderately differentiated NETs, but no difference in OS or CSS for poorly differentiated NETs (P > 0.05). In stratified analyses by NET site, SPCs were associated with worse OS (HR 3.41, 95% CI 3.01-3.87) and CSS (HR 4.96, 95% CI 4.28-5.74) in gastrointestinal NETs and worse OS (HR 1.25, 95% CI 1.03-1.52) with no difference in CSS (HR 1.08, 95% CI 0.85-1.36) in lung NETs. SPCs were not associated with a difference in OS or CSS in pancreatic NETs (P > 0.05). In conclusion, SPCs after NETs were associated with inferior OS and CSS compared to no SPC but were not associated with NET-SS. These data highlight the need for long-term follow-up in NETs to include the detection of SPCs to ensure early diagnosis and timely management. [ABSTRACT FROM AUTHOR]

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best gui dance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas. [ABSTRACT FROM AUTHOR]

Purpose: We report mature outcomes for a cohort of patients with no prior radiation (de novo) to the spine treated with 24 Gy in 2 daily fractions for metastases, which represents the same stereotactic body radiation therapy (SBRT) regimen under evaluation in the current Symptom Control-24 phase 3 randomized trial (NCT02512965).Methods and Materials: The cohort consisted of 279 de novo spinal metastases in 145 consecutive patients treated with 24 Gy in 2 SBRT fractions, identified from a prospective single-institution database. The endpoints were overall survival (OS), imaging-based local failure (LF), and cumulative risk of vertebral compression fractures (VCF).Results: The median follow-up per treated metastasis was 15.0 months (range, 0.1-71.6). The 1-year and 2-year OS rates were 73.1% and 60.7%, respectively. Presence of epidural disease (P < .0001), lung (P = .0415), and renal cell (P < .0001) primary histologies and baseline diffuse metastases (P = .0034) were significant prognostic factors for OS. The 1-year and 2-year LF rates were 9.7% and 17.6%, respectively, and the median time to LF was 9.2 month (range, 0.4-31.3 months). Only the presence of epidural disease predicted for LF (P < .0001). The cumulative risk of VCF at 1 and 2 years was 8.5% and 13.8%, respectively. Lytic (P = .0143) or mixed lytic/blastic (P = .0214) lesions, spinal malalignment (P = .0121), and the dose to 90% of the planning target volume (P = .0085) were significant predictors for VCF.Conclusions: Twenty-four Gray in 2 daily fractions is safe and effective in achieving high tumor control rates for de novo spinal metastases. These outcomes will serve as a benchmark for the ongoing Symptom Control-24 randomized trial comparing 24 Gy in 2 SBRT fractions to 20 Gy delivered in 5 daily conventional fractions. [ABSTRACT FROM AUTHOR]

Stereotactic body radiation therapy (SBRT) for spine metastases improves pain response rates compared with conventional external beam radiation therapy; however, the optimal fractionation schedule is unclear. We report local control and toxicity outcomes after dose-escalated 2-fraction spine SBRT. A prospectively maintained institutional database of over 600 patients and 1400 vertebral segments treated with spine SBRT was reviewed to identify those prescribed 28 or 24 Gy in 2 daily fractions. The primary endpoint was magnetic resonance imaging based local failure (LF), and secondary endpoints included overall survival and vertebral compression fracture (VCF). A total of 947 treated vertebral segments in 482 patients were identified, of which 301 segments in 159 patients received 28 Gy, and 646 segments in 323 patients received 24 Gy in 2 fractions. Median follow-up per patient was 23.5 months, and median overall survival was 49.1 months. In the 28 Gy cohort, the 6-, 12-, and 24-month cumulative incidences of LF were 3.5%, 5.4%, and 11.1%, respectively, versus 6.0%, 12.5%, and 17.6% in the 24 Gy cohort, respectively (P =.008). On multivariable analysis, 24 Gy (hazard ratio [HR], 1.525; 95% confidence interval, 1.039-2.238; P =.031), paraspinal disease extension (HR, 1.422; 95% confidence interval, 1.010-2.002; P =.044), and epidural extension in either radioresistant or radiosensitive histologies (HR, 2.117 and 1.227, respectively; P =.003) were prognostic for higher rates of LF. Risk of VCF was 5.5%, 7.6%, and 10.7% at 6, 12, and 24 months, respectively, and was similar between cohorts (P =.573). Spinal malalignment (P <.001), baseline VCF (P =.003), junctional spine location (P =.030), and greater minimum dose to 90% of planning target volume were prognostic for higher rates of VCF. Dose escalation to 28 Gy in 2 daily fractions was associated with improved local control without increasing the risk of VCF. The 2-year local control rates are consistent with those predicted by the Hypofractionated Treatment Effects in the Clinic spine tumor control probability model, and these data will inform a proposed dose escalation randomized trial. [ABSTRACT FROM AUTHOR]

Purpose: Integrating magnetic resonance (MR) into radiotherapy planning has several advantages. This report details the clinical implementation of an MR simulation (MR-planning) program for external beam radiotherapy (EBRT) in one of North America's largest radiotherapy programs. Methods and materials: An MR radiotherapy planning program was developed and implemented at Sunnybrook Health Sciences Center in 2016 with two dedicated wide-bore MR platforms (1.5 and 3.0 Tesla). Planning MR was sequentially implemented every 3 months for separate treatment sites, including the central nervous system (CNS), gynecologic (GYN), head and neck (HN), genitourinary (GU), gastrointestinal (GI), breast, and brachial plexus. Essential protocols and processes were detailed in this report, including clinical workflow, optimized MR-image acquisition protocols, MR-adapted patient setup, strategies to overcome risks and challenges, and an MR-planning quality assurance program. This study retrospectively reviewed simulation site data for all MR-planning sessions performed for EBRT over the past 5 years. Results: From July 2016 to December 2021, 8798 MR-planning sessions were carried out, which corresponds to 25% of all computer tomography (CT) simulations (CT-planning) performed during the same period at our institution. There was a progressive rise from 80 MR-planning sessions in 2016 to 1126 in 2017, 1492 in 2018, 1824 in 2019, 2040 in 2020, and 2236 in 2021. As a result, the relative number of planning MR/CT increased from 3% of all planning sessions in 2016 to 36% in 2021. The most common site of MR-planning was CNS (49%), HN (13%), GYN (12%), GU (12%), and others (8%). Conclusion: Detailed clinical processes and protocols of our MR-planning program were presented, which have been improved over more than 5 years of robust experience. Strategies to overcome risks and challenges in the implementation process are highlighted. Our work provides details that can be used by institutions interested in implementing an MR-planning program. [ABSTRACT FROM AUTHOR]

Purpose: To perform a comparison of two pelvic lymph node volume delineation strategies used in intensity-modulated radiotherapy (IMRT) for high risk prostate cancer and to determine the role of volumetric modulated arc therapy (VMAT). Methods and Materials: Eighteen consecutive patients accrued to an ongoing clinical trial were identified according to either the nodal contouring strategy as described based on lymphotropic nanoparticle-enhanced magnetic resonance imaging technology (9 patients) or the current Radiation Therapy Oncology Group (RTOG) consensus guidelines (9 patients). Radiation consisted of 45 Gy to prostate, seminal vesicles, and lymph nodes, with a simultaneous integrated boost to the prostate alone, to a total dose of 67.5 Gy delivered in 25 fractions. Prospective acute genitourinary and gastrointestinal toxicities were compared at baseline, during radiotherapy, and 3 months after radiotherapy. Each patient was retrospectively replanned using the opposite method of nodal contouring, and plans were normalized for dosimetric comparison. VMAT plans were also generated according to the RTOG method for comparison. Results: RTOG plans resulted in a significantly lower rate of genitourinary frequency 3 months after treatment. The dosimetric comparison showed that the RTOG plans resulted in both favorable planning target volume (PTV) coverage and lower organs at risk (OARs) and integral (ID) doses. VMAT required two to three arcs to achieve adequate treatment plans, we did not observe consistent dosimetric benefits to either the PTV or the OARs, and a higher ID was observed. However, treatment times were significantly shorter with VMAT. Conclusion: The RTOG guidelines for pelvic nodal volume delineation results in favorable dosimetry and acceptable acute toxicities for both the target and OARs. We are unable to conclude that VMAT provides a benefit compared with IMRT. [ABSTRACT FROM AUTHOR]

Purpose: Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC). Methods: We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000–2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk. Results: A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2–8.2%) vs 7.6% (95%CI 7.2–8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0–33.9%) vs 31.6% (95%CI 30.8–32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3–8.9%] vs. 7.0% [95%CI 6.3–7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3–36.1%] vs. 31.1% [95%CI 29.7–32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5–9.4%] vs. 6.8% [95%CI 5.5–8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8–38.1%] vs. 31.9% [95%CI 29.3–34.4%]; p = 0.02). Conclusions: In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness. [ABSTRACT FROM AUTHOR]

Purpose: Target localization, for stereotactic radiosurgery (SRS) treatment with Gamma Knife, has become increasingly reliant on the co‐registration between the planning MRI and the stereotactic cone‐beam computed tomography (CBCT). Validating image registration between modalities would be particularly beneficial when considering the emergence of novel functional and metabolic MRI pulse sequences for target delineation. This study aimed to develop a phantom‐based methodology to quantitatively compare the co‐registration accuracy of the standard clinical imaging protocol to a representative MRI sequence that was likely to fail co‐registration. The comparative methodology presented in this study may serve as a useful tool to evaluate the clinical translatability of novel MRI sequences. Methods: A realistic human skull phantom with fiducial marker columns was designed and manufactured to fit into a typical MRI head coil and the Gamma Knife patient positioning system. A series of "optimized" 3D MRI sequences—T1‐weighted Dixon, T1‐weighted fast field echo (FFE), and T2‐weighted fluid‐attenuated inversion recovery (FLAIR)—were acquired and co‐registered to the CBCT. The same sequences were "compromised" by reconstructing without geometric distortion correction and re‐collecting with lower signal‐to‐noise‐ratio (SNR) to simulate a novel MRI sequence with poor co‐registration accuracy. Image similarity metrics—structural similarity (SSIM) index, mean squared error (MSE), and peak SNR (PSNR)—were used to quantitatively compare the co‐registration of the optimized and compromised MR images. Results: The ground truth fiducial positions were compared to positions measured from each optimized image volume revealing a maximum median geometric uncertainty of 0.39 mm (LR), 0.92 mm (AP), and 0.13 mm (SI) between the CT and CBCT, 0.60 mm (LR), 0.36 mm (AP), and 0.07 mm (SI) between the CT and T1‐weighted Dixon, 0.42 mm (LR), 0.23 mm (AP), and 0.08 mm (SI) between the CT and T1‐weighted FFE, and 0.45 mm (LR), 0.19 mm (AP), and 1.04 mm (SI) between the CT and T2‐weighted FLAIR. Qualitatively, pairs of optimized and compromised image slices were compared using a fusion image where separable colors were used to differentiate between images. Quantitatively, MSE was the most predictive and SSIM the second most predictive metric for evaluating co‐registration similarity. A clinically relevant threshold of MSE, SSIM, and/or PSNR may be defined beyond which point an MRI sequence should be rejected for target delineation based on its dissimilarity to an optimized sequence co‐registration. All dissimilarity thresholds calculated using correlation coefficients with in‐plane geometric uncertainty would need to be defined on a sequence‐by‐sequence basis and validated with patient data. Conclusion: This study utilized a realistic skull phantom and image similarity metrics to develop a methodology capable of quantitatively assessing whether a modern research‐based MRI sequence can be co‐registered to the Gamma Knife CBCT with equal or less than equal accuracy when compared to a clinically accepted protocol. [ABSTRACT FROM AUTHOR]

Purpose: Integrated MRI-linear accelerator (MR-Linac) technology allows for daily soft tissue visualization, online adaptive replanning and potential for safe margin reduction. We report preliminary findings of weekly tumor reduction in a consecutive series of MGMTmethylated glioblastoma (GBM) patients treated on the MR-Linac (MRL). Methods and materials: UNITED (NCT04726397) is a phase II trial investigating the safety and feasibility of margin reduced MR-guided adaptive radiotherapy in GBM using the MRL. Patients treated with 60 Gy in 30 fractions or 40 Gy in 15 fractions with concomitant temolozomide (TMZ) are eligible. A 5 mm clinical target volume (CTV) expansion is applied to the gross tumor volume (GTV), which is extended to include abnormal T2-FLAIR. Patients undergo weekly on-line adaptive replanning based on a contrast-enhanced T1 and T2- FLAIR MRL-MRI taken in the treatment position. Results: The first five consecutive MGMT-methylated patients are reported. All patients had IDH wild-type GBM and the mean age was 60 years (range: 44- 76 years). Compared to the Day 1 MRL plan, weekly average GTV changes at fraction 6, 11, 16, 21, and 26 were -7.8% (range, +1.1% to -14.0%), -17.6% (range, -3.7% to -24.3%), -15.5% (range, -5.8% to -25.0%), -20.4% (range, -7.4% to -38.1%) and -22.0% (range, -3.6% to -35.7%), respectively. Average CTV reductions were 4.3%, 11.6%, 7.6%, 14.0% and 14.0% at the same respective time points. In comparison, the first five treated unmethylated patients exhibited consistent weekly growth patterns in the GTV during RT. Conclusions: Our preliminary findings support a treatment adaptation protocol for GBM, in particular for patients with methylated GBM, given the volume reductions observed. Clinical outcomes from the UNITED clinical trial will inform endpoints including failure patterns, quality of life, and treatment tolerance. [ABSTRACT FROM AUTHOR]

Introduction: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population. Objective: The objective of this study was to evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM). Methods: A retrospective review of patients with WD-NELM treated with SABR was conducted between January 2015 and July 2019. Demographic, treatment, and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression-free survival (PFS) were determined using the Kaplan-Meier methodology. Toxicity was reported according to the CTCAE v5.0. Results: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were grade 2 (80%), and had high-volume intrahepatic and/or extrahepatic disease (76%). The median number of liver metastases treated was 2, with a median size of 2.5 cm. The median radiation dose delivered was 50 Gy/5 fractions. The median follow-up was 14 months; 24 of the 25 patients were alive at the time of analysis. The objective response rate was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92 and 44%, respectively. No grade 3/4 acute or late toxicity was identified. Conclusions: Liver SABR is a safe and promising means of providing LC for WD-NELM. This treatment modality should be evaluated in selected patients in concert with strategies to manage systemic disease. [ABSTRACT FROM AUTHOR]

• Cholangiocarcinoma is the most common cause of malignant biliary tract obstruction. • HDR intraluminal brachytherapy (ILBT) resulted in longer duration of stent patency. • HDR ILBT resulted in improved survival with low rates of complication and toxicity. • Future studies should consider HDR ILBT with stenting prior to chemotherapy. • This approach may improve patient quality of life, and potentially prolong survival. To conduct a systematic review evaluating the impact of high dose rate (HDR) intraluminal brachytherapy (ILBT) in the management of malignant biliary obstruction and cholangiocarcinoma with specific focus on stent patency, clinical outcomes and toxicities. A review of published articles was conducted using Medline, Embase and Cochrane databases using the search terms "bile duct carcinoma" or "cholangiocarcinoma" or "bile duct neoplasms" in combination with "brachytherapy" or "high dose rate brachytherapy" or "HDR brachytherapy". Studies published in English and reporting outcomes of ≥10 patients were included in the review. Only the most recent experience was included if same patients were included in sequential publications. Seventeen studies were identified that met the inclusion criteria. Significant heterogeneity was observed in treatment regimens, which included use of surgery, external beam radiation (EBRT), and/or intra-arterial and intravenous chemotherapy in conjunction with ILBT. Nevertheless, among the included studies, use of ILBT appeared to result in longer duration of stent patency: 10 months with ILBT compared to 4–6 months without ILBT. A trend was observed towards prolonged local control and improved complete and partial response rates in patients treated with ILBT with or without EBRT. Weighted mean overall survival of patients treated with ILBT alone was 11.8 months compared to 10.5 months for those that received EBRT +/− chemotherapy in addition to ILBT. The included studies reported low complication rates and toxicity related to ILBT. Brachytherapy can be an effective and safe tool in the management of malignant biliary tract obstruction in combination with stenting. Both retrospective and prospective studies have suggested improved outcomes when HDR ILBT is combined with percutaneous stenting. [ABSTRACT FROM AUTHOR]

• Apparent diffusion coefficient (ADC) from MR-Linac in brain was validated. • ADC from MR-Linac and diagnostic scanner similar in tumours, white/grey matter. • Repeatability of MR-Linac ADC is similar to that of diagnostic scanners. • Daily ADC changes in high-grade gliomas are detectable with MR-Linac. MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner. CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans. DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: –0.05 ± 0.03, –0.08 ± 0.05, –0.1 ± 0.1, –0.08 ± 0.07 μm2/ms). ADC differed substantially in CSF (bias: –0.5 ± 0.3 μm2/ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable. It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes. [ABSTRACT FROM AUTHOR]

• CEST MRI is feasible on a 1.5 tesla MR-Linac for imaging CNS tumours. • Differences were found in CEST signals between tumour and white matter. • Detectable signal changes between treatment fractions were observed. • Differences in asymmetry were found between high- and low-grade tumours. To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTR Amide), nuclear Overhauser effect (NOE) MTR (MTR NOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. The gross tumour volume (GTV) exhibited lower MTR Amide and MTR NOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols. [ABSTRACT FROM AUTHOR]

• Outcomes of the largest metastatic breast cancer cohort treated with extra-cranial SBRT. • Patients with oligometastases had a more favorable OS, PFS than other treatment indication. • Extra-cranial SBRT provided an excellent LC of 89% at 1-year and 86.6% at 2-year. To summarize the clinical outcomes of stereotactic body radiotherapy (SBRT) for metastatic breast cancer (mBC) from a large institution. Patients with mBC who received extra-cranial SBRT to metastatic lesions from 2011 to 2017 were identified. Treatment indications were: oligometastases, oligoprogression, and local control of dominant tumor (CDT). Endpoints included overall survival (OS), progression-free survival (PFS), local control (LC) and cumulative incidence of starting/changing chemo or hormonal therapy (SCT). Univariate and multivariate analyses were used to identify predictive factors. We analyzed 120 patients (193 treated metastatic lesions) with a median follow up of 15.25 months. 1-and 2-year LC rates were 89% and 86.6%, respectively. 1-and 2-year OS rates were 83.5% and 70%, respectively, with treatment indication and molecular subtype being the predictive factors on MVA. 1-year OS was 91.0%, 78.5% and 63.9% for oligometastases, oligoprogression and CDT, respectively (p = 0.003). The worst OS was seen in basal subtype with 1-and 2-year OS rates of 59.2% and 39.5% (p = 0.01). Treatment indication was found to be predictive for PFS and lower rates of SCT on MVA. 1-and 2-year PFS rates were 45% and 32%, respectively. The 1-year PFS for oligometastases, oligoprogression, and CDT was 66%, 19.6%, and 14.3%, respectively (p < 0.001). The cumulative incidence of SCT at 1-year was 12% for oligometastases, 39.7% for oligoprogression and 53.3% for CDT (p < 0.001). Patients treated for oligometastases have better OS and PFS than those treated for oligoprogression or CDT. SBRT may delay SCT in mBC patients, particularly those with oligometastases. SBRT provided an excellent LC in mBC patients. [ABSTRACT FROM AUTHOR]

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation.Methods and Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (Vrel), and the migration distance (dmigrate; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model.Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm3 (range, 1.1-110.5 cm3), 14.7 cm3 (range, 0.9-115.1 cm3), 13.7 cm3 (range, 0.6-174.2 cm3), and 13.0 cm3 (range, 0.9-76.3 cm3), respectively, with corresponding median Vrel of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (Vrel ≤1) with a dmigrate >5 mm during chemoradiation therapy.Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation. [ABSTRACT FROM AUTHOR]

[Display omitted] • MR-Linac diffusion MRI (DWI) changes in glioblastoma are prognostic. • DWI changes correlate with survival two to five weeks from radiotherapy start. • DWI changes show greater survival correlation than gross tumour volume changes. Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV). Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm2/ms within GTV). In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV). MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets. [ABSTRACT FROM AUTHOR]

Background: The role of socioeconomic factors as determinants of oncology consultations for advanced cancers in public payer health care systems is unknown. This study examined the association between material deprivation and receipt of cancer care among patients with advanced gastrointestinal (GI) cancer.Methods: This was a population-based, retrospective cohort study of noncuratively treated patients with GI cancer diagnosed from 2007 to 2017. Material deprivation, representing income, quality of housing, education, and family structure, was defined as quintiles on the basis of 2016 census data. The first consultation with a radiation oncologist or medical oncologist and the receipt of 1 or more instances of radiation and/or chemotherapy were measured in the year after diagnosis. Adjusted, cause-specific Cox proportional hazards competing risk analyses were used (competing event = death).Results: This study included 34,022 noncuratively treated patients with GI cancer. Consultation rates ranged from 67.8% for those in the most materially deprived communities to 73.5% for those in the least materially deprived communities. Among those with a consult, rates of cancer-directed therapy ranged from 58.5% for patients in the most materially deprived communities to 62.3% for patients in the least materially deprived communities. Patients living in the most materially deprived communities were significantly less likely to see a radiation and/or medical oncologist after a diagnosis (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.85-0.92) and significantly less likely to receive radiation and/or chemotherapy (HR, 0.80; 95% CI, 0.76-0.85) than those living in the least materially deprived communities.Conclusions: This study identified socioeconomic disparities in accessing cancer care. Continued efforts at examining and developing evidence-based policies for interventions that begin before or at the time of oncologist consultation are required to address root causes of inequities. [ABSTRACT FROM AUTHOR]

Spine metastatic disease is an increasingly common occurrence in cancer patients due to improved patient survival. Close proximity of the bony spinal column to the spinal cord limits many conventional treatments for metastatic disease. In the past decade, we have witnessed dramatic advancements in therapies, with improvements in surgical techniques and recent adoption of spine stereotactic radiotherapy techniques leading to improved patient outcomes. Multidisciplinary approaches to patient evaluation, treatment and follow-up are essential. Imaging plays an ever increasing role in disease detection, pre-treatment planning and assessment of patient outcomes. It is important for the radiologist to be familiar with imaging algorithms, best practices for surgery and/or radiotherapy and imaging findings in the post-treatment period that may indicate disease recurrence. In this review, we present a multidisciplinary discussion of spine metastases, with specific focus on pre-treatment imaging, planning, current treatment approaches, and post-treatment assessment. [ABSTRACT FROM AUTHOR]

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with "molecular GBM." Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of "pediatric‐type" gliomas. [ABSTRACT FROM AUTHOR]

Purpose: Limited data exist quantifying the risk of adverse radiation effect (ARE) specific to hypofractionated stereotactic radiosurgery (HSRS). We present our analyses of the risk of ARE after 5 daily fractions of HSRS to surgical cavities and intact metastases.Methods and Materials: One hundred and eighty-seven consecutively treated patients with 118 surgical cavities and 132 intact metastases were retrospectively reviewed. All patients were treated with 5 daily fractions with a 2 mm planning target volume applied. Clinical and dosimetric variables were assessed to identify predictors of ARE.Results: The median total prescribed dose was 30 Gy (range, 20-35 Gy) and median follow-up was 12 months. One hundred forty-four patients (77%) received treatment to a single target. Median planning target volumes for resection cavity and intact metastases were 24.9 cm3 and 7.7 cm3, respectively. ARE and symptomatic ARE were observed 21.2% and 10.8% of targets, respectively, and the median time to ARE was 8 months. Time to ARE was <6 months for 38%, 6 to 12 months for 43%, and >12 months for 19% of targets. Multivariable analysis identified intact metastases versus cavities (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.33-10) as a significant predictor of symptomatic ARE. Specific to cavity HSRS, prior whole brain radiation therapy (OR 7.73; 95% CI, 1.67-35.69) and prior stereotactic radiosurgery (OR 8.66; 95% CI, 1.14-65.7) were significant predictors of symptomatic ARE. For intact metastases, the total brain minus gross tumor volume (GTV) receiving 30 Gy (BMC30) was a significant predictor of symptomatic ARE (OR, 1.21; 95% CI, 1.02-1.43), and a volume-based BMC30 threshold of 10.5 cm3 was significant with an OR of 7.21 (95% CI, 1.31-39.45).Conclusions: The risk of ARE was greater for intact metastases compared with cavities after HSRS. For intact lesions, the BMC30 was predictive for symptomatic necrosis, and a threshold of 10.5 cm3 may guide treatment planning. [ABSTRACT FROM AUTHOR]

• Higher SBRT doses result in better local control for colorectal metastases. • Liver metastases independently have worse local control compared to other sites. • A good proportion of patients did not have a change in systemic therapy after SBRT. To review the clinical outcomes following the use of stereotactic body radiotherapy (SBRT) in patients with metastatic colorectal cancer (mCRC) from a large academic institution. Patients with mCRC treated with extracranial SBRT between 2008 and 2016 were identified from an institutional database. Treatment indications were oligometastases, oligoprogression, and local control of dominant tumors. Endpoints included local progression (LP), overall survival (OS), progression-free survival (PFS), and cumulative incidence of starting or changing systemic therapy (SCST). Univariate and multivariable analyses (MVA) were performed to identify predictive factors. One hundred and sixty-five patients (262 lesions treated) were included. The 2-year cumulative incidence of LP was 23.8%. Lower SBRT doses and tumor location in the liver were significant predictors of LP on MVA. Median OS was 49.3 months, 19.3 months, and 9.0 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. Primary tumor not in situ, smaller tumors, fewer lines of previous systemic therapy, lower CEA, and oligometastases treatment indications were significant predictors of higher OS on MVA. For the entire cohort, median PFS was 9.9 months, while oligometastatic patients had a median PFS of 12.4 months. 2-year cumulative incidence of SCST was 41.7%. Survival outcomes are favorable after SBRT for mCRC patients. A significant proportion of patients did not have a change in systemic therapy after SBRT. Higher doses are required to obtain the best local control. Efforts should be made to better optimize SBRT delivery for liver metastases given their higher local failure rate. [ABSTRACT FROM AUTHOR]

About 20–40% of cancer patients develop brain metastases, causing significant morbidity and mortality. Stereotactic radiation treatment is an established option that delivers high dose radiation to the target while sparing the surrounding normal tissue. However, up to 20% of metastatic brain tumours progress despite stereotactic treatment, and it can take months before it is evident on follow-up imaging. An early predictor of radiation therapy outcome in terms of tumour local failure (LF) is crucial, and can facilitate treatment adjustments or allow for early salvage treatment. In this study, an MR-based radiomics framework was proposed to derive and investigate quantitative MRI (qMRI) biomarkers for the outcome of LF in brain metastasis patients treated with hypo-fractionated stereotactic radiation therapy (SRT). The qMRI biomarkers were constructed through a multi-step feature extraction/reduction/selection framework using the conventional MR imaging data acquired from 100 patients (133 lesions), and were applied in conjunction with machine learning techniques for outcome prediction and risk assessment. The results indicated that the majority of the features in the optimal qMRI biomarkers characterize the heterogeneity in the surrounding regions of tumour including edema and tumour/lesion margins. The optimal qMRI biomarker consisted of five features that predict the outcome of LF with an area under the curve (AUC) of 0.79, and a cross-validated sensitivity and specificity of 81% and 79%, respectively. The Kaplan-Meier analyses showed a statistically significant difference in local control (p-value < 0.0001) and overall survival (p = 0.01). Findings from this study are a step towards using qMRI for early prediction of local failure in brain metastasis patients treated with SRT. This may facilitate early adjustments in treatment, such as surgical resection or salvage radiation, that can potentially improve treatment outcomes. Investigations on larger cohorts of patients are, however, required for further validation of the technique. [ABSTRACT FROM AUTHOR]

Purpose: To compare normal tissue dosimetry between hippocampal-avoidance whole brain radiation therapy (HA-WBRT) and stereotactic radiosurgery (SRS) in patients with 10 to 30 brain metastases, and to describe a novel SRS strategy we term Spatially Partitioned Adaptive RadiosurgEry (SPARE).Methods and Materials: A retrospective review identified SRS treatment plans with >10 brain metastases located >5 mm from the hippocampi. Our Gamma Knife Icon (GKI) SPARE (GKI-Spr) technique treats multiple metastases with single-fraction SRS partitioned over consecutive days while limiting the total treatment time to ≤60 minutes per day. Hippocampal and normal brain dosimetry were compared among GKI-Spr, single-fraction single-day GKI (GKI-Sfr), and 30 Gy in 10 fractions HA-WBRT. Dose metrics were converted to equivalent dose in 2 Gy fractions.Results: Ten cases were analyzed. Compared with HA-WBRT, GKI-Spr significantly reduced the median equivalent dose in 2 Gy fractions hippocampal maximum point dose, mean dose, and dose to 40% of the hippocampi (D40%) by 86%, 93%, and 93%, respectively, and similarly for GKI-Sfr by 81%, 92%, and 91%, respectively. The normal brain median mean dose was reduced by 95% with GKI-Spr and 94% with GKI-Sfr. Compared with GKI-Sfr, GKI-Spr further reduced all normal brain and hippocampal dose metrics (P ≤ .014).Conclusions: GKI yields superior hippocampal and normal brain dosimetry compared with HA-WBRT, and GKI-Spr results in further dosimetric advantages. [ABSTRACT FROM AUTHOR]

Background: Although advancements in systemic therapy have improved the outlook for pancreatic adenocarcinoma, it is not known if patients get access to these therapies. We aimed to examine the patterns and factors associated with access to specialized cancer consultations and subsequent receipt of cancer-directed therapy for patients with non-curative pancreatic adenocarcinoma.Methods: We conducted a population-based analysis of noncurative pancreatic adenocarcinoma diagnosed over 2005-2016 in Ontario by linking administrative health care data sets. Our primary outcomes were specialized cancer consultation and receipt of cancer-directed therapy (chemotherapy or a combination of chemo- and radiation therapy [chemoradiation therapy]). We examined specialized cancer consultation with hepato-pancreatico-biliary surgery, medical and radiation oncology. We used multivariable logistic regression to identify factors associated with medical oncology consultation and cancer-directed therapy.Results: Of 10 881 patients, 64.9% had a consultation with specialists in medical oncology, 35.1% with hepatopancreatico-biliary surgery and 24.7% with radiation oncology. Sociodemographic characteristics were not associated with the likelihood of medical oncology consultation. Of these patients, 4144 received cancer-directed therapy, representing 38.1% of all patients and 58.6% of those who consulted with medical oncology. Of 6737 patients not receiving cancer-directed therapy, 2988 (44.4%) had a consultation with medical oncology. Older age and lowest income quintile were independently associated with lower likelihood of cancer-directed therapy. If the first specialized cancer consultation was with medical or radiation oncology, the likelihood of cancer-directed therapy was significantly higher compared with surgery.Interpretation: A considerable proportion of patients with noncurable pancreatic adenocarcinoma in Ontario did not have a specialized cancer consultation and most did not receive cancer-directed therapy. We identified disparities in specialized cancer consultation and receipt of systemic cancer-directed therapy that indicate potential gaps in assessment. [ABSTRACT FROM AUTHOR]