The relationship between radiation dose and bevacizumab-related imaging abnormality in patients with brain tumors: A voxel-wise normal tissue complication probability (NTCP) analysis.

PURPOSE: Bevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis. METHODS: Patients (n = 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping. RESULTS: Among 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (ß0 = -5.1, ß1 = 0.03 Gy-1, γ = 1.3). CONCLUSIONS: BRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated.

Neurocognitive considerations in the treatment of meningioma with radiation therapy: applications for quantitative neuroimaging and precision radiation medicine.

This article focuses on the role of radiotherapy in the management of meningioma, in the definitive and adjuvant setting and across the spectrum of meningioma grade. Treatment paradigms, informed by clinical evidence, are discussed. Notably, we focus on the impact of radiotherapy on normal brain tissues and neurocognitive function, particularly the dose-dependent changes in white matter and cerebral cortex thickness. Novel imaging techniques have allowed the identification of microstructural changes to eloquent white matter, cortex, and subcortical regions as biomarkers for understanding RT-induced changes in cognitive functioning. Deficits in multiple domains including attention, memory, language and executive function can become more pronounced following radiation. Longitudinal assessment with imaging and neurocognitive testing pre- and post-radiation have allowed correlation between dose to specific regions of the brain and decline in associated domains of neurocognitive function. These findings suggest incorporation of areas at higher risk for neurocognitive sequelae into precision radiation planning. Volumetric arc therapy, advanced planning with cortical sparing, proton therapy and stereotactic radiosurgery are reviewed as options for delivering therapeutic dose to target volumes while minimizing risk to adjacent sensitive regions. The treatment of meningioma is an evolving area, with improving outcomes for higher grade disease in modern trials, where care must be taken to maximize both disease control as well as quality of life for patients.

Germline genetic biomarkers to stratify patients for personalized radiation treatment.

BACKGROUND: Precision medicine incorporating genetic profiling is becoming a standard of care in medical oncology. However, in the field of radiation oncology there is limited use of genetic profiling and the impact of germline genetic biomarkers on radiosensitivity, radioresistance, or patient outcomes after radiation therapy is poorly understood. In HNSCC, the toxicity associated with treatment can cause delays or early cessation which has been associated with worse outcomes. Identifying potential biomarkers which can help predict toxicity, as well as response to treatment, is of significant interest. METHODS: Patients with HNSCC who received RT and underwent next generation sequencing of somatic tumor samples, transcriptome RNA-seq with matched normal tissue samples were included. Patients were then grouped by propensity towards increased late vs. early toxicity (Group A) and those without (Group B), assessed by CTCAE v5.0. The groups were then analyzed for association of specific germline variants with toxicity and clinical outcomes. RESULTS: In this study we analyzed 37 patients for correlation between germline variants and toxicity. We observed that TSC2, HLA-A, TET2, GEN1, NCOR2 and other germline variants were significantly associated with long term toxicities. 34 HNSCC patients treated with curative intent were evaluated for clinical outcomes. Group A had significantly improved overall survival as well as improved rates of locoregional recurrence and metastatic disease. Specific variants associated with improved clinical outcomes included TSC2, FANCD2, and PPP1R15A, while the HLA-A and GEN1 variants were not correlated with survival or recurrence. A group of five HLA-DMA/HLA-DMB variants was only found in Group B and was associated with a higher risk of locoregional recurrence. CONCLUSIONS: This study indicates that germline genetic biomarkers may have utility in predicting toxicity and outcomes after radiation therapy and deserve further investigation in precision radiation medicine approaches.

Volumetric de-escalation and improved acute toxicity with proton craniospinal irradiation using a vertebral body-sparing technique.

PURPOSE: In growing children, craniospinal irradiation (CSI) has historically treated the entire vertebral body (VB) to avoid potential long-term spinal abnormalities. Vertebral body-sparing proton craniospinal irradiation (VBSpCSI) is a technique that spares the majority of the VB from significant irradiation, and long-term safety outcomes have been reported previously. This retrospective study reviews the acute toxicity profile of children treated with VBSpCSI in a cohort comparison with photon-based craniospinal radiotherapy (3DCRT). METHODS: Thirty-eight pediatric CSI patients treated between 2008 and 2018 were retrospectively evaluated for treatment-related toxicity. Acute toxicity outcomes and acute hematologic profiles were compared according to treatment modality, either VBSpCSI or 3DCRT. Statistical analysis was performed using Fisher's exact test for toxicity. RESULTS: Twenty-five patients received VBSpCSI and 13 patients received photon CSI. Mean patient age at treatment was 7.5 years (range 2-16). The cohorts were well matched with respect to gender, age, and CSI dose. Patients receiving VBSpCSI had lower rates of grade 2+ gastrointestinal (GI) toxicity (24% vs. 76.5%, p = .005), grade 2+ nausea (24% vs. 61.5%, p = .035), and any-grade esophagitis (0% vs. 38%, p = .0026). Patients treated with VBSpCSI had lower red blood cell transfusion rates (21.7% vs. 60%, p = .049) and grade 4+ lymphopenia (33.3% vs. 77.8%, p = .046). CONCLUSIONS: VBSpCSI in children is a volumetric de-escalation from traditional volumes, which irradiate the entire VB to full or intermediate doses. In our study, VBSpCSI was associated with lower rates of acute GI and hematologic toxicities. Long-term growth outcomes and disease control outcomes are needed for this technique.

Salvage image guided radiation therapy to the prostate after cryotherapy failure.

PURPOSE: Cryotherapy is an option for the primary treatment of localized prostate cancer, along with radical prostatectomy, external beam radiation therapy, and brachytherapy. Although it is known that local recurrence can occur in >20% of patients treated with primary cryotherapy, unfortunately there is a paucity of data on later salvage treatments. The use of external beam radiation therapy is an attractive option after cryotherapy failure, but there is little data on its efficacy and toxicity. We evaluated the biochemical control and complication rates of salvage dose-escalated image guided intensity modulated radiation therapy (IG-IMRT) after cryotherapy failure. METHODS AND MATERIALS: Patients who were treated at our institution from 2005 to 2016 were reviewed for those who underwent cryotherapy as initial treatment followed by salvage IGRT. Patients were treated with dose-escalated IG-IMRT using standard treatment margins of 3 mm posterior and 7 mm in all other directions and daily cone beam computed tomography or kv imaging to implanted fiducial markers. Biochemical progression was defined in accordance with the Phoenix consensus conference definition. RESULTS: Eight patients were identified as having received post-cryotherapy salvage radiation within the study period. The median total dose was 77.7 Gy (range, 75.6-81.0 Gy). Median follow-up was 55 months (range, 6-88 months). Six patients remained biochemically controlled at the latest follow-up. One patient developed distant metastases after 22 months and one experienced biochemical failure at 30 months with no evidence of distant metastases. No patients experienced acute gastrointestinal toxicities of grade 2 or higher. There were no cases of late gastrointestinal or genitourinary toxicity. CONCLUSIONS: High-dose IG-IMRT results in high rates of salvage and extremely low rates of serious late toxicity for patients with locally recurrent prostate cancer after cryotherapy. Although the results are encouraging, given the small number of patients in this and other series, we remain cautious with regard to this treatment and believe the use of salvage radiation therapy after cryotherapy warrants further study.

A case-control study using motion-inclusive spatial dose-volume metrics to account for genito-urinary toxicity following high-precision radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: The risk of genitourinary (GU) toxicity is dose-limiting in radiotherapy (RT) for prostate cancer. This study investigated whether motion-inclusive spatial dose/volume metrics explain the GU toxicity manifesting after high-precision RT for prostate cancer. MATERIAL AND METHODS: A matched case-control was performed within a cohort of 258 prostate cancer patients treated with daily cone-beam CT (CBCT)-guided RT (prescription doses of 77.4-81.0 Gy). Twenty-seven patients (10.5%) presented late RTOG GU ≥ Grade 2 toxicity and those without symptoms of toxicity prior treatment (N = 7) were selected as cases. Each case was matched with three controls based on pre-treatment GU symptoms, age, Gleason score, follow-up time, and hormone therapy. Thirteen CBCTs per patient were rigidly registered to the planning CT using the recorded treatment shifts, and the bladder was manually contoured on each CBCT. Planned and actually delivered dose/volume metrics (the latter averaged across the CBCTs) were extracted from the bladder and its subsectors, and compared between cases and controls (two-way ANOVA test). RESULTS: There were no significant differences between planned and delivered dose/volume metrics; also, there were no significant differences between cases and controls at any dose level, neither for planned nor delivered doses. The cases tended to have larger bladder volumes during treatment than controls (221 ±â€¯71 cm3 vs 166 ±â€¯73 cm3; p = 0.09). CONCLUSIONS: High-precision RT for prostate cancer eliminates differences between planned and delivered dose distributions. Neither planned nor delivered bladder dose/volume metrics were associated to the remaining low risk of developing GU toxicity after high-precision radiotherapy for prostate cancer.

Risperidone in the Emergency Setting is Associated with More Hypotension in Elderly Patients.

BACKGROUND: Expert consensus panels have recommended risperidone as first-line treatment for agitation of psychiatric origin. However, there are few if any studies on this medication in the emergency setting. OBJECTIVES: To assess the hemodynamic effects of risperidone in an emergency department (ED) setting, stratified by age. METHODS: This is a structured chart review of all patients who received oral risperidone over a 6-year period in an ED setting, excluding patients who received this medication as a prescription refill. Vital signs were analyzed for this subset prior to and after medication administration, and changes in vital signs were stratified by age. RESULTS: The median dose of risperidone was less in patients aged > 65 years. However, the median drop in systolic blood pressure was larger in this age group compared with younger patients. CONCLUSIONS: Clinicians tend to be more cautious with dosing of risperidone to geriatric patients in the ED. Despite this, decreases in systolic blood pressure are larger and more frequent in this age group. When possible, clinicians should consider or attempt nonpharmacologic methods of agitation treatment prior to administering medications such as risperidone to elderly patients.

Associations between volume changes and spatial dose metrics for the urinary bladder during local versus pelvic irradiation for prostate cancer.

BACKGROUND: Inter-fractional variation in urinary bladder volumes during the course of radiotherapy (RT) for prostate cancer causes deviations between planned and delivered doses. This study compared planned versus daily cone-beam CT (CBCT)-based spatial bladder dose distributions, for prostate cancer patients receiving local prostate treatment (local treatment) versus prostate including pelvic lymph node irradiation (pelvic treatment). MATERIAL AND METHODS: Twenty-seven patients (N = 15 local treatment; N = 12 pelvic treatment) were treated using daily image-guided RT (1.8 Gy@43-45 fx), adhering to a full bladder/empty rectum protocol. For each patient, 9-10 CBCTs were registered to the planning CT, using the clinically applied translations. The urinary bladder was manually segmented on each CBCT, 3 mm inner shells were generated, and semi and quadrant sectors were created using axial/coronal cuts. Planned and delivered DVH metrics were compared across patients and between the two groups of treatment (t-test, p < .05; Holm-Bonferroni correction). Associations between bladder volume variations and the dose-volume histograms (DVH) of the bladder and its sectors were evaluated (Spearman's rank correlation coefficient, rs). RESULTS: Bladder volumes varied considerably during RT (coefficient of variation: 16-58%). The population-averaged planned and delivered DVH metrics were not significantly different at any dose level. Larger treatment bladder volumes resulted in increased absolute volume of the posterior/inferior bladder sector receiving intermediate-high doses, in both groups. The superior bladder sector received less dose with larger bladder volumes for local treatments (rs ± SD: -0.47 ± 0.32), but larger doses for pelvic treatments (rs ± SD: 0.74 ± 0.24). CONCLUSIONS: Substantial bladder volume changes during the treatment course occurred even though patients were treated under a full bladder/daily image-guided protocol. Larger bladder volumes resulted in less bladder wall spared at the posterior-inferior sector, regardless the treatment received. Contrary, larger bladder volumes meant larger delivered doses to the superior bladder sector for pelvic RT but smaller doses for local treatments.

First-generation Antipsychotics Are Often Prescribed in the Emergency Department but Are Often Not Administered with Adjunctive Medications.

BACKGROUND: Although first-generation antipsychotics (FGAs) have long been used in the emergency department (ED) to treat acute agitation, little is known about how these medications are used in modern clinical practice. In particular, little work has been published about whether ED clinicians administer FGAs with adjunctive medications in accordance with expert guidelines or the prescribing practices of FGAs over time. OBJECTIVES: 1) To provide a comparison of the frequency with which FGAs are administered with adjunctive benzodiazepines or anticholinergic medications. 2) To analyze the prescribing trends for FGAs over time, particularly in the years after the U.S. Food and Drug Administration (FDA) black-box warning for droperidol. METHODS: This is a structured review of a retrospective cohort of patients receiving haloperidol or droperidol in two EDs over a 7-year period. RESULTS: Haloperidol or droperidol was administered on 2833 patient visits during the study period, with haloperidol being administered most often. Adjunctive medications are administered less than half of the time. The use of droperidol has remained relatively static, whereas the use of haloperidol has increased. CONCLUSIONS: First-generation antipsychotics are still widely utilized in the ED. When administered, these medications are used with adjunctive medications that may decrease side effects less than half of the time. Droperidol use has remained unchanged in the years after the FDA black-box warning, whereas use of haloperidol has continued to rise.

Ketamine use for acute agitation in the emergency department.

BACKGROUND: Emergency physicians regularly encounter agitated patients. In extremely agitated and violent patients, the onset of many traditional medications is relatively slow and often requires additional medication. Ketamine is frequently used in emergency departments (EDs) for procedural sedation and intubation, but has recently been suggested as a treatment for acute agitation. OBJECTIVES: We sought to examine the use of ketamine in the treatment of acute agitation in an ED setting, including vital sign changes as a result of this medication. METHODS: This is a structured review of an historical cohort of patients over 7 years at two university EDs. Patients were included if they received ketamine as treatment for acute agitation. Abstracted data included age, vital signs including hypoxia, any additional medications for agitation, and alcohol/drug intoxication. RESULTS: Ketamine was administered for agitation on 32 visits involving 27 patients. Preadministration systolic blood pressure was 131 ± 20 mm Hg, with an average postadministration increase of 17 ± 25 mm Hg. The average baseline heart rate was 98 ± 23 beats/min, with an average increase of 8 ± 17 beats/min. No patients became hypoxic; 62.5% of patients required additional calming medication. Alcohol or drug intoxication was present in 40.6% of patients. CONCLUSIONS: We found ketamine was used rarely, but had few major adverse effects on vital signs even in a population with 21.9% alcohol intoxication. However, a high proportion (62.5%) of patients required additional pharmacologic treatment for agitation, implying that administering ketamine is useful only for initial control of severe agitation.