Antipsychotic prescribing patterns in Australia: a retrospective analysis.

BACKGROUND: To examine real-world patterns of antipsychotic use in patients with schizophrenia Australia. METHODS: This retrospective cohort analysis was conducted using the Australian Commonwealth Department of Human Services Pharmaceutical Benefits Scheme (PBS) 10% sample data. Included data were for patients aged 16-years or older who initiated treatment for the first time with a PBS-reimbursed antipsychotic medication for schizophrenia between July 2013 and September 2017. Patterns of treatment usage were summarised descriptively. Differences in prescribing patterns by age and prescribing year were reported. Treatment persistence was estimated using Kaplan-Meier methods, with differences explored using log-rank tests. Values of p < 0.05 were considered statistically significant. RESULTS: 6,740 patients, representing 8,249 non-unique patients, received prescriptions for antipsychotic medications. Patients were aged 16 years to over 85 years (54.5% were < 55 years) and two-thirds of patients were male (61%). The majority of treatment episodes (62%, n = 5,139/8,249) were prescribed an atypical oral antipsychotic. Typical long-acting antipsychotic therapies (LATs) were prescribed 19% of the treatment episodes (n = 1,608/8,249. There was a small increase in prescribing of atypical LAT and typical LAT and a small decrease in atypical oral and clozapine prescribing over the study period. Treatment persistence was greatest in patients treated with clozapine, than in those treated with atypical LATs. CONCLUSIONS: While the majority of patients receive atypical antipsychotic medications, one in five continue to use older typical LAT therapies. Patient age and time on therapy may be associated with choice of therapy. Persistence to atypical LAT therapy is better than for other treatment modalities in this real-world cohort.

HIV treatment regimens and adherence to national guidelines in Australia: an analysis of dispensing data from the Australian pharmaceutical benefits scheme.

BACKGROUND: Treatment guidelines for antiretroviral therapy (ART) have evolved to emphasize newer regimens that address ageing-related comorbidities. Using national Australian dispensing data we compare ART regimens with Australian HIV treatment guidelines in the context of treated comorbidities. METHODS: The study population included all individuals in a 10% sample of national data from the Australian Pharmaceutical Benefits Scheme (PBS) who purchased a prescription of ART during 2016. We defined each patient's most recently dispensed ART regimen and characterized them to evaluate regimen complexity and adherence to national HIV treatment guidelines. We then analyzed ART regimens in the context of other co-prescriptions purchased for defined comorbidities. RESULTS: The 1995 patients in our sample purchased 212 different ART regimens during 2016; 1524 (76.4%) purchased one of the top ten most common regimens of which 62.3% were integrase strand transfer inhibitor-based. Among the 1786 (90%) patients that purchased the most common regimens, 83.7% purchased a regimen recommended by the guidelines for initial antiretroviral therapy and 11.4% purchased antiretrovirals that are not recommended for initial therapy; < 1% of the entire cohort purchased medications not recommended for use. While most patients purchased optimal ART regimens with low potential for significant drug interactions, regimen choices in the setting of risk factors for heart disease, renal disease and low bone mineral density appeared suboptimal. CONCLUSIONS: Australian HIV providers are prescribing ART regimens in accordance with updated treatment guidelines, but could further optimize regimens in the setting of important medical comorbidities.

Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT.

BACKGROUND: Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast. METHODS: Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers. RESULTS: Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91%) with the linear SVM kernel. CONCLUSION: This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91%.

Antidepressant prescribing patterns in Australia.

BACKGROUND: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2015 and MDcpg2020) provide evidence-based and consensus-based recommendations for managing mood disorders. AIMS: We examined Australian real-world prescribing habits to determine whether management in clinical practice aligned with MDcpg2015 recommendations. METHOD: A retrospective analysis of a cohort of patients ≥16 years old who had been dispensed a Pharmaceutical Benefits Scheme (PBS)-listed antidepressant between July 2013 and June 2019 was conducted using Australian Commonwealth Department of Human Services PBS 10% sample data. RESULTS: Between July 2013 and June 2019, 239 944 patients in Australia commenced antidepressant treatment. Of these, 22% (52 694 patients) received a second treatment (a new class of treatment after a period of discontinuation or additional antipsychotic therapy) and 6% (15 741 patients) received a third treatment. Patients were initially prescribed primarily selective serotonin reuptake inhibitors (SSRIs; 52% of prescriptions) or tricyclic antidepressants (TCAs; 25%), even though TCAs are not recommended for first-line treatment. Fewer than one-quarter of patients were prescribed serotonin-noradrenaline reuptake inhibitors (13%) or other agents (10%). General practitioners (GPs) were more likely to initiate TCAs than psychiatrists (22% v. 7%).Once initiated, the overall median time patients remained on treatment was 4.5 months; this was highest with SSRIs (5.8 months) and lowest with TCAs (0.9 months). CONCLUSIONS: First-line prescribing broadly follows guidelines. GP and psychiatrist prescribing patterns differ, perhaps reflecting different patient groups and the need to tailor treatment to individuals. Future guidelines should aim to capture the different presentations and complexity of depression.

Comorbidity Medications Are Dispensed to More People Receiving Antiretroviral Therapy for HIV Compared with the General Population in Australia.

Medical comorbidities occur in more persons with HIV than without HIV. We used a nationally representative 10% sample of 2016 Pharmaceutical Benefits Scheme (PBS) dispensing data to compare the proportions of antiretroviral therapy (ART)-purchasing and non-ART-purchasing patients who also purchased prescriptions for medical comorbidities. Each patient who purchased ART was compared with two gender- and age group-matched patients who did not purchase ART in the same year. We calculated the proportions of patients who also purchased coprescriptions used for hypertension, dyslipidemia, diabetes, cancer, low bone mineral density, and mental health, defined using PBS medication coding categories, and the resulting odds ratios. A total of 1,973 ART-purchasing patients in our sample were matched to 3,946 non-ART-purchasing patients. Compared with non-ART-purchasing patients, a greater proportion of ART-purchasing patients also purchased medications for dyslipidemia (19.8% vs. 16.6%; p-value = .003), low bone mineral density (1.5% vs. 0.8%; p-value = .02), and mental health (29.1% vs. 15.3%; p-value < .0001); a lower proportion purchased diabetes medications (4.8% vs. 6.5%; p-value = .009). These differences remained when our analysis was restricted to persons >55 years of age. Rates of multimorbidity (dispensed ≥2 medications for chronic conditions) were also higher among ART-purchasing patients (19.0% vs. 15.9%; p-value = .003). Using a nationally representative sample of prescription dispensing data, we found that higher proportions of ART-purchasing patients purchased coprescriptions for common comorbidities compared with non-ART-purchasing patients. Our finding that ART-purchasing patients purchased fewer diabetes medications is surprising, but may reflect differences in population characteristics between our two groups.

Treatment persistence of subcutaneous TNF inhibitors among Australian patients with immune-mediated rheumatic disease (IMRD).

INTRODUCTION: To describe the persistence of treatment with subcutaneous tumor necrosis factor inhibitors (TNFi) adalimumab, etanercept, and golimumab in immune-mediated rheumatic disease (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) by treatment sequence (first-line treatment, second-line or further lines of treatment). METHODS: A retrospective cohort analysis was conducted using the Australian Commonwealth Department of Human Services Pharmaceutical Benefits Scheme 10% sample data from January 1, 2010, to June 30, 2016. Pharmaceutical Benefits Scheme indications were used to identify patient prescriptions for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. A patient was considered persistent until a 3-month gap period where a prescription was not dispensed. The 3-month gap interval was chosen because only 1% of all discontinuations occurred beyond this 3-month period. RESULTS: Data from 2,612 first-line patients were included. Treatment discontinuation among first-line patients treated with etanercept or adalimumab was not significantly different from those treated with golimumab (HR 1.10, 95% CI 0.95-1.28, P=0.22; HR 1.06, 95% CI 0.93-1.22, P=0.39; respectively). Among the 1,276 patients in the second-line cohort (etanercept=41%, adalimumab=41%, golimumab=18%) discontinuation was significantly higher for patients on etanercept compared with golimumab (HR 1.24, 95% CI 1.03-1.50, P=0.03); but not for adalimumab compared with golimumab (HR 1.11, 95% CI 0.91-1.34, P=0.31). In the third-line setting, treatment persistence with etanercept was longer than golimumab (HR 0.75, 95% CI 0.59-0.96, P=0.02), but there was no difference between golimumab and adalimumab. Similar findings occurred in the propensity score matched population. CONCLUSION: Our study shows there is variance in real-world persistence to TNFi in patients with immune-mediated rheumatic disease by line of therapy, with the time on therapy decreasing by line. Australian persistence has been reported at lower overall rates than international evidence.

Interprofessional education: evaluation of a radiation therapy and medical physics student simulation workshop.

INTRODUCTION: Interprofessional education (IPE) involves two or more professions engaged in learning with, from and about each other. An initiative was undertaken to explore IPE for radiation therapy (RT) and medical physics (MP) students through a newly developed workshop based around simulated learning. The aims of this study were to explore RT and MP students' perceptions of working as part of a collaborative team and of their own and the other group's professional roles. Student perceptions of the simulation education tool, the virtual environment for radiotherapy training (VERT) system, were also investigated. METHODS: RT and MP students were invited to participate in a 4-hour interprofessional workshop. Pre- and post-workshop surveys were employed to collect demographic data, students' perceptions of interdisciplinary education (interdisciplinary education perception scale (IEPS)) and workshop evaluation (bespoke questionnaire). RESULTS: Fifteen students attended the workshop (RT, n = 8; MP, n = 7). Thirteen pre- and post-questionnaires were returned (Pre-questionnaire: RT, n = 6, response rate, 75%; MP, n = 7, response rate, 100%; post-questionnaire: RT, n = 7, response rate, 87.5%; MP, n = 6, response rate 85.7%). For both student groups combined, IEPS scores ranged from 64 to 108 and 71 to 108 in the pre- and post-questionnaires, respectively, with insignificant differences in the mean scores post-intervention (Z = -1.305, P = 0.192). Satisfaction with VERT as a simulation tool was high for both student groups. CONCLUSIONS: The interprofessional student workshop served to promote interprofessional collaboration for RT and MP students. VERT was reported as an appropriate education tool for this purpose, enabling access to virtual clinical equipment common to both student groups. It is suggested that IPE continues to be offered and investigated in RT and MP students, in order to improve effective interprofessional strategies which may enrich future professional collaboration.

Successful implementation of Virtual Environment for Radiotherapy Training (VERT) in Medical Physics education: The University of Sydney's initial experience and recommendations.

This report outlines the University of Sydney's initial experience with the Virtual Environment for Radiotherapy Training (VERT) system in the Master of Medical Physics program. VERT is a commercially available system, simulating linear accelerators, patient computed tomography (CT) sets, plans and treatment delivery. It was purpose built for radiation therapy (RT) education and offers learners the opportunity to gain knowledge and skills within an interactive, risk-free environment. The integration of VERT into the RT physics module of the Master of Medical Physics program was intended to enhance student knowledge and skills relevant to the curriculum's learning objectives, and to alleviate some of the burden associated with student access to clinical equipment. Three VERT practical sessions were implemented: "RT treatment planning systems", "(CT) Anatomy for physicists" and "Linear accelerator measurements". Our experience and student evaluations were positive and demonstrated the viability of VERT for medical physics (MP) student education. We anticipate that integration of VERT into MP teaching is a valuable addition to traditional methods and can aid MP students' understanding and readiness for practice. Additional evaluations should be conducted to ascertain VERT's role in delivering efficient quantity and quality of MP education, and its potential in alleviating burdens placed on clinical departments.

Quantification of intrafraction prostate motion and its dosimetric effect on VMAT.

Intrafraction prostate motion degrades the accuracy of radiation therapy (RT) delivery. Whilst a number of metrics in the literature have been used to quantify intrafraction prostate motion, it has not been established whether these metrics reflect the effect of motion on the RT dose delivered to the patients. In this study, prostate motion during volumetric modulated arc therapy (VMAT) treatment of 18 patients and a total of 294 fractions was quantified through novel metrics as well as those available in the literature. The impact of the motion on VMAT dosimetry was evaluated using these metrics and dose reconstructions based on a previously validated and published method. The dosimetric impact of the motion on planning target volume (PTV) and clinical target volume (CTV) coverage and organs at risk (OARs) was correlated with the motion metrics, using the coefficient of determination (R 2 ), to evaluate their utility. Action level threshold for the prostate motion metric that best described the dosimetric impact on the PTV D95% was investigated through iterative regression analysis. The average (range) of the mean motion for the patient cohort was 1.5 mm (0.3-9.9 mm). A number of motion metrics were found to be strongly correlated with PTV D95%, the range of R 2 was 0.43-0.81. For all the motion measures, correlations with CTV D99% (range of R 2 was 0.12-0.62), rectum V65% (range of R 2 was 0.33-0.58) and bladder V65% (range of R 2 was 0.51-0.69) were not as strong as for PTV D95%. The mean of the highest 50% of motion metric was one of the best indicator of dosimetric impact on PTV D95%. Action level threshold value for this metric was found to be 3.0 mm. For an individual fraction, when the metric value was greater than 3.0 mm then the PTV D95% was reduced on average by 6.2%. This study demonstrated that several motion metrics are well correlated with the dosimetric impact (PTV D95%) of individual fraction prostate motion on VMAT delivery and could be used for treatment course adaptation.

Kilovoltage intrafraction monitoring for real-time image guided adaptive radiotherapy reduces total dose for lung SABR.

This study presents estimation of typical kV fluoroscopic imaging doses for image-guided real-time adaptive radiotherapy. For a cohort of 10 lung SABR patients the estimated imaging dose to ipsi-lateral lung with real-time adaptation is 9.9-15.1cGy, which is less than the extra lung dose from treatment with potentially larger ITV-based PTV approach.

Does breast composition influence late adverse effects in breast radiotherapy?

BACKGROUND: Large breast size is associated with increased risk of late adverse effects after surgery and radiotherapy for early breast cancer. It is hypothesised that effects of radiotherapy on adipose tissue are responsible for some of the effects seen. In this study, the association of breast composition with late effects was investigated along with other breast features such as fibroglandular tissue distribution, seroma and scar. METHODS: The patient dataset comprised of 18 cases with changes in breast appearance at 2 years follow-up post-radiotherapy and 36 controls with no changes, from patients entered into the FAST-Pilot and UK FAST trials at The Royal Marsden. Breast composition, fibroglandular tissue distribution, seroma and scar were assessed on planning CT scan images and compared using univariate analysis. The association of all features with late-adverse effect was tested using logistic regression (adjusting for confounding factors) and matched analysis was performed using conditional logistic regression. RESULTS: In univariate analyses, no statistically significant differences were found between cases and controls in terms of breast features studied. A statistically significant association (p < 0.05) between amount of seroma and change in photographic breast appearance was found in unmatched and matched logistic regression analyses with odds ratio (95% CI) of 3.44 (1.28-9.21) and 2.57 (1.05-6.25), respectively. CONCLUSIONS: A significant association was found between seroma and late-adverse effects after radiotherapy although no significant associations were noted with breast composition in this study. Therefore, the cause for large breast size as a risk factor for late effects after surgery and optimally planned radiotherapy remains unresolved.

Real-Time 3D Image Guidance Using a Standard LINAC: Measured Motion, Accuracy, and Precision of the First Prospective Clinical Trial of Kilovoltage Intrafraction Monitoring-Guided Gating for Prostate Cancer Radiation Therapy.

PURPOSE: Kilovoltage intrafraction monitoring (KIM) is a new real-time 3-dimensional image guidance method. Unlike previous real-time image guidance methods, KIM uses a standard linear accelerator without any additional equipment needed. The first prospective clinical trial of KIM is underway for prostate cancer radiation therapy. In this paper we report on the measured motion accuracy and precision using real-time KIM-guided gating. METHODS AND MATERIALS: Imaging and motion information from the first 200 fractions from 6 patient prostate cancer radiation therapy volumetric modulated arc therapy treatments were analyzed. A 3-mm/5-second action threshold was used to trigger a gating event where the beam is paused and the couch position adjusted to realign the prostate to the treatment isocenter. To quantify the in vivo accuracy and precision, KIM was compared with simultaneously acquired kV/MV triangulation for 187 fractions. RESULTS: KIM was successfully used in 197 of 200 fractions. Gating events occurred in 29 fractions (14.5%). In these 29 fractions, the percentage of beam-on time, the prostate displacement was >3 mm from the isocenter position, reduced from 73% without KIM to 24% with KIM-guided gating. Displacements >5 mm were reduced from 16% without KIM to 0% with KIM. The KIM accuracy was measured at <0.3 mm in all 3 dimensions. The KIM precision was <0.6 mm in all 3 dimensions. CONCLUSIONS: Clinical implementation of real-time KIM image guidance combined with gating for prostate cancer eliminates large prostate displacements during treatment delivery. Both in vivo KIM accuracy and precision are well below 1 mm.

Prostate motion during radiotherapy of prostate cancer patients with and without application of a hydrogel spacer: a comparative study.

BACKGROUND AND PURPOSE: The use of a tissue expander (hydrogel) for sparing of the rectum from increased irradiation during prostate radiotherapy is becoming popular. The goal of this study is to investigate the effect of a tissue expander (hydrogel) on the intrafraction prostate motion during radiotherapy. METHODS AND MATERIAL: Real time prostate motion was analysed for 26 patients and 742 fractions; 12 patients with and 14 patients without hydrogel (SpaceOAR™). The intra-fraction motion was quantified and compared between the two groups. RESULTS: The average (±standard deviation) of the mean motion during the treatment for patients with and without hydrogel was 1.5 (±0.8 mm) and 1.1 (±0.9 mm) respectively (p < 0.05). The average time of motion >3 mm for patients with and without hydrogel was 7.7 % (±1.1 %) and 4.5 % (±0.9 %) respectively (p > 0.05). The hydrogel age, fraction number and treatment time were found to have no effect (R (2) < 0.05) on the prostate motion. CONCLUSIONS: Differences in intrafraction motion in patients with hydrogel and without hydrogel were within measurement uncertainty (<1 mm). This result confirms that the addition of a spacer does not negate the need for intrafraction motion management if clinically indicated.

The first clinical treatment with kilovoltage intrafraction monitoring (KIM): a real-time image guidance method.

PURPOSE: Kilovoltage intrafraction monitoring (KIM) is a real-time image guidance method that uses widely available radiotherapy technology, i.e., a gantry-mounted x-ray imager. The authors report on the geometric and dosimetric results of the first patient treatment using KIM which occurred on September 16, 2014. METHODS: KIM uses current and prior 2D x-ray images to estimate the 3D target position during cancer radiotherapy treatment delivery. KIM software was written to process kilovoltage (kV) images streamed from a standard C-arm linear accelerator with a gantry-mounted kV x-ray imaging system. A 120° pretreatment kV imaging arc was acquired to build the patient-specific 2D to 3D motion correlation. The kV imager was activated during the megavoltage (MV) treatment, a dual arc VMAT prostate treatment, to estimate the 3D prostate position in real-time. All necessary ethics, legal, and regulatory requirements were met for this clinical study. The quality assurance processes were completed and peer reviewed. RESULTS: During treatment, a prostate position offset of nearly 3 mm in the posterior direction was observed with KIM. This position offset did not trigger a gating event. After the treatment, the prostate motion was independently measured using kV/MV triangulation, resulting in a mean difference of less than 0.6 mm and standard deviation of less than 0.6 mm in each direction. The accuracy of the marker segmentation was visually assessed during and after treatment and found to be performing well. During treatment, there were no interruptions due to performance of the KIM software. CONCLUSIONS: For the first time, KIM has been used for real-time image guidance during cancer radiotherapy. The measured accuracy and precision were both submillimeter for the first treatment fraction. This clinical translational research milestone paves the way for the broad implementation of real-time image guidance to facilitate the detection and correction of geometric and dosimetric errors, and resultant improved clinical outcomes, in cancer radiotherapy.

The validation index: a new metric for validation of segmentation algorithms using two or more expert outlines with application to radiotherapy planning.

Validation is required to ensure automated segmentation algorithms are suitable for radiotherapy target definition. In the absence of true segmentation, algorithmic segmentation is validated against expert outlining of the region of interest. Multiple experts are used to overcome inter-expert variability. Several approaches have been studied in the literature, but the most appropriate approach to combine the information from multiple expert outlines, to give a single metric for validation, is unclear. None consider a metric that can be tailored to case-specific requirements in radiotherapy planning. Validation index (VI), a new validation metric which uses experts' level of agreement was developed. A control parameter was introduced for the validation of segmentations required for different radiotherapy scenarios: for targets close to organs-at-risk and for difficult to discern targets, where large variation between experts is expected. VI was evaluated using two simulated idealized cases and data from two clinical studies. VI was compared with the commonly used Dice similarity coefficient (DSCpair - wise) and found to be more sensitive than the DSCpair - wise to the changes in agreement between experts. VI was shown to be adaptable to specific radiotherapy planning scenarios.

Adaptive breast radiation therapy using modeling of tissue mechanics: a breast tissue segmentation study.

PURPOSE: To validate and compare the accuracy of breast tissue segmentation methods applied to computed tomography (CT) scans used for radiation therapy planning and to study the effect of tissue distribution on the segmentation accuracy for the purpose of developing models for use in adaptive breast radiation therapy. METHODS AND MATERIALS: Twenty-four patients receiving postlumpectomy radiation therapy for breast cancer underwent CT imaging in prone and supine positions. The whole-breast clinical target volume was outlined. Clinical target volumes were segmented into fibroglandular and fatty tissue using the following algorithms: physical density thresholding; interactive thresholding; fuzzy c-means with 3 classes (FCM3) and 4 classes (FCM4); and k-means. The segmentation algorithms were evaluated in 2 stages: first, an approach based on the assumption that the breast composition should be the same in both prone and supine position; and second, comparison of segmentation with tissue outlines from 3 experts using the Dice similarity coefficient (DSC). Breast datasets were grouped into nonsparse and sparse fibroglandular tissue distributions according to expert assessment and used to assess the accuracy of the segmentation methods and the agreement between experts. RESULTS: Prone and supine breast composition analysis showed differences between the methods. Validation against expert outlines found significant differences (P<.001) between FCM3 and FCM4. Fuzzy c-means with 3 classes generated segmentation results (mean DSC = 0.70) closest to the experts' outlines. There was good agreement (mean DSC = 0.85) among experts for breast tissue outlining. Segmentation accuracy and expert agreement was significantly higher (P<.005) in the nonsparse group than in the sparse group. CONCLUSIONS: The FCM3 gave the most accurate segmentation of breast tissues on CT data and could therefore be used in adaptive radiation therapy-based on tissue modeling. Breast tissue segmentation methods should be used with caution in patients with sparse fibroglandular tissue distribution.