Selective Internal Radiation Therapy Using Y-90 Resin Microspheres for Metastatic Colorectal Cancer: An Updated Systematic Review and Network Meta-Analysis.

INTRODUCTION: This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy (SIRT) using yttrium-90 (Y-90) resin microspheres, regorafenib (REG), trifluridine-tipiracil (TFD/TPI), and best supportive care (BSC) in adult patients with chemotherapy-refractory or chemotherapy-intolerant metastatic colorectal cancer (mCRC). METHODS: In light of recently published data, the literature was searched to complement and update a review published in 2018. Studies up to December 2022 comparing two or more of the treatments and reporting overall survival (OS), progression-free survival (PFS), or incidence of adverse events (AE) were included. The NMA compared hazard ratios (HRs) for OS and PFS using Markov chain Monte Carlo techniques. RESULTS: Fifteen studies were included, with eight studies added (none addressing SIRT). All active treatments improved OS in relation to BSC. SIRT had the longest OS among all treatments, although without statistically significant differences (HR [95% credible interval] for SIRT, 0.48 [0.27, 0.87]; TFD/TPI, 0.62 [0.46, 0.83]; REG, 0.78 [0.57, 1.05]) in a fixed effects model. Information regarding SIRT was insufficient for PFS analysis, and TFD/TPI was the best intervention (HR 2.26 [1.6, 3.18]). One SIRT study reported radioembolization-induced liver disease in > 10% of the sample; this was symptomatically managed. Non-haematological AEs (hand-foot skin reaction, fatigue, diarrhoea, hypertension, rash or desquamation) were more common with REG, while haematological events (neutropoenia, leukopenia, and anaemia) were more common with TFD/TPI. CONCLUSION: Current evidence supports SIRT treatment in patients with chemotherapy-refractory or chemotherapy-intolerant mCRC compared to newer oral agents, with comparable OS and low incidence of AEs.

Efficacy of transarterial radioembolization using Y-90 resin microspheres versus atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: A matching-adjusted indirect comparison.

INTRODUCTION: No head-to-head trials compared the efficacy of transarterial radioembolization (TARE, also known as selective internal radiation therapy) to combination immunotherapy in hepatocellular carcinoma (HCC). The analysis objective was to compare effectiveness outcomes of TARE using Y-90 resin microspheres and atezolizumab-bevacizumab (AB) in advanced unresectable HCC. METHODS: Patient-level data from SARAH randomized controlled trial for TARE and aggregate real-world data from AB-real study were used in an unanchored matching-adjusted indirect comparison. The basecase analysis used per-protocol data from SARAH; intention-to-treat data were used in sensitivity analyses. The following prognostic variables and effect modifiers were identified from literature: cause of disease, macrovascular invasion, Eastern Cooperative Oncology Group Performance Status, alpha-fetoprotein level and albumin-bilirubin score. Weights were assigned to patients from SARAH to balance baseline characteristics across studies and reflect characteristics of AB-real patients. Overall survival (OS), progression-free survival (PFS) and response rates (overall response rates [ORR]) were calculated and compared. RESULTS: The analysis of OS and PFS included 140 patients receiving TARE and 131 for the analysis of response rates, compared to 202 receiving AB. Median OS was 15.0 and 14.9 months for TARE and AB, respectively (HR=0.980; 95% confidence interval [CI]: 0.658-1.461; p-value=0.922). Median PFS was 4.4 and 6.8 months for TARE and AB, respectively (HR=0.745; 95%CI: 0.544-1.022; p-value=0.068). ORR were 19.8% and 25% with TARE and AB, respectively (OR for AB=1.386, 95%CI: 0.746-2.668; p-value=0.306). Sensitivity analyses generated similar results. CONCLUSION: In HCC patients receiving treatment, TARE using Y-90 resin microspheres may achieve comparable effectiveness outcomes compared with AB.

Cost-effectiveness of selective internal radiation therapy with Y-90 resin microspheres for intermediate- and advanced-stage hepatocellular carcinoma in Brazil.

AIMS: Hepatocellular carcinoma (HCC) is a severe condition with poor prognosis that places a significant burden on patients, caregivers, and healthcare systems. Selective internal radiation therapy (SIRT) is a treatment available to patients with HCC which addresses some of the limitations of alternative treatment options. A cost-effectiveness analysis was undertaken into the use of SIRT using Y-90 resin microspheres for the treatment of unresectable intermediate- and late-stage HCC in Brazil. MATERIALS AND METHODS: A partitioned-survival model was developed, including a tunnel state for patients downstaged to receive treatments with curative intent. Sorafenib was the selected comparator, a common systemic treatment in Brazil and for which comparative evidence exists. Clinical data were extracted from published sources of pivotal trials, and effectiveness was measured in quality-adjusted life-years (QALYs) and life-years (LYs). The analysis was conducted from the Brazilian private payer perspective and a lifetime horizon was implemented. Comprehensive sensitivity analyses were conducted. RESULTS: LYs and QALYs were higher for SIRT with Y-90 resin microspheres versus sorafenib (0.27 and 0.20 incremental LYs and QALYs, respectively) and costs were slightly higher for SIRT (R$15,864). The base case incremental cost-effectiveness ratio (ICER) was R$77,602 per QALY. The ICER was mostly influenced by parameters defining the sorafenib overall survival curve and SIRT had a 73% probability of being cost-effective at a willingness-to-pay threshold of R$135,761 per QALY (3-times the per-capita gross domestic product in Brazil). Overall, sensitivity analyses confirmed the robustness of the results indicating that SIRT with Y-90 resin microspheres is cost-effective compared with sorafenib. LIMITATIONS: A rapidly evolving treatment landscape in Brazil and worldwide, and the lack of local data for some variables were the main limitations. CONCLUSIONS: SIRT with Y-90 resin microspheres is a cost-effective option compared with sorafenib in Brazil.

Advances in Delivery of Selective Internal Radiation Therapy (SIRT): Economic and Logistical Effects of Same-Stay Work-Up and Procedure in the Treatment of Unresectable Liver Tumors in England.

INTRODUCTION: Selective internal radiation therapy (SIRT) is a targeted method of treatment for unresectable liver tumors in which radiation therapy is directly delivered to the tumor(s) via the hepatic vasculature. Successful outcomes with SIRT are dependent on the specific vasculature of the liver and tumor, and the patient therefore needs to attend a "work-up" to map the hepatic vasculature prior to the SIRT procedure. Recent advances in SIRT delivery have enabled same-day or same-stay work-up and procedure, requiring only one hospital visit rather than two. We aimed to evaluate the economic, travel time, and transport-related environmental impact of a new brachytherapy device delivery program, the order-map-treat (OMT) program, in patients with unresectable hepatocellular carcinoma (HCC) in England. METHODS: A healthcare resource group (HRG)-based analysis of costs from a national payer (Department of Health and Social Care, DHSC) perspective was conducted assuming that, with OMT, patients would have to attend hospital only once for both the SIRT work-up and procedure versus twice without OMT. Patient travel time and CO2 emissions were then estimated by identifying the SIRT center closest to the centroid of each clinical commissioning group (CCG) and calculating straight-line distances with a "detour index" to capture the effect of indirect routes via road or rail. RESULTS: It was estimated that 856 patients per annum would be eligible for SIRT treatment for unresectable HCC in England. OMT would be anticipated to save GBP 2842 per patient versus performing SIRT without OMT. Furthermore, across all patients with HCC eligible for SIRT in England, OMT would avoid 74,500 km of travel, 2299 h of travel time, and 13.9 metric tons of patient transport-related CO2 emissions annually. CONCLUSION: OMT reduces the number of hospital visits required for SIRT by 50%, resulting in financial savings from the DHSC perspective, time savings from the patient perspective, and reduced CO2 emissions arising from patient transport.

Transarterial Radioembolization Versus Atezolizumab-Bevacizumab in Unresectable Hepatocellular Carcinoma: A Matching-Adjusted Indirect Comparison of Time to Deterioration in Quality of Life.

INTRODUCTION: Given the relatively short life expectancy of patients with hepatocellular carcinoma (HCC), quality of life (QOL) plays a significant role in treatment selection. This analysis aimed to compare time to deterioration (TTD) in QOL with transarterial radioembolization (TARE) and atezolizumab-bevacizumab, as well as sorafenib, in advanced and unresectable HCC. METHODS: Patient-level data from SARAH (TARE using SIR-Spheres® Y-90 resin microspheres [SIR-Spheres] versus sorafenib) and aggregate data from IMbrave150 (atezolizumab-bevacizumab versus sorafenib) randomized controlled trials were used to conduct an anchored matching-adjusted indirect comparison (MAIC). Patients with a Child-Pugh score B in SARAH were excluded to align with exclusion criteria in IMbrave150. To identify potential effect modifiers for adjustment, the literature was searched and multivariate Cox proportional hazards models were implemented using SARAH data. Patients from SARAH were then weighted to balance with baseline characteristics from IMbrave150. Median TTD in QOL and hazard ratios (HRs) were calculated. RESULTS: Four potential effect modifiers were identified and used for adjustment: cause of disease (viral/non-viral), macrovascular invasion, Eastern Cooperative Oncology Group performance score, and alpha-fetoprotein level. The MAIC included 217 patients from SARAH (TARE = 94; sorafenib = 123). Median TTD in QOL was 11.23 and 8.64 months for atezolizumab-bevacizumab and TARE, respectively (HR = 1.06; 95% confidence interval [CI] 0.75-1.50; p = 0.725). A sensitivity analysis was conducted adjusting for cause of disease defined as hepatitis B/hepatitis C/non-viral: median TTD in QOL was higher for TARE compared with atezolizumab-bevacizumab (19.88 vs 11.23 months; HR = 0.66; 95% CI 0.36-1.19; p = 0.163). Sorafenib resulted in the shortest TTD in QOL, with statistically significant differences in both base case and sensitivity analyses. CONCLUSION: TARE using SIR-Spheres may achieve similar TTD in QOL compared with atezolizumab-bevacizumab, as the analyses found no statistically significant differences between these two interventions. Both TARE using SIR-Spheres and atezolizumab-bevacizumab seem to be more efficacious than sorafenib in maintaining QOL.

For patients with hepatocellular carcinoma, as well as physicians treating hepatocellular carcinoma, the quality of life that different treatments can offer represents an increasingly important aspect to consider when choosing treatments. Transarterial radioembolization and atezolizumab­bevacizumab are two potential treatments for advanced and unresectable hepatocellular carcinoma, but no clinical trials have directly compared the outcomes of these two therapeutic options. With the data available (patient-level data from a clinical trial of transarterial radioembolization using SIR-Spheres^® Y-90 resin microspheres [SIR-Spheres] versus sorafenib and data from a trial of atezolizumab­bevacizumab versus sorafenib from the literature), this study indirectly compared the time to deterioration of quality of life (i.e., how long quality of life is maintained) after treatment with transarterial radioembolization and atezolizumab­bevacizumab. The study showed that quality of life may be preserved over a similar time period with transarterial radioembolization using SIR-Spheres and atezolizumab­bevacizumab; also, both transarterial radioembolization using SIR-Spheres and atezolizumab­bevacizumab seem to maintain patients' quality of life over a longer period of time compared with sorafenib. These results are expected to enrich the existing evidence on which patients and physicians can base their decisions, allowing them to choose the most appropriate treatment by assessing the treatments' characteristics as a whole.

Effects of Trial Population Selection on Quality of Life and Healthcare Decision-Making: A Systematic Review and Example in the Treatment of Hepatocellular Carcinoma with Radioembolization.

BACKGROUND AND AIMS: Quality of life is among the most important considerations in the treatment of hepatocellular carcinoma (HCC), arguably second only to overall survival. Measuring and modeling patient quality of life is also crucial in the evaluation of the cost-effectiveness of health interventions. In the present study, we aimed to identify cost-utility analyses comparing selective internal radiation therapy (SIRT) with systemic therapy in patients with unresectable HCC and to compare the modeled incremental quality of life differences between the two therapies. METHODS: A systematic literature review was conducted. PubMed, EMBASE, the Cochrane Library, and health technology assessment agency websites were searched to identify cost-utility studies of SIRT versus systemic therapies in the treatment of HCC. Key characteristics of the studies, modeled populations and incremental quality of life outcomes were extracted from the included studies. RESULTS: The systematic literature review retrieved 1140 studies, of which four were ultimately included. Hand searches then identified two distinct analyses, and an updated version of one of the four studies identified initially. From these seven studies, 18 analyses were included. Analyses using data from the overall trial populations reported incremental quality-of-life estimates spanning -0.09 to +0.28 quality-adjusted life years (QALYs), with that range expanding to -0.09 to +0.60 QALYs when also considering post hoc sub-group analyses. CONCLUSION: The wide range of incremental QALYs, with substantial differences between overall trial populations and subgroups, illustrates the impact that the choice of target population may have on the relative quality of life outcomes of the compared interventions, which may in turn affect clinical decision-making. The small differences also highlight both the importance of reporting measures of dispersion around the findings, and the limitations of the incremental cost-effectiveness ratio (ICER) for assessing the relative cost-effectiveness of interventions that are predicted to result in similar quality-of-life outcomes.

Patient preferences for advanced hepatocellular carcinoma treatment: a multicountry stated preference study.

The present study aimed to explore patient preferences for attributes of advanced hepatocellular carcinoma (HCC) treatments. A stated preference survey was completed by 150 patients with HCC living in Europe. Overall survival (OS) was the most important attribute, closely followed by risk of diarrhea and hypertension, and other adverse event (AE) risks. Patients were willing to trade OS to reduce AE risks. While less important than OS and AEs, patients also preferred shorter waiting times, and one-off administration of selective internal radiation therapy and oral tablets over intravenous infusions. Although patients placed the most value on extending OS, they were willing to forego OS to avoid risk of treatment-related AEs, to maintain their quality of life.

Lay abstract This study aimed to understand patient preferences for characteristics of advanced hepatocellular carcinoma (HCC) treatments. A total of 150 people with HCC in Europe were presented a series of questions asking them to choose between two hypothetical treatments. Overall, length of life was the most important issue for patients, followed by avoiding diarrhea and hypertension, and then other side effects and treatment risks. Patients were willing to forego some months of life to avoid side effects or risks. Patients preferred to be given their treatment via a single minimally invasive hospital procedure or oral daily tablets compared with intravenous drips. In conclusion, although patients placed the most value on overall length of life, side effects and treatment risks were also important.

Real-World Budget Impact of the Adoption of Insulin Glargine Biosimilars in Primary Care in England (2015-2018).

BACKGROUND: Lantus, the reference insulin glargine used for the treatment of diabetes, lost its patent protection in 2014, opening the market to biosimilar competitors. OBJECTIVE: First, to analyze the adoption rates of insulin glargine biosimilars in primary care in England and estimate the savings realized and missed, since an insulin glargine biosimilar was first used, and second, to assess potential variations in adoption rates across Clinical Commissioning Groups (CCGs). RESEARCH DESIGN AND METHODS: Data sets capturing information on all insulin glargine items prescribed by all general practitioners up to December 2018 were used. Total costs of insulin glargine and uptake rates of biosimilars were calculated. The real-world budget impact was estimated assuming the cost of reference insulin glargine for all items and comparing the total costs in this scenario with the total costs in the real world. The missed savings were estimated assuming the cost of biosimilars for all insulin glargine items. Choropleth maps were generated to assess potential variations in uptake across CCGs. RESULTS: Insulin glargine biosimilars generated savings of £900,000 between October 2015 (time of first prescription) and December 2018. The missed savings amounted to £25.6 million in this period, indicating that only 3.42% of the potential savings were achieved. The analyses demonstrated a large level of variation in the uptake of insulin glargine biosimilars across CCGs, with market shares ranging from 0 to 53.3% (December 2018). CONCLUSIONS: These results may encourage decision makers in England to promote the use of best-value treatments in primary care and to reevaluate variation across CCGs.

Inequalities in prescription rates of anti-osteoporosis drugs in primary care in England: A practice-level prescribing data analysis in 2013-2018.

OBJECTIVE: To investigate potential variations in prescription rates of anti-osteoporosis drugs at the general practitioner (GP) practice level in England, analysing associations of prescription rates with key demographic and socio-economic variables, and its evolution over time. METHODS: A retrospective database analysis was conducted using prescription data from all GP practices in England between April 2013 and September 2018. Potential associations between prescription rates and other variables (sex, age, ethnicity, rural-urban classification and income deprivation) were analysed using mixed-effects Poisson regressions and concentration indices. RESULTS: Alendronic acid was the most frequently prescribed anti-osteoporosis drug. Exploratory and regression analyses showed the association between GP prescriptions and the characteristics of the population they serve. Income deprivation had a statistically significant and negative effect on prescription levels of alendronic acid, denosumab, ibandronic acid and risedronate sodium. Since 2013, denosumab prescriptions exhibited a steep surge in the least income-deprived areas, compared with a modest rise in the most income-deprived areas. Concentration indices indicated a disproportionate concentration of denosumab and, to a lesser extent, ibandronic acid prescriptions among the least income-deprived. The analyses demonstrated that different prescribing behaviours may exist across GPs according to the Clinical Commissioning Group (CCG) to which they belong. CONCLUSIONS: Variation in the prescription of anti-osteoporosis drugs exists across GPs and CCGs in England, this being more prominent for certain drugs (e.g. denosumab) compared with others (e.g. alendronic acid). Inequalities exist in English primary healthcare and we advocate our findings could support the efforts of decision-makers towards a more equitable system.

STATUS OF DISINVESTMENT INITIATIVES IN LATIN AMERICA: RESULTS FROM A SYSTEMATIC LITERATURE REVIEW AND A QUESTIONNAIRE.

OBJECTIVES: Disinvestment of existing healthcare technologies that deliver low or no health benefit for their cost can be used as a tool to improve access to effective technologies, while ensuring the long-term sustainability of healthcare systems. The objective of this research was to identify disinvestment initiatives in Latin American countries (LAC). METHODS: First, a systematic literature review (SLR) was conducted. In February 2015, MEDLINE, MEDLINE In-Process, EMBASE, The Cochrane Library, and LILACS were searched for relevant journal articles, including terms related to "disinvestment," "reallocation," "obsolete technologies," and "Latin America." Additionally, a manual search of documents from Latin American health technology assessment agencies was performed. Second, an online questionnaire was sent to experts in LAC to assess whether unpublished real-life disinvestment initiatives exist. Questionnaire results were collected in September 2015. RESULTS: From the SLR, 350 records were selected for screening following de-duplication and eleven articles fulfilled inclusion criteria. Only two of these reported information on initiatives potentially identifiable as disinvestment-investment activities in Brazil and Peru. Nine respondents completed the questionnaire, and four reported that disinvestment initiatives had been conducted in their respective organizations in Argentina, Brazil, and Mexico. This lack of agreement between the SLR and the questionnaire responses shows that disinvestment initiatives are ongoing, despite being under reported. CONCLUSIONS: Many challenges need to be overcome for a disinvestment initiative to be successful, and sharing particular experiences with the international community would increase the chances of positive outcomes. The present study highlights the need for publication of such experiences in LAC.

Metabolomic signatures associated with disease severity in multiple sclerosis.

OBJECTIVE: To identify differences in the metabolomic profile in the serum of patients with multiple sclerosis (MS) compared to controls and to identify biomarkers of disease severity. METHODS: We studied 2 cohorts of patients with MS: a retrospective longitudinal cohort of 238 patients and 74 controls and a prospective cohort of 61 patients and 41 controls with serial serum samples. Patients were stratified into active or stable disease based on 2 years of prospective assessment accounting for presence of clinical relapses or changes in disability measured with the Expanded Disability Status Scale (EDSS). Metabolomic profiling (lipids and amino acids) was performed by ultra-high-performance liquid chromatography coupled to mass spectrometry in serum samples. Data analysis was performed using parametric methods, principal component analysis, and partial least square discriminant analysis for assessing the differences between cases and controls and for subgroups based on disease severity. RESULTS: We identified metabolomics signatures with high accuracy for classifying patients vs controls as well as for classifying patients with medium to high disability (EDSS >3.0). Among them, sphingomyelin and lysophosphatidylethanolamine were the metabolites that showed a more robust pattern in the time series analysis for discriminating between patients and controls. Moreover, levels of hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, 13S-hydroxyoctadecadienoic acid, lysophosphatidylcholines, and lysophosphatidylethanolamines were associated with more severe disease (non-relapse-free or increase in EDSS). CONCLUSIONS: We identified metabolomic signatures composed of hormones, lipids, and amino acids associated with MS and with a more severe course.

Cost Utility of Omalizumab Compared with Standard of Care for the Treatment of Chronic Spontaneous Urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) negatively impacts patient quality of life and productivity and is associated with considerable indirect costs to society. OBJECTIVE: The aim of this study was to assess the cost utility of add-on omalizumab treatment compared with standard of care (SOC) in moderate or severe CSU patients with inadequate response to SOC, from the UK societal perspective. METHODS: A Markov model was developed, consisting of health states based on Urticaria Activity Score over 7 days (UAS7) and additional states for relapse, spontaneous remission and death. Model cycle length was 4 weeks, and total model time horizon was 20 years in the base case. The model considered early discontinuation of non-responders (response: UAS7 ≤6) and retreatment upon relapse (relapse: UAS7 ≥16) for responders. Clinical and cost inputs were derived from omalizumab trials and published sources, and cost utility was expressed as incremental cost-effectiveness ratios (ICERs). Scenario analyses included no early discontinuation of non-responders and an altered definition of response (UAS7 <16). RESULTS: With a deterministic ICER of £3183 in the base case, omalizumab was associated with increased costs and benefits relative to SOC. Probabilistic sensitivity analysis supported this result. Productivity inputs were key model drivers, and individual scenarios without early discontinuation of non-responders and adjusted response definitions had little impact on results. ICERs were generally robust to changes in key model parameters and inputs. CONCLUSIONS: In this, the first economic evaluation of omalizumab in CSU from a UK societal perspective, omalizumab consistently represented a treatment option with societal benefit for CSU in the UK across a range of scenarios.

A computational analysis of protein-protein interaction networks in neurodegenerative diseases.

BACKGROUND: Recent developments have meant that network theory is making an important contribution to the topological study of biological networks, such as protein-protein interaction (PPI) networks. The identification of differentially expressed genes in DNA array experiments is a source of information regarding the molecular pathways involved in disease. Thus, considering PPI analysis and gene expression studies together may provide a better understanding of multifactorial neurodegenerative diseases such as Multiple Sclerosis (MS) and Alzheimer disease (AD). The aim of this study was to assess whether the parameters of degree and betweenness, two fundamental measures in network theory, are properties that differentiate between implicated (seed-proteins) and non-implicated nodes (neighbors) in MS and AD. We used experimentally validated PPI information to obtain the neighbors for each seed group and we studied these parameters in four networks: MS-blood network; MS-brain network; AD-blood network; and AD-brain network. RESULTS: Specific features of seed-proteins were revealed, whereby they displayed a lower average degree in both diseases and tissues, and a higher betweenness in AD-brain and MS-blood networks. Additionally, the heterogeneity of the processes involved indicate that these findings are not pathway specific but rather that they are spread over different pathways. CONCLUSION: Our findings show differential centrality properties of proteins whose gene expression is impaired in neurodegenerative diseases.