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.

Changes in treatment pattern and costs in advanced hepatocellular carcinoma (HCC).

INTRODUCTION: While essential for cost-effectiveness analyses, there are no current resource use and cost data available for advanced hepatocellular carcinoma (HCC) and selective internal radiation therapy (SIRT). The study aims to assess current resource use and costs in HCC and for SIRT compared to historical survey data. AREAS COVERED: To address this data gap, resource use was elicited via surveys and interviews with medical professionals experienced with HCC and SIRT in the United Kingdom. Unit costs were from publicly available databases. Resource use and costs were estimated and compared to prior surveys. EXPERT OPINION: From eleven responses, pre-progression costs for SIRT and systemic therapy were £256.77 and £292.27/month, respectively. One-off progression and post-progression costs were £209.98 and £522.84/month. Monthly costs were 54%-79% lower than in previous surveys, due to reduction in hospitalizations and funded social care. Furthermore, substantial differences in resource use associated with SIRT between clinical practice and clinical trials were found. In conclusion, increased availability and familiarity with systemic treatments has led to important changes in HCC care and SIRT administration. The uncertainty from the use of expert opinion and the limited number of hospitals with SIRT experience can be addressed with future research using large databases, registries.

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.

Incorporating Process Utility into Cost-Effectiveness Analysis via a Bolt-On Domain to the SF-6D: An Exploratory Study.

BACKGROUND: Within the UK, standard methods of economic evaluation centre on the maximisation of the quality-adjusted life-year (QALY). However, preference-based measures used to estimate QALYs may not be suited to all economic evaluations, as they routinely measure only health outcomes. AIM: This study used an economic evaluation alongside a clinical trial (EEACT) comparing patients' preferences for a telephone versus a face-to-face consultation to incorporate process utility into cost-effectiveness analyses. METHODS: An EEACT is described that generates QALYs using Short-form 6-dimension version 1 (SF-6Dv1) responses. These results exclude specific consideration of process utility. A health state valuation study is then reported that bolts a process domain onto the SF-6Dv1 using data obtained from the EEACT. These results therefore include the consideration of process utility. The results of the EEACT with and without process utility are then compared. RESULTS: This study shows that the QALY, in its current form, does not capture patient benefits associated with the process of receiving healthcare. The EEACT illustrates this, showing a statistically significant difference between control and intervention groups for the patient experience questionnaire communication domain, indicating that patients preferred the intervention. This preference was not identified in the cost-effectiveness outcomes, and the point estimates lie in the north-west quadrant of the cost-effectiveness plane. The preference is captured after adding a communication domain. The point estimate moves to the north-east quadrant, where the intervention is more effective and more costly than the control. CONCLUSION: This study indicates that it is possible to capture patients' preferences for processes associated with care, in a format compatible with the QALY.

A systematic literature review and network meta-analysis of first-line treatments for unresectable hepatocellular carcinoma based on data from randomized controlled trials.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. First-line treatment options for unresectable HCC include sorafenib, lenvatinib, selective internal radiation therapy (SIRT), and transarterial chemoembolization (TACE). The present study reviewed randomized controlled trials (RCTs) of first-line therapies for unresectable HCC in TACE-ineligible patients. RESEARCH DESIGN AND METHODS: A systematic literature review (SLR) was conducted to identify RCTs of first-line treatments for TACE-ineligible patients with unresectable HCC. Data on overall survival (OS) and progression-free survival were extracted and a contrast-based Bayesian network meta-analysis (NMA) was conducted using Markov Chain Monte Carlo techniques. RESULTS: The SLR identified three RCTs: two comparing Y-90 resin microspheres with sorafenib, and one comparing sorafenib with lenvatinib. No RCTs were identified comparing other SIRT technologies with any other approved first-line HCC therapies. The NMA showed no significant OS differences between Y-90 resin microspheres and sorafenib (hazard ratio [HR] 0.92, 95% credible interval [CrI]: 0.79-1.08) or lenvatinib (HR: 0.88, 95% CrI: 0.63-1.22). CONCLUSIONS: An SLR and NMA showed no significant differences between sorafenib, lenvatinib, and Y-90 resin microspheres in treating unresectable HCC. RCT evidence was not available for any other SIRT technologies and an evaluation of their relative efficacy was therefore not possible.

Cost-utility analysis of selective internal radiation therapy with Y-90 resin microspheres in hepatocellular carcinoma.

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.

Association between objective response rate and overall survival in metastatic neuroendocrine tumors treated with radioembolization: a systematic literature review and regression analysis.

OBJECTIVES: Neuroendocrine tumors (NETs) are a heterogeneous group of cancers arising from neuroendocrine cells. The aim was to evaluate objective response rate (ORR) as a predictor of overall survival (OS) in patients with metastatic NETs (mNETs) treated with radioembolization (RE). METHODS: Randomized controlled trials and observational studies of RE treatment of mNETs were identified by systematic literature review (SLR). Pooled ORR and OS estimates were calculated and a weighted generalized linear model (GLM) of ORR as a predictor of OS was derived, stratified by ORR assessment criteria and RE type (Yttrium-90 resin or glass microspheres). RESULTS: The SLR identified 32 observational studies. Mean ORR was 41% (95% confidence interval 38-45%). The Yttrium-90 resin and glass microsphere GLMs accounted for 59% and 57% of OS deviance, respectively. ORR was a significant predictor of OS in the resin microspheres model (p < 0.001), but not the glass microspheres model (p = 0.11). CONCLUSIONS: A weighted GLM showed a significant relationship between ORR and OS in patients with mNETs treated with Yttrium-90 resin microspheres. ORR could therefore potentially be an OS surrogate in future trials of Yttrium-90 resin microspheres. Further research is needed to confirm the relationship between ORR and OS and the difference between resin and glass microspheres.

A cost analysis of SIR-Spheres yttrium-90 resin microspheres versus tyrosine kinase inhibitors in the treatment of unresectable hepatocellular carcinoma in France, Italy, Spain and the UK.

Background and aims: A wide range of treatment options are available for hepatocellular carcinoma (HCC), including systemic treatment with tyrosine kinase inhibitors (TKIs) such as sorafenib and lenvatinib, immunotherapies, locoregional therapies such as selective internal radiation therapy (SIRT) and treatments with curative intent such as resection, radiofrequency ablation and liver transplantation. Given the substantial economic burden associated with HCC treatment, the aim of the present analysis was to establish the cost of using SIRT with SIR-Spheres yttrium-90 (Y-90) resin microspheres versus TKIs from healthcare payer perspectives in France, Italy, Spain and the United Kingdom (UK).Methods: A cost model was developed to capture the costs of initial systemic treatment with sorafenib (95%) or lenvatinib (5%) versus SIRT in patients with HCC in Barcelona Clinic Liver Cancer (BCLC) stages B and C. A nested Markov model was utilized to model transitions between progression-free survival (PFS), progression and death, in addition to transitions between subsequent treatment lines. Cost and resource use data were identified from published sources in each of the four countries.Results: Relative to TKIs, SIRT with SIR-Spheres Y-90 resin microspheres were found to be cost saving in all four country settings, with the additional costs of the microspheres and the SIRT procedure being more than offset by reductions in drug and drug administration costs, and treatment of adverse events. Across the four country settings, total cost savings with SIR-Spheres Y-90 resin microspheres fell within the range 5.4-24.9% and SIRT resulted in more patients ultimately receiving treatments with curative intent (4.6 vs. 1.4% of eligible patients).Conclusion: SIR-Spheres Y-90 resin microspheres resulted in cost savings relative to TKIs in the treatment of unresectable HCC in all four country settings, while increasing the proportion of patients who become eligible for treatments with curative intent.

Utility estimates for patients with Type 2 diabetes mellitus after experiencing a myocardial infarction or stroke: a systematic review.

A systematic review identified studies eliciting utility decrements from myocardial infarction (MI) and stroke in patients with Type 2 diabetes mellitus (T2DM) and examined their use in economic models of new diabetes treatments. In 16 utility studies in patients with T2DM, utility decrements in the first year ranged from 0.017 to 0.226 for MI and from 0.034 to 0.590 for stroke. Sixteen of 19 economic evaluations of new treatments for T2DM included utility decrements for an MI and/or stroke from one of the 16 utility studies. Decrements for MI ranged from 0.012 to 0.180 in the first year. Decrements for stroke ranged from 0.044 to 0.690 in the first year. Utility studies in patients with T2DM provide little information about changes in utility decrements by time since the event and by disease severity. Cost-effectiveness studies do not always indicate how these values were used in the analysis.

Incremental costs associated with myocardial infarction and stroke in patients with type 2 diabetes mellitus: an overview for economic modeling.

OBJECTIVE: To identify cost estimates related to myocardial infarction (MI) or stroke in patients with type 2 diabetes mellitus (T2DM) for use in economic models. METHODS: A systematic literature review was conducted. Electronic databases and conference abstracts were screened against inclusion criteria, which included studies performed in patients who had T2DM before experiencing an MI or stroke. Primary cost studies and economic models were included. Costs were converted to 2012 pounds sterling. RESULTS: Fifty-four studies were identified: 13 primary cost studies and 41 economic evaluations using secondary sources for complication costs. Primary studies provided costs from 10 countries. Estimates for a fatal event ranged from £2482-£5222 for MI and from £4900-£6694 for stroke. Costs for the year a non-fatal event occurred ranged from £5071-£29,249 for MI and from £5171-£38,732 for stroke. Annual follow-up costs ranged from £945-£1616 for an MI and from £4704-£12,926 for a stroke. Economic evaluations from 12 countries were identified, and costs of complications showed similar variability to the primary studies. DISCUSSION: The costs identified within primary studies varied between and within countries. Many studies used costs estimated in studies not specific to patients with T2DM. Data gaps included a detailed breakdown of resource use, which affected the ability to compare data across countries. CONCLUSIONS: In the development of economic models for patients with T2DM, the use of accurate estimates of costs associated with MI and stroke is important. When country-specific costs are not available, clear justification for the choice of estimates should be provided.

Incorporating process utility into quality adjusted life years: a systematic review of empirical studies.

OBJECTIVE: This review aimed to identify published studies that provide an empirical measure of process utility, which can be incorporated into estimates of QALY calculations. METHODS: A literature search was conducted in PubMed to identify published studies of process utility. Articles were included if they were written in the English language and reported empirical measures of process utility that could be incorporated into the QALY calculation; those studies reporting utilities that were not anchored on a scale of 0 representing dead and 1 representing full health were excluded from the review. RESULTS: Fifteen studies published between 1996 and 2012 were included. Studies included respondents from the USA, Australia, Scotland and the UK, Europe and Canada. Eight of the included studies explored process utility associated with treatments; six explored process utility associated with screening procedures or tests; and one was performed in preventative care. A variety of approaches were used to detect and measure process utility: four studies used standard gamble techniques; four studies used time trade-off (TTO); one study used conjoint analysis and one used a combination of conjoint analysis and TTO; one study used SF-36 data; one study used both TTO and EQ-5D; and three studies used wait trade-off techniques. Measures of process utility for different drug delivery methods ranged from 0.02 to 0.27. Utility estimates associated with different dosing strategies ranged from 0.005 to 0.09. Estimates for convenience (able to take on an empty stomach) ranged from 0.001 to 0.028. Estimates of process utility associated with screening and testing procedures ranged from 0.0005 to 0.031. Both of these estimates were obtained for management approaches to cervical cancer screening. CONCLUSION: The identification of studies through conventional methods was difficult due to the lack of consistent indexing and terminology across studies; however, the evidence does support the existence of process utility in treatment, screening and preventative care settings. There was considerable variation between estimates. The range of methodological approaches used to identify and measure process utility, coupled with the need for further research into, for example, the application of estimates in economic models, means it is difficult to know whether these differences are a true reflection of the amount of process utility that enters into an individual's utility function, or whether they are associated with features of the studies' methodological design. Without further work, and a standardised approach to the methodology for the detection and measurement of process utility, comparisons between estimates are difficult. This literature review supports the existence of process utility and indicates that, despite the need for further research in the area, it could be an important component of an individual's utility function, which should at least be considered, if not incorporated, into cost-utility analyses.

Timing of breast surgery in premenopausal breast cancer patients.

BACKGROUND: The majority of women diagnosed with breast cancer undergo a multidisciplinary treatment with surgical intervention and radiotherapy or chemotherapy, or both. The importance of timing of tumour removal in relation to the menstrual cycle and its influence on disease-free survival and overall survival has been studied by researchers since 1989 but still remains speculative. OBJECTIVES: To determine if surgery performed either during the follicular or luteal phase of the menstrual cycle affects the overall and disease-free survival of premenopausal breast cancer patients. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Trials Register (January 2009), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 1), MEDLINE (1966 to January 2009), EMBASE (1974 to September 2006) and the WHO International Clinical Trials Registry Platform (ICTRP) search portal (July 2010). We checked references of articles and communicated with authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing breast surgery during the follicular phase of the menstrual cycle with the luteal phase in premenopausal women. Prospective non-RCTs or observational studies were considered if randomised studies were lacking. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data and assessed trial quality. MAIN RESULTS: Completed randomised trials were not found. There is one trial that is currently ongoing in Italy; the results have yet to be published.Two prospective observational studies had data on recurrence-free survival. One study reported an odds ratio for recurrence rate at one year (where > 1 favours the luteal phase) of 0.86 (95% confidence interval (CI) 0.69 to 1.08); 0.87 at two years (95% CI 0.69 to 1.09); 0.95 at three years (95% CI 0.75 to 1.21); 1.12 at four years (95% CI 0.87 to 1.43); and 1.12 at five years (95% CI 0.87 to 1.43). Another study reported a hazard ratio for overall survival of 1.02 (95% CI 0.995 to 1.04, P = 0.14) and for disease-free survival of 1.00 (95% CI 0.98 to 1.02, P = 0.92) at three years based on the last and first menstrual period. The results were not significant. There was no difference in the recurrence rate whether the surgery was done during the follicular or luteal phase of the menstrual cycle. AUTHORS' CONCLUSIONS: In the absence of RCTs, this review provides evidence from large prospective observational studies that timing of surgery does not show a significant effect on survival.

True device compliance: the need to consider both competence and contrivance.

Inability to use inhalers effectively is known to adversely affect the delivery of drug. It is assumed that increasing competence to use inhalers will lead to improved drug delivery. However many subjects appear competent (are able to use a device effectively) but contrive to use the device in a sub-optimal way in routine use. This study aimed to explore levels of True device compliance, that is the extent to which devices are used effectively in routine use, and to explore the influences of age and device on this parameter. The ability of 53 asthmatic patients aged 1-88 years to use their corticosteroid inhaler was assessed by a single investigator. In addition information regarding patient behaviour in routine practice was explored in a structured interview. True device compliance was defined to occur when a subject was rated competent and did not report contrivance. Competence was related to device type. All subjects using a holding chamber [pMDI + HC] (N = 21) or breath activated inhaler (N = 5) could demonstrate an adequate technique compared with only 9 (47%) of those prescribed a pMDI. However only 4 (19%) prescribed a pMDI + HC were true device compliant with the majority regularly using the pMDI alone while (42%) of those prescribed a pMDI were True device compliant. Since 82% of patients over 65 were prescribed pMDI alone, and 92% of patients up to 5 years were prescribed pMDI + HC, True device compliance was low among both groups. Only 33% of patients over 65 prescribed pMDIs were able to use them competently. Lack of competence, particularly in the elderly, and contrivance, particularly common amongst those using holding chambers, are two important but independent impediments to effective inhaled therapy.