Stool DNA testing for early detection of colorectal cancer: systematic review using the HTA Core Model® for Rapid Relative Effectiveness Assessment.

Background: Stool DNA testing for early detection of colorectal cancer (CRC) is a non-invasive technology with the potential to supplement established CRC screening tests. The aim of this health technology assessment was to evaluate effectiveness and safety of currently CE-marked stool DNA tests, compared to other CRC tests in CRC screening strategies in an asymptomatic screening population. Methods: The assessment was carried out following the guidelines of the European Network for Health Technology Assessment (EUnetHTA). This included a systematic literature search in MED-LINE, Cochrane and EMBASE in 2018. Manufacturers were asked to provide additional data. Five patient interviews helped assessing potential ethical or social aspects and patients' experiences and preferences. We assessed the risk of bias using QUADAS-2, and the quality of the body of evidence using GRADE. Results: We identified three test accuracy studies, two of which investigated a multitarget stool DNA test (Cologuard®, compared fecal immunochemical test (FIT)) and one a combined DNA stool assay (ColoAlert®, compared to guaiac-based fecal occult blood test (gFOBT), Pyruvate Kinase Isoenzyme Type M2 (M2-PK) and combined gFOBT/M2-PK). We found five published surveys on patient satisfaction. No primary study investigating screening effects on CRC incidence or on overall mortality was found. Both stool DNA tests showed in direct comparison higher sensitivity for the detection of CRC and (advanced) adenoma compared to FIT, or gFOBT, respectively, but had lower specificity. However, these comparative results may depend on the exact type of FIT used. The reported test failure rates were higher for stool DNA testing than for FIT. The certainty of evidence was moderate to high for Cologuard® studies, and low to very low for the ColoAlert® study which refers to a former version of the product and yielded no direct evidence on the test accuracy for ad-vanced versus non-advanced adenoma. Conclusions: ColoAlert® is the only stool DNA test currently sold in Europe and is available at a lower price than Cologuard®, but reliable evidence is lacking. A screening study including the current product version of ColoAlert® and suitable comparators would, therefore, help evaluate the effectiveness of this screening option in a European context.

Occupational therapy for persons with cognitive impairments.

Background: Damage to the central nervous system can occur in adulthood, for example, due to stroke, trauma, tumours, or chronic diseases. After damage to the central nervous system, cognitive impairments occur in addition to physical limitations. Occupational therapy is most often prescribed for neurological diagnoses, including stroke and traumatic brain injury. Methods: The health technology assessment (HTA) report this HTA article is based on investigates the clinical effectiveness, cost-effectiveness, and patient-related, social and ethical aspects of occupational therapy for patients with cognitive impairments compared to no occupational therapy. In addition, the effects of different occupational therapy interventions with and without cognitive components were compared in an explorative overview. Patients with moderate or severe dementia are excluded from the assessment. Systematic overviews, that is, systematic reviews of systematic reviews, were conducted. Results: For the evaluation of clinical effectiveness, a total of nine systematic reviews were included. No systematic review was identified for the assessment of costs or cost-effectiveness. Five systematic reviews were included for the assessment of patient and social aspects. For the assessment of clinical effectiveness compared with no occupational therapy, five systematic reviews comprising 20 randomised controlled trials with a total of 1,316 subjects reported small positive effects for the outcomes "global cognitive function" and "activities of daily living" as well as a non-quantified positive effect on the outcomes "health-related quality of life" and "behavioural control". No effect was found for individual components of cognition and measures of perception. The quality of the evidence for all outcomes is low due to a high risk of bias. In the supplementary presentations, no positive effects could be demonstrated on the basis of the available evidence. The quality of this evidence was not assessed. For the assessment of patient and social aspects, five systematic reviews on patients with a stroke or a traumatic brain injury - without specification regarding cognitive deficits or studies with their relatives - were included. It was reported that patients and family caregivers go through different phases of rehabilitation in which the discharge home is a decisive turning point. The discharge home represents a crucial breaking point. Regaining an active, self-determining role is a process that requires therapists to find the right level of support for patients and relatives. For the assessment of ethical aspects, nine documents were included. We identified ethical problem-solving models for occupational therapy and 16 ethical aspects in occupational therapy for cognitive deficits. The central theme of the analysis is the limited autonomy due to the consequences of the disease as well as the resulting tensions with those treating the patient. Conclusions: Based on this systematic overview, it can neither be proven nor excluded with certainty that occupational therapy for cognitive impairment is an effective therapy for adult patients with central nervous system injuries compared to no occupational therapy. There is a lack of randomised trials with sufficient sample size, well-defined interventions, and comparable concomitant therapies in the control groups, but there is also a lack of well-designed observational studies in routine care and health economic studies. The identified systematic reviews on patient and social aspects provide information on the needs of patients after stroke or traumatic brain injury and their relatives, but there is a lack of studies on this aspect in German-speaking countries. For the ethical assessment, in addition to the identified theoretical models for solving ethical conflicts in occupational therapy, more empirical studies on ethical aspects with patients with cognitive deficits and their relatives as well as occupational therapists are needed.

Determinants of low health-related quality of life in patients with myelodysplastic syndromes: EUMDS Registry study.

Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 µg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin <10 g/dL (1.34, 1.12-1.61), and high body mass index (≥30 vs 23-29.9 kg/m2: 1.26, 1.02-1.57). Sex, KPS, comorbidity burden, hemoglobin count, and transfusion burden were determinants for all EQ-5D dimensions. Low HRQoL is determined by multiple factors, which should be considered in the management and shared decision making of patients with MDS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Familial hypercholesterolemia: A systematic review of modeling studies on screening interventions.

BACKGROUND AND AIMS: FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models. METHODS: A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines. RESULTS: Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS. CONCLUSIONS: Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.

Core set of patient-reported outcomes for myelodysplastic syndromes: an EUMDS Delphi study involving patients and hematologists.

Patient-reported outcomes (PROs) are relevant and valuable end points in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. According to international guidelines, candidate PROs were identified from a comprehensive literature search of MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first round and 38 patients and 32 hematologists in the second round. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected "general quality of life" as a core PRO. Hematologists also selected "transfusion-dependency burden" and "ability to work/activities of daily living" as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; P < .05) in the first round and for 19 PROs in the second round, with "disease knowledge" and "confidence in health care services" rated notably higher by patients. The overall mean PRO ratings correlation between the 2 groups was moderate (Spearman's rank correlation coefficient = 0.5; P < .05). This first consensus on a core set of PROs jointly developed by patients and hematologists forms the basis for patient-centered care in daily practice and clinical research.

The anemia-independent impact of myelodysplastic syndromes on health-related quality of life.

Myelodysplastic syndromes (MDS) are in the majority of cases characterized by anemia. Both anemia and MDS per se may directly contribute to impairments in health-related quality of life (HRQoL). In this study, we aimed to investigate the anemia-independent impact of MDS on HRQoL. We evaluated participants (≥ 50 years) from the large population-based Lifelines cohort (N = 44,694, mean age 59.0 ± 7.4 years, 43.6% male) and the European MDS Registry (EUMDS) (N = 1538, mean age 73.4 ± 9.0 years, 63.0% male), which comprises a cohort of lower-risk MDS patients. To enable comparison concerning HRQoL, SF-36 scores measured in Lifelines were converted to EQ-5D-3L index (range 0-1) and dimension scores. Lower-risk MDS patients had significantly lower HRQoL than those from the Lifelines cohort, as illustrated in both the index score and in the five different dimensions. Multivariable linear regression analysis demonstrated that MDS had an adjusted total impact on the EQ-5D index score (B = - 0.12, p < 0.001) and an anemia-independent "direct" impact (B = - 0.10, p < 0.001). Multivariable logistic regression analysis revealed an anemia-independent impact of MDS in the dimension mobility, self-care, usual activities, and anxiety/depression (all except pain/discomfort). This study demonstrates that the major part of the negative impact of lower-risk MDS on HRQoL is not mediated via anemia. Thus, the therapeutic focus should include treatment strategies directed at underlying pathogenic mechanisms to improve HRQoL, rather than aiming predominantly at increasing hemoglobin levels.

Cost-Effectiveness of Early Detection and Prevention Strategies for Endometrial Cancer-A Systematic Review.

Endometrial cancer is the most common female genital tract cancer in developed countries. We systematically reviewed the current health-economic evidence on early detection and prevention strategies for endometrial cancer based on a search in relevant databases (Medline/Embase/Cochrane Library/CRD/EconLit). Study characteristics and results including life-years gained (LYG), quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratios (ICERs) were summarized in standardized evidence tables. Economic results were transformed into 2019 euros using standard conversion methods (GDP-PPP, CPI). Seven studies were included, evaluating (1) screening for endometrial cancer in women with different risk profiles, (2) risk-reducing interventions for women at increased or high risk for endometrial cancer, and (3) genetic testing for germline mutations followed by risk-reducing interventions for diagnosed mutation carriers. Compared to no screening, screening with transvaginal sonography (TVS), biomarker CA-125, and endometrial biopsy yielded an ICER of 43,600 EUR/LYG (95,800 EUR/QALY) in women with Lynch syndrome at high endometrial cancer risk. For women considering prophylactic surgery, surgery was more effective and less costly than screening. In obese women, prevention using Levonorgestrel as of age 30 for five years had an ICER of 72,000 EUR/LYG; the ICER for using oral contraceptives for five years as of age 50 was 450,000 EUR/LYG. Genetic testing for mutations in women at increased risk for carrying a mutation followed by risk-reducing surgery yielded ICERs below 40,000 EUR/QALY. Based on study results, preventive surgery in mutation carriers and genetic testing in women at increased risk for mutations are cost-effective. Except for high-risk women, screening using TVS and endometrial biopsy is not cost-effective and may lead to overtreatment. Model-based analyses indicate that future biomarker screening in women at increased risk for cancer may be cost-effective, dependent on high test accuracy and moderate test costs. Future research should reveal risk-adapted early detection and prevention strategies for endometrial cancer.

Development of a core outcome set for myelodysplastic syndromes - a Delphi study from the EUMDS Registry Group.

Treatment options for myelodysplastic syndromes (MDS) vary widely, depending on the natural disease course and patient-related factors. Comparison of treatment effectiveness is challenging as different endpoints have been included in clinical trials and outcome reporting. Our goal was to develop the first MDS core outcome set (MDS-COS) defining a minimum set of outcomes that should be reported in future clinical studies. We performed a comprehensive systematic literature review among MDS studies to extract patient- and/or clinically relevant outcomes. Clinical experts from the European LeukemiaNet MDS (EUMDS) identified 26 potential MDS core outcomes and participated in a three-round Delphi survey. After the first survey (56 experts), 15 outcomes met the inclusion criteria and one additional outcome was included. The second round (38 experts) resulted in six included outcomes. In the third round, a final check on plausibility and practicality of the six included outcomes and their definitions was performed. The final MDS-COS includes: health-related quality of life, treatment-related mortality, overall survival, performance status, safety, and haematological improvement. This newly developed MDS-COS represents the first minimum set of outcomes aiming to enhance comparability across future MDS studies and facilitate a better understanding of treatment effectiveness.

Alternative Conversion Methods for Transition Probabilities in State-Transition Models: Validity and Impact on Comparative Effectiveness and Cost-Effectiveness.

Background. In state-transition models (STMs), decision problems are conceptualized using health states and transitions among those health states after predefined time cycles. The naive, commonly applied method (C) for cycle length conversion transforms all transition probabilities separately. In STMs with more than 2 health states, this method is not accurate. Therefore, we aim to describe and compare the performance of method C with that of alternative matrix transformation methods. Design. We compare 2 alternative matrix transformation methods (Eigenvalue method [E], Schure-Padé method [SP]) to method C applied in an STM of 3 different treatment strategies for women with breast cancer. We convert the given annual transition matrix into a monthly-cycle matrix and evaluate induced transformation errors for the transition matrices and the long-term outcomes: life years, quality-adjusted life-years, costs and incremental cost-effectiveness ratios, and the performance related to the decisions. In addition, we applied these transformation methods to randomly generated annual transition matrices with 4, 7, 10, and 20 health states. Results. In theory, there is no generally applicable correct transformation method. Based on our simulations, SP resulted in the smallest transformation-induced discrepancies for generated annual transition matrices for 2 treatment strategies. E showed slightly smaller discrepancies than SP in the strategy, where one of the direct transitions between health states was excluded. For long-term outcomes, the largest discrepancy occurred for estimated costs applying method C. For higher dimensional models, E performs best. Conclusions. In our modeling examples, matrix transformations (E, SP) perform better than transforming all transition probabilities separately (C). Transition probabilities based on alternative conversion methods should therefore be applied in sensitivity analyses.

Budget Impact Analysis of Cancer Screening: A Methodological Review.

BACKGROUND: Budget impact analyses (BIAs) describe changes in intervention- and disease-related costs of new technologies. Evidence on the quality of BIAs for cancer screening is lacking. OBJECTIVES: We systematically reviewed the literature and methods to assess how closely BIA guidelines are followed when BIAs are performed for cancer-screening programs. DATA SOURCES: Systematic searches were conducted in MEDLINE, EMBASE, EconLit, CRD (Centre for Reviews and Dissemination, University of York), and CEA registry of the Tufts Medical Center. STUDY ELIGIBILITY CRITERIA: Eligible studies were BIAs evaluating cancer-screening programs published in English, 2010-2018. SYNTHESIS METHODS: Standardized evidence tables were generated to extract and compare study characteristics outlined by the ISPOR BIA Task Force. RESULTS: Nineteen studies were identified evaluating screening for breast (5), colorectal (6), cervical (3), lung (1), prostate (3), and skin (1) cancers. Model designs included decision-analytic models (13) and simple cost calculators (6). From all studies, only 53% reported costs for a minimum of 3 years, 58% compared to a mix of screening options, 42% reported model validation, and 37% reported uncertainty analysis for participation rates. The quality of studies appeared to be independent of cancer site. LIMITATIONS: "Gray" literature was not searched, misinterpretation is possible due to limited information in publications, and focus was on international methodological guidelines rather than regional guidelines. CONCLUSIONS: Our review highlights considerable variability in the extent to which BIAs evaluating cancer-screening programs followed recommended guidelines. The annual budget impact at least over the next 3-5 years should be estimated. Validation and uncertainty analysis should always be conducted. Continued dissemination efforts of existing best-practice guidelines are necessary to ensure high-quality analyses.

Parameterization of hyperpolarized (13)C-bicarbonate-dissolution dynamic nuclear polarization.

OBJECTIVE: (13)C metabolic MRI using hyperpolarized (13)C-bicarbonate enables preclinical detection of pH. To improve signal-to-noise ratio, experimental procedures were refined, and the influence of pH, buffer capacity, temperature, and field strength were investigated. MATERIALS AND METHODS: Bicarbonate preparation was investigated. Bicarbonate was prepared and applied in spectroscopy at 1, 3, 14 T using pure dissolution, culture medium, and MCF-7 cell spheroids. Healthy rats were imaged by spectral-spatial spiral acquisition for spatial and temporal bicarbonate distribution, pH mapping, and signal decay analysis. RESULTS: An optimized preparation technique for maximum solubility of 6 mol/L and polarization levels of 19-21% is presented; T1 and SNR dependency on field strength, buffer capacity, and pH was investigated. pH mapping in vivo is demonstrated. CONCLUSION: An optimized bicarbonate preparation and experimental procedure provided improved T1 and SNR values, allowing in vitro and in vivo applications.

The ONCOTYROL Prostate Cancer Outcome and Policy Model: Effect of Prevalence Assumptions on the Benefit-Harm Balance of Screening.

BACKGROUND: The ONCOTYROL Prostate Cancer Outcome and Policy (PCOP) model is a state-transition microsimulation model evaluating the benefits and harms of prostate cancer (PCa) screening. The natural history and detection component of the original model was based on the 2003 version of the Erasmus MIcrosimulation SCreening ANalysis (MISCAN) model, which was not calibrated to prevalence data. Compared with data from autopsy studies, prevalence of latent PCa assumed by the original model is low, which may bias the model toward screening. Our objective was to recalibrate the original model to match prevalence data from autopsy studies as well and compare benefit-harm predictions of the 2 model versions differing in prevalence. METHODS: For recalibration, we reprogrammed the natural history and detection component of the PCOP model as a deterministic Markov state-transition cohort model in the statistical software package R. All parameters were implemented as variables or time-dependent functions and calibrated simultaneously in a single run. Observed data used as calibration targets included data from autopsy studies, cancer registries, and the European Randomized Study of Screening for Prostate Cancer. Compared models were identical except for calibrated parameters. RESULTS: We calibrated 46 parameters. Prevalence from autopsy studies could not be fitted using the original parameter set. Additional parameters, allowing for interruption of disease progression and age-dependent screening sensitivities, were needed. Recalibration to higher prevalence demonstrated a considerable increase of overdiagnosis and decline of screening sensitivity, which significantly worsened the benefit-harm balance of screening. CONCLUSIONS: Our calibration suggests that not all cancers are at risk of progression, and screening sensitivity may be lower at older ages. PCa screening models that use calibration to simulate disease progression in the unobservable latent phase are highly sensitive to prevalence assumptions.

Comparison of acquisition schemes for hyperpolarised ¹³C imaging.

The aim of this study was to characterise and compare widely used acquisition strategies for hyperpolarised (13)C imaging. Free induction decay chemical shift imaging (FIDCSI), echo-planar spectroscopic imaging (EPSI), IDEAL spiral chemical shift imaging (ISPCSI) and spiral chemical shift imaging (SPCSI) sequences were designed for two different regimes of spatial resolution. Their characteristics were studied in simulations and in tumour-bearing rats after injection of hyperpolarised [1-(13)C]pyruvate on a clinical 3-T scanner. Two or three different sequences were used on the same rat in random order for direct comparison. The experimentally obtained lactate signal-to-noise ratio (SNR) in the tumour matched the simulations. Differences between the sequences were mainly found in the encoding efficiency, gradient demand and artefact behaviour. Although ISPCSI and SPCSI offer high encoding efficiencies, these non-Cartesian trajectories are more prone than EPSI and FIDCSI to artefacts from various sources. If the encoding efficiency is sufficient for the desired application, EPSI has been proven to be a robust choice. Otherwise, faster spiral acquisition schemes are recommended. The conclusions found in this work can be applied directly to clinical applications.

Cost-effectiveness of the sequential application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) are approved for chronic myeloid leukemia (CML) therapy. We evaluated the long-term cost-effectiveness of seven sequential therapy regimens for CML in Austria. A cost-effectiveness analysis was performed using a state-transition Markov model. As model parameters, we used published trial data, clinical, epidemiological and economic data from the Austrian CML registry and national databases. We performed a cohort simulation over a life-long time-horizon from a societal perspective. Nilotinib without second-line TKI yielded an incremental cost-utility ratio of 121,400 €/quality-adjusted life year (QALY) compared to imatinib without second-line TKI after imatinib failure. Imatinib followed by nilotinib after failure resulted in 131,100 €/QALY compared to nilotinib without second-line TKI. Nilotinib followed by dasatinib yielded 152,400 €/QALY compared to imatinib followed by nilotinib after failure. Remaining strategies were dominated. The sequential application of TKIs is standard-of-care, and thus, our analysis points toward imatinib followed by nilotinib as the most cost-effective strategy.

Multimodality multiparametric imaging of early tumor response to a novel antiangiogenic therapy based on anticalins.

Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40) is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI), dynamic contrast enhanced magnetic resonance imaging (DCE)-MRI and positron emission tomography with the tracer [18F]fluorodeoxyglucose (FDG-PET) for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13), Avastin (n = 6) or PBS (n = 12). Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09). In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P<0.001). There was a strong correlation of the early changes in DWI, DCE-MRI and FDG-PET at day 2 after therapy onset and the change in tumor size at the end of therapy (r = -0.58, 0.71 and 0.67 respectively). The imaging results were confirmed by histopathology, showing early necrosis and necroptosis in the tumors. Thus multimodality multiparametric imaging was able to predict therapeutic success of PRS-050-PEG40 and Avastin as early as 2 days after onset of therapy and thus promising for monitoring early response of antiangiogenic therapy.

Medical decision analysis for first-line therapy of chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) are approved for the treatment of chronic myeloid leukemia (CML). Our goal was to develop a clinical decision-analytic model for evaluation of the long-term effectiveness of different therapy regimens. We developed a Markov cohort model with a lifelong time horizon for first-line treatment with imatinib, dasatinib or nilotinib. Seven strategies including combinations of TKIs, chemotherapy and stem cell transplant were evaluated. The model was parameterized using published trial data, the Austrian CML registry and practice patterns estimated by experts. Health outcomes evaluated were life-years (LYs) and quality-adjusted LYs (QALYs). Based on our decision analysis, dasatinib following nilotinib failure was the most effective treatment in terms of LYs (19.8 LYs) and QALYs (16.1 QALYs). Sensitivity analyses showed that the ranking of strategies was mostly influenced by the duration of first- and second-line therapies. Our results may support decision-making regarding the sequential application of TKIs.

Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is an emerging problem in public health. In most countries, the majority of HCV infected people are yet undiagnosed. Early detection and treatment may result in better health outcomes and save costs by preventing future advanced liver disease. The evidence for long-term effectiveness and cost-effectiveness of HCV screening was systematically reviewed. METHODS: We performed a systematic literature search on long-term health-economic effects of HCV screening and included Health Technology Assessment (HTA) reports, systematic reviews, long-term clinical trials, full health economic and decision-analytic modelling studies with a sufficiently long time horizon and patient-relevant long-term outcomes such as life-years gained (LYG) or quality-adjusted life years (QALY) gained. Economic results were converted to 2005 Euros. RESULTS: Seven studies were included. Target population, HCV prevalence, study perspective, discount rate, screening and antiviral treatment mode varied. The incremental effectiveness of HCV screening and early treatment compared to no screening and standard care varied from 0.0004 to 0.066 LYG, and from 0.0001 to 0.072 QALY. Incremental cost-effectiveness and cost-utility ratios of HCV screening vs. no screening were 3900-243,700 euro/LYG and 18,300-1,151,000 euro/QALY. HCV screening seems to be cost-effective in populations with high HCV prevalence, but not in low HCV prevalence populations. CONCLUSIONS: HCV screening and early treatment have the potential to improve average life-expectancy, but should focus on populations with elevated HCV prevalence to be cost-effective. Further research on the long-term health-economic impact of HCV screening when combined with appropriate monitoring strategies in different European health care systems is needed.

Progression-free survival as a surrogate endpoint in advanced breast cancer.

OBJECTIVES: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint. METHODS: A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROS from observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption. RESULTS: Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n = 4,323) and seventeen T (n = 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROS and HRPFS was 0.71 for A (p = .0029) and 0.75 for T (p = .0028). While HRPFS was a statistically significant predictor of HROS for both A (p = .0019) and T (p = .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROS agreed with observed HROS in 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses. CONCLUSIONS: This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.