UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients.

AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs. RESULTS: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient. CONCLUSION: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.

Cost-Effectiveness Assessment of Monitoring Abiraterone Levels in Metastatic Castration-Resistant Prostate Cancer Patients.

OBJECTIVES: Abiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (Cmin) of abiraterone. Patients with a plasma Cmin below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone Cmin in patients with mCRPC. METHODS: A Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone Cmin followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate Cmin taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER). RESULTS: Monitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively. CONCLUSIONS: Monitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.

Cost-utility and cost-effectiveness analysis of a clinical medication review focused on personal goals in older persons with polypharmacy compared to usual care: Economic evaluation of the DREAMeR study.

AIMS: The ageing society may lead to increasing healthcare expenditure. A clinical medication review (CMR) could potentially reduce costs. The aim of this study is to perform a cost-utility and cost-effectiveness analysis from a societal perspective of a patient-centred CMR. METHODS: A trial-based cost-utility and cost-effectiveness analysis was performed as part of the DREAMeR study, a pragmatic controlled trial that randomised patients aged ≥70 years using at least seven drugs to either CMR or usual care. Over six months, healthcare consumption and drug use were collected to estimate costs, and effects were collected in terms of quality-adjusted life years (QALYs) measured with EQ-5D-5 L and EQ-VAS and as reduced health-related complaints with impact on patients' daily lives. RESULTS: The total mean costs per patient (n = 588) over six months were €4,189 ± 6,596 for the control group (n = 294) and €4,008 ± 6,678 for the intervention group (n = 294), including estimated intervention costs of €199 ± 67, which resulted in a mean incremental total cost savings of €181 for the intervention group compared to the control group. Compared to the control group, for the intervention group, the mean incremental QALYs over six months were: -0.00217 measured with EQ-5D and 0.003 measured with EQ-VAS. The incremental effect of reduced health-related complaints with impact was -0.34. There was a likelihood of >90% that the intervention was cost-saving. CONCLUSIONS: The benefits of a patient-centred CMR were inconsistent with no benefits on HR-QoL measured with EQ-5D-5 L and small benefits on HR-QoL measured with EQ-VAS and health-related complaints with impact on patients' daily lives. Additionally, a CMR could potentially be cost saving from a societal perspective.

Increasing the information provided by probabilistic sensitivity analysis: The relative density plot.

BACKGROUND: Results of probabilistic sensitivity analyses (PSA) are frequently visualized as a scatterplot, which is limited through overdrawing and a lack of insight in relative density. To overcome these limitations, we have developed the Relative Density plot (PSA-ReD). METHODS: The PSA-ReD combines a density plot and a contour plot to visualize and quantify PSA results. Relative density, depicted using a color gradient, is transformed to a cumulative probability. Contours are then plotted over regions with a specific cumulative probability. We use two real-world case studies to demonstrate the value of the PSA-ReD plot. RESULTS: The PSA-ReD method demonstrates proof-of-concept and feasibility. In the real-world case-studies, PSA-ReD provided additional visual information that could not be understood from the traditional scatterplot. High density areas were identified by color-coding and the contour plot allowed for quantification of PSA iterations within areas of the cost-effectiveness plane, diminishing overdrawing and putting infrequent iterations in perspective. Critically, the PSA-ReD plot informs modellers about non-linearities within their model. CONCLUSIONS: The PSA-ReD plot is easy to implement, presents more of the information enclosed in PSA data, and prevents inappropriate interpretation of PSA results. It gives modelers additional insight in model functioning and the distribution of uncertainty around the cost-effectiveness estimate.

A novel method for predicting the budget impact of innovative medicines: validation study for oncolytics.

BACKGROUND: High budget impact (BI) estimates of new drugs have led to decision-making challenges potentially resulting in restrictions in patient access. However, current BI predictions are rather inaccurate and short term. We therefore developed a new approach for BI prediction. Here, we describe the validation of our BI prediction approach using oncology drugs as a case study. METHODS: We used Dutch population-level data to estimate BI where BI is defined as list price multiplied by volume. We included drugs in the antineoplastic agents ATC category which the European Medicines Agency (EMA) considered a New Active Substance and received EMA marketing authorization (MA) between 2000 and 2017. A mixed-effects model was used for prediction and included tumor site, orphan, first in class or conditional approval designation as covariates. Data from 2000 to 2012 were the training set. BI was predicted monthly from 0 to 45 months after MA. Cross-validation was performed using a rolling forecasting origin with e^|Ln(observed BI/predicted BI)| as outcome. RESULTS: The training set and validation set included 25 and 44 products, respectively. Mean error, composed of all validation outcomes, was 2.94 (median 1.57). Errors are higher with less available data and at more future predictions. Highest errors occur without any prior data. From 10 months onward, error remains constant. CONCLUSIONS: The validation shows that the method can relatively accurately predict BI. For payers or policymakers, this approach can yield a valuable addition to current BI predictions due to its ease of use, independence of indications and ability to update predictions to the most recent data.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Affordability of oncology drugs: accuracy of budget impact estimations.

Background: In many countries, Budget Impact (BI) informs reimbursement decisions. Evidence has shown that decision-makers have restricted access based on high BI estimates but studies show that BI estimates are often inaccurate. Objective: To assess the accuracy of BI estimations used for informing access decisions on oncology drugs in the Netherlands. Study Design: Oncology products for which European Medicines Agency Marketing Authorisation was granted between 1-1-2000 and 1-10-2017 were selected. Observed BI data were provided by FarmInform. BI estimates were extracted from the reimbursement dossiers of the Dutch Healthcare Institute. Products without an estimated BI in the reimbursement dossier were excluded. Accuracy is defined as the ratio observed BI/estimated BI. Setting: General community, the Netherlands. Results: Ten products were included in the base case analysis. Mean accuracy was 0.64 and observed BI deviated by more than 40% and 100% from the estimated BI for 4 and 5 products, respectively. For all products together, €141 million BI was estimated and €82 million BI was observed, a €59 million difference. Conclusions: The findings indicate that BI estimates for oncology drugs in the Netherlands are inaccurate. The role and use of BI in reimbursement decisions for these potentially life-saving drugs should therefore be considered carefully, as well as BI estimation methodology.

Phase I/II Clinical Trial-Based Early Economic Evaluation of Acalabrutinib for Relapsed Chronic Lymphocytic Leukaemia.

OBJECTIVES: The objective of this study was to construct an early economic evaluation for acalabrutinib for relapsed chronic lymphocytic leukaemia (CLL) to assist early reimbursement decision making. Scenarios were assessed to find the relative impact of critical parameters on incremental costs and quality-adjusted life-years (QALYs). METHODS: A partitioned survival model was constructed comparing acalabrutinib and ibrutinib from a UK national health service perspective. This model included states for progression-free survival (PFS), post-progression survival (PPS) and death. PFS and overall survival (OS) were parametrically extrapolated from ibrutinib publications and a preliminary hazard ratio based on phase I/II data was applied for acalabrutinib. Deterministic and probabilistic sensitivity analyses were performed, and 1296 scenarios were assessed. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) was £61,941/QALY, with 3.44 incremental QALYs and incremental costs of £213,339. Deterministic sensitivity analysis indicated that survival estimates, utilities and treatment costs of ibrutinib and acalabrutinib and resource use during PFS have the greatest influence on the ICER. Probabilistic results under different development scenarios indicated that greater efficacy of acalabrutinib would decrease the likelihood of cost effectiveness (from 63% at no effect to 2% at maximum efficacy). Scenario analyses showed that a reduction in PFS did not lead to great QALY differences (- 8 to - 14% incremental QALYs) although it did greatly affect costs (- 47 to - 122% incremental pounds). For OS, the opposite was true (- 89 to - 93% QALYs and - 7 to - 39% pounds). CONCLUSIONS: Acalabrutinib is not likely to be cost effective compared with ibrutinib under current development scenarios. The conflicting effects of OS, PFS, drug costs and utility during PFS show that determining the cost effectiveness of acalabrutinib without insight into all parameters complicates health technology assessment decision making. Early assessment of the cost effectiveness of new products can support development choices and reimbursement processes through effective early dialogues between stakeholders.

Cost of illness of metastatic prostate cancer: a perspective of costs for new treatment options in The Netherlands.

AIM: To assess the resource use and associated costs of treating patients with metastatic prostate cancer with a focus on skeletal-related events (SREs). METHODS: We performed a bottom-up cost of illness study in The Netherlands. RESULTS: A total of 136 patients were studied. The mean total costs were €17,931 per patient. SREs that required hospitalization (n = 53) were, at median costs of €2039-9346, depending on care. These SREs had median costs of €200-1912. CONCLUSION: Our data provide a basis to investigate the cost-effectiveness of novel treatment options for metastatic prostate cancer. The impact of SREs on total costs could justify policy aimed at actively preventing SREs, possibly resulting in better quality of life and cost-reduction.

The impact of structural uncertainty on cost-effectiveness models for adjuvant endocrine breast cancer treatments: the need for disease-specific model standardization and improved guidance.

INTRODUCTION: Structural uncertainty relates to differences in model structure and parameterization. For many published health economic analyses in oncology, substantial differences in model structure exist, leading to differences in analysis outcomes and potentially impacting decision-making processes. The objectives of this analysis were (1) to identify differences in model structure and parameterization for cost-effectiveness analyses (CEAs) comparing tamoxifen and anastrazole for adjuvant breast cancer (ABC) treatment; and (2) to quantify the impact of these differences on analysis outcome metrics. METHODS: The analysis consisted of four steps: (1) review of the literature for identification of eligible CEAs; (2) definition and implementation of a base model structure, which included the core structural components for all identified CEAs; (3) definition and implementation of changes or additions in the base model structure or parameterization; and (4) quantification of the impact of changes in model structure or parameterizations on the analysis outcome metrics life-years gained (LYG), incremental costs (IC) and the incremental cost-effectiveness ratio (ICER). RESULTS: Eleven CEA analyses comparing anastrazole and tamoxifen as ABC treatment were identified. The base model consisted of the following health states: (1) on treatment; (2) off treatment; (3) local recurrence; (4) metastatic disease; (5) death due to breast cancer; and (6) death due to other causes. The base model estimates of anastrazole versus tamoxifen for the LYG, IC and ICER were 0.263 years, €3,647 and €13,868/LYG, respectively. In the published models that were evaluated, differences in model structure included the addition of different recurrence health states, and associated transition rates were identified. Differences in parameterization were related to the incidences of recurrence, local recurrence to metastatic disease, and metastatic disease to death. The separate impact of these model components on the LYG ranged from 0.207 to 0.356 years, while incremental costs ranged from €3,490 to €3,714 and ICERs ranged from €9,804/LYG to €17,966/LYG. When we re-analyzed the published CEAs in our framework by including their respective model properties, the LYG ranged from 0.207 to 0.383 years, IC ranged from €3,556 to €3,731 and ICERs ranged from €9,683/LYG to €17,570/LYG. CONCLUSION: Differences in model structure and parameterization lead to substantial differences in analysis outcome metrics. This analysis supports the need for more guidance regarding structural uncertainty and the use of standardized disease-specific models for health economic analyses of adjuvant endocrine breast cancer therapies. The developed approach in the current analysis could potentially serve as a template for further evaluations of structural uncertainty and development of disease-specific models.

The cloudy crystal ball of cost-effectiveness studies.

Despite the use of identical clinical trial data (Anastrazole, Tamoxifen, Alone or in Combination for the adjuvant treatment of postmenopausal women with localised hormone receptor-positive breast cancer data), not dependent on differences between countries, the outcome of 11 published cost-effectiveness analyses varied more than 20-fold. The observed wide variation in predicted life-years gained (a parameter derived from clinical trial data) demonstrates that authors used substantially different methods for handling the same data. We therefore consider it to be of utmost importance to strive for standardization of and better guidance for disease-specific modeling in economic evaluations.

Utility and work productivity data for economic evaluation of breast cancer therapies in the Netherlands and Sweden.

OBJECTIVE: This study aimed to estimate utility values in laypeople and productivity loss for women with breast cancer in Sweden and the Netherlands. METHODS: To capture utilities, validated health state vignettes were used, which were translated into Dutch and Swedish. They described progressive disease, stable disease, and 7 grade 3/4 adverse events. One hundred members of the general public in each country rated the states using the visual analog scale and time trade-off method. To assess productivity, women who had recently completed or were currently receiving treatment for early or advanced breast cancer (the Netherlands, n = 161; Sweden, n = 52) completed the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire. Data were analyzed using means (SD). RESULTS: The utility study showed that the Swedish sample rated progressive and stable disease (mean, 0.61 [0.07] and 0.81 [0.05], respectively) higher than did the Dutch sample (0.49 [0.06] and 0.69 [0.05]). The health states incorporating the toxicities in both countries produced similar mean scores. Results of the WPAI-GH showed that those currently receiving treatment reported productivity reductions of 69% (the Netherlands) and 72% (Sweden); those who had recently completed therapy reported reductions of 41% (the Netherlands) and 40% (Sweden). CONCLUSIONS: The differences in the utility scores between the 2 countries underline the importance of capturing country-specific values. The significant impact of adverse events on health-related quality of life was also highlighted. The WPAI-GH results demonstrated how the negative impact of breast cancer on productivity persists after women have completed their treatment.

Development of a framework for cohort simulation in cost-effectiveness analyses using a multistep ordinary differential equation solver algorithm in R.

INTRODUCTION: Dynamic processes in cost-effectiveness analysis (CEA) are typically described using cohort simulations, which can be implemented as Markov models, or alternatively using systems of ordinary differential equations (ODEs). In the field of CEA, simple and potentially inaccurate single-step algorithms are commonly used for solving ODEs, which can potentially induce bias, especially if an incorrect step size is used. The aims of this project were 1) to implement and demonstrate the use of a modern and well-established hybrid linear multistep ODE solver algorithm (LSODA) in the context of CEA using the statistical scripting language R and 2) to quantify bias in outcome for a case example CEA as generated by a commonly used single-step ODE solver algorithm. METHODS: A previously published CEA comparing the adjuvant breast cancer therapies anastrozole and tamoxifen was used as a case example to implement the computational framework. A commonly used single-step algorithm was compared with the proposed multistep algorithm to quantify bias in the single-step method. RESULTS: A framework implementing the multistep ODE solver LSODA was successfully developed. When a single-step ODE solver with step size of 1 year was used, incremental life-years gained was underestimated by 0.016 years (5.6% relative error, RE) and £158 (6.8% RE) compared with the multistep method. CONCLUSION: The framework was found suitable for the conduct of CEAs. We demonstrated how the use of single-step algorithms with insufficiently small step sizes causes unnecessary bias in outcomes measures of CEAs. Scripting languages such as R can further improve transparency, reproducibility, and overall integrity in the field of health economics.

Reviewing the cost-effectiveness of endocrine early breast cancer therapies: influence of differences in modeling methods on outcomes.

OBJECTIVES: The purpose of this systematic review is primarily to identify published cost-effectiveness analyses and cost-utility analyses of endocrine therapies for the treatment of early breast cancer. A secondary objective is to identify whether differences in seven modeling characteristics are related to differences in outcome of these cost-effectiveness and cost-utility analyses. METHODS: A systematic literature review was conducted to identify peer-reviewed full economic evaluations of endocrine treatments of early breast cancer published in the English language between 2000 and December 2010. Information from these publications was abstracted regarding outcome, quality, and modeling methods. RESULTS: We identified 20 economic evaluations comprising 5 different endocrine therapeutic strategies, which are all assessed more then once. The incremental cost-effectiveness ratios (ICERs) of the reported outcomes varied widely for identical therapies. For anastrazole compared to tamoxifen, incremental life-years gained even ranged from 0.16 to 0.550 with an ICER ranging from €3,958 to €75,331. Incremental quality-adjusted life-years (QALYs) gained ranged from 0.092 to 0.378 with a cost per QALY gained varying from €3,696 to €120,265. These large differences in outcome were related to different modeling methods, with differences in time horizon and use of a carryover effect as most prominent causes. CONCLUSION: Despite similar comparators and logical differences due to transferability issues, the outcomes of the included studies varied widely. To increase comparability and transparency of pharmacoeconomic evaluations, standardization of modeling methods for different therapeutic groups/diseases and the availability of a detailed and complete description of the model used in the evaluation is advocated. Recommendations for standardization in modeling treatment strategies in early breast cancer are presented.

Cost-effectiveness of MR lymphography for the detection of lymph node metastases in patients with prostate cancer.

PURPOSE: To apply a decision analytic model to determine whether the addition of magnetic resonance (MR) lymphography to the diagnostic workup of patients with intermediate or high probability of lymph node metastases is cost effective from a health care perspective. MATERIALS AND METHODS: The data that were used for the decision analytic model were obtained from an empiric study population of 375 patients. As the input of the decision analytic model was made given prospective patient data from several hospitals, the ethics review board of each hospital approved the study. Written consent was obtained from all patients. To investigate possible differences between strategies that utilize MR lymphography and those that do not (pelvic lymph node dissection [PLND]), two outcome measures were examined and combined in an incremental cost-effectiveness ratio (ICER) of health care resources consumed and quality-adjusted life-years (QALYs). Probabilistic and one-way sensitivity analyses were performed. RESULTS: The PLND strategy is dominated by the MR lymphography strategy. Probabilistic sensitivity analysis showed that in 63% of simulations, MR lymphography was cost saving and resulted in better patient outcome for patients with prostate cancer and intermediate or high probability of lymph node metastases. The probability of MR lymphography being inferior (more expensive and worse patient outcome) is less than 3%. CONCLUSION: MR lymphography is an efficient strategy in the detection of lymph node metastases of prostate cancer when compared with the PLND strategy.

Prostate cancer: detection of lymph node metastases outside the routine surgical area with ferumoxtran-10-enhanced MR imaging.

PURPOSE: To prospectively evaluate the feasibility of magnetic resonance (MR) imaging with ferumoxtran-10 in patients with prostate cancer to depict lymph node metastases outside the routine pelvic lymph node dissection (PLND) area. MATERIALS AND METHODS: The study was approved by the institutional review boards at all four hospitals; patients provided written informed consent. Two hundred ninety-six consecutive men (mean age, 67 years; range, 47-83 years) with prostate cancer and an intermediate-to-high risk for nodal metastases (prostate-specific antigen level >10 ng/mL, Gleason score >6, or stage T3 disease) were enrolled. MR lymphography of the pelvis was performed 24 hours after intravenous drip infusion of ferumoxtran-10. Positive nodes at MR lymphography were indicated to be inside or outside the routine dissection area (RDA). On the basis of MR lymphography computed tomographic (CT)-guided biopsy, routine PLND, or MR imaging-guided minimal extended PLND was performed. RESULTS: MR lymphography findings were positive in 58 patients. Of these, 44 had histopathologic confirmation of lymph node metastases. In 18 of 44 patients (41%), MR lymphography findings showed nodes exclusively outside the RDA, which were confirmed with MR lymphography-guided extended PLND (n = 13) and CT-guided biopsy (n = 5). In another 18 patients (41%), positive nodes were located both inside and outside the RDA at MR lymphography. In these 18 patients, routine PLND was used to confirm the nodes inside the RDA (n = 11); CT-guided biopsy was used to confirm nodes outside the RDA (n = 7). In the remaining eight patients, MR lymphography findings showed only nodes inside the RDA, which was confirmed with PLND (n = 5) and CT-guided biopsy (n = 3). In 14 of the 58 patients (24%), there was no histologic confirmation. CONCLUSION: In 41% of patients with prostate cancer, nodal metastases outside the area of routine PLND were detected by using MR imaging with ferumoxtran-10.

MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study.

BACKGROUND: In patients with prostate cancer who are deemed to be at intermediate or high risk of having nodal metastases, invasive diagnostic pelvic lymph-node dissection (PLND) is the gold standard for the detection of nodal disease. However, a new lymph-node-specific MR-contrast agent ferumoxtran-10 can detect metastases in normal-sized nodes (ie, <8 mm in size) by use of MR lymphoangiography (MRL). In this prospective, multicentre cohort study, we aimed to compare the diagnostic accuracy of MRL with up-to-date multidetector CT (MDCT), and test the hypothesis that a negative MRL finding obviates the need for a PLND. METHODS: We included consecutive patients with prostate cancer who had an intermediate or high risk (risk of >5% according to routinely used nomograms) of having lymph-node metastases. All patients were assessed by MDCT and MRL, and underwent PLND or fine-needle aspiration biopsy. Imaging results were correlated with histopathology. The primary outcomes were sensitivity, specificity, accuracy, NPV, and PPV of MRL and MDCT. This study is registered with ClinicalTrials.gov, number NCT00185029. FINDINGS: The study was done in 11 hospitals in the Netherlands between April 8, 2003, and April 19, 2005. 375 consecutive patients were included. 61 of 375 (16%) patients had lymph-node metastases. Sensitivity was 34% (21 of 61; 95% CI 23-48) for MDCT and 82% (50 of 61; 70-90) for MRL (McNemar's test p<0.05). Specificity was 97% (303 of 314; 94-98) for MDCT and 93% (291 of 314; 89-95) for MRL. Positive predictive value (PPV) was 66% (21 of 32; 47-81) for MDCT and 69% (50 of 73; 56-79) for MRL. Negative predictive value (NPV) was 88% (303 of 343; 84-91) for MDCT and 96% (291 of 302; 93-98) for MRL (McNemar's test p<0.05). Of the 61 patients with lymph-node metastases, 50 were detected by MRL, of which 40 (80%) had metastases in normal-sized lymph nodes. The high sensitivity and NPV of MRL imply that in patients with a negative MRL, the chance of positive lymph nodes is less than 11/302 (4%). INTERPRETATION: MRL had significantly higher sensitivity and NPV than MDCT for patients with prostate cancer who had intermediate or high risk of having lymph-node metastases. In such patients, after a negative MRL, the post-test probability of having lymph-node metastases is low enough to omit a PLND.

Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: early experience.

PURPOSE: To prospectively evaluate the feasibility of ferumoxtran-10-enhanced magnetic resonance (MR) imaging at high magnetic field strength (3.0 T) and to compare image quality between 1.5- and 3.0-T MR imaging in terms of lymph node detection in patients with prostate cancer. MATERIALS AND METHODS: This study was institutional review board approved, and all patients gave written informed consent. Forty-eight consecutive patients aged 51-79 years (mean, 65.5 years) with prostate cancer were enrolled. T2*-weighted 1.5- and 3.0-T MR images of the pelvis were acquired in a sagittal plane parallel to the psoas muscle 24 hours after ferumoxtran-10 administration. A pelvic and body phased-array coil was used and yielded an in-plane resolution of 0.56 x 0.56 x 3.00 mm at 1.5 T and 0.50 x 0.50 x 2.50 mm at 3.0 T. All images were evaluated by three readers for total image quality, lymph node border delineation, muscle-fat contrast, and vessel-fat contrast. Statistical significance was calculated by using the Mann-Whitney U test. Subsequently, the general linear mixed model was used to estimate the contributions of three factors-patient, reader, and technique-to the variability of the imaging results. RESULTS: Significantly (P < .05) better muscle-fat contrast, vessel-fat contrast, lymph node border delineation, and total image quality were observed at 3.0-T MR imaging. The general linear mixed model revealed that the variability of all results could be attributed to the use of 3.0-T imaging. CONCLUSION: Ferumoxtran-10-enhanced MR imaging can be performed at high magnetic field strengths and result in improved image quality, which may lead to improved detection of small positive lymph nodes.

Cost-analysis of staging methods for lymph nodes in patients with prostate cancer: MRI with a lymph node-specific contrast agent compared to pelvic lymph node dissection or CT.

The aim of this study was to compare the costs of three strategies in patients with prostate cancer in a specific setting: firstly, a strategy including MR lymphography (MRL) in which pelvic lymph node dissection (PLND) is foregone in case of a negative result. The second strategy involves computed tomography (CT) followed by a biopsy or PLND. The third strategy consists of PLND without imaging beforehand. A decision analytic model was constructed. This model represented the diagnostic process for patients with prostate cancer and intermediate or high risk for nodal metastases, comparing the costs of the three strategies. Cost analysis was done from the health care perspective. The model indicated that the expected costs for the MRL strategy were 2,527 euro. The expected costs for the strategy using CT were 3,837 euro and for PLND 3,994 euro. These results show that potential savings performing MRL instead of CT were 1,310 euro and 1,467 euro for PLND. Sensitivity analyses show that variation in costs of PLND was most influential on the costs of all strategies. However, the overall savings pattern did not alter. Average costs of MRL staging in our institution are less than for CT and PLND in staging lymph nodes of patients with prostate cancer and who are intermediate or high risk for nodal metastases.