Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (±â€ˆ1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals.

Cost-effectiveness of everolimus plus reduced tacrolimus in de novo liver-recipients in the Italian setting.

INTRODUCTION: Long-term exposure to calcineurin inhibitor-based immunosuppressant (IS) therapy in liver transplant (LT) recipients is associated with renal complications. In the randomized trial H2304, everolimus + reduced-dose tacrolimus (EVR + rTAC) demonstrated equivalent efficacy and superior renal function compared to standard-dose tacrolimus. METHODS: To evaluate the cost-effectiveness of EVR + rTAC vs TAC, in de novo LT patients, a Markov model simulating both liver and kidney function was developed and estimated the long-term outcomes of IS following LT. The analysis used the Italian healthcare payer perspective. RESULTS: Patients treated with EVR + rTAC gained on average 1.92 years and 1.62 quality-adjusted life years (QALYs). The incremental cost-effectiveness ratios (ICER) were €35,851 and €42,567 for LY gained and QALY gained, respectively. For the hepatitis-c sub-population, the ICERs decreased to €22,519 and €30,658, respectively. CONCLUSION: EVR + rTAC improves survival and quality-of-life and is a cost-effective alternative to calcineurin-inhibitor monotherapy for patients requiring LT.

Patterns of resource utilization and cost for postmenopausal women with hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer in Europe.

BACKGROUND: Healthcare resource utilization in breast cancer varies by disease characteristics and treatment choices. However, lack of clarity in guidelines can result in varied interpretation and heterogeneous treatment management and costs. In Europe, the extent of this variability is unclear. Therefore, evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed. METHODS: This retrospective chart review (N = 355) examined primarily direct costs for chemotherapy versus hormone therapy in postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer across 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden). RESULTS: Total direct costs across the first 3 treatment lines were approximately €10,000 to €14,000 lower for an additional line of hormone therapy-based treatment versus switching to chemotherapy-based treatment. Direct cost difference between chemotherapy-based and hormone therapy-based regimens was approximately €1900 to €2500 per month. Chemotherapy-based regimens were associated with increased resource utilization (managing side effects; concomitant targeted therapy use; and increased frequencies of hospitalizations, provider visits, and monitoring tests). The proportion of patients taking sick leave doubled after switching from hormone therapy to chemotherapy. CONCLUSIONS: These results suggest chemotherapy is associated with increased direct costs and potentially with increased indirect costs (lower productivity of working patients) versus hormone therapy in HR+, HER2- advanced breast cancer.

Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial.

BACKGROUND: The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). METHODS: Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. RESULTS: Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). CONCLUSIONS: In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.

Economic impact and long-term graft outcomes of mycophenolate mofetil dosage modifications following gastrointestinal complications in renal transplant recipients.

INTRODUCTION: Gastrointestinal (GI) complications are common following renal transplantation. Discontinuing or reducing the dosage of mycophenolate mofetil can improve GI tolerability but adversely affect graft outcomes. This analysis was undertaken to assess the 3-year economic and clinical impact of mycophenolate mofetil dosage modifications or discontinuation following post-transplant GI events compared with no dosage modification. METHODS: Adult renal transplant recipients with a Medicare-covered mycophenolate mofetil prescription at the time of GI complication between 1995 and 2000 were drawn from the US Renal Data System (USRDS). The 3-year graft survival rates after first diagnosis of a GI complication were obtained in four cohorts of patients according to mycophenolate mofetil administration within 6 months of initial GI diagnosis: (i) no dosage change in mycophenolate mofetil (NC); (ii) one or more episodes of mycophenolate mofetil dosage reduction <50% of the initial dosage, lasting >30 days (DR <50%); (iii) one or more episodes of mycophenolate mofetil dosage reduction >or=50% of the initial dosage, lasting >30 days (DR >or=50%); and (iv) one or more episodes of mycophenolate mofetil discontinuation >30 days (DC).Two multivariate models were used to estimate the association between DR and DC and graft survival <6 months after GI diagnosis and 6-36 months after diagnosis. In each cohort, Medicare costs for maintaining a patient with stable function were calculated using regression and were augmented with cost of graft failure, resumed maintenance dialysis and death post-graft loss using Medicare data supplied by the USRDS. Survival and cost outcomes were integrated in a 3-year Markov model with 6-month cycles. The perspective was that of Medicare, and costs and outcomes were discounted by 3% per annum. RESULTS: Adult patients (n = 3589) with a mycophenolate mofetil prescription at time of diagnosis of GI event were identified: NC = 2230 (62.1%); DR <50% = 247 (6.9%); DR >or=50% = 348 (9.7%); and DC = 764 (21.3%). In the first 6 months after GI diagnosis, DC was associated with increased risk of graft failure (hazard ratio [HR] 3.20; 95% CI 1.71, 5.99; p < 0.0001). During the period 6-36 months after GI diagnosis, the HR for graft loss was higher for the DR >or=50% group (HR 1.32; 95% CI 1.02, 1.70; p < 0.05) and DC group (HR 1.35; 95% CI 1.09, 1.69; p < 0.01) relative to the NC group.Expected 3-year cumulative Medicare costs per patient were USD 68,495 for the NC and DR <50% groups, USD 70,886 for the DR >or=50% group, USD 79,015 for the DC group and USD 70,967 overall. Respective QALYs were 2.32, 2.30, 2.27 and 2.31. In sensitivity analysis, reducing the rate of DR and DC by 25% would have lowered expected costs by USD 2.2 million in the study population and increased QALYs by 11.2. Monte Carlo simulation indicated a 93% probability that such reduction in the relative risk of mycophenolate mofetil DR/DC was cost saving or cost neutral. CONCLUSION: Dosage reduction or discontinuation of mycophenolate mofetil in the first 6 months after diagnosis of GI complications is associated with significantly increased risk of graft failure and increased healthcare costs in adult renal transplant recipients.

Economic evaluation of tegaserod vs. placebo in the treatment of patients with irritable bowel syndrome: an analysis of the TENOR study.

OBJECTIVES: Tegaserod is effective, safe, and well-tolerated in the treatment of patients with irritable bowel syndrome (IBS) with constipation. The aim of this study was to assess, from a payer perspective, the cost-effectiveness of tegaserod in the treatment of IBS patients, based on the TEgaserod in NORdic region (TENOR) trial data. METHODS: Female and male patients (Rome II criteria) were randomized to receive tegaserod 6 mg b.i.d. or placebo for 12 weeks. Patients (247 tegaserod; 238 placebo) completed the EuroQol EQ-5D questionnaire at baseline, Week 4, and Week 12. A 12-week economic study was undertaken to assess the incremental cost-effectiveness ratio (ICER) of tegaserod in terms of cost per quality-adjusted life-year (QALY) gained. Cost-effectiveness acceptability curves were calculated to estimate the probability of tegaserod being cost-effective at different benchmark values of cost per QALY gained. RESULTS: By assuming a daily drug cost to payers of Euro 2, Euro 3, and Euro 4, the ICER of tegaserod ranges between Euro 19,000 and Euro 38,000 per QALY gained, with the percentage of the bootstrap estimates below the willingness to pay level of Euro 50,000 per QALY gained ranging between 90% and 69%. CONCLUSIONS: This study established directly from a randomized controlled clinical trial that tegaserod is cost-effective in the treatment of non-D-IBS patients.

Linking the US transplant registry to administrative claims data: expanding the potential of transplant research.

OBJECTIVE: In the United States, data on transplanted and waitlisted patients collected by the Organ Procurement and Transplantation Network (OPTN) have been widely used in transplantation research. Administrative claims data, collected by health plans for reimbursement purposes, are also commonly used in health-services research. This study linked OPTN and private payer claims data to assess the relationship between data elements common to both sources. METHODS: All transplanted or waitlisted patients in the registry were considered for inclusion. A multistep match algorithm was employed to link OPTN and payer data from years 1995 to 2004. Variables common to both datasets that contained relevant information for similar time periods were compared. RESULTS: A total of 21,419 solid organ transplant recipients and 8808 waitlist patients were included in the final linked database. Organ type and demographic variable distributions in the linked dataset were similar to the overall OPTN database. Using claims as the reference group, sensitivity and specificity values were on average 0.72 and 0.69, respectively, and were highest for the indicators of immunosuppression use at discharge and follow-up. CONCLUSION: This comparison of payer data with information reported by transplant centers to the OPTN provides important insight into the value of both data sources. Using administrative claims to augment the registry data with utilization and cost information will be useful for evaluation of both economic and clinical endpoints in solid organ transplantation.

Performance of the EQ-5D in patients with irritable bowel syndrome.

OBJECTIVE: The EQ-5D is a standardized, nondisease-specific instrument for evaluating patients' preference-based valuations of health-related quality of life (HRQoL). This study's purpose was to determine the psychometric properties of EQ-5D in patients with irritable bowel syndrome (IBS). METHODS: Data from four European IBS studies were assessed: UK (n = 161 and n = 297), Spain (n = 503), and Germany (n = 100). The EQ-5D is a five-item health state descriptive system used to develop health states (EQ-5D(INDEX)) and a visual analog scale (VAS) (0-100 from worst to best imaginable health state, EQ-5D(VAS)). Measures used with the EQ-5D included the SF-36, Irritable Bowel Syndrome--Quality of Life (IBS-QOL), and both subjective and clinical global assessments of IBS. Convergent validity was assessed using SF-36 and IBS-QOL data, discriminant validity using global ratings of IBS severity, and responsiveness by subjective and physician assessment of condition. RESULTS: Moderate-to-high associations (r >or= 0.33) were seen between the EQ-5D(VAS) and the SF-36 and IBS-QOL subscales. Mean response scores to EQ-5D(INDEX) dimensions and the EQ-5D(VAS) score were significantly better for control patients than for patients with IBS (all P < 0.01). The EQ-5D(VAS) was able to discriminate between levels of pain severity (quartiles, P < 0.001; mild/moderate/severe, P < 0.05) and general health severity (mild/moderate/severe, P < 0.001). The EQ-5D(VAS) and the EQ-5D(INDEX) were responsive in patients using both a self-perceived (Subject's Global Assessment) and physician-rated (Clinic Global Assessment) improvement. CONCLUSIONS: The EQ-5D performs well in comparison to general and disease-specific outcomes. It is a valid and responsive measure that can be used to generate preference-based valuations of HRQoL in patients with IBS and useful for comparisons in clinical and cost-effectiveness studies.

Validation of electronic data capture of the Irritable Bowel Syndrome--Quality of Life Measure, the Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome and the EuroQol.

OBJECTIVES: To assess the comparability, reliability, and subject acceptability of electronic data capture (EDC) versions of Irritable Bowel Syndrome-Quality of Life (IBS-QOL), EuroQoL (EQ-5D) and Work Productivity and Activity Impairment (WPAI:IBS) instruments. METHODS: Comparability of EDC and paper questionnaires was evaluated in 72 subjects with IBS who completed a baseline EDC or paper questionnaire, a crossover questionnaire 24 hours later, and a retest of the crossover version at 1 week. The EDC version was presented on a hand-held device. Comparability was assessed using paired t-test statistics, intraclass correlation coefficients (ICC) and tests for internal consistency (Cronbach's alpha). RESULTS: No significant differences were found between scores obtained by paper questionnaire and EDC at the baseline and crossover assessments. ICCs between baseline and crossover assessments ranged from 0.83 to 0.96 for the IBS-QOL scores, 0.82 to 0.96 for the WPAI:IBS scores, and 0.77 to 0.82 for the EQ-5D. Internal consistency was comparable for the two data collection methods for the IBS-QOL overall score (0.96) and subscales and the EQ-5D Index (0.70 vs. 0.74). Retest statistics (ICC) were generally comparable between the EDC and paper versions for all scores. Ease of use was comparable for the two modes of administration, but more patients preferred EDC (47.2%) than the paper questionnaire (23.6%). CONCLUSIONS: EDC versions of the IBS-QOL, EQ-5D, and WPAI:IBS are comparable to paper questionnaires in internal consistency and test-retest reliability, and have greater patient acceptability.