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Objective: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. Methods: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient's disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. Results: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. Conclusions: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Advanced non-small-cell lung cancer (NSCLC) harbours many genetic aberrations that can be targeted with systemic treatments. Whole-genome sequencing (WGS) can simultaneously detect these (and possibly new) molecular targets. However, the exact added clinical value of WGS is unknown. Objective: The objective of this study was to determine the early cost effectiveness of using WGS in diagnostic strategies compared with currently used molecular diagnostics for patients with inoperable stage IIIB,C/IV non-squamous NSCLC from a Dutch healthcare perspective. Methods: A decision tree represented the diagnostic pathway, and a cohort state transition model represented disease progression. Three diagnostic strategies were modelled: standard of care (SoC) alone, WGS as a diagnostic test, and SoC followed by WGS. Treatment effectiveness was based on a systematic review. Probabilistic cost-effectiveness analyses were performed, and threshold analyses (using €80,000 per quality-adjusted life-year [QALY]) was used to explore the early cost effectiveness of WGS. Results: WGS as a diagnostic test resulted in more QALYs (0.002) and costs (€1534 [incremental net monetary benefit –€1349]), and SoC followed by WGS resulted in fewer QALYs (–0.002) and more costs (€1059 [–€1194]) compared with SoC alone. WGS as a diagnostic test was only cost effective if it was priced at €2000 per patient and identified 2.7% more actionable patients than SoC alone. Treating these additional identified patients with new treatments costing >€4069 per month decreased the probability of cost effectiveness. Conclusions: Our analysis suggests that providing WGS as a diagnostic test is cost effective compared with SoC followed by WGS and SoC alone if costs for WGS decrease and additional patients with actionable targets are identified. This cost-effectiveness model can be used to incorporate new findings iteratively and to support ongoing decision making regarding the use of WGS in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the cost-effectiveness of risk-based strategies to improve the selection of surgically treated stage II colon cancer (CC) patients for adjuvant chemotherapy. Methods: Using the 'Personalized Adjuvant TreaTment in EaRly stage coloN cancer' (PATTERN) model, we evaluated five selection strategies: (1) no chemotherapy, (2) Dutch guideline recommendations assuming observed adherence, (3) Dutch guideline recommendations assuming perfect adherence, (4) biomarker mutation OR pT4 stage strategy in which patients with MSS status combined with a pT4 stage or a mutation in BRAF and/or KRAS receive chemotherapy assuming perfect adherence and (5) biomarker mutation AND pT4 stage strategy in which patients with MSS status combined with a pT4 stage tumor and a BRAF and/or KRAS mutation receive chemotherapy assuming perfect adherence. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Analyses were conducted from a societal perspective. The robustness of model predictions was assessed in sensitivity analyses. Results: The reference strategy, that is, no adjuvant chemotherapy, resulted in 139 CC deaths in a cohort of 1000 patients, 8.077 QALYs pp and total costs of €22,032 pp. Strategies 2–5 were more effective (range 8.094–8.217 QALYs pp and range 118–136 CC deaths per 1000 patients) and more costly (range €22,404–€25,102 pp). Given a threshold of €50,000/QALY, the optimal use of resources would be to treat patients with either the full adherence strategy and biomarker mutation OR pT4 stage strategy. Conclusion: Selection of stage II CC patients for chemotherapy can be improved by either including biomarker status in the selection strategy or by improving adherence to the Dutch guideline recommendations. [ABSTRACT FROM AUTHOR]

Background: Our aim was to evaluate the cost effectiveness of 3 months' adjuvant chemotherapy versus 6 months in high-risk (T4 stage + microsatellite stable) stage II colon cancer (CC) patients. Methods: Using the validated PATTERN Markov cohort model, which simulates the disease progression of stage II CC patients from diagnosis to death, we first evaluated a reference strategy in which high-risk patients were treated with chemotherapy for 6 months. In the second strategy, treatment duration was shortened to 3 months. Both strategies were evaluated for CAPOX (capecitabine plus oxaliplatin) and FOLFOX (fluorouracil, leucovorin and oxaliplatin). Based on trial data, we assumed that shortened treatment duration compared with a 6-month regimen was equally effective for CAPOX and less effective for FOLFOX. Adverse events were highest in the 6-month strategy. Analyses were conducted from a societal perspective using a lifelong time horizon. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Incremental net monetary benefit (iNMB) was calculated using a willingness-to-pay value of €50,000/QALY. Results: For CAPOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €41,257 pp. The 3-month strategy resulted in an equal number of CC deaths, but higher QALYs (6.80 pp) and lower costs (€37,645 pp), leading to a iNMB of €8454 per person for 3 months versus 6 months. For FOLFOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €47,135 pp. The 3-month strategy resulted in more CC deaths (393), lower QALYs (6.19 pp) and lower costs (€44,389 pp). An iNMB of −€23,189 was found for 3 months versus 6 months. Conclusion: Our findings indicate that 3 months' adjuvant chemotherapy should be considered as standard of care in high-risk stage II CC patients for CAPOX, but not for FOLFOX. [ABSTRACT FROM AUTHOR]

Aim: To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy.Methods: A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy.Results: Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively.Conclusion: This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies. [ABSTRACT FROM AUTHOR]

Background: Uncomplicated Urinary Tract Infections (UTIs) are common in primary care resulting in substantial costs. Since antimicrobial resistance against antibiotics for UTIs is rising, accurate diagnosis is needed in settings with low rates of multidrug-resistant bacteria. Objective: To compare the cost-effectiveness of different strategies to diagnose UTIs in women who contacted their general practitioner (GP) with painful and/or frequent micturition between 2006 and 2008 in and around Amsterdam, The Netherlands. Methods: This is a model-based cost-effectiveness analysis using data from 196 women who underwent four tests: history, urine stick, sediment, dipslide, and the gold standard, a urine culture. Decision trees were constructed reflecting 15 diagnostic strategies comprising different parallel and sequential combinations of the four tests. Using the decision trees, for each strategy the costs and the proportion of women with a correct positive or negative diagnosis were estimated. Probabilistic sensitivity analysis was used to estimate uncertainty surrounding costs and effects. Uncertainty was presented using cost-effectiveness planes and acceptability curves. Results: Most sequential testing strategies resulted in higher proportions of correctly classified women and lower costs than parallel testing strategies. For different willingness to pay thresholds, the most cost-effective strategies were: 1) performing a dipstick after a positive history for thresholds below €10 per additional correctly classified patient, 2) performing both a history and dipstick for thresholds between €10 and €17 per additional correctly classified patient, 3) performing a dipstick if history was negative, followed by a sediment if the dipstick was negative for thresholds between €17 and €118 per additional correctly classified patient, 4) performing a dipstick if history was negative, followed by a dipslide if the dipstick was negative for thresholds above €118 per additional correctly classified patient. Conclusion: Depending on decision makers’ willingness to pay for one additional correctly classified woman, the strategy consisting of performing a history and dipstick simultaneously (ceiling ratios between €10 and €17) or performing a sediment if history and subsequent dipstick are negative (ceiling ratios between €17 and €118) are the most cost-effective strategies to diagnose a UTI. [ABSTRACT FROM AUTHOR]

Background: Considerable variation exists in diagnostic tests used for local response evaluation after chemoradiation in patients with advanced oropharyngeal cancer. The yield of invasive examination under general anesthesia (EUA) with biopsies in all patients is low and it may induce substantial morbidity. We explored four response evaluation strategies to detect local residual disease in terms of diagnostic accuracy and cost-effectiveness.Methods: We built a decision-analytic model using trial data of forty-six patients and scientific literature. We estimated for four strategies the proportion of correct diagnoses, costs concerning diagnostic instruments and the proportion of unnecessary EUA indications. Besides a reference strategy, i.e. EUA for all patients, we considered three imaging strategies consisting of 18FDG-PET-CT, diffusion-weighted MRI (DW-MRI), or both 18FDG-PET-CT and DW-MRI followed by EUA after a positive test. The impact of uncertainty was assessed in sensitivity analyses.Results: The EUA strategy led to 96% correct diagnoses. Expected costs were €468 per patient whereas 89% of EUA indications were unnecessary. The DW-MRI strategy was the least costly strategy, but also led to the lowest proportion of correct diagnoses, i.e. 93%. The PET-CT strategy and combined imaging strategy were dominated by the EUA strategy due to respectively a smaller or equal proportion of correct diagnoses, at higher costs. However, the combination of PET-CT and DW-MRI had the highest sensitivity. All imaging strategies considerably reduced (unnecessary) EUA indications and its associated burden compared to the EUA strategy.Conclusions: Because the combined PET-CT and DW-MRI strategy costs only an additional €927 per patient, it is preferred over immediate EUA since it reaches the same diagnostic accuracy in detecting local residual disease while leading to substantially less unnecessary EUA indications. However, if healthcare resources are limited, DW-MRI is the strategy of choice because of lower costs while still providing a large reduction in unnecessary EUA indications. [ABSTRACT FROM AUTHOR]

Background: Total laryngectomy with or without adjuvant (chemo)radiation often induces speech, swallowing and neck and shoulder problems. Speech, swallowing and shoulder exercises may prevent or diminish these problems. The aim of the present paper is to describe the study, which is designed to investigate the effectiveness and cost-utility of a guided self-help exercise program built into the application "In Tune without Cords" among patients treated with total laryngectomy.Methods/design: Patients, up to 5 years earlier treated with total laryngectomy with or without (chemo)radiation will be recruited for participation in this study. Patients willing to participate will be randomized to the intervention or control group (1:1). Patients in the intervention group will be provided access to a guided self-help exercise program and a self-care education program built into the application "In Tune without Cords". Patients in the control group will only be provided access to the self-care education program. The primary outcome is the difference in swallowing quality (SWAL-QOL) between the intervention and control group. Secondary outcome measures address speech problems (SHI), shoulder disability (SDQ), quality of life (EORTC QLQ-C30, QLQ-H&N35 and EQ-5D), direct and indirect costs (adjusted iMCQ and iPCQ measures) and self-management (PAM). Patients will be asked to complete these outcome measures at baseline, immediately after the intervention or control period (i.e. at 3 months follow-up) and at 6 months follow-up.Discussion: This randomized controlled trial will provide knowledge on the effectiveness of a guided self-help exercise program for patients treated with total laryngectomy. In addition, information on the value for money of such an exercise program will be provided. If this guided self-help program is (cost)effective for patients treated with total laryngectomy, the next step will be to implement this exercise program in current clinical practice.Trial Registration: NTR5255 Protocol version 4 date September 2015. [ABSTRACT FROM AUTHOR]

Several colorectal cancer (CRC) screening models have been developed describing the progression of adenomas to CRC. Currently, there is increasing evidence that serrated lesions can also develop into CRC. It is not clear whether screening tests have the same test characteristics for serrated lesions as for adenomas, but lower sensitivities have been suggested. Models that ignore this type of colorectal lesions may provide overly optimistic predictions of the screen-induced reduction in CRC incidence. To address this issue, we have developed the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model that includes the adenoma-carcinoma pathway and the serrated pathway to CRC as well as characteristics of colorectal lesions. The model structure and the calibration procedure are described in detail. Calibration resulted in 19 parameter sets for the adenoma-carcinoma pathway and 13 for the serrated pathway that match the age- and sex-specific adenoma and serrated lesion prevalence in the COlonoscopy versus COlonography Screening (COCOS) trial, Dutch CRC incidence and mortality rates, and a number of other intermediate outcomes concerning characteristics of colorectal lesions. As an example, we simulated outcomes for a biennial fecal immunochemical test screening program and a hypothetical one-time colonoscopy screening program. Inclusion of the serrated pathway influenced the predicted effectiveness of screening when serrated lesions are associated with lower screening test sensitivity or when they are not removed. To our knowledge, this is the first model that explicitly includes the serrated pathway and characteristics of colorectal lesions. It is suitable for the evaluation of the (cost)effectiveness of potential screening strategies for CRC. [ABSTRACT FROM AUTHOR]

In past decades, studies focusing on new chemotherapeutic agents for patients with inoperable non-small-cell lung cancer have reported only modest gains in survival. These health gains are achieved at considerable cost, but economic evidence is lacking on superiority of one agent in terms of cost effectiveness. The objective of this systematic review was to assess fully published cost-effectiveness studies comparing the new agents docetaxel, paclitaxel, vinorelbine, gemcitabine and pemetrexed, and the targeted therapies erlotinib and gefitinib with one another. We performed systematic searches in the bibliographic databases PubMed, EMBASE and Health Economic Evaluations (HEED) [via the Cochrane Library] for fully published studies from the past 10 years. Studies were screened by two independent reviewers according to a priori inclusion criteria. The methodological quality of the included studies was evaluated by two independent reviewers using standardized assessment tools. A total of 222 potential studies were identified; 11 studies and six reviews were included. The methodological quality of the full economic evaluations was fairly good. Transparency in costs and resource use, details on statistical tests and sensitivity analysis were points for improvement. In first-line treatment, gemcitabine+cisplatin was cost effective compared with other platinum-based regimens (paclitaxel, docetaxel and vinorelbine). In one study, pemetrexed+ cisplatin was cost effective compared with gemcitabine+cisplatin in patients with non-squamous-cell carcinoma. In second-line treatment, docetaxel was cost effective compared with best supportive care; erlotinib was cost effective compared with placebo; and docetaxel and pemetrexed were dominated by erlotinib. We found indications of superiority in terms of cost effectiveness for gemcitabine+ cisplatin in a first-line setting, and for erlotinib in a second-line setting [ABSTRACT FROM AUTHOR]

Background: Hypertensive disease in pregnancy remains the leading cause of maternal mortality in the Netherlands. Seventeen percent of the clinical pregnancies are complicated by hypertension and 2% by preeclampsia. The Dutch Society of Obstetrics and Gynaecology (NVOG) has developed evidence-based guidelines on the management of hypertension in pregnancy and chronic hypertension. Previous studies showed a low adherence rate to other NVOG guidelines and a large variation in usual care in the different hospitals. An explanation is that the NVOG has no general strategy of practical implementation and evaluation of its guidelines. The development of an effective and cost effective implementation strategy to improve adherence to the guidelines on hypertension in pregnancy is needed.Methods/design: The objective of this study is to assess the cost effectiveness of an innovative implementation strategy of the NVOG guidelines on hypertension including a computerised decision support system (BOS) compared to a common strategy of professional audit and feedback. A cluster randomised controlled trial with an economic evaluation alongside will be performed. Both pregnant women who develop severe hypertension or pre-eclampsia and professionals involved in the care for these women will participate. The main outcome measures are a combined rate of major maternal complications and process indicators extracted from the guidelines. A total of 472 patients will be included in both groups. For analysis, descriptive as well as regression techniques will be used. A cost effectiveness and cost utility analysis will be performed according to the intention-to-treat principle and from a societal perspective. Cost effectiveness ratios will be calculated using bootstrapping techniques. [ABSTRACT FROM AUTHOR]

Background: Emergency Departments (EDs) are confronted with progressive overcrowding. As a consequence, the workload for ED physicians increases and waiting times go up with the risk of unnecessary complications and patient dissatisfaction. To cope with these problems, Specialized Emergency Nurses (SENs), regular ED-nurses receiving a short, injury-specific course, were trained to assess and treat minor injuries according to a specific protocol. Methods: An economic evaluation was conducted alongside a randomized controlled trial comparing House Officers (HOs) and SENs in their assessment of ankle and foot injuries. Cost prices were established for all parts of healthcare utilization involved. Total costs of health care utilization were computed per patient in both groups. Cost-effectiveness was investigated by comparing the difference in total cost between groups with the difference in sensitivity and specificity between groups in diagnosing fractures and severe sprains. Finally, cost-effectiveness ratios were calculated and presented on a cost-effectiveness plane. Results: No significant differences were seen between treatment groups for any of the health care resources assessed. However, the waiting times for both first assessment by a treatment officer and time spent waiting between hearing the diagnosis and final treatment were significantly longer in the HO group. There was no statistically significant difference in costs between groups. The total costs were € 186 (SD € 623) for patients in the SEN group and € 153 (SD € 529) for patients in the HO group. The difference in total costs was € 33 (95% CI: - € 84 to € 155). The incremental cost-effectiveness ratio was € 27 for a reduction of one missed diagnosis and € 18 for a reduction of one false negative. Conclusion: Considering the benefits of the SEN-concept in terms of decreased workload for the ED physicians, increased patient satisfaction and decreased waiting times, SENs appear to be a useful solution to the problem of ED crowding. [ABSTRACT FROM AUTHOR]