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Background: Gene expression profiling tests can predict the risk of disease recurrence and select patients who are expected to benefit from therapy, while allowing other patients to forgo therapy. For breast cancers, these tests were initially designed to tailor chemotherapy decisions, but recent evidence suggests that they may also guide the use of endocrine therapy. This study evaluated the cost effectiveness of a prognostic test, MammaPrint®, to guide the use of adjuvant endocrine therapy in patients eligible according to Dutch treatment guidelines. Methods: We constructed a Markov decision model to calculate the lifetime costs (in 2020 Euros) and effects (survival and quality-adjusted life-years) of MammaPrint® testing versus usual care (endocrine therapy for all patients) in a simulated cohort of patients. The population of interest includes patients for whom MammaPrint® testing is currently not indicated, but for whom it may be possible to safely omit endocrine therapy. We applied both a health care perspective and a societal perspective and discounted costs (4%) and effects (1.5%). Model inputs were obtained from published research (including randomized controlled trials), nationwide cancer registry data, cohort data and publicly available data sources. Scenario and sensitivity analyses were conducted to explore the impact of uncertainty around input parameters. Additionally, threshold analyses were performed to identify under which circumstances MammaPrint® testing would be cost effective. Results: Adjuvant endocrine therapy guided by MammaPrint® resulted in fewer side effects, more (quality-adjusted) life-years (0.10 and 0.07 incremental QALYS and LYs, respectively) and higher costs (€18,323 incremental costs) compared with the usual care strategy in which all patients receive endocrine therapy. While costs for hospital visits, medication costs and productivity costs were somewhat higher in the usual care strategy, these did not outweigh costs of testing in the MammaPrint® strategy. The incremental cost-effectiveness ratio was €185,644 per QALY gained from a healthcare perspective and €180,617 from a societal perspective. Sensitivity and scenario analyses showed that the conclusions remained the same under changed input parameters and assumptions. Our results show that MammaPrint® can become a cost-effective strategy when either the price of the test is reduced (> 50%), or the proportion of patients for which treatment is altered (i.e. those with ultra-low risk) increases to > 26%. Conclusion: Standard MammaPrint® testing to guide the use of endocrine therapy in our simulated patient population appears not to be a cost-effective strategy compared with usual care. The cost effectiveness of the test can be improved by reducing the price or preselecting a population more likely to benefit from the test. [ABSTRACT FROM AUTHOR]

Background Over the past decades, the therapeutic landscape has markedly changed for patients with metastatic solid cancer, yet few studies have evaluated its effect on population-based survival. The objective of this study was to evaluate the change in survival of patients with de novo metastatic solid cancers during the last 30 years. Methods For this retrospective study, data from almost 2 million patients diagnosed with a solid cancer between January 1, 1989, and December 31, 2018, were obtained from the Netherlands Cancer Registry, with follow-up until January 31, 2021. We classified patients as with or without de novo metastatic disease (M1 or M0, respectively) at diagnosis and determined the proportion with M1 disease over time. Changes in age-standardized net survival were calculated as the difference in the 1- and 5-year survival rates of patients diagnosed in 1989-1993 and 2014-2018. Results Different cancers showed divergent trends in the proportion of M1 disease and increases in net survival for M1 disease (approximately 0-50 percentage points at both 1 and 5 years). Patients with gastrointestinal stromal tumors saw the largest increases in 5-year survival, but we also observed substantial 5-year survival increases for patients with neuroendocrine tumors, melanoma, prostate cancer, and breast cancer. Conclusion Over 30 years, the survival of patients with de novo M1 disease modestly and unevenly increased among cancers. Metastatic cancer still remains a very lethal disease. Next to better treatment options, we call for better preventive measures and early detection to reduce the incidence of metastatic disease. [ABSTRACT FROM AUTHOR]

Purpose: The addition of two years of abemaciclib treatment to standard adjuvant endocrine therapy in all patients with high risk ER+, HER2- early breast cancer (EBC) has been approved by the US Food and Drug Administration (FDA). Pre-selection of patients with an immediate risk of recurrence within the group of clinically high risk patients using detection of minimal residual disease (MRD) using patient-informed circulating tumor DNA assays during follow-up could enhance efficacy. Here, we investigate the cost-effectiveness of the addition of two years abemaciclib in all high risk HR+, HER2- patients and in MRD-guided high risk patients only. Methods: Two semi-Markov models were developed to evaluate the cost-effectiveness of adding two years of abemaciclib compared to "standard treatment": 1) "abemaciclib all" and 2) "MRD-guided abemaciclib" using MRD-guidance. Data of the MonarchE trial were used to model the invasive disease-free survival (iDFS). Since iDFS and overall survival (OS) data of abemaciclib were currently limited, abemaciclib effects were extrapolated using a favorable, intermediate and unfavorable effect scenario. Results: The addition of abemaciclib in all high-risk EBC patients prolonged iDFS slightly (0.04 additional quality adjusted life years (QALYs)) and led to higher costs compared to standard ET, leading to a high incremental cost effectiveness ratio (ICER) of € 1,551,876/QALY. Neither the favorable effect scenario (additional 1.09 QALYs) was cost-effective (ICER € 62,935/QALY), using a willingness-to-pay threshold of € 50,000/QALY. The "MRD-guided abemaciclib" strategy resulted in lower costs and an increase in QALYs (1.27) compared to "standard treatment" in the unfavorable effect scenario. Conclusion: The addition of abemaciclib to adjuvant endocrine therapy in all high-risk ER+, HER2- EBC patients is not cost-effective. However, using MRD detection to justify the addition of abemaciclib treatment dominates standard treatment in this cost-effectiveness analysis. Further evaluation of MRD detection in EBC by means of prospective clinical trials assessing clinical utility is recommended and promising in terms of cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background There is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N -acetyltransferase 2 (NAT2) gene explain >88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) are unknown. Methods We constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Results In Brazil, PGT gained 19 discounted life-years (23 QALYs) and cost $11 064 per 1000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life-years (19 QALYs) and cost $33 182 per 1000 patients, a value of $1780 per QALY gained. In India, PGT gained 20 life-years (24 QALYs) and cost $13 195 per 1000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita gross domestic product in all 3 countries in 99% of simulations. Conclusions Isoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India. [ABSTRACT FROM AUTHOR]

Background: EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA). Methods: A systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments. Results: Thirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib. Conclusion: Our study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Background: Primary postpartum haemorrhage is an obstetrical emergency often causing acute anaemia that may require immediate red blood cell (RBC) transfusion. This anaemia results in symptoms such as fatigue, which may have major impact on the health-related quality of life. RBC transfusion is generally thought to alleviate these undesirable effects although it may cause transfusion reactions. Moreover, the postpartum haemoglobin level seems to influence fatigue only for a short period of time. At present, there are no strict transfusion criteria for this specific indication, resulting in a wide variation in postpartum policy of RBC transfusion in the Netherlands. Methods/Design: The WOMB trial is a multicentre randomised non-inferiority trial. Women with acute anaemia due to postpartum haemorrhage, 12-24 hours after delivery and not initially treated with RBC transfusion, are eligible for randomisation. Patients with severe physical complaints are excluded. Patients are randomised for either RBC transfusion or expectant management. Health related quality of life (HRQoL) will be assessed at inclusion, at three days and one, three and six weeks postpartum with three validated measures (Multi-dimensional Fatigue Inventory, ShortForm-36, EuroQol-5D). Primary outcome of the study is physical fatigue three days postpartum. Secondary outcome measures are general and mental fatigue scores and generic health related quality of life scores, the number of RBC transfusions, length of hospital stay, complications and health-care costs. The primary analysis will be by intention-to-treat. The various longitudinal scores will be evaluated using Repeated Measurements ANOVA. A costs benefit analysis will also be performed. The power calculation is based on the exclusion of a difference in means of 1.3 points or greater in favour of RBC transfusion arm regarding physical fatigue subscale. With missing data not exceeding 20%, 250 patients per arm have to be randomised (one-sided alpha = 0.025, power = 80%). Discussion: This study will provide evidence for a guideline regarding RBC transfusion in the postpartum patient suffering from acute anaemia. Equivalence in fatigue score, remaining HRQoL scores and physical complications between both groups is assumed, in which case an expectant management would be preferred to minimise transfusion reactions and costs. Trial registration: ClinicalTrials.gov NCT00335023, Nederlands Trial Register NTR335. [ABSTRACT FROM AUTHOR]

Currently, up to 50% of the operations in early-stage non-small cell lung cancer (NSCLC) are futile owing to the presence of locally advanced tumour or distant metastases. More accurate pre-operative staging is required in order to reduce the number of futile operations. The cost-effectiveness of fluorine-18 fluorodeoxyglucose positron emission tomography ([sup 18]FDG-PET) added to the conventional diagnostic work-up was studied in the PLUS study. Prior to invasive staging and/or thoracotomy, 188 patients with (suspected) NSCLC were randomly assigned to conventional work-up (CWU) and whole-body PET or to CWU alone. CWU was based on prevailing guidelines. Pre-operative staging was followed by 1 year of follow-up. Outcomes are expressed in the percentage of correctly staged patients and the associated costs. The cost price of PET varied between €736 and €1,588 depending on the (hospital) setting and the procurement of [sup 18]FDG commercially or from on-site production. In the CWU group, 41% of the patients underwent a futile thoracotomy, whereas in the PET group 21% of the thoracotomies were considered futile (P=0.003). The average costs per patient in the CWU group were €9,573 and in the PET group, €8,284. The major cost driver was the number of hospital days related to recovery from surgery. Sensitivity analysis on the cost and accuracy of PET showed that the results were robust, i.e. in favour of the PET group. The addition of PET to CWU prevented futile surgery in one out of five patients with suspected NSCLC. Despite the additional PET costs, the total costs were lower in the PET group, mainly due to a reduction in the number of futile operations. The additional use of PET in the staging of patients with NSCLC is feasible, safe and cost saving from a clinical and from an economic perspective. [ABSTRACT FROM AUTHOR]

It has frequently been questioned whether results of trials can be generalized to routine clinical practice. Results obtained with standard cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy for aggressive non-Hodgkin's lymphoma in the control arm of prospective randomized phase III clinical trials during the past 25 years appear to be comparable. As the possibility to generalize trial results is favored by such consistency, we tested this hypothesis and tried to indicate explanatory ‘moderator variables’ (inclusion and exclusion criteria, therapy characteristics, sample sizes, inequalities in the distribution of patients over prognostic categories across different trials) in the case of divergent trial results. Trial results on conventional CHOP chemotherapy were obtained from literature research. Overall response (OR), complete response (CR) and two-year overall survival (2YS) were considered as outcome measures.Although OR rates and 2YS rates were within acceptable limits of comparability, the absolute differences within the results were remarkably wide, particularly with regard to CR and 2YS. Divergent rates could not be properly explained by differences in the moderator variables. We conclude that absolute results obtained with CHOP in the control arm of trials appeared to be poorly generalizable to routine clinical practice, particularly in the case of elderly patients. This analysis underlines the need for the strict application of internationally agreed response criteria and the WHO classification system, large sample sizes and stratifying patients on the basis of prognostic factors, preferably in intergroup clinical trials. We expect those factors to lead to a better consistency of results in future trials and improved possibilities to generalize the results.The Hematology Journal (2003) 4, 399-409. doi:10.1038/sj.thj.6200323 [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to calculate the costs of chemotherapy and high–dose-rate brachytherapy in advanced-stage nasopharyngeal cancer. It is argued whether the effect of chemotherapy and this type of high-dose, high-precision radiation therapy is worth the costs.Methods and Materials: Clinical results of Stage III–IVB nasopharyngeal cancer in patients treated between 1991 and 2000 are reported. Treatment was broken down into five categories: workup, chemotherapy, preparation of radiation therapy, and application of radiation. For each category, costs were computed. Nasopharyngeal cancer treatment costs were compared with costs previously reported on patients treated for cancers of the oral cavity, larynx, and oropharynx.Results: With the addition of neoadjuvant chemotherapy and high cumulative doses of radiation (77–81 Gy) with brachytherapy, disease-free survival increased from 48% to 74% (p = 0.002), and overall survival increased from 35% to 72% (p = 0.005). The Rotterdam protocol has been implemented stepwise: as of 1991, costs per patient increased from 4521 Euros (US$5023; 2001 exchange rate [December]: 1 Euro ~ 0.88 US$) for conventional external beam radiation therapy to 13,728 Euros (US$15,253) in 2000 for combinations of chemotherapy, conventional external beam radiation therapy, and brachytherapy. In case of stereotactic radiotherapy, the cost was 14,516 Euros (US$16,495).Conclusions: Costs for cancer in the nasopharynx vary from 14,528 Euros (US$16,509) to 15,316 Euros (US$17,405) in case of brachytherapy and stereotactic radiotherapy, respectively, if follow-up costs are added. The treatment cost for other head and neck sites was 21,858 Euros (US$24,126). Given the improvement in survival, the sparing capabilities of current high-dose, high-precision radiotherapy techniques, and the favorable cost profile compared with other sites, it is argued that costs should not be considered prohibitive for the introduction of chemotherapy and high–technology-based radiotherapy in advanced nasopharyngeal cancer. [Copyright &y& Elsevier]