Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. METHODS: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. RESULTS: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. DISCUSSION: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

The intranasal dexmedetomidine plus ketamine for procedural sedation in children, adaptive randomized controlled non-inferiority multicenter trial (Ketodex): a statistical analysis plan.

BACKGROUND: Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. METHODS/DESIGN: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. DISCUSSION: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.