General Population Mortality Adjustment in Survival Extrapolation of Cancer Trials: Exploring Plausibility and Implications for Cost-Effectiveness Analyses in HER2-Positive Breast Cancer in Sweden

Background In economic evaluations of novel therapies, assessing lifetime effects based on trial data often necessitates survival extrapolation, with the choice of model affecting outcomes. The aim of this study was to assess accuracy and variability between alternative approaches to survival extrapolation.Methods Data on HER2-positive breast cancer patients from the Swedish National Breast Cancer Register were used to fit standard parametric distribution (SPD) models and excess hazard (EH) models adjusting the survival projections based on general population mortality (GPM). Models were fitted using 6-y data for stage I and II, 4-y data for stage III, and 2-y data for stage IV cancer reflecting an early data cutoff while maintaining sufficient events for comparison of model estimates with actual long-term outcomes. We compared model projections of 15-y survival and restricted mean survival time (RMST) to 15-y registry data and explored the variability between models in extrapolations of long-term survival.Results Among 11,224 patients compared with the observed registry 15-y RMST estimates across the disease stages, EH cure models provided the most accurate estimates in patients with stage I to III cancer, whereas EH models without cure most closely matched survival in patients with stage IV cancer, in which cure assumption was less plausible. The Akaike information criterion-averaged model projections varied as follows: -8.2% to +5.3% for SPD models, -4.9% to +5.2% for the EH model without a cure assumption, and -19.3% to -0.2% for the EH model with a cure assumption. EH models significantly reduced between-model variance in the predicted RMSTs over a 50-y time horizon compared with SPD models.Conclusions EH models may be considered as alternatives to SPD models to produce more accurate and plausible survival extrapolation that accounts for general population mortality.