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An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

ABSTRACT: Objectives. Uncertainty in survival prediction beyond trial follow-up is highly influential in cost-effectiveness analyses of oncology products. This research provides an empirical evaluation of the accuracy of alternative methods and recommendations for their implementation. Methods. Mature (15-year) survival data were reconstructed from a published database study for "no treatment," radiotherapy, surgery plus radiotherapy, and surgery in early stage non-small cell lung cancer in an elderly patient population. Censored data sets were created from these data to simulate immature trial data (for 1- to 10-year follow-up). A second data set with mature (9-year) survival data for no treatment was used to extrapolate the predictions from models fitted to the first data set. Six methodological approaches were used to fit models to the simulated data and extrapolate beyond trial follow-up. Model performance was evaluated by comparing the relative difference in mean survival estimates and the absolute error in the difference in mean survival v. the control with those from the original mature survival data set. Results. Model performance depended on the treatment comparison scenario. All models performed reasonably well when there was a small short-term treatment effect, with the Bayesian model coping better with shorter follow-up times. However, in other scenarios, the most flexible Bayesian model that could be estimated in practice appeared to fit the data less well than the models that used the external data separately. Where there was a large treatment effect (hazard ratio = 0.4), models that used external data separately performed best. Conclusions. Models that directly use mature external data can improve the accuracy of survival predictions. Recommendations on modeling strategies are made for different treatment benefit scenarios.

SUBMITTER: Vickers A

PROVIDER: S-EPMC6900572 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

Vickers Adrian A

Medical decision making : an international journal of the Society for Medical Decision Making 20191020 8

<b>Objectives.</b> Uncertainty in survival prediction beyond trial follow-up is highly influential in cost-effectiveness analyses of oncology products. This research provides an empirical evaluation of the accuracy of alternative methods and recommendations for their implementation. <b>Methods.</b> Mature (15-year) survival data were reconstructed from a published database study for "no treatment," radiotherapy, surgery plus radiotherapy, and surgery in early stage non-small cell lung cancer in ...[more]

PMID: 31631772

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Project description:BackgroundDue to limited duration of follow up in clinical trials of cancer treatments, estimates of lifetime survival benefits are typically derived using statistical extrapolation methods. To justify the method used, a range of approaches have been proposed including statistical goodness-of-fit tests and comparing estimates against a previous data cut (i.e. interim data collected). In this study, we extend these approaches by presenting a range of extrapolations fitted to four pre-planned data cuts from the JAVELIN Merkel 200 (JM200) trial. By comparing different estimates of survival and goodness-of-fit as JM200 data mature, we undertook an iterative process of fitting and re-fitting survival models to retrospectively identify early indications of likely long-term survival.MethodsStandard and spline-based parametric models were fitted to overall survival data from each JM200 data cut. Goodness-of-fit was determined using an assessment of the estimated hazard function, information theory-based methods and objective comparisons of estimation accuracy. Best-fitting extrapolations were compared to establish which one provided the most accurate estimation, and how statistical goodness-of-fit differed.ResultsSpline-based models provided the closest fit to the final JM200 data cut, though all extrapolation methods based on the earliest data cut underestimated the 'true' long-term survival (difference in restricted mean survival time [RMST] at 36 months: - 1.1 to - 0.5 months). Goodness-of-fit scores illustrated that an increasingly flexible model was favored as data matured. Given an early data cut, a more flexible model better aligned with clinical expectations could be reasonably justified using a range of metrics, including RMST and goodness-of-fit scores (which were typically within a 2-point range of the statistically 'best-fitting' model).ConclusionsSurvival estimates from the spline-based models are more aligned with clinical expectation and provided a better fit to the JM200 data, despite not exhibiting the definitively 'best' statistical goodness-of-fit. Longer-term data are required to further validate extrapolations, though this study illustrates the importance of clinical plausibility when selecting the most appropriate model. In addition, hazard-based plots and goodness-of-fit tests from multiple data cuts present useful approaches to identify when a more flexible model may be advantageous.Trial registrationJAVELIN Merkel 200 was registered with ClinicalTrials.gov as NCT02155647 on June 4, 2014.

Project description:IntroductionTraditional statistical techniques for extrapolating short-term survival data for anticancer therapies assume the same mortality rate for noncured and "cured" patients, which is appropriate for projecting survival of non-curative therapies but may lead to an underestimation of the treatment effectiveness for potentially curative therapies. Our objective was to ascertain research trends in survival extrapolation techniques used to project the survival benefits of chimeric antigen receptor T cell (CAR-T) therapies.MethodsA global systematic literature search produced a review of survival analyses of CAR-T therapies, published between January 1, 2015 and December 14, 2020, based on publications sourced from MEDLINE, scientific conferences, and health technology assessment agencies. Trends in survival extrapolation techniques used, and the rationale for selecting advanced techniques, are discussed.ResultsTwenty publications were included, the majority of which (65%, N = 13) accounted for curative intent of CAR-T therapies through the use of advanced extrapolation techniques, i.e., mixture cure models [MCMs] (N = 10) or spline-based models (N = 3). The authors' rationale for using the MCM approach included (a) better statistical fits to the observed Kaplan-Meier curves (KMs) and (b) visual inspection of the KMs indicated that a proportion of patients experienced long-term remission and survival which is not inherently captured in standard parametric distributions.DiscussionOur findings suggest that an advanced extrapolation technique should be considered in base case survival analyses of CAR-T therapies when extrapolating short-term survival data to long-term horizons extending beyond the clinical trial duration.ConclusionAdvanced extrapolation techniques allow researchers to account for the proportion of patients with an observed plateau in survival from clinical trial data; by only using standard-partitioned modeling, researchers may risk underestimating the survival benefits for the subset of patients with long-term remission. Sensitivity analysis with an alternative advanced extrapolation technique should be implemented and re-assessment using clinical trial extension data and/or real-world data should be conducted as longer-term data become available.

Dataset Information

An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

Publications

An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

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