Modeling Diagnostic Strategies to Manage Toxic Adverse Events following Cancer Immunotherapy

Frederik van Delft, Mirte Muller, Rom Langerak, Hendrik Koffijberg, Valesca Retèl, Daan van den Broek and Maarten IJzerman
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Frederik van Delft: Health Technology and Services Research Department, Technical Medical Centre, University of Twente, Enschede, Overijssel, the Netherlands
Mirte Muller: Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Noord-Holland, the Netherlands
Rom Langerak: Formal Methods and Tools Group, Faculty of EEMCS, University of Twente, Enschede, Overijssel, the Netherlands
Hendrik Koffijberg: Health Technology and Services Research Department, Technical Medical Centre, University of Twente, Enschede, Overijssel, the Netherlands
Valesca Retèl: Health Technology and Services Research Department, Technical Medical Centre, University of Twente, Enschede, Overijssel, the Netherlands
Daan van den Broek: Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Noord-Holland, the Netherlands
Maarten IJzerman: Health Technology and Services Research Department, Technical Medical Centre, University of Twente, Enschede, Overijssel, the Netherlands

Medical Decision Making, 2021, vol. 41, issue 6, 693-705

Abstract: Background Although immunotherapy (IMT) provides significant survival benefits in selected patients, approximately 10% of patients experience (serious) immune-related adverse events (irAEs). The early detection of adverse events will prevent irAEs from progressing to severe stages, and routine testing for irAEs has become common practice. Because a positive test outcome might indicate a clinically manifesting irAE that requires treatment to (temporarily) discontinue, the occurrence of false-positive test outcomes is expected to negatively affect treatment outcomes. This study explores how the UPPAAL modeling environment can be used to assess the impact of test accuracy (i.e., test sensitivity and specificity), on the probability of patients entering palliative care within 11 IMT cycles. Methods A timed automata-based model was constructed using real-world data and expert consultation. Model calibration was performed using data from 248 non–small-cell lung cancer patients treated with nivolumab. A scenario analysis was performed to evaluate the effect of changes in test accuracy on the probability of patients transitioning to palliative care. Results The constructed model was used to estimate the cumulative probabilities for the patients’ transition to palliative care, which were found to match real-world clinical observations after model calibration. The scenario analysis showed that the specificity of laboratory tests for routine monitoring has a strong effect on the probability of patients transitioning to palliative care, whereas the effect of test sensitivity was limited. Conclusion We have obtained interesting insights by simulating a care pathway and disease progression using UPPAAL. The scenario analysis indicates that an increase in test specificity results in decreased discontinuation of treatment due to suspicion of irAEs, through a reduction of false-positive test outcomes.

Keywords: adverse event; immunotherapy; lung cancer; NSCLC; timed automata; toxicity; UPPAAL (search for similar items in EconPapers)
Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:sae:medema:v:41:y:2021:i:6:p:693-705

DOI: 10.1177/0272989X211002756

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