Improving adverse event capture and reporting in oncology trials of systemic therapy to better inform assessment of treatment tolerability

Abstract

Cancer treatment decision making requires potential benefit to be considered alongside treatment tolerability. Harms from treatment, and the impact of harms on adherence to therapy is a core component of a tolerability assessment. Yet harms reporting in clinical trials, with its focus on safety using “worst-grade” adverse event AE reporting, does not adequately capture or report treatment tolerability. This reporting was developed in the era of cytotoxic chemotherapy, but the modern landscape of cancer treatment has evolved. Newer classes of treatment including targeted therapies and immune checkpoint inhibitors have been added, and treatment is often continued indefinitely. These agents are more likely to prove burdensome due to persistent or recurrent AEs, even when the AE are considered low grade. These and other aspects of treatment tolerability are poorly detailed by current methods of AE capture and reporting. In this PhD thesis I aimed to improve the potential for harms reporting to inform the tolerability of cancer treatments by (1) identifying limitations of current methods of AE collection and reporting to accurately communicate tolerability, (2) developing new approaches to address these limitations, and (3) investigating the relationship between adherence and clinical outcomes. Using data from published clinical trials I demonstrate the discrepancy between AEs reported in clinical trials and harms from treatment, develop and illustrate two new methods to summarize and visualise the trajectories of AEs over the course of treatment, and investigate the association between reduced treatment adherence and outcomes. The empirical work and methods developed in this thesis are generalisable across different settings in cancer treatment trials, and other fields of medicine. Uptake of these recommendations may lead to a more accurate assessment of a treatment’s tolerability, which is critical to inform optimal therapy choices and may improve treatment outcomes.