A Bayesian mixed effects and competitive risk approach for analysis of real-world treatment outcomes in small cell lung cancer (Preprint)

<sec> <title>BACKGROUND</title> Small cell lung cancer (SCLC) is a challenging disease to treat due to rapid progression, development of chemo-resistance, and discrepancies in outcomes between real-world data and clinical trials. There is a lack of comprehensive analyses in other studies with regards to intermediate events and the treatment process, such as treatment decisions, progression of disease, and the occurrence of adverse events (AEs) over time. </sec> <sec> <title>OBJECTIVE</title> The aim of this study was to apply advanced statistical methods on a longitudinal SCLC data set in order to identify factors of importance for the risk of AEs and for survival. </sec> <sec> <title>METHODS</title> Treatment pathways of 421 SCLC patients collected from Karolinska University Hospital between 2016-2022 (Stockholm, Sweden) were analysed with data-driven modelling. The analysis focused on the impact of dose-adjustment on AEs, including neutropenia, by estimating odds ratios (OR) using Bayesian mixed-effects modelling. Covariate’s effects on ECOG performance status (PS) deterioration and early discontinuation of chemotherapy with cause-specific hazard ratios (csHR) were explored using competitive risk models. This approach was applied to patient cohorts receiving combinatorial first line platinum/ etoposide, and second line platinum/ etoposide or platinum/ irinotecan. </sec> <sec> <title>RESULTS</title> At the end of the first line treatment, most patients exhibited tumour regression (n=167). Patients with neutropenia had longer overall survival (HR: 0.70 [0.53, 0.92]). Higher etoposide dose levels were associated with subsequent occurrences of AEs (OR: 5.97 [1.41, 30.5]) and neutropenia (OR: 3.55 [1.03, 13.3]). Dose adjustment did not affect overall survival if the patient completed the four-dose regimen treatment. With regards to second-line therapy, fewer patients completed four treatment cycles and the most common reason of early discontinuation was tumour progression (n=72, 58%). Male patients (n=118) experienced fewer AEs and better first line treatment response compared to females (csHR: 0.51 [0.25, 0.90]). High-risk patients (defined as ECOG PS 2-3, or age &gt; 75 years) with early discontinuation of therapy had survival outcomes similar to those who did not receive any therapy. </sec> <sec> <title>CONCLUSIONS</title> Our results indicate that first line therapies may benefit from more individualized dosing strategies. It would also be beneficial to assess the risk-benefit of treating specific subgroups, including patients receiving second line therapy. Real-world data proved beneficial for studying therapy response and risk-benefit of treating patient groups that are underrepresented in clinical trials. </sec>