Real-World Evidence of Treatment Outcomes in Small Cell Lung Cancer: A Bayesian Mixed Effects and Competitive Risk Approach.

Background: Small cell lung cancer (SCLC) is a challenging disease to treat due to rapid progression, development of chemoresistance, and discrepancies in outcomes between real-world data and clinical trials. There is a lack of comprehensive analyses in other studies with regard to intermediate events and the treatment process, such as treatment decisions, progression of disease, and the occurrence of adverse events (AEs) over time. Objective: The aim of this study was to apply advanced statistical methods to a longitudinal SCLC dataset in order to identify factors of importance for the risk of AEs and for survival. Methods: Treatment pathways of 421 patients with SCLC collected from Karolinska University Hospital, located in Stockholm, Sweden, between 2016 and 2022, were analyzed with data-driven modeling. The analysis focused on the impact of dose adjustment on AEs, including neutropenia, by estimating odds ratios (ORs) using Bayesian mixed effects modeling. Covariates' effects on Eastern Cooperative Oncology Group performance status (ECOG 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. Results: At the end of the first-line treatment, most patients exhibited tumor regression (n=167). Patients with neutropenia had longer overall survival (hazard ratio 0.70, 95% CI 0.53-0.92). Higher etoposide dose levels were associated with subsequent occurrences of AEs (OR 5.97, 95% CI 1.41-30.5) and neutropenia (OR 3.55, 95% CI 1.03-13.3). Dose adjustment did not affect overall survival if the patient completed the 4-dose regimen treatment. With regard to second-line therapy, fewer patients completed 4 treatment cycles, and the most common reason for early discontinuation was tumor progression (n=72, 58%). Male patients (n=118) experienced fewer AEs and better first-line treatment response compared to females (csHR 0.51, 95% CI 0.25-0.90). High-risk patients (defined as ECOG PS 2-3 or age >75 years) with early discontinuation of therapy had survival outcomes similar to those who did not receive any therapy. Conclusions: 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.