Background: 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. Previous studies lack comprehensive analyses of intermediate events and the treatment process, such as treatment decisions, progression of disease, and the occurrence of adverse events (AEs) over time. 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. Methods: Information was collected on the treatment pathways of 421 SCLC patients treated at the Karolinska University Hospital between 2016-2022 (Stockholm, Sweden). Analysis focused on the impact of dose-adjustment on adverse events (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 cohorts of patients receiving first line platinum etoposide, and second line platinum etoposide or platinum irinotecan. Results: 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 as long as the patient completed the four-dose regimen treatment. For the second-line, fewer patients completed four treatment cycles and the most common reason of early discontinuation was tumour progression (n=72). Male patients experienced fewer AEs and better first line treatment response compared to females (csHR: 0.51 [0.25, 0.90]). High-risk patients (here defined as ECOG PS 2-3, or age over 75 years) with early discontinuation of therapy had survival outcomes similar to those who did not receive therapy. Conclusions: Our results indicate that SCLC therapies may benefit from more individualized dosing strategies. These strategies would aim to balance improved survival with reduced risk of AEs, particularly neutropenia. It would also be beneficial to assess the risk-benefit of treating specific subgroups, including patients receiving second line therapy. Real-world data are crucial for studying therapy response and risk-benefit of treating patient groups that are underrepresented in clinical trials.

The authors have declared no competing interest.

This study was funded by The Swedish Cancer Society (grant no. CAN 2018/597 and CAN2021/1469 Pj01) to R. Lewensohn and from the Stockholm Cancer Society (grant no. #201202 to R. Lewensohn and #174063, #201103 and #231123 to L. De Petris).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study received ethical approval by the Swedish Ethical Review Authority (approval number: 2023-07389-01).

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the authors upon reasonable request. Data are located in a controlled access data storage at Karolinska University Hospital.