Background: Small-cell lung cancer (SCLC), an aggressive malignancy comprising ~15% of lung cancers, is marked by rapid progression and frequent brain metastases. While immunotherapy has improved SCLC management, preventing and controlling brain metastases remains challenging.
Methods: We enrolled 889 patients with extensive-stage SCLC (ES-SCLC) without baseline brain metastases from three Chinese hospitals. Patients received first-line immunotherapy plus chemotherapy or chemotherapy alone, with regular imaging to monitor progression. Progression was classified as brain metastases (brain-only or with extracranial progression) or extracranial-only. Second-line treatments included continuing original systemic therapy (OTP), switching systemic therapy (Sub-Tx), or adding brain radiotherapy (BRT). Primary endpoints were overall survival (OS) and second-line progression-free survival (PFS2), analyzed using Kaplan-Meier and log-rank tests (p<0.05).
Results: By March 2025, 293 of 889 patients developed brain metastases post-first-line therapy (33.0% immunotherapy vs. 33.4% chemotherapy, p=0.23), indicating immunotherapy’s limited impact on preventing brain metastases. Of these, 203 had brain-only progression, and 93 had concurrent extracranial progression. For brain-only progression, OTP+BRT significantly improved PFS2 (6.98 vs. 6.12 vs. 3.93 months) and OS (25.98 vs. 16.96 vs. 16.33 months) compared to Sub-Tx+BRT and Sub-Tx, with greater benefits in the immunotherapy subgroup (PFS2: 27.14 months, OS: 38.28 months). For 594 patients with extracranial-only progression, continuing immunotherapy extended PFS2 (4.82 vs. 2.98 months, p=0.01) and OS (17.65 vs. 15.50 months, p<0.001).
Conclusion: Brain metastases remain a significant challenge in ES-SCLC, unaffected by first-line immunotherapy. For brain-only progression, OTP+BRT significantly enhances OS and PFS2, particularly with immunotherapy. For extracranial progression, second-line immunotherapy improves outcomes. Progression-site-specific strategies are crucial for optimizing ES-SCLC treatment, warranting further research into OTP+BRT’s long-term efficacy.