Small cell lung cancer (SCLC), representing 13-15% of global pulmonary malignancies,. This aggressive neuroendocrine carcinoma demonstrates remarkable etiological dependence on tobacco exposure in 94% of cases (1, 2). Unlike in high-income countries, there is a rising environmental carcinogen exposure that contributes to increasing disease burden in developing regions (3).SCLC is usually classified into two stage, extensive-stage SCLC (ES-SCLC)and limited-stage SCLC (LS-SCLC), according to staging system of the Veterans Administration Lung Study Group (VALG) instead of Tumor, Node, Metastasis (TNM) staging system.Based on VALG stage system, appropriate treatment model could be recommend to patients (4).

Platinum-etoposide chemotherapy combined with thoracic radiotherapy remains the cornerstone for LS-SCLC, achieving 20-25% of 5-year survival rates. The immunotherapy revolution has reshaped ES-SCLC management, where the addition of PD-L1/PD-1 inhibitors (atezolizumab/durvalumab) to first-line chemotherapy demonstrated unprecedented survival benefits in pivotal phase III trials (5, 6). Nevertheless, disease progression in over 80% of responders occurs within 12 months due to the limited efficacy and rapidly acquired chemoresistance (7).The survival benefits derived from subsequent-line treatments remain constrained.leaves less than 7% of patients with 5-year survival rates (8).

Clinical implementation of therapies faces multifaceted barriers in countryside area of China, despite guideline recommendations from Chinese Society of Clinical Oncology(CSCO) (9) and NCCN (10). We have found that factors such as the accuracy of disease staging, standardization of treatment protocols, consistency in efficacy evaluation, effective management of adverse reactions, and patient compliance significantly influence treatment outcomes.Therefore, it is necessary to obtain a comprehensive analysis of the real-world evidence for its clinical multimodal therapy utilization in developing country,especially rural area.

This multicenter retrospective cohort study (N = 132; 2014-2023),systematically evaluates survival outcomes, treatment attrition patterns, and multimodal therapeutic efficacy in real-world SCLC management. By elucidating the determinants of therapeutic failure across disease stages and healthcare settings, our findings aim to address critical knowledge gaps in treatment sequencing strategies while informing health policy interventions to mitigate global disparities in SCLC care.

Small cell lung cancer (SCLC) remains a challenging malignancy with limited therapeutic breakthroughs, though recent advancements have modestly improved outcomes (7). Current first-line therapy for both limited-stage (LS) and extensive-stage (ES) disease relies on platinum-etoposide combinations, with the integration of immune checkpoint inhibitors in ES-SCLC demonstrating survival benefits in phase III trials (5). For LS-SCLC, concurrent chemoradiotherapy (CCRT) remains the standard, supported by meta-analyses showing a 5–10% absolute survival advantage over sequential approaches (12). Prophylactic cranial irradiation (PCI) continues to reduce brain metastasis rates, though its survival impact in ES-SCLC remains debated amid advances in MRI surveillance (13). Second-line options, such as topotecan or irinotecan, provide limited efficacy, while third-line anlotinib—a multi-targeted tyrosine kinase inhibitor—has emerged as a guideline-recommended option with modest PFS gains (9–11, 14). Despite these strides, rapid relapse, cumulative toxicities, and a paucity of targeted therapies underscore unmet needs. Our study’s findings align with and extend these observations, particularly in real-world survival outcomes and the evolving role of radiotherapy across disease stages.

The findings of this retrospective analysis provide critical insights into the differential outcomes of second-line therapy in SCLC based on platinum sensitivity, while reinforcing the prognostic value of staging and the survival benefits conferred by consolidative radiotherapy strategies. Our results underscore the importance of risk stratification and personalized therapeutic approaches in this aggressive malignancy, particularly in the context of limited treatment options beyond first-line therapy.

The study highlights a stark divergence in outcomes between platinum-sensitive (PS, 180≥TFI ≥90 days) and platinum-resistant (PR, TFI <90 days) patients. PS patients rechallenged with platinum-based regimens exhibited significantly prolonged median OS compared to non-platinum regimens (17.7 vs. 12.5 months, p < 0.05), aligning with ESMO guidelines (11) advocating platinum reintroduction in this subgroup. This benefit likely stems from retained tumor susceptibility to platinum-induced DNA damage and synergistic effects with salvage chemotherapy. In contrast, PR patients derived no survival advantage from platinum rechallenge, reflecting intrinsic or acquired resistance mechanisms such as enhanced DNA repair or reduced drug accumulation (4). Notably, the irinotecan-lobaplatin (IL) combination failed to improve outcomes in either subgroup, with a concerning trend toward reduced survival. These observations suggest that merely recycling cytotoxic agents—particularly those sharing resistance pathways with prior therapies—may exacerbate toxicity without overcoming resistance (15, 16). The IL regimen’s inefficacy, despite theoretical synergy between topoisomerase inhibitors and platinum, may reflect overlapping toxicities limiting dose intensity.

The analysis reaffirms the pivotal role of CCRT and PCI in optimizing outcomes across disease stages.In the context of limited-stage small-cell lung cancer (LS - SCLC), concurrent chemoradiotherapy (CCRT) exhibited a clinically significant overall survival (OS) advantage compared to sequential therapy (54.9 months versus 50.2 months;HR = 0.72, p = 0.08). This finding is in line with meta - analyses, which indicate that concurrent treatment approaches yield an absolute survival gain of 5 - 10% (11). This benefit likely arises from radiotherapy’s dual mechanisms: direct cytoreduction of chemoresistant clones and immunogenic cell death enhancing systemic T-cell responses. Likewise, PCI could significantly decrease the risk of brain metastasis and was correlated with an extended OS (50.2 months vs. 36.4 months, HR = 0.47), which validates its selective efficacy in patients attaining complete remission. While recent debates question PCI’s universal application—particularly given advanced MRI surveillance—our data support its integration into risk-adapted algorithms (13). The NCCN-endorsed strategy of reserving PCI for MRI-negative LS-SCLC patients with robust chemotherapy responses balances survival benefits against neurocognitive risks, a approach mirrored in ongoing trials like MAVERICK (NCT04155034) (17).

The stark contrast in PS vs. PR outcomes underscores the need for dynamic biomarkers beyond TFI to guide second-line therapy. While TFI remains a pragmatic clinical tool, emerging biomarkers such as circulating tumor DNA (ctDNA) mutational burden (18) or SLFN11 expression could refine sensitivity prediction (19). The null effect of IL regimens across subgroups further highlights the futility of empiric cytotoxic combinations without mechanistic rationale. Instead, the striking efficacy of novel agents like DLL3-targeted BiTE therapy (tarlatamab, ORR 40%) (20) and PARP inhibitors in SLFN11-high tumors—as reported in CheckMate 032 (21, 22).

Immunotherapy has demonstrated significant efficacy in small cell lung cancer (SCLC), including both LS-SCLC and ES-SCLC. Particularly in LS-SCLC, consolidation treatment with durvalumab has notably improved overall survival and progression-free survival (23, 24). In extensive-stage SCLC, combination therapy with immunotherapy and chemotherapy has also significantly enhanced patient prognosis, although the overall survival remains limited (7).Radiotherapy’s systemic immunomodulatory effects warrant particular emphasis. The prolonged PFS observed in ES-SCLC patients receiving symptom-directed radiotherapy (16.1 vs. 7.8 months) aligns with preclinical evidence of radiation-induced PD-L1 upregulation and myeloid-derived suppressor cell depletion (25). These findings suggest that localized radiotherapy may potentiate immunotherapy responses through abscopal effects. Future studies should prioritize sequencing strategies to maximize immune activation while mitigating overlapping toxicities.

This study’s retrospective design and modest sample size (n=132) limit statistical power to detect subtle survival differences. Heterogeneity in radiotherapy protocols and inconsistent biomarker profiling further constrain mechanistic interpretations.

There also exist certain analyses with p - values marginally exceeding 0.05, along with inevitable treatment bias. However, upon comprehensive consideration of all analyses, it is still posited that this conclusion is robust. In summary, this analysis validates platinum sensitivity as a crucial determinant of second - line therapy outcomes, while casting doubt on the efficacy of non - targeted cytotoxic combinations such as IL regimens. Concurrent chemoradiotherapy (CCRT) and prophylactic cranial irradiation (PCI) remain fundamental interventions for limited - stage small cell lung cancer (LS - SCLC), and emerging evidence supports the immunomodulatory role of radiotherapy in extensive - stage (ES) disease. Given the retrospective nature of the study, cautious interpretation of the findings is necessary. Nevertheless, the results offer a framework for optimizing therapeutic stratification and integrating novel agents. As the management of small cell lung cancer (SCLC) enters an era of biomarker - driven therapy, prospective validation of these insights is imperative to translate incremental survival improvements into meaningful patient outcomes.