This study retrospectively compared the survival outcomes of patients with simple BM after first-line treatment failure in LS-SCLC between the monotherapy and the combined therapy, with the aim of evaluating the clinical benefits of combined therapy. This study compared 50 patients in each group and adjusted for background factors related to clinical importance and prognosis through PSM. The main finding of our study is that compared to RT alone, RT combined with ST significantly prolongs the patient’s ePFS. The combination of treatment and less than 6 BMs significantly reduced the risk of extracranial recurrence in patients. BMFS is not associated with prognosis after BM. The rate of AEs was not significantly different between the two groups.

Currently, cranial RT is used as standard treatment for patients with SCLC BM. However, BM are a blood-borne disease, so RT as a local treatment may not be sufficient for systemic control of the disease. The combination of ST can reduce the occurrence of extracranial lesions, and the combination of systemic and local control can achieve overall survival benefits [11]. Therefore, many pilot studies conducted in cancer patients with BM have explored the efficacy of ST combined with RT. Several controlled studies have found that ST can improve the response rate to intracranial lesions, prolong patients’ PFS and even OS [14,15,16,17]. Koide et al. performed a retrospective study for patients with BM from the institutional disease database between 2016 and 2021. They evaluated the clinical benefits of ST combined with stereotactic radiosurgery (SRS) for BM. Their conclusion shows that the combined therapy group showed significantly longer PFS (median, 7.4 vs. 5.0 months, P < 0.001) and OS (median, 23.1 vs. 17.2 months, P = 0.036) than the monotherapy group [17]. However, The studies by Neuhaus et al. and Ge et al. had several notable differences from these studies, the results of their studies did not find a clinical benefit of ST [18, 19]. In most studies, patients often had metastases to extracerebral sites in addition to BM, and it is possible that, for ethical reasons, some studies were designed to allow ST to be administered to the RT alone group after completion of the treatment, resulting in non-comparable results for BM in the studies. To our knowledge, there are no reports comparing RT combined with ST with RT alone for simple BM after failure of first-line treatment for LS-SCLC. One of the advantages of this study is that the research subjects are patients with simple BM, and no patients in the RT only group receive ST, avoiding ethical issues. To further explore this issue, we conducted a retrospective study and collected 133 patients who met the inclusion criteria for the study.

The results of this study indicate that RT combined with ST can prolong ePFS in SCLC BM patients, without significant effects on OS, PFS, and iPFS. The proportion of SCLC BM patients receiving ST is not yet clear. However, in this study population, 50% of patients adopted a combination therapy regimen, indicating that combination therapy is not uncommon in clinical practice. A study conducted by European Organization for Research and Treatment of Cancer (EORTC) on the efficacy of WBRT for SCLC BM showed a higher recurrence rate after WBRT, proving that almost no patients have long-term benefits from WBRT. Therefore, even in SCLC patients with simple BM, it may be proposed to increase systemic therapy on the basis of WBRT [20]. The results of this study demonstrate that combined ST can reduce the occurrence of extracranial lesions and prolong the patient’s ePFS (P = 0.04). It may be due to the abundance of blood supply and lymphatic tissue in the lung tissue that cancer cells metastasis to the brain tissue mainly through lymphatic and blood circulation [21], and systemic therapy eliminates the tumor cells in the lymphatic and blood circulation, thus delaying the onset of extracranial progression. A study included 698 patients with SCLC BM, divided into four groups: the WBRT group (n = 178), the CT group (n = 129), the WBRT plus CT group (n = 273), and the best supportive care group (n = 118), and the results of the study demonstrated that WBRT plus CT improved the OS of patients with BM from SCLC, CT alone and WBRT alone did not show any survival benefits [22]. Although the number of patients is greater than that in this study, it includes patients with extracerebral metastasis other than BM, and the research results may be biased. In the present study, although there was no increase in OS and PFS in the combination therapy group, this is not surprising. It is possible that because of the small number of patients, we were unable to show the improved results when using combined therapy. ST is active, but it has been shown that the response of BM lesions to systemic CT (relative risk = 27%) is much lower than that of extracranial lesions (relative risk = 73%) [23, 24], and the drug diffuses poorly on the blood-brain barrier, resulting in limited impact of combined therapy on iPFS. Although the results of this study indicate that combined therapy does not reduce the risk of intracranial progression, we believe that cautious selection of ST may have the opportunity to improve iPFS. Studies have shown that ICIs with potential intracranial responses, such as atezolizumab and durvalumab, also have effects in the treatment of SCLC BM [25, 26]. A single-arm multicenter trial of platinum-etoposide plus atezolizumab for the treatment of untreated SCLC BM patients was recently initiated (NCT04610684). Therefore, RT combined with CT or ICIs is a promising research direction for SCLC BM [27].

In our study, multivariate regression analysis showed that combined therapy and fewer than 6 BMs significantly reduced the risk of extracranial recurrence in patients. Combined therapy was independently associated with better ePFS (HR = 0.617, P = 0.034), and more than 5 BMs were associated with worse ePFS (HR = 1.808, P = 0.012). PCI can not only eliminate small lesions that cannot be detected by imaging, but also increase the permeability of the blood-brain barrier, promote drug entry into the brain to eliminate lesions, reduce the occurrence of BM, and bring survival benefits to patients. A study has found that adding PCI to standard treatment for limited period SCLC reduces the 3-year incidence of BM from 59 to 33%, and improves the 3-year survival rate by 5.4% [28]. The incidence of BM in patients undergoing PCI decreased. The patients included in this study were those who developed BM after first-line treatment, so the number of patients who received PCI was relatively low (12%). History of PCI (P = 0.019) was significantly correlated with ePFS in univariate analysis, However, the results of the multivariate analysis showed that PCI was not associated with ePFS (P = 0.063). We believe that PCI, as a local treatment, has a limited impact on the risk of extracranial recurrence, which is consistent with the results of the multivariate analysis. In previous retrospective analysis, several prognostic factors have been identified for SCLC BM patients. Significant adverse prognostic factors include lower KPS, older age, presence of extracranial metastasis, and number of BMs [29, 30]. Due to the limited number of patients in previous analyses, SCLC BM patients were grouped with other solid tumors, especially non-small cell lung cancer (NSCLC), or the number of patients was too small to reasonably evaluate valuable prognostic factors [31, 32]. This study avoided the limitations of previous studies and conducted prognostic analysis on 100 patients with SCLC BM. We believe that it may be due to the fact that those with a higher number of BMs are prone to combine with more severe occupying effects and more brain tissue edema. In the absence of differences in other influencing factors, the tumor load may increase, leading to a shortened ePFS. Therefore, we believe that patients with more than 5 BMs should be actively treated with a combined therapy.

There is currently no consensus on whether the occurrence of BM is related to prognosis. The results of this study indicate that BMFS is not associated with prognosis after BM. The research results of Bernhardt on SCLC BM showed that patients with BMFS = 0–3 had better survival after BM than those with BMFS > 3 (P = 0.000) [31]. This study suggests that due to the high sensitivity of SCLC to early radiotherapy and chemotherapy regimens, but the early development of resistance to conventional treatment, the treatment effect of late onset BM is not satisfactory. The disadvantage of this study is that it did not consider the patient’s extracranial metastasis. To exclude the impact of extracranial metastasis on the results, this study selected SCLC patients with the first distant metastasis as BM. The results showed that BMFS had no significant impact on the survival of patients after BM occurred. This may be due to most patients have multiple BMs, which can cause significant damage to central nervous system function, and the general condition of patients can rapidly decline in a short period of time.

There are some limitations to this study. First, the results of this study may be confounded by other unobserved variables, and although we used rigorous statistical methods to adjust for baseline characteristics between the groups, these unobserved confounders may have been unbalanced between the groups and may have affected survival differences. Therefore, our findings should be interpreted with caution; second, the lack of data on the cause of death of patients (cancer-related or noncancer-related) and the fact that our analysis was not related to competing risks of death due to nonlung cancer may have led to bias in the calculated survival data. However, because the two groups did not show differences in age and KPS, we assumed that the competing risks of death were similar. Therefore, we believe that this bias, although present, did not significantly affect our results. A multicentre prospective study could be conducted in the future to further validate the conclusions of this study.

In summary, for patients with simple BM after first-line treatment of LS-SCLC, RT combined with ST shows the potential to improve ePFS compared to RT alone. Especially for patients with more than 5 BMs, an active combination therapy model should be adopted. The research results support the recent trend of combining systemic and local therapies, and encourage future randomized controlled trials to explore the best combination regimen and reasonable combination strategies.