Background
Small cell lung cancer (SCLC), which is well known for its aggressiveness and early dissemination, is associated with a high propensity for brain metastases (BMs) [
1]. According to statistics, 10% of SCLC patients have BMs at the time of the initial diagnosis, which increases to 50% of patients by 2 years after the diagnosis [
2]. For those SCLC patients with BMs, the prognosis of the disease is generally poor with a median survival of fewer than five months [
3]. Based on the 2018 National Comprehensive Cancer Network (NCCN) guidelines, whole brain radiation therapy (WBRT) is the standard treatment for SCLC patients with BMs [
4], and 50–80% of patients respond positively to treatment [
3].
MRI is extensively utilized to detect BMs in the clinic and more microscopic tumor infiltrates can be discovered during the early stages of metastasis. The detection of BMs has increased by more than 14% since the beginning of the MRI era [
5]. Patients with a limited number (1 to 3) of BMs are more readily diagnosed, which has led to favorable patient outcomes and increased life expectancies [
6]. With the current expansion of the highly effective stereotactic surgery (SRS) as a locally ablative treatment modality, randomized trials have demonstrated that BMs could be safely and effectively treated with SRS-alone in patients having up to 10 BMs [
7,
8]. While some retrospective studies have recommended SRS as the first-line treatment for providing effective local control of BMs in SCLC [
9,
10], SRS-alone is less frequently used in this cohort because of the development of diffuse intracranial metastases. Previous randomized trials showed that the combination of SRS and WBRT could improve the overall survival of cancer patients with a single BM [
11,
12]. However, the dose escalation strategy has not been extensively investigated in SCLC patients, and it is unknown whether the combination of WBRT with an additional radiation boost is a feasible treatment option to increase the survival of SCLC patients with BMs. In this study, we retrospectively evaluate the outcome and prognosis of SCLC patients with BMs when treated with WBRT plus a radiation boost or WBRT-alone.
Discussion
This single-institution study retrospectively evaluated a cohort of LS-SCLC patients who had not suffered from extracranial metastases before being diagnosed with BMs. Our results demonstrated that WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone.
It is generally believed that SCLC-derived BMs are rarely solitary and characterized by early intracranial dissemination [
1].Even in stage I-III SCLC patients treated with surgical resection, the cumulative incidence of BMs is up to 25% [
15]. WBRT remains the standard treatment because of the limited life expectancy of SCLC patients with BMs, in addition to the lack of other effective treatments available [
16]. Considering the high frequency of intracranial recurrences, SRS or surgery-alone are rarely curative in SCLC patients. However, there is a growing body of evidence suggesting feasibility of SRS alone for treatment of BMs in patients with SCLC. Currently, a German phase 2 study is evaluating this concept [
17] and the optimal management of BMs remains obscure. Several clinical trials have reported the use of WBRT plus a radiation boost in the management of BMs. Andrews et al. [
11] recruited 331 patients with 1 to 3 BMs. In the entire cohort, WBRT plus SRS significantly improved the local control of intracranial metastases at 1 year (82% vs. 71%,
p = 0.013), as well as the KPS scores (43% vs 27%,
p = 0.03), compared with WBRT-alone. In addition, a survival benefit was observed in patients with a single BM with the median OS of 6.5 and 4.9 months for WBRT and WBRT plus SRS, respectively (
p = 0.039). Of note, only 24 patients (7%) in this cohort were diagnosed with SCLC. A secondary analysis of JROSG 99–1 compared WBRT plus SRS with SRS-alone in 132 non-small cell lung cancer (NSCLC) patients who had 1 to 4 BMs. Aoyama et al. [
12] reported that WBRT plus SRS significantly improved the OS in the subgroup of DS-GPA 2.5–4.0 with a median OS of 16.7 months vs. 10.6 months, respectively (
p = 0.04).
Is WBRT plus a radiation boost also a feasible treatment for patients with SCLC? Currently, no previous studies have comprehensively investigated this issue. Wegner et al. [
9] compared 44 SCLC patients who underwent SRS with or without WBRT, and WBRT plus SRS was found to be associated with improved OS in patients from 6 months to 14 months after treatment (
p = 0.04). However, this result should be interpreted cautiously as the sample size was small, consisting of only six patients who were treated in the WBRT plus SRS group. In a large-scale cohort of 4259 patients, Sperduto et al. [
6] reviewed the records of 299 SCLC patients with BMs. From the cohort, 247 patients were treated with WBRT-alone, while 21 patients were treated with WBRT plus SRS. The OS was significantly higher in the WBRT plus SRS patients with the median OS of 15.23 months vs. 3.87 months, respectively (
p = 0.003). Traditionally, WBRT patients may have more BMs and worse functional autonomy (KPS) than patients treated with WBRT plus SRS. However, Sperduto et al. failed to correct the differences between two treatment groups. Our study validated these characteristics and further analyzed those patients with 1 to 3 BMs. The OS benefit in the WBRT plus boost group remained significant, while the median OS in the WBRT plus boost group was similar to that from previous studies [
6,
9].
In several previous analyses, some prognostic factors such as KPS, age, extracranial metastases status, number of BMs, and metachronous disease have been identified in SCLC patients with BMs [
6,
18‐
20]. In this study, symptomatic BMs, extracranial disease status and maximum diameter of the largest tumor were significantly associated with OS in both the univariate and the multivariate analyses. Furthermore, the OS was significantly affected by the number of BMs and KPS in the univariate analysis.
One of the novel discoveries of this study was that there was no significant difference in OS between patients with 1 to 3 BMs and more than 3 BMs in the WBRT group (
p = 0.384). Based on the DS-GPA classification, the number of BMs was a significant prognostic factor [
6]. However, the patients in this cohort were managed using different treatment modalities, including WBRT, SRS, or WBRT plus SRS or surgery, which may lead to inappropriate conclusions. Bernhardt et al. [
19] retrospectively analyzed 229 SCLC patients who were treated with WBRT, and showed that the number of BMs was not a significant prognostic factor in the univariate (
p = 0.06) or the multivariate analysis (
p = 0.511). Another study compared the different courses of WBRT in 146 SCLC patients and showed that the number of BMs was significantly associated with improved OS (
p = 0.011) and local intracranial control (
p = 0.027) [
21]. These contradictory results may be due, at least in part, to the different size of BMs. For this reason, we further analyze the tumor size in the entire cohort. Similar to previous studies [
7], the patients with the smaller tumor size were significantly associated with improved OS in both the univariate (
p = 0.002) and the multivariate analyses (
p = 0.015). While WBRT-alone could provide active remission for small or subclinical lesions, it might have limited effect against larger metastases.
There are several limitations to this analysis. First, the proportion of patients with multiple BMs was significantly higher in the WBRT group. Although we further analyzed the patients 1 to 3 BMs, the results may be limited by the treatment selection bias. Secondly, because of missing data points about intracranial recurrence and uniform toxicity assessments, we failed to evaluate local intracranial control and dose escalation-related toxicities in the present study. Thirdly, this is a small-sample retrospective study with certain inherent bias, and the conclusion should be validated in further prospective studies.