Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE)

Abstract

Introduction: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established.

Methods: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC.

Results: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007).

Conclusions: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Figure 1.

Overall survival (OS) and central nervous system (CNS) progression after first-line SRS for patients with small-cell lung cancer (SCLC) vs non-small cell lung cancer (NSCLC). A) Retrospective dataset, OS. B) Retrospective dataset, first CNS progression (FCP). C) Retrospective dataset, distant CNS progression (DCP). D) Retrospective dataset, local CNS progression (LCP). E) Japanese Leksell Gamma Knife Society (JLGK0901) (prospective dataset), OS. F) JLGK0901, FCP. G) JLGK0901, DCP. H) JLGK0901, LCP. The hazard ratio (HR) and 95% confidence interval (CI) for OS analyses were modeled using multivariable Cox proportional hazard regression (CoxPH). Hazard ratio and 95% confidence interval were modeled for CNS progression analyses using multivariable Fine-Gray models treating death as a competing risk. Multivariable models were adjusted for cofactors as described in the methods section.

Figure 2.

Propensity score-matched (PSM) analyses in the retrospective dataset with NSCLC stratified by EGFR and ALK status. A) Overall survival (OS). B) First central nervous system (CNS) progression (FCP). C) Distant CNS progression (DCP). D) Local CNS progression (LCP). Three-way (1:1:1) PSM was performed to create cohorts balanced for number of brain metastases (BrM), cumulative BrM volume, extracranial metastases, Karnofsky Performance Status, extracranial metastases, presence of BrM at diagnosis, sex, year, and region. Patient characteristics displayed in Supplementary Table 3 (available online). The hazard ratio (HR) and 95% confidence interval (CI) for overall survival analyses were modeled using Cox proportional hazard regression (CoxPH). The hazard ratio and confidence interval were modeled for CNS progression analyses using Fine-Gray models treating death as a competing risk. Small-cell lung cancer (SCLC) represents the reference (HR = 1) for the OS and CNS progression models. EGFR = Epidermal growth factor receptor; ALK = Anaplastic lymphoma kinase.

Figure 3.

Neurological mortality and leptomeningeal disease (LMD) progression after first-line SRS. A) Retrospective dataset, neurological mortality. B) Japanese Leksell Gamma Knife Society (JLGK0901) (prospective dataset), neurological mortality. C) Retrospective dataset, LMD progression. D) JLGK0901, LMD progression. The hazard ratio (HR) and 95% confidence interval (CI) for overall survival analyses were modeled using multivariable Fine-Gray models treating any death as competing risk for LMD and nonneurological mortality as a competing-risk for neurological mortality. Multivariable models were adjusted for cofactors as described in the methods section.

Figure 4.

Number of lesions at first central nervous system (CNS) progression with non-small cell lung cancer (NSCLC) stratified by mutation status. Horizontal lines within the shaded boxes represent the median. Shaded boxes represent the interquartile range (IQR). Vertical thin solid lines (whiskers) extending above and below boxes represent quartile 3 + 1.5*IQR and quartile 1 − 1.5*IQR, respectively. Crosses above the vertical lines represent individual patient outliers. Six outliers above the y-axis are not shown due to display limitations (3 SCLC patients with 2-4 mets treated with first-line stereotactic radiosurgery (SRS) who had 32, 40, and 58 lesions at CNS progression and 3 non-mutated [no mut] NSCLC patients with 1 [n=1] and 2-4 [n=2] mets treated with first-line SRS who had 46, 33, and 50 lesions at CNS progression, respectively). The molecularly stratified analyses above were limited to patients treated in years 2005 and later as described in the methods. For statistical analyses: for comparison of all patients a log-linear regression was used and adjusted for number of lesions treated with SRS, for comparisons stratified by the number of lesions treated with SRS (1, 2-4, 5-10, >10 lesions) the Wilcoxon rank sum test was used, and for extensive (>10 lesions at CNS progression) comparisons a Fisher exact test was used. EGFR = Epidermal growth factor receptor; ALK = Anaplastic lymphoma kinase.