Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE)
Authors: Rusthoven Chad G , Staley Alyse W , Gao Dexiang , Yomo Shoji , Bernhardt Denise , Wandrey Narine , El Shafie Rami , Kraemer Anna , Padilla Oscar , Chiang Veronica , Faramand Andrew M , Palmer Joshua D , Zacharia Brad E , Wegner Rodney E , Hattangadi-Gluth Jona A , Levy Antonin , Bernstein Kenneth , Mathieu David , Cagney Daniel N , Chan Michael D , Grills Inga S , Braunstein Steve , Lee Cheng-Chia , Sheehan Jason P , Kluwe Christien , Patel Samir , Halasz Lia M , Andratschke Nicolaus , Deibert Christopher P , Verma Vivek , Trifiletti Daniel M , Cifarelli Christopher P , Debus Jürgen , Combs Stephanie E , Sato Yasunori , Higuchi Yoshinori , Aoyagi Kyoko , Brown Paul D , Alami Vida , Niranjan Ajay , Lunsford L Dade , Kondziolka Douglas , Camidge D Ross , Kavanagh Brian D , Robin Tyler P , Serizawa Toru , Yamamoto Masaaki 
Published: May 2023

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 &lt; .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 &lt; 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.