Findings from the CROSS-FIRE study may inform individualized decision-making regarding stereotactic radiosurgery for patients with small cell lung cancer, according to Chad Rusthoven, MD.
Small cell lung cancer (SCLC) histology correlated with worse overall survival (OS) outcomes compared with non–small cell lung cancer (NSCLC) following treatment with frontline stereotactic radiosurgery (SRS), according to findings from The Comparison of First-line Radiosurgery for SCLC and NSCLC Brain Metastases (CROSS-FIRE) study published in Journal of the National Cancer Institute.
Analysis of a retrospective dataset highlighted a median OS of 10.5 months for patients with NSCLC vs 8.6 months for those with SCLC (multivariable HR, 0.79; 95% CI, 0.73-0.86; P <.001). There was a statistically significant decrease in risk of first central nervous system (CNS) progression for those with NSCLC compared with the SCLC population (HR, 0.82; 95% CI, 0.73-0.92; P = .001). Investigators identified a similar trend between these disease types with respect to distant CNS progression (HR, 0.82; 95% CI, 0.73-0.93; P = .002).
Based on an analysis of comparative prospective data from the Japanese Leksell Gamma Knife Society (JLGK0901) study evaluating single-fraction SRS across mixed tumor histology, the median OS was 13.0 months for patients with NSCLC vs 8.7 months for those with SCLC (HR, 0.68; 95% CI, 0.54-0.85; P = .001). Additionally, estimates of HRs for first CNS progression and distant CNS progression in the JLGK0901 study were comparable with estimates in the retrospective CROSS-FIRE dataset.
Investigators observed no differences in neurological mortality between the SCLC and NSCLC populations in the retrospective data set (HR, 0.98; 95% CI, 0.80-1.20; P = .83) and the JLGK0901 dataset (HR, 1.35; 95% CI, 0.56-3.26; P = .50). Leptomeningeal disease risk appeared higher among those with NSCLC in the retrospective data set (HR, 1.61; 95% CI, 1.14-2.26; P = .007), and investigators identified no statistically significant differences in the JLGK0901 study. In the retrospective dataset, EGFR- or ALK-positive disease conferred an increased leptomeningeal disease risk in NSCLC compared with SCLC (HR, 2.19; 95% CI, 1.42-3.39; P <.001), although this did not apply to mutation-negative NSCLC relative to SCLC (HR, 1.10; 95% CI, 0.66-1.85; P = .71).
“Overall, the results of [the] CROSS-FIRE [study] were nuanced, in some areas supporting conventional wisdom—inferior OS in SCLC vs NSCLC after SRS—and in other areas directly challenging it—no significant differences in number of lesions at CNS progression and neurological mortality after SRS between SCLC and NSCLC,” lead study author Chad Rusthoven, MD, stated in a written comment to CancerNetwork®. “These data place expected outcomes with SRS in SCLC in the familiar context of SRS in NSCLC and may better inform individualized decision-making regarding SRS for patients [with] SCLC.”
Rusthoven is an associate professor of Radiation Oncology in the Department of Radiation Oncology at the University of Colorado School of Medicine.
Investigators of the CROSS-FIRE study analyzed outcomes in patients who received frontline SRS without prior whole-brain radiotherapy (WBRT) or prophylactic cranial irradiation in a retrospective and prospective dataset from the JLGK0901 study. Of 1194 patients enrolled across 23 treatment centers in Japan as part of the JLGK0901 study, 912 had brain metastases from lung cancer and were thus included in the analysis.
The primary end points of the CROSS-FIRE study were OS, first CNS progression, distant CNS progression, and local CNS progression in SRS-treated lesions. Secondary end points included neurological mortality, leptomeningeal disease progression, rates of salvage therapy, and treatment-related adverse effects (TRAEs).
Overall, 892 patients with SCLC and 4785 patients with NSCLC were included in the retrospective data set, with corresponding populations of 98 and 814 patients in the JLGK0901 dataset for each respective histology. The median follow up was 61.9 months in the retrospective dataset vs 49.0 months in the JLGK0901 dataset.
In the retrospective dataset, 193 patients with SCLC had a median of 2 brain metastases at CNS progression vs 3 among 620 patients with NSCLC (P = .83). Rates of progression with extensive brain metastases were 16.6% vs 14.5% in each group (P =.49).
Among 449 patients with SCLC and 1131 patients with NSCLC with available data in the retrospective dataset, any-grade treatment-related necrosis occurred in 7.8% and 9.4% of those in each respective group (P = .38). Moreover, rates of any-grade toxicity in the JLGK0901 population were 5.1% for those with SCLC and 9.6% for those with NSCLC (P = .19).
In the retrospective dataset, salvage SRS was performed for 36.7% of those with SCLC and 36.9% of those with NSCLC (P = .38). Rates of salvage WBRT were 15.0% and 7.3% in each respective group (P <.001). In the JLGK0901 population, the salvage SRS rates were 39.8% and 44.1% (P = .58), and the salvage WBRT rates were 20.4% and 10.9% for each disease type (P <.001).
“There are important ongoing randomized trials comparing SRS vs WBRT specifically in patients [with] SCLC, including the randomized phase 2 ENCEPHALON trial [NCT03297788] and the randomized phase 3 NRG CC009 study [NCT04804644],” Rusthoven stated regarding the next steps for research in this patient population. “Results from these prospective randomized trials will be essential to defining the role of SRS for patients [with] SCLC going forward.”
Rusthoven CG, Staley AW, Gao D, et al. Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE). J Natl Cancer Inst. 2023;115(8):926-936. doi:10.1093/jnci/djad073