Leptomeningeal Metastases More Common in NSCLC With EGFR Mutations, May Be Responsive to Tyrosine Kinase Inhibitors
Leptomeningeal metastases, a serious complication in lung cancer patients, were found to be more prevalent in patients with non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In a recent study of leptomeningeal metastases published by Li et al in the Journal of Thoracic Oncology, patients receiving tyrosine kinase inhibitors targeting EGFR mutations had a longer overall survival than those who did not receive tyrosine kinase inhibitors, demonstrating the effectiveness of these agents for treatment of leptomeningeal metastases.
Leptomeningeal metastases occur in 10% to 26% of lung cancer cases, and their presence is often associated with poor survival. Treatment strategies for leptomeningeal metastases include epidermal growth factor receptor tyrosine kinase inhibitors, chemotherapy, whole-brain radiotherapy, intrathecal chemotherapy, surgery, and ventriculoperitoneal shunt operations. However, therapeutic options for treating leptomeningeal metastases are challenging with no standard treatment. The use of EGFR tyrosine kinase inhibitors markedly prolongs survival in patients with EGFR mutations.
Study Methodology
A group of Chinese investigators retrospectively screened 5,387 NSCLC patients at Guangdong Lung Cancer Institute, Guangdong General Hospital, from January 2011 to June 2015 to examine the prevalence of EGFR mutations in NSCLC patients with leptomeningeal metastases as well as treatments and clinical outcomes. Medical records of patients were reviewed for demographics, tumor-related features, and major treatments.
Patients with known EGFR status were screened for leptomeningeal metastases by cerebrospinal fluid cytology test or gadolinium-enhanced brain magnetic resonance imaging (MRI). Overall survival was determined from the diagnosis of leptomeningeal metastasis to death or last follow-up. Overall survival was estimated using the Kaplan-Meier method and presented as a median value with a two-sided 95% confidence interval (CI).
Key Findings
Results showed that of the 5,387 patients examined, only 3,775 patients were tested for EGFR gene status. Of those tested for EGFR status, 1,258 patients had confirmed EGFR mutations and 2,517 had wild-type EGFR. The incidence of leptomeningeal metastases in all 5,387 patients was 3.4% (184 of 5,387). However, the incidence of patients with leptomeningeal metastases harboring EGFR mutations (9.4%, 118 of 1258) was significantly higher than those with a wild-type EGFR status (1.7%; 42 of 2,517; χ2 = 122.9, P < .001). Of the 118 patients harboring EGFR mutations, 109 patients had the most common EGFR mutations, 53 had exon 19 deletions, and 56 had Leu858Arg mutations (L858R).
Patients given tyrosine kinase inhibitors for treatment of leptomeningeal metastases had longer overall survival than patients that did not take tyrosine kinase inhibitors (10 months, 95% CI = 8.9–11.1 vs 3.3 months, 95% CI = 0.5–6.1; P < .001). Patients who had not taken tyrosine kinase inhibitors prior to the discovery of leptomeningeal metastases demonstrated a longer overall survival than those for whom initial tyrosine kinase inhibitor therapy had failed (12.2 months, 95% CI=9.7–14.8 vs 9.2 months, 95% CI=7.8–10.5; P = .016).
Patients who underwent whole-brain radiotherapy for leptomeningeal metastases did not show longer overall survival than those without whole-brain radiotherapy (9.3 months, 95% CI=8.4–10.3 vs 8.1 months, 95% CI=4.8–11.4; P = .448). Patients treated with both whole-brain radiotherapy and tyrosine kinase inhibitors did not have longer overall survival than those who only received tyrosine kinase inhibitors (9.7 months, 95% CI = 8.7–10.8 vs 10.1 months, 95% CI=7.1–13.1; P = .778).
Chemotherapy after leptomeningeal metastases was associated with prolonged survival compared to those not receiving chemotherapy (21.0 months, 95% CI = 14.8–27.1 vs 8.7 months, 95% CI = 6.8–10.6; P = .001). Overall, the two factors that significantly affected prolonged survival after leptomeningeal metastases were tyrosine kinase inhibitors (P < .001, hazard ratio [HR] = 0.218, 95% CI = 0.116–0.411) and chemotherapy (P < .001, HR = 0.206, 95% CI = 0.092–0.460).
Conclusions
The authors commented: “This study had some limitations; however, we showed that overall survival after [leptomeningeal metastases] was longer than that in previous reports, and [leptomeningeal metastases] were much more frequent in NSCLC patients harboring EGFR mutations. EGFR-tyrosine kinase inhibitors were the optimal strategy for [leptomeningeal metastases] with EGFR mutations, especially [in] tyrosine kinase inhibitor treatment–naive patients. Nevertheless, active treatment with whole-brain radiotherapy, with or without EGFR tyrosine kinase inhibitors, was not supported by our study.”
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