High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor that induces an early and dramatic response in 10% of patients with advanced nonsmall cell lung carcinoma (NSCLC). Long- term outcome and patterns of disease recurrence after response have not been described. The authors evaluated 139 patients with NSCLC treated with gefitinib at Memorial Sloan-Kettering Cancer Center (New York, NY) between 1998 and 2002. They focused on patterns of disease recurrence, risk of brain metastases (BM) and leptomeningeal metastasis (LM), and long-term outcome after initial response to gefitinib. Of the 139 patients treated with gefitinib, 21 (15%) achieved a partial response. The median age of the responders was 64 years (range, 38-87 years), the median Karnofsky performance score was 80 (range, 60-90), and 4 of the patients were men. All responders had adenocarcinoma. The central nervous system (CNS) was the initial site of disease recurrence in 7 (33%) patients (BM in 5 and LM in 2). In 9 (43%) patients, the initial site of disease recurrence was the lung and in 1 it was the liver and bone. Four (57%) of the patients with disease recurrence in the CNS had lung disease under control. BM also developed in 2 patients who had initial disease recurrence in the lungs. The actuarial 5-year incidence of CNS metastases was 60%. The median overall survival periods were 15 months and 23 months for patients with and without CNS metastases, respectively (P = 0.24). The CNS was a frequent site of disease recurrence in patients with NSCLC after an initial response to gefitinib, regardless of disease control in the lungs. Patients should be carefully monitored for neurologic symptoms. Intrinsic resistance of metastatic clones, incomplete CNS penetrance of the drug, and longer survival are possible explanations for this high incidence.