Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy

Abstract

IntroductionTo explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT).Patients and MethodsEnrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS.ResultsFifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively.ConclusionThe BBB permeability of gefitinib increased in accordance with escalated dose of WBRT.

Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation

“…EGFR-TKIs, which are small molecular inhibitors of the EGFR pathway, have been proven much more effective than cisplatinbased chemotherapy in the progression-free survival of NSCLC patients (24). WBRT can also increase the bloodbrain barrier permeability of gefitinib (11). Therefore, EGFR-TKIs are effective in the management of NSCLC patients with brain metastasis.…”

“…The concomitant use of WBRT and gefitinib is well tolerated with a median OS time of 12.0 to 15.4 months (10,11). Some studies reported that the blood-brain barrier permeability of EGFR-TKIs could be increased in accordance with the escalated dose of WBRT (11,12). The cerebrospinal fluid-to-plasma ratio of NSCLC patients with brain metastasis reaches its peak (1.87%±0.72%) at a WBRT dose of 30 Gy (11).…”

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…Patients can often develop CNS metastases during treatment, even when their extracranial tumors are still under control (31). CNS concentrations of all currently available agents are lower than plasma [gefitinib has a CSF concentration approximately 1% of serum and erlotinib has a CSF concentration 5% of serum (32,33)]. Many EGFR TKIs that have been designed for improved CNS penetration are currently under investigation.…”

Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

“…Potential mechanisms of synergism include cell cycle arrest, induction of apoptosis, inhibition of radiation-induced DNA repair mechanisms and increased EGFR expression in radioresistant clones (69)(70)(71). In addition, radiotherapy might disrupt the BBB, facilitating passage of drugs into the brain (72).…”