Elsevier

Lung Cancer

Volume 82, Issue 2, November 2013, Pages 282-287
Lung Cancer

Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma

https://doi.org/10.1016/j.lungcan.2013.08.016Get rights and content

Abstract

Background

Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma.

Materials and methods

Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250 mg orally once a day until tumor progression or unacceptable toxicity.

Results

Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2–18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5–30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free (p = 0.003) and overall survival (p = 0.025).

Conclusion

Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.

Introduction

Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at diagnosis, and another 15% of patients develop them during the course of their disease. These rates of clinically-diagnosed brain metastases are, however, inferior to the rate in autopsy, and nearly half of patients with lung cancer may have brain metastases [1]. Selected patients may be treated by stereotactic radiosurgery (RS) alone, but the increased risk of brain recurrence after RS alone had been reported [2]. The effect of whole-brain radiation therapy (WBRT) on prevention of recurrence both at the initial site and at new sites after RS had been also reported [3]. Furthermore, more than half of the patients with brain metastases from NSCLC have multiple intracranial lesions [4]. Therefore, the standard treatment for brain metastases is surgical removal or RS followed by WBRT [5], even though the neurocognitive toxicity of WBRT is still debated [6], [7], [8].

A considerable proportion of patients with brain metastases also have extracranial lesions, and require systemic chemotherapy after treatment of brain metastases. However, delivery of anti-cancer agents to the intracranial tumors penetrating brain–blood barriers (BBBs) has been believed to be limited. This is the reason why radiation therapy is still the current standard of care for patients with brain metastases.

Recently, some reports indicated the safety of chemotherapy without radiation therapy for unselected NSCLC patients with brain metastases [9], [10]. If chemotherapy has sufficient effect on control of intracranial lesions, it may replace WBRT and patients can avoid the risk of their neurocognitive deterioration related to irradiation. Furthermore, small lesions may be controlled by chemotherapy alone without RS.

The aim of this study is to evaluate the safety and effect of gefitinib without radiation therapy for the selected patients whose tumors are expected to be sensitive to tyrosine kinase inhibitors (TKIs), and to clarify how long can TKIs delay irradiation for these patients.

Section snippets

Patients

Eligibility criteria included newly radiographically diagnosed brain metastasis from lung adenocarcinoma with mutations of epidermal growth factor receptor (EGFR), without history of chemotherapy using TKIs, with active extracranial lesions which required chemotherapy, age > 18 years, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤2. Smoking history was not included in eligibility criteria but obtained during the patient's first evaluation. The mutation status of

Patients

Between January 2007 and August 2012, 41 patients entered onto this study at Chiba Cancer Center. All of the patients were Asian Japanese and their characteristics were provided in Table 1.

Neurological deficit owing to brain metastasis was the primary symptom in only 3 cases (7.3%), and majority of the intracranial lesions were diagnosed by systemic evaluation at diagnosis of lung cancer (28 cases, 68.3%). Overall, brain metastases were diagnosed prior to initiation of any treatments in 31

Discussion

Gefitinib is a large molecule and a substrate of p-glycoprotein [12]. These suggested the inadequate delivery of this agent penetrating BBBs to the intracranial lesions and disappointed response of brain metastases. However, gefitinib showed favorable effect on control of brain metastases in this study. The excellent response of brain metastases to gefitinib indicated the permeability of this agent to the brain metastases which showed enhancement by contrast medium on MRIs. The response rate of

Conflict of interest

The authors have declared no conflict of interest.

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