Clinical Investigation
Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

https://doi.org/10.1016/j.ijrobp.2014.02.022Get rights and content

Purpose/Objectives

Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM.

Methods and Materials

Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified.

Results

222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004).

Conclusions

The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

Introduction

Lung cancer is the leading cause of death in the United States, with an estimated 226,000 diagnoses and 160,000 deaths in 2012 (1). Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancer diagnoses. Approximately 20% to 40% of patients with NSCLC experience brain metastases (BM) during the course of their illness (2). Historically, whole brain radiation therapy (WBRT), alone or in combination with surgery and stereotactic radiosurgery (SRS), has been the standard of care for BM. In historical series of WBRT for solid tumors, the median overall survival (OS) is only 4.5 months (3). More recent data examining survival in patients with BM in a population selected for patients with EGFR mutations have shown survival rates of 14.5 to 17 months from the time of BM development 4, 5, 6.

In recent years, EGFR tyrosine kinase inhibitors (TKI) have replaced cytotoxic chemotherapy as first-line therapy for patients with metastatic EGFR-mutant disease, based on randomized trials demonstrating improved survival with EGFR-TKI compared with cytotoxic chemotherapy 7, 8, 9. Yet, the treatment of patients with EGFR mutations and BM remains controversial. There are lower rates of central nervous system (CNS) progression in patients with EGFR-mutant advanced NSCLC treated with an EGFR-TKI than in those receiving chemotherapy (10). Phase 2 trials have demonstrated the efficacy of EGFR-TKI as treatment for BM in patients with EGFR-mutant NSCLC without the upfront use of radiation 5, 11. Other phase 1 and phase 2 trials have explored the concurrent use of WBRT and erlotinib 12, 13, and a phase 3 trial investigated the combination of WBRT, SRS, and erlotinib (14). However, the relative benefits of radiation therapy (RT) versus EGFR-TKI in EGFR-mutated patients with BM have not been determined. Because brain RT is associated with potential neurocognitive long-term toxicities, it is of significant clinical interest whether EGFR-TKI therapy is sufficient to manage BM in this population.

We therefore conducted a retrospective review of patients at our institution who received diagnoses of EGFR-mutated adenocarcinoma with BM. To our knowledge, this is the first analysis that directly compares RT against EGFR-TKI as first-line therapy for BM in EGFR-mutant adenocarcinoma. We hypothesized that there would be no difference in OS between patients treated with upfront WBRT versus EGFR-TKI and that the rates of intracranial progression (ICP) would be lower in the WBRT group.

Section snippets

Study design and patients

Using an institutional query system, we identified all patients with BMs and lung adenocarcinoma who harbored EGFR mutations and were treated at our institution from 2006 to 2012. The starting date, 2006, was when our institution initiated reflex testing for EGFR mutations in all NSCLC patients. Because our goal was to compare RT and EGFR-TKI in the treatment of EGFR-TKI–naïve patients, we excluded all patients who experienced BM while already receiving EGFR-TKI. In the majority of these

Patient characteristics

Between January 1, 2006, and December 31, 2012, 222 patients were identified with metastatic EGFR-mutated adenocarcinoma with BM. Fifty-seven patients were excluded because they received EGFR-TKI prior to the development of BM, and 7 patients were excluded with de novo EGFR-TKI resistance mutations. Forty-eight additional patients were excluded because they came to our institution for consultation only, or because there was no pretreatment imaging. The remaining 110 patients were treated for BM

Discussion

To our knowledge, this is the first report directly comparing EGFR-TKI treatment with brain RT in a molecularly selected group of patients with NSCLC and BM. We found similar rates of survival but a significantly increased time to ICP among patients treated with WBRT versus erlotinib, with 1-year and 2-year rates of intracranial control of 73% and 52% in the WBRT group. This difference in intracranial control lost significance on MVA.

For patients with metastatic EGFR-mutant NSCLC, EGFR-TKIs are

Acknowledgment

The authors thank Lawrence Herman for editorial assistance with the manuscript.

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  • Cited by (0)

    Conflict of interest: none.

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