Elsevier

Lung Cancer

Volume 77, Issue 3, September 2012, Pages 556-560
Lung Cancer

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation

https://doi.org/10.1016/j.lungcan.2012.05.092Get rights and content

Abstract

Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8–9.3 months) and 15.9 months (95% CI, 7.2–24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6–17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.

Introduction

During the last decade, treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients has been changed dramatically than before. Especially, it is recommended as an option to treat the NSCLC patients who harbor an epidermal growth factor receptor (EGFR) mutation with EGFR tyrosine kinase inhibitors (TKIs) as first line treatment, replacing conventional cytotoxic chemotherapy owing to its good and rapid response [1], [2], [3], [4]. However, there are still some controversies to use an EGFR TKI as first-line treatment for metastatic brain tumors, especially symptomatic ones. Traditionally, whole brain radiotherapy (WBRT) has been regarded as a standard treatment against brain metastases, and in some cases surgical resection or stereotactic radiosurgery can be used [5]. Even though these local therapies showed a higher response in terms of local control, they have some limitations for their use; WBRT might deteriorate patient's performance status and limit further systemic chemotherapy in patients who have metastases outside the brain [6], [7], [8], [9], therefore surgical resection or radiosurgery can be considered for limited number of tumors and/or rather small or well-located tumors [10], [11]. In addition, the concept of “a pharmacologic sanctuary site” that systemic chemotherapy cannot penetrate into metastatic brain tumors due to the blood–brain barrier is not true for at least clinically overt tumors [8], [12].

Based on our prior retrospective study that EGFR TKI therapy was very effective for a clinically enriched population of patients with brain metastases, that is, never-smokers with adenocarcinoma [13], we prospectively investigated the efficacy of EGFR TKI therapy as first-line treatment for metastatic brain tumors in NSCLC patients whose tumor harbors an activating EGFR mutation.

Section snippets

Eligible patients

The two main eligibility criteria were pathologically confirmed NSCLC harboring an activating EGFR mutation and documented measurable brain metastases. Prior local therapy to metastatic brain tumors, such as radiosurgery or surgical resection as well as WBRT was not allowed but systemic chemotherapy was allowed. Followings are other eligibility criteria: (1) age over 21 years, (2) Eastern Cooperative Oncology Group (ECOG) performance status  3, and (3) adequate organ functions defined as

Patient characteristics

Between October 2006 and December 2010, a total of 28 patients participated in this study (Table 1). Sixteen patients (57%) had synchronous brain metastases at diagnosis. At the time of commencement of EGFR TKI therapy, 6 patients (22%) had only brain lesions without systemic disease, but curative local treatment such as brain surgery or radiosurgery was not indicated because of the size and number of their brain lesions. Eighteen had a mutation in exon 19 and the other 10 in exon 21. Fifteen

Discussion

We observed a very high response rate of 83% in patients having metastatic brain tumors with a median PFS of 6.6 months and OS of 15.9 months, which might be rather shorter than those in previous studies which enrolled the patients with metastatic NSCLC harboring EGFR mutations without brain metastases [14], [15], [16]. This might reflect aggressiveness of the disease itself or NSCLC with brain metastases. However, our study included significant proportion of patients with neurologic symptoms

Conflict of interest

None declared.

Acknowledgments

This study was supported by grants of the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (Grant Number: A070001 and A102059).

References (22)

  • D.H. Lee et al.

    Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first: result of a randomized pilot study

    Cancer

    (2008)
  • Cited by (303)

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    These authors contributed equally to this work.

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