Multiple Small Brain Metastases with Limited Focal Brain Edema from Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

Introduction

Lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of cases of primary lung cancer ( ). Lung cancer is also the most frequent origin of metastatic brain tumors and accounts for 50% of cases. In addition, more than 25% of patients with lung cancer develop brain metastases (BM) during the clinical course of their illness ( ). Despite treatment with systemic chemotherapy and/or local radiotherapy, the prognosis of NSCLC patients with BM remains extremely poor. Most cases of BM are characterized by the presence of multiple tumors, up to four in number ( ). Although stereotactic radiosurgery is a treatment option for BM with up to four tumors ( ), the standard therapy for multiple BM is still whole brain radiotherapy (WBRT). Since the results of treatment with WBRT are not satisfactory, an alternative promising therapeutic option for multiple BM is needed ( ).

Recently, epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have been developed as molecular-targeted drugs for use in the treatment of lung and other cancers. Dramatic effects of EGFR-TKIs have been reported with regard to the treatment of NSCLC with EGFR mutations ( ). In addition, a positive effect of these molecular-targeted drugs on multiple BM from NSCLC with EGFR mutations has also been demonstrated in comparison with the effects of conventional systemic chemotherapy ( ). Therefore, EGFR-TKIs have become an efficient therapeutic option for multiple BM. This chapter discusses the clinical characteristics, management, and treatment of BM in NSCLC patients with EGFR mutations.

Epidermal Growth Factor Receptor Mutations

EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, and its dysregulation leads to the development and progression of NSCLC ( ). EGFR-TKI blocks this signaling pathway and has proved effective for NSCLC with EGFR mutations within the TK domain ( ). Ninety percent of EGFR mutations are an exon 19 deletion and exon 21 point mutation, which are called major EGFR mutations ( ). These mutations are commonly associated with Asian ethnicity, female gender, and a never or former light smoking history. EGFR mutations are identified in approximately 60–70% of Asian NSCLC patients with a never or former light smoking history ( ). On the other hand, 6–11% non-Asian current smokers possess EGFR mutations. To date, the assessment of EGFR mutation status is generally considered necessary for all NSCLC patients if possible ( ). Since the advent of EGFR-TKIs, the overall survival of NSCLC patients with EGFR mutations ranges from 24 to 30 months compared with a 10–15 month overall survival of NSCLC patients with EGFR wild-type ( ). The presence of EGFR mutations has been reported as a better prognostic factor, regardless of the presence or absence of BM ( ).

Multiple Brain Metastases and EGFR Mutations: Influence of the Exon 19 Deletion on Radiographical Features

first reported that EGFR mutations were frequently identified in NSCLC patients with multiple BM. demonstrated the association of an exon 19 deletion with miliary lung metastases. With reference to these two reports, we investigated the radiographical characteristics of synchronous BM from NSCLC with major EGFR mutations at the time of NSCLC diagnosis and found that NSCLC patients with the exon 19 deletion possessed multiple small BM with limited focal edema, unlike the features of NSCLC patients with EGFR wild-type ( ). A typical case of BM from NSCLC with the exon 19 deletion is presented in Figure 10.1 . The mechanism to explain these results remains unclear. Although very few reports have examined the clinical characteristics of NSCLC patients with the exon 19 deletion, we propose the following three mechanisms. First, NSCLC with the exon 19 deletion may metastasize more easily to other organs, including the brain. In fact, EGFR mutations have been frequently identified in NSCLC patients with multiple brain and lung metastases ( ). Second, NSCLC with the exon 19 deletion may be related to smaller tumor diameter compared with NSCLC with EGFR wild-type. In primary site tumors, a correlation has been reported between EGFR mutations and smaller tumor diameter ( ). Finally, NSCLC with the exon 19 deletion may have less ability to produce edemagenic factors and destroy the blood–brain barrier. Previous reports have demonstrated that brain edema is generally caused by the production of edemagenic factors such as vascular endothelial growth factor and aquaporin, and by destruction of the blood–brain barrier ( ). In addition, our results may indicate that BM from NSCLC with the exon 19 deletion has some features in common with miliary BM. This possibility is discussed below.