Keywordsbrain metastases, non-small cell lung cancer, EGFR mutations, epidermal growth factor receptor tyrosine-kinase inhibitors, treatment, gefitinib, erlotinib
Epidermal Growth Factor Receptor Mutations 106
Multiple Brain Metastases and EGFR Mutations: Influence of the Exon 19 Deletion on Radiographical Features 107
Miliary Brain Metastases and EGFR Mutations 108
Management of Brain Metastases from NSCLC with EGFR Mutations 108
Management of Neurologically Asymptomatic NSCLC Patients with EGFR Mutations 109
Management of Neurologically Symptomatic NSCLC Patients with EGFR Mutations 109
Treatment of Multiple Brain Metastases from NSCLC with EGFR Mutations 109
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.
Miliary Brain Metastases and EGFR Mutations
Miliary BM is a rarity and refers to the presence of numerous small tumors in a perivascular distribution without focal brain edema and intraparenchymal invasion. The primary site of miliary BM is mostly lung. Histologically, miliary BM is mainly identified as papillary adenocarcinoma ( ), which is frequently recognized in NSCLC patients with EGFR mutations ( ). These characteristics of miliary BM may be similar to those of BM from NSCLC patients with the exon 19 deletion ( ). In our study, evaluation was limited to synchronous BM at the time of NSCLC diagnosis; therefore, it remains unclear whether the characteristics of metachronous BM may differ from those of synchronous BM. However, miliary BM in most reports are metachronous. reported the cases of two patients who developed miliary BM during the clinical course of their illness and possessed the exon 19 deletion. Taking into account these results and those of our previous study, BM from NSCLC with the exon 19 deletion may have some features in common with miliary BM, regardless of the time of BM diagnosis.
To the best of our knowledge, detailed clinical characteristics of NSCLC with other EGFR mutations, including an exon 21 point mutation, have not been reported. However, two cases of NSCLC patients with miliary BM accompanied by an exon 20 deletion and exon 21 point mutation, respectively, have been reported ( ). In addition, our study showed that NSCLC patients with an exon 21 point mutation tended to have smaller BM with limited focal edema compared with NSCLC patients with EGFR wild-type, although the difference was not significant ( ). Therefore, BM from NSCLC with other EGFR mutations may share some features with those with the exon 19 deletion to some extent. Further studies on BM from NSCLC with each EGFR mutation are required to clarify this issue.
Management of Brain Metastases from NSCLC with EGFR Mutations
EGFR-TKIs improve the prognosis of NSCLC patients with EGFR mutations. However, this improved prognosis would result in a new problem: long-term survival is associated with a higher risk of developing BM. The incidence of BM in one report was 40% in 2-year survivors and 52% in 3-year survivors ( ). Particularly in EGFR-TKIs responders, isolated central nervous system progression has been reported to develop frequently without other systemic progression ( ). BM sometimes cause seizures and decreased quality of life. Therefore, early tumor detection is important to facilitate the appropriate treatment before the development of neurological symptoms ( ). However, the optimal management of NSCLC patients at the point of BM diagnosis remains to be determined. With consideration of the results of previous reports, the following management measures may be necessary.
Management of Neurologically Asymptomatic NSCLC Patients with EGFR Mutations
Importantly, numerous small BM resembling miliary BM do not always cause neurological symptoms ( ). Patients with BM from NSCLC with the exon 19 deletion tend to be neurologically asymptomatic compared with NSCLC patients with EGFR wild-type because of smaller tumor size and limited focal brain edema ( ). However, even in NSCLC patients with asymptomatic BM, multiple BM like miliary BM might develop during their clinical courses, unless an appropriate treatment can be provided. In fact, most reported cases of miliary BM were those of metachronous BM ( ). Considering the similarity between BM from NSCLC with the exon 19 deletion and miliary BM, regular evaluation should be performed, particularly in NSCLC patients with the exon 19 deletion, regardless of the presence or absence of neurologic symptoms.
Management of Neurologically Symptomatic NSCLC Patients with EGFR Mutations
Although radiographical evaluation should be performed in neurologically symptomatic patients, the presence of BM cannot be denied even in the absence of radiological abnormalities. Some reports showed the inability of enhanced computed tomography and magnetic resonance imaging to detect BM in a certain number of NSCLC patients ( ). Micrometastatic tumors are generally so avascular that their detection requires a certain amount of time. When the tumors become vascular and expand in size, detection becomes easier ( ). Considering the characteristics of BM in NSCLC patients with the exon 19 deletion, the presence of micrometastatic BM may be more likely. Therefore, repeated radiographical evaluation should be considered, particularly in NSCLC patients with the exon 19 deletion, if progressive neurological symptoms develop.