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Page 2 of 8 Niu et al. Neuroimmunol Neuroinflammation 2018;5:32 I http://dx.doi.org/10.20517/2347-8659.2018.39

[3,4]
diagnosis, and up to 50% will develop BM at some point during the course of the disease . The incidence
of BM appears to have increased in the past decade due to the wide use of magnetic resonance imaging to
detect smaller lesions as well as to the evolution of more effective systemic therapy leading to better control
[5,6]
of extra-cranial disease and prolonged survival . Historically, the development of BM is associated with
poor prognosis with median overall survival (OS) ranging from 3.4 to 7.1 months after whole brain radiation
[7]
therapy (WBRT) .

LOCAL THERAPY
Local therapy with surgery and/or radiation therapy has been the mainstay of treatment for decades. For
younger patients with a newly diagnosed solitary BM, surgical resection followed by WBRT is supported
[8]
by level I evidence and incorporated in some clinical guidelines . WBRT has been the standard of care for
NSCLC patients with multiple BM. This practice was recently called into question. In the QUARTZ trial,
WBRT failed to show any survival or quality of life benefit compared with steroid and best supportive care
[9]
in NSCLC patients with multiple BM, although majority of the patients had poor performance status (PS) .
On the other hand, WBRT was deemed inadequate in the long-term control of BM in patients with good PS
and prolonged survival due to effective systemic therapy. Moreover, these patients may survive long enough
to experience significant neurocognitive sequelae associated with WBRT. To avoid neurotoxicity from
WBRT, stereotactic radiosurgery (SRS) has been advocated in patients with better prognosis and a limited
number of BM. A meta-analysis demonstrated that WBRT with or without SRS did not improve OS com-
pared with SRS alone in patients with up to four BM; whereas SRS was substantially superior in preserving
[10]
PS and neurocognitive function . A Japanese study of SRS alone for patients with one to ten BM showed
that distant brain failure rate and survival did not differ significantly in patients with two to four versus five
[11]
to ten lesions . In patients with BM who underwent resection, SRS to the surgical cavity was compared
head-to-head with WBRT in a randomized phase 3 study. It demonstrated no difference in OS, but less fre-
quent decline in cognitive function (52% vs. 85% at 6 months) in SRS group. Thus, SRS is regarded as one of
[12]
the standards of care after resection of a brain metastasis . For appropriate patients, SRS has been getting
increasingly utilized in practice in recent years.

CHEMOTHERAPY
For years the role of systemic therapy in treating BM in NSCLC patients has been neglected owing to the
prevailing belief that therapeutic drugs cannot cross the blood brain barrier. Traditional chemotherapy with
platinum-based doublets has been shown in the first-line setting to be active in controlling BM in small
studies. The commonly used regimens for adenocarcinoma of a platinum plus pemetrexed were shown in
phase 2 studies to demonstrate roughly 40% intracranial response rate (ICRR), comparable to systemic re-
sponse rate [13,14] .

TARGET THERAPY
With recent advances in understanding NSCLC biology, many highly specific target agents have become
available, redefining the role of systemic therapy in treating BM in NSCLC. In recent years, several distinct
molecular driver mutations have been discovered, and the list is getting longer over time. The most com-
mon epidermal growth factor receptor (EGFR) mutation constitutes 10%-15% of lung adenocarcinoma in
[15]
the Western population . Early-generation tyrosine kinase inhibitors (TKIs) have poor penetration to the
[16]
brain, although they were shown to have variable success in treating BM in a pool analysis . Weekly inter-
mittent “pulsatile” administration of high-dose erlotinib (1500 mg/week) in a small retrospective analysis
[17]
of 9 patients exhibited an ICRR of 67%, with median time to progression of merely 2.7 months . The 3rd-
generation TKI represented by osimertinib, was designed to overcome resistant EGFR mutation T790M and
was found to have better permeability in brain. In a pooled analysis of two phase 2 trials, 50 patients with