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Page 2 of 9 Mudra et al. J Cancer Metastasis Treat 2019;5:27 I http://dx.doi.org/10.20517/2394-4722.2019.09

INTRODUCTION
[1]
Lung cancer remains the leading cause of cancer-related mortality . Eighty-five percent of diagnoses
[2]
represent non-small cell lung cancer (NSCLC) ; the remaining 10%-14% are diagnoses of small cell lung
[3]
cancer. Brain metastases (BM) are diagnosed in approximately 10% of lung cancers at time of diagnosis
[3,4]
and approximately 40%-50% will be diagnosed with BM during the course of their disease . BM in lung
cancer are known to be associated with poor prognosis. Historically, standard treatment for BM from lung
[5]
[5,6]
cancer involves neurosurgical resection , radiotherapy and/or chemotherapy .
Recent advances in NSCLC, including molecular analysis, matched targeted therapies and immunotherapy,
[7]
has altered the standard of care. These novel approaches have shifted the paradigm in lung cancer and
[7,8]
improved median overall survival in lung cancer patients with BM . Survival now ranges between
9-15 months and can be as high as 46 months in patients with favorable prognostic factors such as good
performance status and epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK)
[9]
positivity . In addition, over the past decade, standard of care in radiotherapy for BM has increasingly
favored SRS [10,11] . Precise delivery of high-dose radiation localized to the tumor results in higher local tumor
[11]
[10]
control and fewer side effects such as neurocognitive damage compared to whole brain radiotherapy
(WBRT).

The trifold advancement in targeted therapies, immunotherapy and SRS has revolutionized the treatment
of BM in lung cancer. Employing these novel therapies, lung cancer patients are living longer, becoming
more likely to develop brain metastases. Certainly, the use of these therapies - either individually or in
combination - is anticipated for the treatment of lung cancer BM.

In this review, we discuss the current evidence regarding the use of SRS employed alone and in combination
with novel therapies for treatment of lung cancer BM.

BRAIN METASTASIS IN LUNG CANCER LACKING A DRIVER MUTATION
SRS
SRS, typically delivered in a single fraction, serves as a key modality for delivering high-dose radiation to
[12]
smaller target sites (usually < 3 cm) , sparing adjacent structures from exposure and mitigating the harmful
[11]
effects of radiation .
For single BM, SRS has demonstrated efficacy and safety. Therefore, both surgical resection plus
postoperative radiation and SRS alone are reasonable options and treatment should be individualized as
[13]
comparative data is lacking . Surgery plus postoperative radiation is preferred for a single, large and
[13]
symptomatic BM to allow for decompression, lower morbidity and higher local control . One small
[14]
retrospective study found similar survival when comparing surgical resection vs. SRS for solitary BM .
[14]
However, more local recurrence was demonstrated in the surgery group .
For surgically-resected brain metastases, post-operative SRS (post-SRS) is the current standard of care.
Some concerns with post-SRS include radiation necrosis and leptomeningeal disease (LMD) recurrence.
The hypothesis behind LMD recurrence is the intra-operative seeding of viable tumor cells, which is
[15]
supported by a study where post-SRS demonstrated higher rates of LMD compared to adjuvant WBRT . A
new approach, pre-operative SRS (pre-SRS), is being evaluated as a potential method to decrease radiation
necrosis and LMD. Potential benefits of pre-SRS include: (1) better local tumor control through improved
delineation when contouring an intact metastasis compared to an irregularly-shaped surgical cavity; (2)
reduced risk of radiation necrosis, as there is no need to treat surrounding brain tissue and the majority
of the treated BM will be resected; (3) reduced risk of LMD as a result of a potential sterilizing effect via
the intraoperative seeding of treated tumor cells; and (4) the potential to treat more patients, as with post-