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Mudra et al. J Cancer Metastasis Treat 2019;5:27 I http://dx.doi.org/10.20517/2394-4722.2019.09 Page 3 of 9
[16]
[15]
SRS some patients are lost to follow-up. A potential disadvantage includes reduced wound healing . Asher et al.
evaluated pre-SRS in 47 patients, demonstrating its safety and efficacy with local control rates of 85.6% at
12 months. One retrospective study evaluating pre- and post-SRS cohorts of 180 BM patients (including
approximately 40% with NSCLC) showed similar rates of local recurrence and overall survival. However,
[17]
pre-SRS was associated with significantly reduced rates of radiation necrosis and LMD . Clinical trials
currently comparing pre-SRS and post-SRS in BM include NCT03741673 and NCT03750227.

SRS plays a major role in patients with multiple small BM (< 3 cm) or surgically inaccessible BM. Younger
lung cancer patients of high Karnofsky performance status with limited BM and a low burden of extracranial
disease may derive the most benefit from SRS [10,18] . Generally, SRS use has been limited to patients with few,
[2]
small, easily radio-accessible BM . Although a multi-center retrospective analysis demonstrated a survival
advantage for patients treated with SRS possessing fewer than four BM (n = 189 for NSCLC) compared to
[19]
WBRT (adjusted HR for NSCLC, 0.58; 95%CI: 0.38-0.87; P = 0.01) , Yamamoto and colleagues recently
evaluated SRS alone in 1,194 patients with up to ten lesions (largest tumor < 10 mL in volume and < 3 cm in
[20]
longest diameter; total cumulative volume ≤ 15 mL) . Their group found no difference in overall survival
(10.8 months) or treatment-related adverse events (9%) between patients with two to four tumors and patients
[20]
with five to ten tumors . These results suggest expanding SRS for the treatment of patients with up to ten
[10]
[2,5]
BM . Further data propose total BM volume as potentially more significant than the total number of BM .
Adverse effects of SRS
Overall, the adverse effects of SRS are consistent with known toxicities of intracranial irradiation. Both acute
(developing over weeks to months) and late-onset (developing over months to years) toxicities may result.
Certainly, the risk, severity and incidence of radiation-induced toxicities is highly dependent on the site,
[21]
dose, fractionation and volume of tissue irradiated along with the patient’s comorbidities . Acute toxicities
[22]
are uncommon and include nausea, headache, dizziness, seizure or new transient focal deficits . Patients
are usually treated with a short course of glucocorticoids.

The most common delayed adverse effect of SRS treatment to BM is radiation necrosis, occurring in
[23]
approximately 5%-10% of patients . However, this risk rapidly increases with increasing BM size and/
or volume as well as with a history of radiation to same lesion [21,23-25] . A study suggests employing
multifractionated SRS in three to five fractions rather than single fraction SRS as a means of decreasing
[26]
the risk of radiation necrosis and improving local control . The use of fractionated SRS also allows for the
safe treatment of larger BM (> 3 cm) [26,27] . Data on long-term effects of SRS on neurocognition is limited but
[25]
reassuring .

SRS in combination with immunotherapy
Immune checkpoint inhibitors (ICIs) have become a routine part of the treatment of advanced NSCLC
lacking a driver mutation, administered with chemotherapy doublet or alone in patients with ≥ 50%
[8]
expression of programmed cell death-ligand 1 (PD-L1) . Most patients with advanced NSCLC and BM are
eligible to receive ICIs - either alone or with chemotherapy.

Concerns to using ICIs to treat BM include: (1) pseudo-progression with the potential of symptom
aggravation; and (2) steroid use for symptomatic BM which may reduce ICI activity, as demonstrated by
[28]
a decreased objective brain response with the addition of steroids during ICI treatment in melanoma .
Present data on ICIs for BM from advanced NSCLC is limited. Most ICI clinical trials in NSCLC excluded
patients with untreated or unstable BM, yet included stable and treated BM, comprising 6%-17% of included
[29]
[29]
patients . Overall, in the small subgroups of BM patients included in these trials, ICI appears safe .
However, outcomes were mixed as some trials demonstrated benefit over chemotherapy and others did
[29]
not . A rationale for positive response to ICIs includes the inflammatory microenvironment of BM, with