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Page 8 of 12 Kirakli et al. J Cancer Metastasis Treat 2019;5:10 I http://dx.doi.org/10.20517/2394-4722.2018.73

Japanese Leksell Gamma Knife Society reported the results of a prospective observational multicenter phase
2 (JLGK0901) study in which survival outcomes and treatment related toxicity of SRS without WBRT in 1,194
patients with single, 2-4 and 5-10 brain metastases were evaluated. Patients with solitary brain metastasis had
the longest survival (median 13.9 months, 95% CI 12.0-15.6). In this non-inferiority study, overall survival,
local failure, distant in-brain recurrences, neurological death and toxicity were found to be similar both
in patients presenting with 2-4 and 5-10 metastases. There was not any survival difference in lung cancer
[56]
patients with 2-4 or 5-10 metastases either . An update of this study which was planned to see the radiation
related complications and changes in NCF in long-term reported that toxicity and MMSE scores were similar
[57]
among the three groups . There have been two clinical trials recruiting patients with estimated study
completion date of 2022. One of them led by National Cancer Information Center, is ramdomizing patients
with 5-15 brain metastases to SRS or WBRT plus memantine. Overall and neurocognitive deterioration free
[58]
survival are the primary endpoints . The other one is from Dana-Farber Cancer Institute and ramdomizing
patients with 5-20 brain metastases to SRS or WBRT plus hippocampal sparing in available cases, the QOL
[59]
is the primary end-point .

SRS vs. fractionated SRS
In the absence of randomized trial comparing SRS vs. fractionated SRS (FSRS); FSRS might be the option
[60]
with lower risk of radionecrosis in large lesions .

TKI and radiotherapy
NSCLC patients having driver mutations (EGFR mutation and ALK rearrangement) in NSCLC have
[3,4]
increased risks of brain metastases both at the time of diagnosis and during the course of the disease .
TKI targeting EGFR and ALK pathways have resulted in encouraging intracranial control rates compared to
[61]
chemotherapy .

Witholding radiotherapy in asymptomatic patients with driver mutations
Recently reported three phase II trials advocate witholding radiotherapy (SRS or WBRT) until progression
if small asymptomatic brain metastases are present in an EGFR mutation positive NSCLC patient [62-64] . There
are several explanations; first, targeted therapies have greater intracranial activity compared to historical
chemotherapeutic agents. Secondly, prolongation of survival with these agents allows time for manifestation
[65]
of neurocognitive side effects if radiotherapy is the treatment of choice . But patients should have the
willingness to close surveillance with MRI, though the optimal interval is unknown. Contrary to these
trials, recently, a retrospective multiinstitutional analysis reported inferior survival with up-front EGFR-
TKI in EGFR mutant NSCLC patients with brain metastases, both up-front SRS and up-front WBRT were
found to be associated with higher survival compared to up-front EGFR-TKI in multivariate analysis, (HR:
[66]
0.39, 95% CI 0.26-0.58 and HR: 0.70, 95% CI 0.50-0.98), respectively . The debate will be going on until a
randomized trial’s results, comparing up-front radiotherapy followed by EGFR-TKI to up-front EGFR-TKI
followed by radiotherapy at progression in EGFR mutated NSCLC patients.

A retrospective analysis of NSCLC patients with brain metastases and ALK rearrangement, showed
prolonged time to intracranial progression with up-front cranial radiotherapy adjunct to first generation
ALK inhibitor (crizitonib) compared to patients without cranial radiotherapy, (13.2 months vs. 7 months,
[67]
respectively) . Second and third generation ALK inhibitors have better blood brain barrier penetration
[61]
kinetics which might change the indications for cranial radiotherapy in the near future . Updated ALEX
trial comparing crizotinib vs. alectinib in stage IIIB/IV (asymptomatic brain metastases were allowed)
reported median PFS 27.7 months with alectinib vs. 7.4 months with crizotinib (HR: 0.35, 95% CI 0.22-
0.56), cranial response rates were 59% vs. 26% and complete cranial response rates were 45% vs. 9% in
[68]
patients presented with brain metastases at the time of diagnosis, respectively . As a result of these striking
results, postponing the cranial radiotherapy might be reasonable in ALK rearrangement positive patients if
Alectinib was the treatment of choice in first line.