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Kirakli et al. J Cancer Metastasis Treat 2019;5:10 I http://dx.doi.org/10.20517/2394-4722.2018.73 Page 9 of 12

Sequencing of radiotherapy and TKI
It’s recommended to withold TKI during WBRT to decrease unexpected toxicity which was observed with
[69]
concurrent use of erlotinib and WBRT . If SRS were the treatment of choise, similarly witholding TKI and
resuming one day after SRS is usually recommended in the absence of data.

Immune checkpoint inhibitors and radiotherapy
Although the prospective data is lacking, the data on immune checkpoint inhibitors targeting the
programmed cell death 1 pathway (PD1) in NSCLC patients with brain metastases has been growing. In a
[70]
phase II trial it was reported that pembrolizumab showed 33% intracranial response rate . But nivolumab
led to discontinuation of treatment in 58% of patients, because of progression of neurologic symptoms which
[71]
might be the reflection of pseudoprogression or hyperprogression . A recent retrospective study reported
higher OS in multivariate analysis that concurrent use of anti-PD1 and SRS resulted higher OS compared to
sequential use (P = 0.006) or SRS alone (P = 0.002) or anti cytotoxic T-lymphocyte-associated protein 4 (P =
[72]
0.045). Concurrent use also reduced distant intracranial relapses .

Sequencing of radiotherapy and immune checkpoint inhibitors
Several retrospective data have reported no increased toxicity with the concurrent use of immunotherapy
[73]
and cranial radiotherapy in NSCLC, though prospective studies are needed to confirm this finding . There
have been several clinical trials recruiting patients testing the efficacy of immunotherapy in combination
with radiotherapy in NSCLC patients with brain metastases (NCT02978404, NCT02858869, NCT02696993)

CONCLUSION
Taken together, these trials suggest survival advantage of surgery or SRS in selected patients with sollitary
metastasis but no survival advantage of certain treatment option in oligometastatic patients; they differ
only in terms of local or distant in-brain control. Besides, QOL assesements have inconsistent results and
has yet to be defined. Optimal treatment planning should consider both patient (age, performance status,
expected life span) and tumor related factors (number and volume of brain metastases, extracranial disease
control, molecular subtype) by using new prognostic models which is in line with personalised medicine
and tailored therapy approach rather than “one size fits all”. In light of today’s knowledge, it is quite
likely that the trade would be going on between doctors and patients, considering QOL as an outcome of
neurocognitive function that might be deteriorated either by symptomatic brain recurrence(s) or treatment
related morbidity.

Surgical cavity directed SRS seems to be effective in local control and preservation of NCF compared to
WBRT but the optimal sequencing (postopereative or preoperative) should be defined.

In non-oligometastatic patients the role of SRS has been evolving, the results of randomized studies might
help in decision making.

Targeted therapy and immune checkpoint inhibitors have resulted in increased intracranial activity
compared to chemotherapy, but the evidence is not strong enough to defer local therapy and the use as up-
front therapy. Also, there are ongoing trials exploring the technique and the methods to spare the NCF.

DECLARATIONS
Authors’ contributions
All authors contributed equally to the article.

Availability of data and materials
Not applicable.