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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 5 of 12

As seen from these three randomized controlled trials, intracranial control (both local and distant sites) was
almost equal in both SRS and SRS plus WBRT groups but survival outcomes were conflicting though none
of these trials were intended to address survival as the primary endpoint; both JRSOG and EORTC trials
reported same survival rates with both treatment approaches, wheras MD Anderson trial reported higher
survival in SRS only group. An individual patient data metaanalysis considering JRSOG, MD Anderson
[40]
trials and only 199 patients treated with SRS plus or minus WBRT in EORTC was perfomed by Sahgal et al. It
was reported that, in patients with single brain metastasis, overall survival was higher and distant in-brain
recurrence was lower compared to the patients with 2-4 metastases. SRS alone resulted in survival advantage
in patients ≤ 50 years of age compared to their age-matched control treated with SRS plus WBRT without
increase in distant brain recurrences. But there was no significantly higher neurological death in patients ≤
50 years treated with SRS only (39% vs. 22%). In patients > 50 years of age distant in-brain recurrence risk
was significantly higher in SRS only group but this increased recurrence did not translate to any survival
disadvantage. When the data was re-evaluated considering only NSCLC patients the results were similar.
But the authors emphasize that firm conclusion concerning histology could not be done because of limited
sample size and reflection of subset analysis. As a conclusion, the authors suggest that SRS might be the
[40]
treatment of choice in patients ≤ 50 years with 1-4 metastases .
[37]
Recently, Brown et al. have reported the effects of adjuvant WBRT on cognitive function in a randomized
phase III (N0574-Alliance) trial in patients with 1-3 metastases. The primary end-point was the amount of
neurocognitive decline at 3 months compared to baseline. The local control was increased at 1 year with
addition of WBRT to SRS (85% vs. 51%). There wasn’t any difference in terms of survival (10.1 months vs.
[37]
7.5 months) . Recently secondary analysis of N0574-Alliance has been reported in 126 NSCLC patients to
determine if WBRT might be associated with prolonged survival in NSCLC patients with good performance
status. The patients were scored according to DS-GPA scores. There was no significant differences in OS
between SRS only or WBRT plus SRS groups in NSCLC patients with favorable DS-GPA scores. This study
[41]
further supports the approach of SRS alone in the majority of patients with limited brain metastases .
Neurocognitive impairement following WBRT after surgery or SRS vs. observation after surgery or SRS
The impact of adjuvant WBRT on NCF have been utilized in these previously mentioned 4 studies by
different methods. JRSOG trial evaluated the Mini Mental State Examination (MMSE) results in SRS only
and SRS plus adjuvant WBRT groups in long term. They revealed that the control of metastases increased the
MMSE scores in 2-3 months after radiotherapy in both groups and but in late-term (36 months) deterioration
of NCF in WBRT group was prominent. In the post hoc analysis, average time to neurocognitive decline
was shorter in SRS only group compared to SRS plus WBRT group 7.6 months vs. 16.5 months, respectively.
The authors claim that distant in-brain recurrence might have a bigger negative effect on neurocognition
[42]
and control of metastases is the most important factor in stabilizing cognitive fuction . But it should
[43]
be mentioned that MMSE has been accepted as having lower sensitivity in detection of NCF changes .
Besides, the paucity of the data on neurocognition in this study prevents us from making a conclusion on
[34]
the effect of WBRT on NCF .
MD Anderson trial reported significant decrease in recall memory and learning at 4 months after WBRT
plus SRS compared to SRS alone patients (52% vs. 24%) despite the decreased local and in-brain recurrences
as described previously. The authors claimed that adverse effects of WBRT on neurogenesis in hippocampus
might have a greater effect on neurocognition than in-brain recurrences and related salvage therapies seen
[34]
more often in SRS only group .
QOL analysis of EORTC 22952 trial declared a significant neurocognitive decline at 12 months and lower
[44]
QOL scores in WBRT arm after surgery or SRS .