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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 7 of 12

preferred strategy in amenable patients willing to have frequent brain surveillance with MRI.

Similarly, the American Society for Radiation Oncology (ASTRO) does not recommend routine adjuvant
[45]
WBRT in oligometastatic brain metastases in it’s choosing wisely initiative organisation .
On the other hand there have been several opposers to this approach, because they claim that there should
be a trade between the risk of neurocognitive dysfunction and the risk of in-brain recurrences which
could adversely worsen cognitive function even more than WBRT that might not be reversed by salvage
therapies [46,47] .

Solitary or oligometastatic or non-oligometastatic: WBRT only
Brain metastases from the primary tumors occur mainly by hematogenous route making the whole brain
under the risk for micrometastatic disease. This concept has been the rationale of WBRT even in case of
small solitary metastasis but recently has started to be questioned in the context of true oligometastatic brain
[33]
disease . In patients with life expectancy less than 3 months and/or poor performance status, short course
[48]
WBRT or best supportive care with corticosteroids are reasonable options .
A phase III non-inferiority Medical Research Council trial (QUARTZ), comparing best supportive care alone
and best supportive care plus WBRT in NSCLC patients with brain metastases not amenable to surgery or
SRS, reported similar survival and QOL. Solitary metastasis rate was 30% but median number of metastatic
lesions and distribution of patients among two treatment arms according to number of metastastic lesions
[49]
were not available in the data . But there has been some debates on this article; 38% of the cohort had poor
[7]
performance, the median survival was only 8 weeks which was much inferior compared to previous data .
Besides, due to heterogenity of prognosis in patients with brain metastases with different primaries the
[6]
results can not be generalized .
Hippocampus sparing WBRT
WBRT related neurocognitive complications have led to the developement of new radiotherapy techniques;
hippocampus sparing WBRT (HS-WBRT) is one of them. The rationale lies on that; new memory is
composed by neural stem cells located in the subgranular zone of the hippocampus and there is a dose-
[50]
response-related risk of decline in NCF due to radiation dose received by the HP . Until recently, there
have been only 2 prospective data on this subject. The first one, single-armed phase II RTOG-0933 trial,
reported no increased risk of recurrence with HS-WBRT and better preservation of cognitive function with
[51]
[52]
this technique compared to historical controls . The second data is from Oehlke et al. the progression
in the hippocampus avoiding area was 2 (10%) of 20 in 40 weeks. But recently, the preliminary results of a
randomized trial (NRG-CC001) composed of 518 randomized patients to memantine and HS-WBRT arm vs.
memantine and WBRT arm have been presented in the last ASTRO meeting. HS-WBRT has prolonged time
to neurocognitive failure, decrease in neurocognitive function at 6 months was 59.5% vs. 68.2% (HR: 0.76, P
= 0.03) favoring HS-WBRT without any difference in intracranial brain recurrences or overall survival (P =
[53]
0.208 and P = 0.307, respectively) .

Memantine and WBRT
Memantine has been tested in prevention of cognitive dysfunction as a neuroprotective agent in a
randomized placebo controlled trial (RTOG 0614) and shown to be effective in decreasing the rate and
[54]
delaying the time to cognitive decline . There is an ongoing randomized clinical trial comparing
[55]
memantine and WBRT with or wihout HA-WBRT .

Non-oligometastatic: SRS without WBRT
There have been growing data on SRS without WBRT in patients with more than 3 brain metastases
[49]
although the maximum number of metastases appropriate for SRS has not been established, yet . The