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Page 4 of 12 Kirakli et al. J Cancer Metastasis Treat 2019;5:10 I http://dx.doi.org/10.20517/2394-4722.2018.73

SRS resulted in increased local control in all patients (82% vs. 71%, P = 0.01). There were improvement in
survival, local control, performance status and decreased steroid dependence in NSCLC patients with 1-3
[17]
in post hoc analysis . In the secondary analysis, the patients were re-statified according to GPA scoring
system. There were 211 lung cancer patients out of 252 (84%) re-analysed patients. It was found that SRS
boost after WBRT resulted in increased survival in patients with GPA 3.5-4.0 score (good prognosis); the
median survival was 21 months in WBRT + SRS vs. 10.3 monhs in WBRT only. The benefit was irrespective
[32]
of the number of metastases .
Oligometastases: omitting adjuvant WBRT after surgery or SRS
The indication of adjuvant WBRT after surgery or SRS has been evolving. The rationale of omitting
immediate WBRT after surgery or SRS with close follow-up lies on the availibility to treat in-brain
recurrences with salvage focal therapies or WBRT at relapse with the aim of avoiding neurocognitive
dysfunction. To meet this challenge four phase 4 randomised trials and a metaanalysis was carried out [33-37] .

In this concept, the first randomized trial came from Japan (JRSOG-99 trial). The primary end point was the
survival difference between SRS and WBRT plus SRS, but at interim analysis it was realized that sample size
[33]
would be unachiavable and accrual was terminated. Aoyama et al. reported same survival rates (8 months
vs. 7.5 months, P = 0.42) and same neurologic death rates (19% vs. 23%) in spite of higher local recurrences
(27% vs. 11%) and distant brain recurrences (64% vs. 41%) in 132 patients with 1 to 4 brain metastases treated
with SRS alone vs. WBRT plus SRS. The authors claim that SRS alone might be a viable approach if the
patient is compatible with close brain monitoring for the early detection of recurrence to have the ability for
[33]
early salvage . In a secondary analysis, 88 NSCLC patients were poststratified by DS-GPA and survival was
the primary end-point. Forty seven patients with favorable DS-GPA score (2.5-4.0) had better OS with the
[38]
addition of WBRT (16.7 months vs. 10.6 months, P = 0.04) .

[34]
From MD Anderson, Chang et al. reported the second randomized trial: 58 patients with 1-3 brain
metastases were randomized to SRS alone vs. SRS followed by WBRT. The primary end-point of the study
was declin in neurocognitive function measured by Hopkins Verbal Learning Test-Revised at 4 months
compared to baseline but was terminated early due to high probability (96%) of inferior outcome in learning
and memory at 4 months in SRS plus WBRT arm. Local and distant in-brain controls were higher in SRS
plus WBRT arm compared to SRS only (100% vs. 67% and 73% vs. 45%, respectively). An addition of WBRT
resulted in less need for salvage therapies (11% vs. 90%) but higher risk for neurological deaths in SRS plus
WBRT group. (HR: 2.1, 95% CI 0.8-6.0, P = 0.15) and median survival was higher in SRS only group (15.2 months vs.
5.7 months). Higher survival in SRS only group was explained by higher rate of local surgical salvage and
[34]
ability of the patients to have systemic chemotherapy 1 month earlier and median 2 more cycles .
EORTC 22952 phase III randomized trial was the third with the largest patient number, unique in enrolling
both SRS and surgicaly resected patients. Besides, in contrast to other two studies, it included only patients
with systemic disease under control. The design was more complex; randomizing adjuvant WBRT vs.
observation after surgery or SRS in systemically controlled 359 patients with 1-3 brain metastases. The
primary end-point was survival time with functional independence. The local (surgery: 27% vs. 59%, P < 0.001;
SRS: 19% vs. 31%, P = 0.04) and distant brain recurrences (surgery: 23% vs. 42%, P < 0.008; SRS: 33% vs. 48%, P
= 0.023), need for salvage therapy (16% vs. 51%) and neurological death rates because intracranial progression
(28% vs. 44%) were decreased with addition of WBRT after surgery or SRS compared to observation but
without difference in median duration of functional independence (9.5 months vs.10 months, P = 0.71) and
[35]
survival (10.9 months vs. 10.7 months, P = 0.89) . In secondary analysis of EORTC 175 NSCLC patients
were re-analyzed to evaluate the benefit of WBRT on survival of patients with favorable prognosis (high
[39]
GPA); there wasn’t any significant survival difference between patients with high or low GPA scores .