The present study demonstrated that there was no statistically significant difference in local recurrence or distant recurrence between patients receiving SRS versus WBRT following neurosurgical resection of brain metastases in retrospective cohorts. Of note, there was a significant increased risk for the development of LMD in patients who received postoperative SRS as compared to WBRT, and a possible survival benefit to WBRT shown only in the fixed effects model with considerable heterogeneity. Though there was little published on leukoencephalopathy and radiation necrosis in these patients, it appeared that SRS reduced the risk of leukoencephalopathy and increased the risk for radiation necrosis as compared to WBRT. These results were in support of our hypothesis regarding similar rates of local control between the two treatment arms, but against our hypothesis predicting that SRS would lead to poorer rates of distant control. The possible survival benefit with WBRT in the fixed effects model was consistent with our hypothesis.

No randomized controlled trials have yet been completed for post-operative radiation modalities. However, a meta-analysis on the effect of the addition of WBRT to SRS or surgery did show less intracranial disease progression, but no effect on overall survival [29]. This is in line with the results of a trial evaluating additional WBRT to SRS that found improved intracranial tumor control but no effect on survival [15]. However, the addition of SRS to WBRT was found to result in longer survival in a randomized trial [30]. A systematic review evaluating linac-based SRS to resection cavities concluded that this treatment strategy provided good local control rates but poor distant intracranial control. This is different form our study that focused on a comparison between SRS and WBRT after resection [31].

Other studies have reported on the high risk of LMD in patients receiving SRS to the resection cavity, and have cited incidence rates around 12–14% [32,33,34]. Breast cancer metastases have been shown to have a particularly high rate of LMD [32,33,34]. Additionally, many studies reported on the adverse side effects of WBRT, including physical symptoms such as alopecia, somnolence, hearing loss, skin changes, and neurocognitive decline, manifested as memory loss and learning impairment [2, 7, 18, 26]. In particular, the cognitive decline following WBRT has been linked to leukoencephalopathy, which is supported by the increased risk for leukoencephalopathy in patients receiving post-operative WBRT [20, 35] Another study, evaluating 59 patients treated with primary SRS, found that even after multiple courses of SRS, quality of life (QOL), measured with the EQ-5D instrument, was preserved in 77% of patients at 12 month follow-up [36]. Thus, considering that our present analysis demonstrates similar results with respect to local recurrence, distant progression, and potentially survival in post-operative SRS patients, SRS is a valid treatment option that can help maintain neurocognition and QOL.

In patients with a limited number of brain metastases receiving resection, the results of this study suggest that it is important to understand the risks and benefits of both WBRT and SRS. The possibility for an improved quality of life should be considered when discussing treatment options. Although there is still not a clear formula to guide use of SRS or WBRT following resection, the fact that SRS may offer similar tumor control as WBRT, with the potential for fewer cognitive side effects and less invasiveness, suggests that SRS should be considered as a valid treatment option for brain metastases [26, 37]. While it has been widely acknowledged that WBRT is associated with cognitive decline, SRS has also been associated with radiation induced necrosis [38]. While these studies showed a potential survival improvement in WBRT as compared to SRS in the random effects model, it is important to note that the fixed effects model was not significant and that the considerable heterogeneity between the studies limits the conclusions that can be drawn from this. Both continent and journal impact factor were identified as significant sources of heterogeneity. Lastly, we demonstrated an increased risk for LMD in patients receiving postoperative SRS to the resection cavity, which is an important outcome to discuss with patients considering SRS.

Limitations and strengths

A major limitation of this review and meta-analysis was the heterogeneity among the included studies. Amongst the nine studies included, one included only colon cancer patients, one included melanoma patients only, and the remaining six consisted of patient populations with varying proportions of melanoma, colon, renal, breast, and unknown histologies [5, 18, 20, 24, 26, 28]. Additionally, the number of brain metastases was not reported homogenously between studies, and reported outcomes were not specific to the number of brain metastases and treatment modalities. Therefore, it was not possible to perform a subgroup analysis by histology type or number of metastases, or address potential sources of heterogeneity by these covariates. This is most likely of importance, because certain tumors, such as melanoma, colon, and renal carcinomas, are considered radioresistant for WBRT [10, 39, 40] and it is possible that outcomes could differ in patients with only a single metastasis [41, 42]. Of note, one study included in the analysis reported patients with 2–4 metastases in a single group, but noted that the number of metastases did not have an effect on the outcomes [24]. A further limitation of this analysis was that some studies reported death as a hazard ratio, while other used the Kaplan Meier method. Reporting a hazard ratio is a more accurate method and the variation in reporting limits the strength of the conclusions. Lastly, the studies included in the analysis were all retrospective in nature. Therefore, the different treatment-strategies implemented for each set of patients were the result of the tumor boards’ selection of patients whom they felt would benefit from that regimen, resulting in a selection bias. This is further complicated by the different forms of radiation administered in each study, as some studies described outcomes of IORT instead of SRS [18]. No studies were identified that compared WBRT with hypofractionated SRS, which has become a viable treatment strategy for lesions not treatable with a single fraction SRS [43, 44].

Despite these limitations, this meta-analysis based on cohort studies evaluated several different outcomes after extensive review of the literature. To our knowledge, this is the first meta-analysis on this topic. The use of both random- and fixed-effect models together with heterogeneity analysis resulted in a critical evaluation of our outcomes. Furthermore, an increased risk for the development of LMD after SRS compared to WBRT following surgical resection was identified.

Future directions

There is a clear necessity for the improvement of care for brain metastasis patients as they tend to live longer. Currently, several treatment strategies exist for brain metastasis, but data on the most effective strategy is lacking. Factors such as radiation dose, treatment timing, chemotherapy combinations among others should be evaluated in future studies in order to evaluate the most effective treatment modalities. The wide range of treatment modalities also provides a potential to strive towards more individualized patient care. In addition, evaluated outcomes should not be limited to survival or progression and should include quality of life. Indeed, currently a phase III randomized trial is being conducted to evaluate postoperative SRS versus WBRT in brain metastasis patients (NCT01372774) [45]. Primary endpoints will be evaluation of survival and neurocognitive progression and secondary endpoints will be QOL, adverse events, and functional independence among others. Last, the use of “big data” may provide a method to evaluate these outcomes more thoroughly.