Is adding focused radiation (radiosurgery) to whole brain radiation therapy beneficial to people with brain metastases?

The issue
The benefit of adding stereotactic radiosurgery (SRS), which is non-surgical targeted radiation therapy, to whole brain radiation therapy (WBRT), where radiation is given to the whole brain when tumours cannot be removed by surgery, for people with brain metastases is unclear.

The aim of the review
We sought to determine whether adding SRS to WBRT is beneficial compared to WBRT alone in the treatment of brain metastases.

What are the main findings?
We identified three randomised controlled trials (RCTs), which are studies that randomly assign participants into different treatment groups, that looked at whether adding focused (targeted) radiation (radiosurgery) to WBRT is beneficial to people with brain metastases. Overall, participants who underwent WBRT and SRS did not survive longer than participants who were treated with WBRT alone. However, participants with high functional status to perform activities of daily life and those with a single metastasis did survive longer after SRS and WBRT. Participants treated with WBRT and SRS did experience improved local control and performance status, as well as decreased steroid use compared to participants treated with WBRT alone.

Quality of the evidence
The overall quality of the evidence was moderate based on the GRADE assessments for our outcomes of interest, and the overall risk of bias was unclear.

What are the conclusions?
Most of our conclusions are based on the results of one large trial with unclear risk of bias and therefore, we cautiously make the following remarks: we found that when radiosurgery was added to WBRT, there was no evidence to suggest that people lived any longer than if they had WBRT alone, except for people with only one brain metastasis (who may live longer if they receive the combination treatment). People having combination treatment also seemed to function better in daily life, their treated tumors were associated with having less chance of growing back, and they had to take less steroid medication. The side effects of combined therapy and WBRT alone were similar.

Authors' conclusions: 

Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.

Read the full abstract...
Background: 

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012.

Objectives: 

To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases.

Search strategy: 

For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.

For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review.

Selection criteria: 

We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer.

Data collection and analysis: 

We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis.

Main results: 

We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear.

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