The benefits and side effects of adding upfront whole brain radiotherapy to surgery or radiosurgery for treatment of brain metastases

Background
For certain patients with a single brain metastasis, surgery to remove the single brain metastasis may be undertaken.  For certain patients with small brain metastatic disease, a highly focused single radiation treatment called radiosurgery, may be used.  It is unclear the benefits and side effects of adding upfront (i.e. a therapy given to previously untreated patients) whole brain radiation to surgery or radiosurgery.  We wanted to establish whether adding upfront whole brain radiation to surgery or radiosurgery was a useful treatment for brain metastases.

Study characteristics
We included five studies. These studies reported the effect of adding whole brain radiation to surgery or radiosurgery in terms of survival, brain disease progression, quality of life and treatment side effects. The sample size of these studies ranged from 19 to 359 patients.

Key findings
Adding whole brain radiotherapy to surgery or radiosurgery reduces brain metastases progression rates substantially but there was no clear evidence of an effect on survival and it is unclear whether it may cause side effects such as memory loss.

Quality of the evidence
We considered the evidence on survival, intracranial disease progression, neurocognitive function, quality of life and treatment side effects to be of low quality.

Authors' conclusions: 

There is low quality evidence that adding upfront WBRT to surgery or SRS decreases any intracranial disease progression at one year. There was no clear evidence of an effect on overall and progression free survival. The impact of upfront WBRT on neurocognitive function, health related quality of life and neurological adverse events was undetermined due to the high risk of performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies

Read the full abstract...
Background: 

The benefits of adding upfront whole-brain radiotherapy (WBRT) to surgery or stereotactic radiosurgery (SRS) when compared to surgery or SRS alone for treatment of brain metastases are unclear.

Objectives: 

To compare the efficacy and safety of surgery or SRS plus WBRT with that of surgery or SRS alone for treatment of brain metastases in patients with systemic cancer.

Search strategy: 

We searched MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL) up to May 2013 and annual meeting proceedings of ASCO and ASTRO up to September 2012 for relevant studies.

Selection criteria: 

Randomised controlled trials (RCTs) comparing surgery or SRS plus WBRT with surgery or SRS alone for treatment of brain metastases.

Data collection and analysis: 

Two review authors undertook the quality assessment and data extraction. The primary outcome was overall survival (OS). Secondary outcomes include progression free survival (PFS), local and distant intracranial disease progression, neurocognitive function (NF), health related quality of life (HRQL) and neurological adverse events. Hazard ratios (HR), risk ratio (RR), confidence intervals (CI), P-values (P) were estimated with random effects models using Revman 5.1

Main results: 

We identified five RCTs including 663 patients with one to four brain metastases. The risk of bias associated with lack of blinding was high and impacted to a greater or lesser extent on the quality of evidence for all of the outcomes. Adding upfront WBRT decreased the relative risk of any intracranial disease progression at one year by 53% (RR 0.47, 95% CI 0.34 to 0.66, P value < 0.0001, I2 =34%, Chi2 P value = 0.21, low quality evidence) but there was no clear evidence of a difference in  OS (HR 1.11, 95% CI 0.83 to 1.48, P value = 0.47, I2 = 52%, Chi2 P value = 0.08, low quality evidence) and PFS (HR 0.76, 95% CI 0.53 to 1.10, P value = 0.14, I2 = 16%, Chi2 P value = 0.28, low quality evidence). Subgroup analyses showed that the effects on overall survival were similar regardless of types of focal therapy used, number of brain metastases, dose and sequence of WBRT. The evaluation of the impact of upfront WBRT on NF, HRQL and neurological adverse events was limited by the unclear and high risk of reporting, performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies.

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