Abstract: We added 10 RCTs to this updated review. The review now includes 54 published trials (45 fully published reports, four abstracts, and five subsets of data from previously published RCTs) involving 11,898 participants. Lower biological WBRT doses versus control  The hazard ratio (HR) for overall survival (OS) with lower biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 1.21 (95% confidence interval (CI) 1.04 to 1.40; P = 0.01; moderate-certainty evidence) in favour of control. The HR for neurological function improvement (NFI) was 1.74 (95% CI 1.06 to 2.84; P = 0.03; moderate-certainty evidence) in favour of control fractionation. Higher biological WBRT doses versus control The HR for OS with higher biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 0.97 (95% CI 0.83 to 1.12; P = 0.65; moderate-certainty evidence). The HR for NFI was 1.14 (95% CI 0.92 to 1.42; P = 0.23; moderate-certainty evidence). WBRT and radiosensitisers  The addition of radiosensitisers to WBRT did not confer additional benefit for OS (HR 1.05, 95% CI 0.99 to 1.12; P = 0.12; moderate-certainty evidence) or for brain tumour response rates (odds ratio (OR) 0.84, 95% CI 0.63 to 1.11; P = 0.22; high-certainty evidence). Radiosurgery and WBRT versus WBRT alone  The HR for OS with use of WBRT and radiosurgery boost as compared with WBRT alone for selected participants was 0.61 (95% CI 0.27 to 1.39; P = 0.24; moderate-certainty evidence). For overall brain control at one year, the HR was 0.39 (95% CI 0.25 to 0.60; P < 0.0001; high-certainty evidence) favouring the WBRT and radiosurgery boost group. Radiosurgery alone versus radiosurgery and WBRT The HR for local brain control was 2.73 (95% CI 1.87 to 3.99; P < 0.00001; high-certainty evidence)favouring the addition of WBRT to radiosurgery. The HR for distant brain control was 2.34 (95% CI 1.73 to 3.18; P < 0.00001; high-certainty evidence) favouring WBRT and radiosurgery. The HR for OS was 1.00 (95% CI 0.80 to 1.25; P = 0.99; moderate-certainty evidence). Two trials reported worse neurocognitive outcomes and one trial reported worse quality of life outcomes when WBRT was added to radiosurgery. We could not pool data from trials related to chemotherapy, optimal supportive care (OSC), molecular targeted agents, neurocognitive protective agents, and hippocampal sparing WBRT. However, one trial reported no differences in quality-adjusted life-years for selected participants with brain metastases from non-small-cell lung cancer randomised to OSC and WBRT versus OSC alone. None of the trials with altered higher biological WBRT dose-fractionation schemes reported benefit for OS, NFI, or symptom control compared with standard care. However, OS and NFI were worse for lower biological WBRT dose-fractionation schemes than for standard dose schedules. The addition of WBRT to radiosurgery improved local and distant brain control in selected people with brain metastases, but data show worse neurocognitive outcomes and no differences in OS. Selected people with multiple brain metastases from non-small-cell lung cancer may show no difference in OS when OSC is given and WBRT is omitted. Use of radiosensitisers, chemotherapy, or molecular targeted agents in conjunction with WBRT remains experimental. Further trials are needed to evaluate the use of neurocognitive protective agents and hippocampal sparing with WBRT. As well, future trials should examine homogeneous participants with brain metastases with focus on prognostic features and molecular markers.

Plain-language summary: This review includes 54 published trials involving 11,898 participants. Data show no apparent additional benefit of altered WBRT dose schedules compared with standard dose schedules. Use of other treatments such as chemotherapy, radiosensitisers, and molecular targeted agents in conjunction with WBRT has not yet been shown to be of benefit. Radiosurgery boost with WBRT does not improve survival among selected people with multiple brain metastases. WBRT when added to radiosurgery improves local and distant brain control. However, neurocognitive outcomes are better for selected people treated with radiosurgery alone as compared with WBRT and radiosurgery. For selected individuals with metastatic non-small-cell lung cancer to brain, survival may not be better with WBRT and optimal supportive care than with optimal supportive care alone. Studies have provided evidence of moderate to high certainty. Altered higher biological WBRT dose-fractionation schemes, as reported in randomised trials, did not confer benefit for overall survival, neurological function, or symptom control compared with standard treatment (3000 cGy in 10 daily fractions, or 2000 cGy in 4 or 5 daily fractions). However, overall survival and neurological function were worse for lower biological WBRT dose-fractionation schemes than for standard dose schedules. The addition of WBRT to radiosurgery improved local and distant brain control (i.e. absence of new intracranial lesions at the site or outside of treated lesions after treatment) among selected people with brain metastases, but investigators reported worse cognitive outcomes and no differences in overall survival. Selected people with multiple brain metastases from non-small-cell lung cancer may show no difference in overall survival when optimal supportive care is given and WBRT is omitted. Use of other treatments (radiosensitisers, chemotherapy, or molecular targeted agents) in conjunction with WBRT remains experimental. Additional trials are needed to evaluate strategies to protect cognitive decline associated with WBRT. As well, future trials should examine people with brain metastases with focus on prognostic features and tumour characteristics.