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. 2018 Jan 25;1(1):CD003869.
doi: 10.1002/14651858.CD003869.pub4.

Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases

May N Tsao  1 , Wei Xu, Rebecca Ks Wong, Nancy Lloyd, Normand Laperriere, Arjun Sahgal, Eileen Rakovitch, Edward Chow
Affiliations

Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases

May N Tsao et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an update to the review published in the Cochrane Library (2012, Issue 4).It is estimated that 20% to 40% of people with cancer will develop brain metastases during the course of their illness. The burden of brain metastases impacts quality and length of survival.

Objectives: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) given alone or in combination with other therapies to adults with newly diagnosed multiple brain metastases.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase to May 2017 and the National Cancer Institute Physicians Data Query for ongoing trials.

Selection criteria: We included phase III randomised controlled trials (RCTs) comparing WBRT versus other treatments for adults with newly diagnosed multiple brain metastases.

Data collection and analysis: Two review authors independently assessed trial quality and abstracted information in accordance with Cochrane methods.

Main results: 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 controlThe 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 controlThe 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 radiosensitisersThe 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 aloneThe 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 WBRTThe 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

MNT: none known. WX: none known. RW: none known. NLloyd: none known. NLap: none known. AS: A Sahgal has conducted educational seminars for Medtronic, Elekta AB, Accuray Inc., and Varian Medical Systems; received a research grant from Elekta AB; received travel accommodations/expenses from Medtronic, Elekta, and Varian; and serves as a member of the Elekta MR Linac Research Consortium. ER: none.

Figures

1
1
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Study flow diagram.
1.1
1.1. Analysis
Comparison 1 Altered WBRT fractionation schedules versus WBRT control, Outcome 1 Overall survival: lower‐dose WBRT vs control WBRT (3000 cGy/10 daily fractions).
1.2
1.2. Analysis
Comparison 1 Altered WBRT fractionation schedules versus WBRT control, Outcome 2 Overall survival: higher‐dose WBRT vs control (3000 cGy/10 daily fractions).
1.3
1.3. Analysis
Comparison 1 Altered WBRT fractionation schedules versus WBRT control, Outcome 3 Overall survival: WBRT 4000 cGy/20 fractions BID vs control WBRT (2000 cGy/4‐5 daily fractions).
2.1
2.1. Analysis
Comparison 2 Altered WBRT fractionation schedules versus WBRT control: neurological function improvement, Outcome 1 Neurological function improvement: lower‐dose WBRT vs control dose WBRT (3000 cGy/10 fractions).
2.2
2.2. Analysis
Comparison 2 Altered WBRT fractionation schedules versus WBRT control: neurological function improvement, Outcome 2 Neurological function improvement: higher‐dose WBRT vs control dose WBRT (3000 cGy/10 fractions).
3.1
3.1. Analysis
Comparison 3 WBRT with radiosensitisers (radiosen) versus WBRT alone, Outcome 1 Overall survival.
3.2
3.2. Analysis
Comparison 3 WBRT with radiosensitisers (radiosen) versus WBRT alone, Outcome 2 Brain tumour response rates: complete response (CR) and partial response (PR) combined.
4.1
4.1. Analysis
Comparison 4 WBRT and radiosurgery versus WBRT, Outcome 1 Overall survival.
4.2
4.2. Analysis
Comparison 4 WBRT and radiosurgery versus WBRT, Outcome 2 1‐Year overall brain control rates.
5.1
5.1. Analysis
Comparison 5 Radiosurgery alone versus WBRT and radiosurgery, Outcome 1 Overall survival.
5.2
5.2. Analysis
Comparison 5 Radiosurgery alone versus WBRT and radiosurgery, Outcome 2 1‐Year radiosurgery‐targeted lesion control.
5.3
5.3. Analysis
Comparison 5 Radiosurgery alone versus WBRT and radiosurgery, Outcome 3 1‐Year distant brain control.
See this image and copyright information in PMC

Update of

References

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Ramlau 2013 {published data only}
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Sperduto 2013 {published data only}
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References to studies excluded from this review

Haie‐Meder 1993 {published data only}
    1. Haie‐Meder C, Pellae‐Cosset B, Laplanche A, Lagrange JL, Tuchais C, Nogues C, et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiotherapy and Oncology 1993;26:111‐6. - PubMed
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References to ongoing studies

CCCWFU‐97600 {published data only (unpublished sought but not used)}
    1. Shaw EG. Phase 3 randomised study of d‐methylphenidate to improve quality of life in patients receiving radiotherapy for primary or metastatic brain tumours. www.clinicaltrials.gov/ct2/show/record/NCT00031798.
EORTC‐18981 {published data only (unpublished sought but not used)}
    1. EORTC Melanoma Group. Phase III randomised study of temozolomide with or without WBRT in patients with stage IV melanoma with asymptomatic brain metastases. www.clinicaltrials.gov/ct/show/NCT00020839.
NCT00075166 {published data only (unpublished sought but not used)}
    1. Surgery versus radiosurgery to treat metastatic brain tumours. clinicaltrials.gov/ct2/show/record/NCT00075166.
NCT00076856 {published data only (unpublished sought but not used)}
    1. Temozolomide for treatment of brain metastases from non‐small‐cell lung cancer. www.clinicaltrials.gov/ct2/show/NCT00076856.
NRG‐CC001 {published data only}
    1. A randomized phase III trial of memantine and whole brain radiotherapy with or without hippocampal avoidance in patients with brain metastases. https://clinicaltrials.gov/ct2/show/NCT02360215.
RTOG‐BR0118/ DEV1006 {published data only (unpublished sought but not used)}
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References to other published versions of this review

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