Main Points

• We identified a large number of relevant radiation therapy studies (97 studies reported in 190 publications). Studies assessed whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), alone and in combination with or without systemic therapy, and for resected or unresected lesions.
• Most studies evaluated WBRT as initial treatment, with or without SRS; 10 randomized controlled trials (RCTs) evaluated post-surgery interventions.
• Risk of bias varied, 25 RCTs were terminated early, predominantly due to poor accrual.
• Due to the variation in interventions, co-interventions, comparators, and outcome measures and reporting, the number of studies that could be combined for analyses was limited.
• There is insufficient evidence for important outcomes including quality of life, functional status, and cognitive effects.
• Studies evaluating WBRT as initial treatment addressed a variety of questions, including the use of radiosensitizers, the effect of neuroprotection, and the addition of systemic therapy.
• Data on neuroprotective strategies is sparse. We did not detect effects of hippocampal sparing WBRT on overall survival, disease-free survival, or quality of life, but time to cognitive decline likely increased.
• The addition of systemic therapy to WBRT was assessed in 19 RCTS. Effects were small and not statistically significant across studies. The combination treatment SRS plus WBRT compared to SRS alone or WBRT alone found no statistically significant difference in overall survival or deaths due to brain metastases.
• Adding postoperative radiation therapy (WBRT or SRS) (moderate strength of evidence [SoE]) or postoperative WBRT specifically (moderate SoE) did not improve survival over surgery alone.
• Evidence was insufficient for several SRS evaluations and outcomes of interest. Studies varied by intervention, comparator, measures used to assess effects, and reported detail.
• Postoperative radiation (WBRT or SRS) therapy or postoperative WBRT specifically did not improve survival over surgery alone.
• We detected no difference between postoperative SRS and postoperative WBRT in overall survival across studies.
• We did not detect consistent differences in serious adverse events, number of reported adverse events, radiation necrosis, headaches, fatigue and seizures across interventions. WBRT plus systemic therapy was associated with increased risk for vomiting.
• There is insufficient evidence for important clinical outcomes including cognitive effects and functional status. The strength of evidence for quality of life is insufficient to low.

Structured Abstract

Objective. This evidence report synthesizes the available evidence on radiation therapy for brain metastases.

Data sources. We searched PubMed®, Embase®, Web of Science, Scopus, CINAHL®, clinicaltrials.gov, and published guidelines in July 2020; assessed independently submitted data; consulted with experts; and contacted authors.

Review methods. The protocol was informed by Key Informants. The systematic review was supported by a Technical Expert Panel and is registered in PROSPERO (CRD42020168260). Two reviewers independently screened citations; data were abstracted by one reviewer and checked by an experienced reviewer. We included randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to non-small cell lung cancer, breast cancer, or melanoma.

Results. In total, 97 studies, reported in 190 publications, were identified, but the number of analyses was limited due to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied; 25 trials were terminated early, predominantly due to poor accrual. Most studies evaluated WBRT, alone or in combination with SRS, as initial treatment; 10 RCTs reported on post-surgical interventions.

The combination treatment SRS plus WBRT compared to SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; confidence interval [CI], 0.69 to 1.73; 4 RCTs; low strength of evidence [SoE]) or death due to brain metastases (relative risk [RR], 0.93; CI, 0.48 to 1.81; 3 RCTs; low SoE). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; CI, 0.76 to 1.26; 5 RCTs; moderate SoE). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or post-surgical interventions.

We did not find systematic differences across interventions in serious adverse events radiation necrosis, fatigue, or seizures (all low or moderate SoE). WBRT plus systemic therapy (RR, 1.44; CI, 1.03 to 2.00; 14 studies; moderate SoE) was associated with increased risks for vomiting compared to WBRT alone.

Conclusion. Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.

Journal Citation

Garsa A, Jang JK, Baxi S, et al. Radiation Therapy for Brain Metastases: A Systematic Review. Practical Radiation Oncology. 9 June 2021. [Epub ahead of print.] DOI: 10.1016/j.prro.2021.04.002.

Citation

Garsa A, Jang JK, Baxi S, Chen C, Akinniranye O, Hall O, Larkin J, Motala A, Newberry S, Hempel S. Radiation Therapy for Brain Metastases. Comparative Effectiveness Review No. 242. (Prepared by the Southern California Evidence-based Practice Center under Contract No. 290-2015-00001-I.) AHRQ Publication No. 21-EHC021. PCORI Publication No. 2020-SR-02. Rockville, MD: Agency for Healthcare Research and Quality; June 2021. DOI: 10.23970/AHRQEPCCER242. Posted final reports are located on the Effective Health Care Program search page.