WBRT (Key Question 1)

Regarding the effectiveness of whole brain radiation therapy (WBRT) alone or in combination with other treatments, we identified a small number of studies that assessed the role of adding stereotactic radiosurgery (SRS) or surgery to WBRT. Two identified studies compared WBRT alone or in combination with SRS.^{75, 93} Due to differences in reported outcomes a combined analysis could not be performed. The individual study results showed no survival benefit for the addition of SRS, with the exception of the subgroup of patients with a single brain metastasis in the Radiation Therapy Oncology Group (RTOG) 9508 trial.⁷⁵ Local control was improved with the addition of SRS in both studies. The previously reported American Society for Radiation Oncology (ASTRO) guideline found that SRS added to WBRT improves survival for good prognosis patients with single brain metastasis, and it improves local control. Based on the results from individual studies, our findings are consistent.

For WBRT alone versus WBRT plus surgery, the three identified studies reported conflicting results, and there was no systematic difference across studies (low strength of evidence [SoE]).^{131, 160} The previously reported ASTRO guideline concluded that selected patients with good performance status, limited extracranial disease, and a single brain metastasis may have improved survival with the addition of surgery to WBRT.¹¹ Of note, one of the studies referenced by the ASTRO guideline was excluded from our analysis because it was conducted before 1990.²⁶⁴ This excluded study by Patchell et al. showed an improvement in survival with the addition of surgery to WBRT for patients with a single brain metastasis.

The addition of radiosensitizers to WBRT showed no significant difference in overall survival. The studies evaluated different radiosensitizing agents in different tumor types, and none of the individual studies showed a survival advantage.

For the potential effects of dose fractionation of WBRT, the variation in interventions and comparators among studies limited the analysis, but there was no significant effect of dose on overall survival, disease-free survival or deaths due to brain metastases (low SoE). This finding is consistent with the findings of the previously reported ASTRO guideline.¹¹

Only one identified study assessed the effect of the addition of memantine to WBRT treatment.⁸² WBRT plus memantine delayed the risk of cognitive decline and reduced the rates of decline in memory, executive function, and processing speed compared with WBRT alone. However, the finding has not yet been replicated in other studies and definitive effect estimates are still missing to guide patients, providers, and policy makers.

Three randomized controlled trials (RCTs) evaluated hippocampal avoidance WBRT versus conventional WBRT and reported sufficient information for effect estimates.^{80, 104, 166} The individual studies did not report statistically significant differences for effectiveness outcomes of interest. NRG CC001 trial reported detailed neurocognitive outcomes for hippocampal avoidance WBRT.⁸⁰ Comparing patients treated with hippocampal avoidance WBRT with memantine versus those treated with WBRT with memantine, hippocampal avoidance WBRT was associated with a lower risk of cognitive failure, with less deterioration of executive function and learning and memory.⁸⁰ However, the finding has not yet been replicated in other studies, and definitive effect estimates are still missing to guide patients, providers, and policy makers.

For WBRT, our analyses detected no systematic effect of prognosis on overall survival, however the number of studies with patients with predominantly good or poor prognosis was very limited, hindering meaningful analyses (low SoE). More research targeting patients with exclusively good prognosis and exclusively poor prognosis are needed to detect effects of the prognosis. The majority of existing studies on radiation therapy comprises patient samples with mixed or unclear prognosis; hence results should be treated with caution. The previously reported ASTRO guideline recommended the use of histology-specific prognostic indices for research and clinical decision making.¹¹ Prognostic indices such as the diagnosis-specific graded prognostic assessment (DS-GPA) have been developed using diagnosis and DS-GPA score to estimate median survival.^5–8 The prognostic index studies did not meet eligibility criteria for this review, however they remain an important resource to guide providers, patients, researchers and policy makers .

The addition of systemic therapy to WBRT may be beneficial with regard to overall survival, but the effect was small and not statistically significant (low SoE). Individual study results varied; studies evaluated many different chemotherapy or targeted therapy approaches. Meta-regressions did not suggest that a specific type of chemotherapy or targeted therapy is associated with larger treatment effects, hence we were unable to determine subgroups of systemic therapy that showed positive effects. It should be noted that most identified studies evaluated chemotherapy or targeted therapy rather than immunotherapy. Research on immunotherapy and targeted therapy is rapidly expanding and evolving, and future research may change the role of systemic therapy.⁴

Strength of evidence was insufficient to assess the effects of treatment on functional status and cognitive effects and we were unable to formulate evidence statements. In addition, data on quality of life that allows accurate treatment effect estimates are also lacking. While 12 RCTs reported quality of life and cognitive effects, and 11 studies reported functional status, the measures and reported details varied (e.g., no measure of dispersion was reported), or the intervention, co-intervention, and comparator combination could not be combined. Hence, there was insufficient data to compute effect sizes despite the large number of identified research studies on radiation therapy. This is particularly unfortunate as Key Informants and Technical Expert Panel members had repeatedly indicated that these patient-centered outcomes are critical and that information on these outcomes would meaningfully inform decisional dilemmas regarding treatment choice following a diagnosis of brain metastases. These outcomes are as important as the clinical effectiveness and adverse events information and the lack of reporting of sufficient detail is problematic for patients and their caregivers.

SRS (Key Question 2)

Regarding SRS as initial treatment, there was no significant difference in overall survival or death due to brain metastases for SRS alone versus SRS plus WBRT, based on pooled analysis (low SoE).^{75, 77, 81, 86} The previously reported ASTRO guideline supported SRS alone as a treatment option for selected patients (good prognosis, metastases ≤3–4 cm).¹¹ However, the individual trials they reviewed were noted to be underpowered for survival. Our pooled analysis indicates that survival is not impacted by the omission of WBRT.

Three studies reported on cognitive function for SRS alone versus SRS plus WBRT.^{77, 81, 86} Reported results varied by intervention, comparator, and measures used to assess effects; the studies reported insufficient details to compute effect sizes (low SoE favoring SRS alone). It is important to note that two of these studies, Chang et al. 2009⁸⁶ and Brown et al.⁸¹, utilized rigorous neurocognitive assessments and the individual study results showed significantly greater risk of cognitive decline for patients receiving WBRT and SRS compared with SRS alone.

Patient prognosis had no significant effect on overall survival, however the analyzable studies had a narrow range of differences in prognosis (all analyzable studies were mixed or good prognosis), so the results should be interpreted with caution (low SoE). We found no difference in survival based on primary cancer type. This result should also be interpreted with caution, since there were only several studies limited to a particular primary tumor type to contribute to the analyses and the findings were based on indirect comparisons across studies (low SoE). In addition, this review already included only the most common primary tumor types and represents a more homogenous study pool, hence the finding may not generalize to other cancer origin sites.

Unlike the evidence base for WBRT, regarding the role of systemic therapy with SRS, only a small number of studies was identified. There was insufficient information to analyze several key efficacy outcomes. Furthermore, evidence on immunotherapy and targeted therapy is emerging and its role in patients with brain metastases should be explored further.

Combination With Surgery (Key Question 3)

For patients who had surgery (Key Question 3), postoperative WBRT or SRS did not show a significant difference in overall survival compared with surgery alone (moderate SoE). Radiation therapy may decrease the risk of dying from brain metastases (low SoE). There were no RCTs for preoperative radiation therapy that contributed to the analyses. The number of identified post-surgery studies was small and due to the lack of reporting of details, analyses were very restricted. In particular, robust effect estimates are missing for important outcomes including intracranial progression, quality of life, functional status and cognitive effects, which can help patients decide whether additional treatment should be undertaken (insufficient SoE). The previously reported ASTRO guideline found that post-operative WBRT improved treated brain metastasis control and overall brain control without improving survival, and recommended post-operative WBRT (level 1 evidence) or post-operative SRS (level 3 evidence).¹¹ While our analysis found that data were insufficient to compute effect sizes for intracranial progression, radiation therapy may reduce the risk of death due to brain metastases.

Post-surgical WBRT and post-surgical SRS were compared in three RCTs.^{79, 111, 112} SRS after surgery may improve overall survival compared to WBRT but no effect estimate could be determined (low SoE). Other outcomes were either reported in a single study or could not be combined for analysis. The larger North Central Cancer Treatment Group (NCCTG) N107C/CEC·3 trial had a low risk of bias.⁷⁹ Results from the NCCTG N107C/CEC·3 trial showed shorter time to intracranial progression with post-surgical SRS compared with post-surgical WBRT, but no difference in overall survival. Post-surgical SRS was associated with improved cognitive function and quality of life.

Adverse Effects (Key Question 4)

A substantial number of identified studies reported on adverse events. Review of adverse events (Key Question 4) showed no increased risk of serious adverse events or the reported number of adverse events with the combination of WBRT plus SRS compared to WBRT alone or SRS alone (moderate SoE). We also did not detect differences in serious adverse events for surgery plus SRS compared to surgery plus WBRT (low SoE).

One RCT that compared WBRT with observation in patients who had received surgery or SRS as initial treatment reported more serious adverse events and a higher incidence of radiation necrosis in the WBRT arm.¹¹⁶ However, this evaluation has not yet been replicated in another study; we did not identify studies confirming the increased risk or contributing to a reliable treatment effect estimate across multiple, independent studies.

Individual radiosensitizer studies^{138, 155} indicated an increased risk of serious adverse events, but no meaningful summary effect across available studies could be determined. Studies evaluating systemic therapy with WBRT show an increased risk of vomiting with the addition of systemic therapy (moderate SoE).

We did not detect differences in number of adverse events based on tumor type for patients receiving WBRT or SRS. Other effects were not detected but the findings should be interpreted with caution as studies varied in multiple aspects that hindered the detection of effect modifiers. Indirect comparisons of SRS dose did not find an association between dose and adverse events, but only a small number of studies has been identified and these varied in multiple aspects that hindered the detection of effects.