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Radiation Therapy for Brain Metastases

Systematic Review Draft

Open for comment through Sep 14, 2020

This report is available in PDF only (Draft Report [3 MB]). For additional assistance, please contact us.

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; assessed independently submitted data, and consulted with experts.

Review methods. Two reviewers independently screened citations, data was 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 (immunotherapy and chemotherapy) for adults with brain metastases due to lung cancer, breast cancer, or melanoma. The systematic review was supported by a technical expert panel and is registered in PROSPERO.

Results. In total, 91 studies reported in 177 publications, were identified but the number of analyses was limited. We found that WBRT using radiosensitizers improved overall survival compared with WBRT alone (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.83, 0.90; 3 RCTs; moderate strength of evidence [SoE]). Quality of life of patients receiving SRS plus WBRT was not different from patients receiving SRS alone (standardized mean difference [SMD] -0.04; CI -0.83, 0.75; 2 RCTs; low SoE). Adding radiation therapy (HR 1.04; CI 0.84, 1.28; 4 RCTs; moderate SoE), or WBRT specifically (HR 0.98; CI 0.91, 1.04; 3 RCTs; moderate SoE), did not improve overall survival compared with surgery alone. Radiation therapy post-surgery may decrease the risk of dying from brain metastases, but the effect was not statistically significant and estimates ranged widely (relative risk [RR] 0.64; CI 0.22, 1.84; 3 RCTs; low SoE). Data for functional status and cognitive effects were insufficient to determine effects across WBRT, SRS, or post-surgery studies.

We did not find systematic differences across interventions in serious adverse events, number of adverse events, radiation necrosis, fatigue or seizures (all low or moderate SoE). WBRT plus radiosensitizer (RR 1.67; CI 1.12, 2.48, 2 studies; moderate SoE) and WBRT plus chemotherapy (RR 1.41; CI 1.04, 1.92; 14 studies; moderate SoE) were associated with increased risks for vomiting compared to WBRT alone and there may be a dose-response relationship between headaches and the fractionation schedule of WBRT (low SoE).

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.

Evidence Summary

Main Points

  • We identified a large number of relevant radiation therapy studies (91 studies reported in 177 publications). Studies assessed whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), alone and in combination with or without systemic therapy, pre- or post- surgery.
  • Due to the variation in interventions, co-interventions, comparators, and outcome measures, analyses were limited.
  • There is insufficient evidence for important outcomes including quality of life, functional status and cognitive effects.
  • Most research is available for WBRT and studies addressed different questions, including the use of radiosensitizer, memantine or steroids. Fewer studies have evaluated SRS and only few post-surgery studies have been published.
  • With respect to WBRT, the use of radiosensitizers in WBRT showed a small advantage for overall survival (moderate strength of evidence [SoE]). Adding chemotherapy to WBRT may be beneficial for overall survival (low SoE), but the effect was small and may vary by chemotherapy agent. We found no systematic effect of chemotherapy on disease free survival (moderate SoE) and data are lacking for immunotherapy.
  • The combination of SRS plus WBRT showed no differences in quality of life compared with SRS alone (low SoE) but only two studies contributed to the analysis.
  • Adding postoperative radiation therapy (moderate SoE) or postoperative WBRT specifically (moderate SoE) did not improve survival over surgery alone.
  • Postoperative radiation therapy may decrease the risk of dying from brain metastases, but the pooled effect was not statistically significant due to substantial variation in effect estimates in individual studies (low SoE). WBRT after surgery, specifically, may decrease deaths from brain metastases (low SoE) but no concrete effect estimate could be determined. SRS after surgery may improve overall survival more than WBRT (low SoE) but no concrete effect estimate could be determined.
  • 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 radiosensitizer (moderate SoE) and WBRT plus chemotherapy (moderate SoE) were 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.

Background and Purpose

Brain metastases are a common problem in cancer care and the incidence is increasing as diagnostic tools are refined and advances in cancer therapy improve survival. The development of brain metastases may have substantial prognostic implications by causing neurologic symptoms or death.

Treatment options for brain metastases include WBRT, SRS, surgery, and systemic therapies. WBRT is administered to the entire brain, typically over multiple treatments (although hippocampal-avoidance WBRT is more selective regarding the dose for different areas of the brain). SRS is a treatment option that delivers precisely-targeted radiation to the brain metastases. Surgery for brain metastases aims to remove the tumor. Systemic therapy includes chemotherapy and immunotherapy regimens. For some patients, supportive care alone may be appropriate. Each of these treatment options may be considered alone or in combination. Other therapies have been investigated as co-interventions with radiation therapy to either increase efficacy or reduce toxicity. Radiosensitizers are agents that make cancer cells more sensitive to radiation therapy. Memantine is a N-methyl-D-aspartate receptor antagonist that may have neuroprotective effects.

Outcomes including efficacy, impact on quality of life and neurocognition, and adverse effects are important to guide policy makers, clinicians, patients and caregivers. For radiation therapy options, information on the optimal technique (e.g. hippocampal avoidance WBRT), dose and fractionation, and efficacy of co-interventions is needed to inform decisions.

This Agency for Healthcare Research and Quality (AHRQ) evidence report, commissioned and funded by the Patient-Centered Outcomes Research Institute (PCORI), synthesizes the available evidence on radiation therapy for brain metastases. The synthesis aims to support an update of the American Society for Radiation Oncology (ASTRO) guidelines.

Methods

We employed methods outlined in the AHRQ EPC Program Methods Guidance, as described in the full report. We included studies evaluating radiation therapy, including WBRT and SRS alone or in combination, as initial or postoperative treatment, with or without systemic therapy (immunotherapy and chemotherapy) for adults with brain metastases. Eligible studies included randomized controlled trials (RCTs) as well as large non-randomized controlled trials and cohort studies comparing two cohorts (for safety and sensitivity analyses).

Studies had to report on effects of radiation therapy in the 1990s or later and we included studies published to July 2019 at the time of the draft report. We restricted to studies that included patients with non-small cell lung cancer, breast cancer, and melanoma.

A technical expert panel advised on key outcomes: overall survival, disease-free survival, deaths due to brain metastases, intracranial progression, quality of life, functional status, cognitive effects, serious adverse events, adverse events, radiation necrosis, headaches, fatigue, seizure, vomiting. Random effects meta-analyses computed hazard ratios (HR), relative risks (RR), and standardized mean differences (SMD) together with a 95 percent confidence interval (CI) where possible. We assessed the strength of evidence (SoE) as either high, moderate, low, or insufficient. The systematic review is registered in PROSPERO.

Results

We identified 91 studies reported in 177 publications in the 8,402 identified citations. Throughout, data for quality of life, functional status, and cognitive function were too limited to determine effect estimates across studies. Risk of bias varied but was better for effectiveness than adverse events outcomes.

WBRT effects

A large number of studies addressed WBRT (60 RCTs), but co-interventions, comparators, and assessed outcomes varied. Patients receiving WBRT plus radiosensitizer showed improved overall survival compared with WBRT alone (HR 0.87; CI 0.83, 0.90; 3 RCTs; moderate SoE).

There was insufficient evidence to determine the effects of WBRT plus surgery, WBRT plus memantine, and hippocampal avoidance WBRT. Although key outcomes, data were insufficient for assessing quality of life, functional status and cognitive effects.

Adding systemic therapy to WBRT may be beneficial with regard to overall survival, but the pooled effect was small and not statistically significant (HR 0.94; CI 0.87, 1,01; 6 RCTs; low SoE). We were unable to determine subgroups of systemic agents that showed particular promise. We found no systematic effect of chemotherapy on disease free survival (moderate SoE). Data are lacking for the role of immunotherapy.

Evidence was insufficient for assessing cognitive effects, quality of life and functional status.

SRS effects

Thirteen RCTs assessed SRS interventions, alone or in combination with WBRT. Quality of life (SMD -0.04; CI -0.83, 0.75; 2 RCTs; low SoE) of patients receiving SRS plus WBRT was not different from patients receiving SRS alone but only two studies contributed to the finding. Evidence was insufficient for assessing overall survival, disease-free survival, deaths due to brain metastases, intracranial progression, functional status, and cognitive effects.

Effects of post-surgery interventions

We identified 10 RCTs assessing postsurgical interventions. Radiation therapy after surgery (HR 1.04; CI 0.84, 1.28; 4 RCTs; moderate SoE) or WBRT specifically (HR 0.98; CI 0.91, 1.04; 3 RCTs; moderate SoE) did not improve overall survival compared to surgery alone. Radiation therapy post-surgery may decrease the risk of dying from brain metastases but the pooled effect was not statistically significant (RR 0.64; CI 0.22, 1.84; 3 RCTs; moderate SoE). There is insufficient evidence for outcomes including disease-free survival, intracranial progression, quality of life, functional status and cognitive effects.

Adverse events

The 91 RCTs and cohort studies reported on adverse events. We did not identify systematic differences between interventions for serious adverse events, number of adverse events, radiation necrosis, fatigue, and seizures. WBRT plus radiosensitizer showed an increased risk for vomiting compared with WBRT alone (RR 1.67; CI 1.12, 2.48, 2 studies; moderate SoE) and WBRT plus chemotherapy showed an increased risk for vomiting compared with WBRT alone (RR 1.44; CI 1.02, 2.03; moderate SoE). There was evidence of a slight dose-response relationship between the number of patients experiencing headaches and the fractionation schedule of WBRT (p=0.03, low SoE) but the finding should be interpreted with caution because it is based on an indirect comparison across studies.

Effects of patient characteristics

Across interventions and outcomes, we did not detect systematic differences in study results based on cancer site (low SoE) and patient prognosis (low SoE), but the results should be interpreted with caution as they were based on limited data and indirect comparisons. Most identified studies used mixed samples in terms of original cancer site and prognosis, only WBRT studies allowed analyses at all, and analyses were only possible for selected outcomes.

Strengths and Limitations

This report provides a comprehensive collection of research on radiation treatment in brain metastases. Despite the large number of identified research studies, analyses were limited as studies evaluated unique intervention and comparator combinations and reported insufficient detail on outcomes of interest. Most research was available for WBRT. Fewer studies assessed SRS and post-surgery interventions have only been addressed in few studies to date. Throughout, data are missing on important patient-centered outcomes such as quality of life.

Implications and Conclusions

Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. The use of radiosensitizers in WBRT appears to improve overall survival. The studies evaluated different radiosensitizing agents in different tumor types and the applicability of this finding is unclear; more research is needed. The effects of interventions such as memantine and hippocampal avoidance WBRT have only been reported in individual studies and summary estimates across multiple studies do not exist yet. Other intervention characteristics did not show consistent effects or have only been reported in individual studies. We did not detect consistent advantages of combining SRS and WBRT or radiation therapy and systemic therapy, but information was only available for selected outcomes. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects. Standardizing the use of validated scales and standardizing outcome reporting in studies would allow for better data synthesis in the future. Existing data should be made available, through journal publications or data repositories of trial records.