This is the current release of the guideline.

Brain metastases

Adults with newly diagnosed brain metastases

Note: For the purposes of the systematic review and the clinical practice guidelines, brain metastases have been defined as solid metastases to the brain from systemic cancer. The definition excludes leptomeningeal metastatic disease.

Management

1. Whole brain radiation therapy (WBRT)
2. Surgical resection plus WBRT
3. WBRT dosing/fractionation schedule

The following electronic databases were searched from 1990 to September 2008: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane Database of Abstracts of Reviews of Effects. The search strategy used a combination of subheadings and text words. The specific search terms used for MEDLINE are provided in Appendix A of the methodology companion (see the "Availability of Companion Documents" field); this search strategy was modified accordingly for appropriate terms for each database searched. Reference lists of included studies were also screened for potentially relevant studies.

An additional electronic database search was conducted to identify randomized trials published from 1970 forward that evaluated different dose/fractionation schedules of whole-brain radiation for the treatment of brain metastases. This was done to capture seminal studies in this area known to have been undertaken in this earlier time frame. The initial electronic search commenced at 1990 given the lack of any known comparative data for radiation, surgical resection and radiosurgery prior to this date, although additional searches were conducted as far back as 1970 as outlined above.

Conference proceedings from the 2006–2008 meetings of the American Association of Neurological Surgeons (AANS), the Congress of Neurological Surgeons (CNS), Society for Neuro-Oncology (SNO), American Society for Radiation Oncology (ASTRO), American Society for Clinical Oncology (ASCO) and the AANS/CNS joint section on tumors satellite symposiums were searched for abstracts eligible for inclusion in the emerging and investigational therapies guideline question.

These citations were screened in duplicate using an online systematic review management system designed by TrialStat. Two independent reviewers evaluated titles and abstracts using a priori eligibility criteria in standardized forms. Cases of disagreement were resolved by a third reviewer. The same process was applied to full text screening of potentially relevant studies. Articles that met the eligibility criteria for one or more of the questions were grouped according to the questions they addressed. Reasons for exclusion were documented.

Eligibility Criteria

(a) For whole-brain radiation therapy (WBRT) versus surgical resection plus WBRT question:

• Published in English with a publication date of 1990 forward.
• Patients with newly diagnosed single brain metastases.
• Fully published peer-reviewed primary comparative studies (all comparative study designs for primary data collection included; e.g., randomized controlled trials [RCTs], non-randomized trials, cohort studies or case–control studies)
• Study comparisons include: WBRT versus surgery + WBRT
• Number of participants with newly diagnosed brain metastases >5 per study arm
• Baseline information on study participants is provided by treatment group in studies evaluating interventions exclusively in patients with newly diagnosed brain metastases. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline information is provided for the intervention sub-groups of participants with newly diagnosed brain metastases.

(b) For optimal dosing/fractionation schedule for WBRT question:

• Published in English.
• Patients with newly diagnosed brain metastases.
• Fully published peer-reviewed primary comparative studies (all comparative study designs for primary data collection included; e.g., RCT, nonrandomized trials, cohort studies or case–control studies) for studies published 1990 forward; RCTs published 1970 forward.
• Study comparisons include: WBRT dose/fractionation schedule 1 versus WBRT dose/fractionation schedule 2.
• Number of participants with newly diagnosed brain metastases >5 per study arm.
• Baseline information on study participants is provided by treatment group in studies evaluating interventions exclusively in patients with newly diagnosed brain metastases. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline information is provided for the intervention sub-groups of participants with newly diagnosed brain metastases.

(c) For whether tumor histopathology has an impact on WBRT treatment outcomes:

• Published in English with a publication date of 1990 forward.
• Patients with newly diagnosed brain metastases.
• Fully published peer-reviewed primary studies (all study designs for primary data collection included; e.g., RCT, non-randomized trials, cohort studies, case–control studies or case series).
• Any study evaluating the outcome(s) of WBRT by tumor histopathology (or primary tumor type).
• Number of participants with newly diagnosed brain metastases >5 per study arm for comparative studies and >5 overall for non-comparative studies.
• For studies evaluating the outcome(s) of WBRT by histopathology (or primary tumor type) exclusively in patients with newly diagnosed brain metastases, baseline characteristics are presented and stratified by histologic/primary tumor group. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline characteristics are presented and stratified by histologic/primary tumor group for the sub-group of participants with newly diagnosed brain metastases.

Overall, 24 primary studies and seven companion papers met the eligibility criteria for this systematic review.

Evidence Classification

Class I: Evidence provided by one or more well-designed randomized controlled clinical trials, including overview (meta-analyses) of such trials

Class II: Evidence provided by well-designed observational studies with concurrent controls (e.g., case control and cohort studies)

Class III: Evidence provided by expert opinion, case series, case reports and studies with historical controls

Studies which met the eligibility criteria were data extracted by one reviewer and the extracted information was checked by a second reviewer. The PEDro scale was used to evaluate the methodological quality (internal validity) of randomized trials. The quality of comparative studies using non-randomized designs was evaluated using eight items selected and modified from existing scales (see Appendix B in the methodology companion [see the "Availability of Companion Documents" field]).

Evidence and summary tables, reporting the extracted study information and quality assessment, were generated for all of the included studies.

Meta-analyses

Meta-analyses of randomized controlled trials (RCTs) were undertaken when sufficient data for pooling was available for the outcomes of interest. For the following outcomes, 6 month mortality, overall survival and neurologic function, the altered whole-brain radiation therapy (WBRT) dose/fractionation schedules were compared to conventional scheduling. The pooled relative risk (RR) was estimated using a random-effects model and each RCT was weighted by the inverse of its variance. Chi-square heterogeneity tests were used to test for statistical heterogeneity amongst the RCTs. I² was calculated in order to quantify inconsistency across trials and assess the impact of heterogeneity on the meta-analysis. Publication bias was evaluated graphically with funnel plots. All statistical analyses were carried out using Revman 5.

The McMaster University Evidence-based Practice Center (EPC), which is an academic research unit partially funded by an EPC grant from the Agency for Healthcare Research and Quality (AHRQ), with specialized expertise in evidence-based medicine and the development of systematic reviews, was contracted to performed the systematic review in consultation with the guideline panel assembled for the initiative. The McMaster EPC also served as facilitators during the guideline development, consensus and writing processes.

The Joint Tumor Section of the American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) recruited representatives from surgical neuro-oncology (including microsurgical, stereotactic radiosurgery and experimental therapies), radiation oncology (fractionated radiotherapy, stereotactic radiosurgery and brachytherapy) and medical neuro-oncology (chemotherapy and experimental therapies) to form a multi-disciplinary panel of 17 clinical experts who developed the evidence-based practice guidelines from the systematic review results. These 17 experts across several disciplines were all nominated and selected by the Executive Committee of the AANS/CNS Tumor Section based on their clinical expertise and recognized contributions to the field of neuro-oncology in general and brain metastases in particular. The Tumor Section Executive Committee then selected a chairperson for this endeavor to organize and lead the effort, serving also to encourage and manage debate on the various topics involved.

Scope of the Systematic Review and Clinical Practice Guidelines

The specific questions regarding the treatment of brain metastases addressed by the systematic review and the resulting practice guidelines were determined collaboratively by the clinical guideline panel and methodologists at the McMaster EPC. In total, eight questions were agreed upon and these correspond to the eight practice guideline papers in this series. Four of the questions specifically focus on the treatment of patients with newly diagnosed brain metastases (Table 1 in the methodology companion [see the "Availability of Companion Documents" field]), one question addresses the treatment of recurrent/progressive metastatic brain disease (Table 2) and the remaining three questions are relevant to all patients with brain metastases (Table 3). Some of the questions had several parts.

Guideline Panel Consensus and Practice Guideline Approval Process

Small writing groups composed of four to eight members of the clinical guideline panel were assigned to each of the eight questions, and each question had at least one member from each subspecialty as part of the initial writing team. Each group was provided with the included studies and the evidence/summary tables for their specific question, as well as an exhaustive statistical analysis, from the McMaster EPC team. Using this information, the small writing groups were responsible for drafting the clinical practice guideline for their respective questions. The draft guidelines were then circulated to the entire clinical guideline panel for feedback, discussion, and ultimately approval.

Levels of Recommendation

Level 1: Generally accepted principles for patient management, which reflect a high degree of clinical certainty (usually this requires Class I evidence which directly addresses the clinical questions or overwhelming Class II evidence when circumstances preclude randomized clinical trials)

Level 2: Recommendations for patient management which reflect clinical certainty (usually this requires Class II evidence or a strong consensus of Class III evidence)

Level 3: Other strategies for patient management for which the clinical utility is uncertain (inconclusive or conflicting evidence or opinion)

A formal cost analysis was not performed and published cost analyses were not reviewed.

In accordance with the initial goal of a 1-year time horizon, the completed evidence-based clinical practice guidelines on the management of brain metastases were presented to the Joint Guidelines Committee (JGC) of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons (AANS/CNS) for approval approximately 12 months after starting the evidence review process. As part of their approval process, the JGC could provide input on the content of the clinical practice guidelines. Once approved by the AANS/CNS, the guidelines were also presented to the executive leadership of the Society for Neuro-Oncology (SNO), the American Society for Radiation Oncology (ASTRO), in addition to the AANS/CNS Joint Tumor Section, to offer multidisciplinary review and endorsement with plans for online publication and dissemination in all of the various organized societies concerned with the treatment of brain metastases.

The rating schemes used for the strength of the evidence (Class I-III) and the levels of recommendations (1-3) are defined at the end of the "Major Recommendations" field.

Should Whole Brain Radiation Therapy (WBRT) Be Used as the Sole Therapy in Patients with Newly Diagnosed, Surgically Accessible, Single Brain Metastases, Compared with WBRT Plus Surgical Resection, and in What Clinical Settings?

Target Population

This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumor histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma).

Recommendation

Surgical Resection Plus WBRT versus WBRT Alone

Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.

If WBRT Is Used, Is There an Optimal Dosing/Fractionation Schedule?

Target Population

This recommendation applies to adults with newly diagnosed brain metastases.

Recommendation

Level 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with "standard" WBRT dose/fractionation (i.e., 30 Gy in 10 fractions or a biologically effective dose [BED] of 39 Gy₁₀).

If WBRT Is Used, What Impact Does Tumor Histopathology Have on Treatment Outcomes?

Target Population

This recommendation applies to adults with newly diagnosed brain metastases.

Recommendation

Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology.

The following question is fully addressed in the surgery guideline paper within this series by Kalkanis et al. (see the National Guideline Clearinghouse [NGC] summary of American Association of Neurological Surgeons/Congress of Neurological Surgeons [AANS/CNS] guideline The Role of Surgical Resection in the Management of Newly Diagnosed Brain Metastases). Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of WBRT in the management of brain metastases, this recommendation has been included below.

Does the Addition of WBRT after Surgical Resection Improve Outcomes When Compared with Surgical Resection Alone?

Target Population

This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection.

Recommendation

Surgical Resection Plus WBRT versus Surgical Resection Alone

Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone.

Definitions:

Evidence Classification

Class I: Evidence provided by one or more well-designed randomized controlled clinical trials, including overview (meta-analyses) of such trials

Class II: Evidence provided by well-designed observational studies with concurrent controls (e.g., case control and cohort studies)

Class III: Evidence provided by expert opinion, case series, case reports and studies with historical controls

Levels of Recommendation

Level 1: Generally accepted principles for patient management, which reflect a high degree of clinical certainty (usually this requires Class I evidence which directly addresses the clinical questions or overwhelming Class II evidence when circumstances preclude randomized clinical trials)

Level 2: Recommendations for patient management which reflect clinical certainty (usually this requires Class II evidence or a strong consensus of Class III evidence)

Level 3: Other strategies for patient management for which the clinical utility is uncertain (inconclusive or conflicting evidence or opinion)

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Appropriate use of whole brain radiation therapy in the management of newly diagnosed brain metastases

Not stated

The information in these guidelines reflects the current state of knowledge at the time of completion. The presentations are designed to provide an accurate review of the subject matter covered. These guidelines are disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

American Association of Neurological Surgeons (AANS) Board, the Congress of Neurological Surgeons (CNS) Executive Committee, and the AANS/CNS Joint Tumor Section Executive Committee

Management of Brain Metastases Guideline Panel

Authors: L. E. Gaspar, Department of Radiation Oncology, University of Colorado-Denver, Denver, CO, USA; M. P. Mehta, Department of Human Oncology, University of Wisconsin School of Public Health and Medicine, Madison, WI, USA; R. A. Patchell, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA; S. H. Burri, Department of Radiation Oncology, Carolinas Medical Center, Charlotte, NC, USA; P. D. Robinson, R. E. Morris, McMaster University Evidence-Based Practice Center, Hamilton, ON, Canada; M. Ammirati, Department of Neurosurgery, Ohio State University Medical Center, Columbus, OH, USA; D. W. Andrews, Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, USA; A. L. Asher, Department of Neurosurgery, Carolina Neurosurgery and Spine Associates, Charlotte, NC, USA; C. S. Cobbs, Department of Neurosciences, California Pacific Medical Center, San Francisco, CA, USA; D. Kondziolka, Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; M. E. Linskey, Department of Neurosurgery, University of California-Irvine Medical Center, Orange, CA, USA; J. S. Loeffler, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; M. McDermott, Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA; T. Mikkelsen, Department of Neurology, Henry Ford Health System, Detroit, MI, USA; J. J. Olson, Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA; N. A. Paleologos, Department of Neurology, Northshore University Health System, Evanston, IL, USA; T. C. Ryken, Department of Neurosurgery, Iowa Spine and Brain Institute, Iowa City, IA, USA; S. N. Kalkanis, Department of Neurosurgery, Henry Ford Health System, Hermelin Brain Tumor Center, Detroit, MI, USA

All panel members provided full disclosure of conflicts of interest, if any, prior to establishing the recommendations contained within these guidelines.

This is the current release of the guideline.

Electronic copies: Available from the Journal of Neuro-Oncology Web site .

The following are available:

• Evidence-based clinical practice parameter guidelines for the treatment of patients with metastatic brain tumors: introduction. J Neurooncol 2010;96:7–10. Electronic copies: Available from the Journal of Neuro-Oncology Web site .
• Methodology used to develop the AANS/CNS management of brain metastases evidence-based clinical practice parameter guidelines. J Neurooncol 2010;96:11–16. Electronic copies: Available from the Journal of Neuro-Oncology Web site .

None available

This NGC summary was completed by ECRI Institute on September 15, 2011. The information was verified by the guideline developer on November 5, 2011.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.