Background

Brain metastases, which occur in approximately 20–40% of individuals with systemic cancer, represent a significant cause of morbidity and mortality and overwhelm all other types of brain tumors in terms of incidence and public health impact [1]. Considerable research has focused on improving survival and quality of life for this patient population. Given the expanding knowledge base and the rapid emergence of new therapies, the American Association of Neurological Surgeons (AANS), the Congress of Neurological Surgeons (CNS), and the AANS/CNS Joint Tumor Section jointly funded an initiative to produce methodologically rigorous evidence-linked clinical practice parameter guidelines on this topic. The overall objective of this series of guideline papers is to provide the latest up-to-date evidence-based recommendations for the management of patients with brain metastases centering on eight questions related to commonly encountered clinical scenarios (Tables 1, 2, 3). Accomplishment of this goal required undertaking a systematic review of the literature.

Table 1 Guideline questions specifically addressing treatment of patients with newly diagnosed brain metastases
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Table 2 Guideline questions specifically addressing treatment of patients with recurrent and/or progressive brain metastases
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Table 3 Guideline questions addressing all patients with brain metastases
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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 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 (Table 4). These seventeen 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.

Table 4 Management of brain metastases guideline panel
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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), 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.

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.

Literature search strategy

A broad literature search strategy was undertaken to identify all citations relevant to the management of brain metastases. 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; 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 AANS, CNS, Society for NeuroOncology (SNO), American Society for Therapeutic Radiation and 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.

Study selection, quality assessment and statistical methods

The search of the bibliographic databases identified 16,966 possibly relevant citations. These citations were screened in duplicate using an online systematic review management system designed by TrialStat! (http://www.ESRNEXUS.com). 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. The eligibility criteria for each of the eight questions are documented in the individual clinical practice guideline papers in this series.

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 [2, 3] 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 (Appendix B).

Evidence and summary tables, reporting the extracted study information and quality assessment, were generated for all of the included studies for each of the eight questions. Meta-analyses were undertaken when sufficient data for pooling was available for the outcomes of interest. In only one of the eight guideline papers in this series was the criteria for pooling met. The specific details of the meta-analyses undertaken for this question are provided in the whole-brain radiation therapy (WBRT) guideline paper by Gaspar et al. [4].

Evidence classes and levels of recommendations endorsed by the AANS/CNS

Both the evidence classification and the strength of the recommendations were graded according to the criteria endorsed by the AANS/CNS (Table 5). The class of evidence assigned to each study was based on study design alone (i.e., class I, II, or III). The strength of the recommendations made (i.e., level 1, 2, or 3) took into account aspects of study quality, not just study design. Specifically, the level of a recommendation made could be decreased, based on consensus input, if there were methodological concerns regarding the studies that provided evidence for that particular recommendation.

Table 5 AANS/CNS evidence classes and levels of recommendation
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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.

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 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 American Association of Neurological Surgeons and the Congress of Neurological Surgeons, 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.

Development of this set of evidence-based clinical practice guidelines was editorially independent from the funding agencies. The funding agencies (AANS Board, CNS Executive Committee, and AANS/CNS Joint Tumor Section Executive Committee) review of these guideline papers, following JGC approval but prior to submission for publication, was limited to whether or not to endorse or reject this body of work. Figure 1 provides an outline of the key steps in the process of developing these clinical practice guidelines.

Fig. 1
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Overview of the guideline development process

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Plans for updating the guidelines

Searches of a clinical trial registry (clinicaltrials.gov) identified several on-going randomized trials that are evaluating treatment comparisons directly addressed by questions in this guideline series. The outcome of these trials will be monitored and updates to the relevant guidelines will be undertaken as new evidence develops and as clinical need indicates.