Guideline:
EFNS guidelines on diagnosis and treatment of brain metastases
Bibliographic Source(s)
- Soffietti R Cornu P Delattre JY Grant R Graus F Grisold W Heimans J Hildebrand J Hoskin P Kalljo M Krauseneck P Marosi C Siegal T Vecht C. EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol 2006 Jul;13(7):674-81. [44 references] PubMed
Guideline Status
This is the current release of the guideline.
Guidelines will be reviewed and updated at least every 2 years.
Guideline Category
Diagnosis
Evaluation
Management
Treatment
Intended Users
Physicians
Guideline Objective(s)
To establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases
Target Population
Patients with brain metastases
Interventions and Practices Considered
Diagnosis/Evaluation
- Medical history and physical examination
- Computed tomography (CT) or magnetic resonance imaging (MRI)
- Tissue diagnosis/histopathologic studies (by stereotactic or open surgery) if needed
- Fluorodeoxyglucose positron-emission tomography (FDG PET) for detecting the primary tumor
- Electroencephalogram (EEG)
- CT of the chest/abdomen and mammography
- Cerebrospinal fluid cytology if indicated
Management/Treatment
- Surgical resection
- Stereotactic radiosurgery (SRS)
- Whole-brain radiotherapy (adjuvant or alone)
- Chemotherapy
- Supportive care (dexamethasone anticonvulsants in patients with seizures low-molecular-weight heparin (LMWH) in patients with venous thromboembolism (VTE)
Major Outcomes Considered
- Sensitivity and specificity of diagnostic tests
- Effectiveness of treatment in improving median and overall survival local tumor control and functional independence and reducing relapse rate
Methods Used to Collect/Select Evidence
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods used to Collect/Select the Evidence
The Task Force members searched the following databases: the Cochrane Library to date; Medline–Ovid (January 1966 to date); Medline–ProQuest; Medline-EIFL; Embase–Ovid (January 1990 to date); CancerNet; Science Citation Index (ISI). They used specific and sensitive keywords as well as combinations of keywords and publications in any language of countries represented in the Task Force. The Task Force members also collected guidelines from national and European multidisciplinary neuro-oncological societies and groups (from Italy France Netherlands Germany and UK). Moreover they performed an investigation (by e-mail questionnaire) regarding the attitudes of members of the Task Force on several critical issues reflecting the different national situations (10 countries) and specializations (11 neurologists one neurosurgeon one radiation oncologist and one medical oncologist).
Number of Source Documents
Not stated
Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition using a "gold standard" for case definition where the test is applied in a blinded evaluation and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls where test is applied in a blinded evaluation and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective randomized controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies case series case reports or expert opinion
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence
Not stated
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
The scientific evidence of papers collected from the literature was evaluated and graded according to European Federation of Neurological Societies (EFNS) Guidelines and recommendations were given according to the same paper (see "Availability of Companion Documents"). When sufficient evidence for recommendations A–C was not available the Task Force gave a recommendation as a 'Good Practice Point' if agreed by all members of the Task Force. When analyzing results and drawing recommendations at any stage the differences were resolved by discussions and if persisting were reported in the text.
Rating Scheme for the Strength of the Recommendations
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective ineffective or harmful) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (probably effective ineffective or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective ineffective or harmful) requires at least two convincing class III studies.
Good Practice Point When sufficient evidence for recommendations A–C was not available the Task Force gave a recommendation as a 'Good Practice Point' if agreed by all members of the Task Force.
Cost Analysis
A formal cost analysis was not performed and published cost analyses were not reviewed.
Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation
The guidelines were validated according to the European Federation of Neurological Societies (EFNS) criteria (see "Availability of Companion Documents").
Major Recommendations
The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C Good Practice Point) are defined at the end of the "Major Recommendations" field.
Diagnosis
When neurological symptoms and/or signs develop in a patient with known systemic cancer brain metastases must always be suspected. Careful medical history and physical examination with special emphasis on the presence/activity of the systemic disease and the general physical condition (estimation of the performance status) are recommended. All these recommendations are Good Practice Points.
Computed tomography (CT) (including double-dose delayed contrast) is inferior to magnetic resonance imaging (MRI) but it is sufficient when shows multiple brain metastases. Contrast-enhanced MRI is indicated when (a) surgery or radiosurgery are considered one or two metastases on contrast-enhanced CT and a Karnofsky Performance Status (KPS) >70 (refer to Table 1 in the original guideline document); (b) contrast-enhanced CT is negative but the history is strongly suggestive of the presence of brain metastases in a patient with established malignant disease; and (c) CT is not conclusive to eliminate non-neoplastic lesions (abscesses infections demyelinating diseases and vascular lesions). All these recommendations are level B. Diffusion MRI is useful for the differential diagnosis of ring-enhancing lesions (level C recommendation). Electroencephalogram (EEG) is indicated in patients who suffer from seizures that cannot be classified as epileptic (Good Practice Point) (refer to Table 1 in the original guideline document).
Tissue diagnosis (by stereotactic or open surgery) should be obtained when (i) the primary tumor is unknown (ii) the systemic cancer is well controlled and the patient is a long-term survivor (iii) lesions on MRI do not show the typical aspect of brain metastases and (iv) there is clinical suspicion of an abscess (fever meningism) (level B recommendation). In patients with unknown primary tumor CT of the chest/abdomen and mammography are recommended by most members of the Task Force but a further extensive evaluation is not appropriate in the absence of specific symptoms or indications from the brain biopsy (Good Practice Point). Fluorine-18-labeled deoxyglucose positron-emission tomography (FDG PET) can be useful for detecting the primary tumor (Good Practice Point). The histopathologic studies on the brain metastasis may provide valuable information in indicating a likely organ of origin and guiding further specialized diagnostic work-up: in this regard immunohistochemical staining to detect tissue- organ- or tumor-specific antigens is useful (Good Practice Point). Cerebrospinal fluid (CSF) cytology is needed when the coexistence of a carcinomatous meningitis is suspected (Good Practice Point).
Supportive Care
Dexamethasone is the corticosteroid of choice and twice-daily dosing is sufficient (Good Practice Point). In most cases starting doses should not exceed 4 to 8 mg/day but patients with severe symptoms including impaired consciousness or other signs of increased intracranial pressure may benefit from higher doses such as 16 mg/day or even more (level B recommendation). An attempt to reduce the dose should be undertaken within 1 week of initiation of treatment; if possible steroids should be weaned off within two weeks. If complete weaning off is not possible the lowest possible dose should be looked for. Asymptomatic patients do not require steroids. Steroids may reduce the acute side effects of radiation therapy. All these recommendations are Good Practice Points.
Anticonvulsants should not be prescribed prophylactically (level A recommendation). In patients who suffer from epileptic seizures and need a concomitant treatment with chemotherapeutics enzyme-inducing antiepileptic drugs should be avoided (level B recommendation).
In patients with venous thromboembolism (VTE) low-molecular-weight heparin (LMWH) is effective and well tolerated for both initial therapy and secondary prophylaxis (level A recommendation). A duration ranging from 3 to 6 months is recommended for the anticoagulant treatment (Good Practice Point). Prophylaxis in patients undergoing surgery is recommended (level B recommendation).
Treatment of Single Brain Metastasis
Surgical resection should be considered in patients with single brain metastasis in an accessible location especially when the size is large the mass effect is considerable and an obstructive hydrocephalus is present (Good Practice Point). Surgery is recommended when the systemic disease is absent/controlled and the Karnofsky Performance score is 70 or more (level A recommendation). When the combined resection of a solitary brain metastasis and a non-small cell lung carcinoma (stage I and II) is feasible surgery for the brain lesion should come first with a maximum delay between the two surgeries not exceeding 3 weeks (Good Practice Point). Patients with disseminated but controllable systemic disease (i.e. bone metastases from breast cancer) or with a radioresistant primary tumor (melanoma renal cell carcinoma and colon cancer) may benefit from surgery (Good Practice Point). Surgery at recurrence is useful in selected patients (level C recommendation).
Stereotactic radiosurgery (SRS) should be considered in patients with metastases of a diameter of <3–3.5 cm and/or located in eloquent cortical areas basal ganglia brain stem or with comorbidities precluding surgery (level B recommendation). Gamma-knife or linear accelerator (Linac) are equally effective (level B recommendation). SRS may be effective at recurrence after prior radiation treatment (level B recommendation).
The role of adjuvant whole-brain radiotherapy (WBRT) after surgery or radiosurgery remains to be clarified. In case of absent/controlled systemic disease and Karnofsky Performance score of 70 or more one can either withhold initial WBRT if close follow-up with MRI (every 3 to 4 months) is performed or deliver early WBRT with fractions of 1.8–2 Gy to a total dose of 40–55 Gy to avoid late neurotoxicity (Good Practice Point).
Whole-brain radiotherapy alone is the therapy of choice for patients with active systemic disease and/or poor performance status and should employ hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in five fractions (level B recommendation). For elderly patients with poor performance status WBRT can be withheld and supportive care only employed (Good Practice Point).
The Treatment of Multiple Brain Metastases
In patients with up to three brain metastases good performance status (KPS of 70 or more) and controlled systemic disease SRS is an alternative to WBRT (level B recommendation) whilst surgical resection is an option when the lesions are in an accessible location (level C recommendation). In patients with more than three brain metastases WBRT with hypofractionated regimens is the treatment of choice (level B recommendation). In bedridden patients it should be considered to withhold active radiation treatment and restrict therapy to supportive care (Good Practice Point).
The Role of Chemotherapy
Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors like small cell lung cancers lymphomas germ cell tumors and breast cancers especially for chemonaive patients or if an effective chemotherapy schedule for the primary is still available (Good Practice Point). Radiation therapy with or without chemotherapy is still the treatment of choice for patients needing a palliation of neurological symptoms (Good Practice Point).
Definitions:
Evidence Classification Scheme for a Diagnostic Measure:
Class I: A prospective study in a broad spectrum of persons with the suspected condition using a "gold standard" for case definition where the test is applied in a blinded evaluation and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls where test is applied in a blinded evaluation and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective randomized controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies case series case reports or expert opinion
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective ineffective or harmful) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (probably effective ineffective or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective ineffective or harmful) requires at least two convincing class III studies.
Good Practice Point When sufficient evidence for recommendations A–C was not available the Task Force gave a recommendation as a 'Good Practice Point' if agreed by all members of the Task Force.
Clinical Algorithm(s)
None provided
Type of Evidence supporting the Recommendations
The type of supporting evidence is identified and graded for selected recommendations (see "Major Recommendations").
Potential Benefits
Appropriate diagnosis and treatment of brain metastases
Potential Harms
- Side effects from chronic dexamethasone administration including myopathy are frequent and contribute to disability.
- Subtherapeutic levels of anticonvulsants were extremely common and the severity of side effects appeared to be higher (20–40%) in brain tumor patients than in the general population receiving anticonvulsants probably because of drug interactions. Some antiepileptic drugs stimulate the cytochrome P450 system and accelerate the metabolism of corticosteroids and chemotherapeutic agents and thus reduce their efficacy.
- Acute (early) and chronic (late) complications following radiosurgery for brain metastases are relatively modest. Acute reactions (due to edema) occur in 7 to 10% of patients more often within 2 weeks from treatment and include headache nausea and vomiting worsening of preexistent neurological deficits and seizures. These reactions are generally reversible with steroids. Chronic complications consist of hemorrhage and radionecrosis (1 to 17%) requiring reoperation in up to 4% of patients.
- Whole-brain radiotherapy (WBRT) may cause early adverse effects (fatigue alopecia Eustachian tube dysfunction) and late neurotoxicity. Long-term survivors after WBRT frequently develop radiographic changes on computed tomography (CT) or magnetic resonance imaging (MRI) including cortical atrophy ventriculomegaly and hyperintensity of the periventricular white matter in T2 and fluid-attenuated inversion recovery images. Up to 11% of patients have clinical symptoms such as memory loss progressing to dementia frontal gait disorders and urinary incontinence. The risk of late neurotoxicity is higher with hypofractionated schedules of radiotherapy (size fraction >2 Gy). Nausea vomiting headache fever and transient worsening of neurological symptoms in the initial phase of therapy may be observed.
Qualifying Statements
This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.
Description of Implementation Strategy
The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies national ministries of health World Health Organisation European Union and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels provided there is no advertising attached.
Implementation Tools
Staff Training/Competency Material
For information about availability see the "Availability of Companion Documents" and "Patient Resources" fields below.
IOM Care Need
End of Life Care
Getting Better
IOM Domain
Effectiveness
Bibliographic Source(s)
- Soffietti R Cornu P Delattre JY Grant R Graus F Grisold W Heimans J Hildebrand J Hoskin P Kalljo M Krauseneck P Marosi C Siegal T Vecht C. EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol 2006 Jul;13(7):674-81. [44 references] PubMed
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
European Federation of Neurological Societies
Guideline Committee
European Federation of Neurological Societies Task Force on the Diagnosis and Treatment of Brain Metastases
Composition of Group that Authored the Guideline
Task Force Members: R. Soffietti Department of Neurology and Oncology San Giovanni Battista Hospital and University Torino Italy; P. Cornu Department of Neurosurgery Pitiè-Salpétrière and University Paris; J. Y. Delattre Department of Neurology Pitiè-Salpétrière Paris France; R. Grant Department of Neurology Western General Hospital and University Edinburgh UK; F. Graus Service of Neurology Hospital Clinic Villaroel Barcelona Spain; W. Grisold Department of Neurology Kaiser-Franz-Josef Spital Vienna Austria; J. Heimans Department of Neurology Academisch Ziekenhuis V.U. Amsterdam The Netherlands; J. Hildebrand Consultant Neurologist Brussels Belgium; P. Hoskin Department of Radiotherapy Mount Vernon Hospital and University Northwood Middlesex UK; M. Kalljo Department of Neurology University Hospital Helsinki Finland; P. Krauseneck Neurologische Clinic Bamberg Germany; C. Marosi Division Oncology Vienna General Hospital and University Vienna Austria; T. Siegal Neuro-Oncology Clinic Hadassah Hebrew University Jerusalem Israel; C. Vecht Department of Neurology Med Center Haaglanden The Hague The Netherlands
Financial Disclosures/Conflicts of Interest
None of the Members of the Task Force including the chairperson had any form of conflict of interest.
Guideline Status
This is the current release of the guideline.
Guidelines will be reviewed and updated at least every 2 years.
Guideline Availability
Electronic copies: Available to registered users from the European Federation of Neurological Societies Web site.
Print copies: Available from Dr Riccardo Soffietti MD Chairperson of the Task Force Neuro-Oncology Service Department of Neuroscience and Oncology University and San Giovanni Battista Hospital V. Cherasco 15 10126 Torino Italy; Phone: ++39 011 6334904; Fax: ++39 011 6963487; E-mail: riccardo.soffietti@unito.it
Availability of Companion Documents
The following are available:
- Brainin M Barnes M Baron JC Gilhus NE Hughes R Selmaj K Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site.
- Guideline papers. European Federation of Neurological Societies. Electronic copies: Available from the European Federation of Neurological Societies Web site.
- Continuing Medical Education questions available from the European Journal of Neurology Web site.
Patient Resources
None available
NGC STATUS
This NGC summary was completed by ECRI on April 6 2007. The information was verified by the guideline developer on May 25 2007. This summary was updated by ECRI Institute on June 26 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on March 14 2008 following the updated FDA advisory on heparin sodium injection. This summary was updated by ECRI Institute on December 26 2008 following the FDA advisory on Innohep (tinzaparin).
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