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.
