Treatment of Adults with Metastic Brain Tumors

Publication Date: March 1, 2019
Last Updated: March 14, 2022

Recommendations

Prophylactic Anticonvulsants

Prophylactic AEDs are not recommended for patients with brain metastases who did not undergo surgical resection and are otherwise seizure-free. (Level III)
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Routine postcraniotomy AED use for seizure-free patients with brain metastases is not recommended. (Level III)
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Surgery

Surgery + whole brain radiotherapy (WBRT) is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. (Level I)
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Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors. (Level III)
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Multimodal treatments including either surgery + WBRT + stereotactic radiosurgery (SRS) boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits. (Level III)
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Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. (Level I)
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Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. (Level III)
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It is recommended that SRS alone be considered equivalent to surgery + WBRT. (Level III)
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Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS. (Level III)
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En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases. (Level III)
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Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. (Level III)
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Stereotactic Radiosurgery

SRS is recommended as an alternative to surgical resection in solitary metastases when surgical resection is likely to induce new neurological deficits, and tumor volume and location are not likely to be associated with radiation-induced injury to surrounding structures.

(Level III)
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SRS should be considered as a valid adjunctive therapy to supportive palliative care for some patients with brain metastases when it might be reasonably expected to relieve focal symptoms and improve functional quality of life in the short term if this is consistent with the overall goals of the patient.

(Level III)
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After open surgical resection of a solitary brain metastasis, SRS should be used to decrease local recurrence rates.

(Level III)
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For patients with solitary brain metastasis, SRS should be given to decrease the risk of local progression.

(Level III)
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For patients with 2 to 4 brain metastases, SRS is recommended for local tumor control, instead of whole brain radiotherapy, when their cumulative volume is <7 mL.

(Level III)
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The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume <7 mL.

(Level III)
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Chemotherapy

Routine use of chemotherapy following WBRT for brain metastases is not recommended. (Level III)
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Routine use of WBRT plus temozolomide is recommended as a treatment for patients with triple negative breast cancer. (Level III)
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Routine use of chemotherapy following SRS is not recommended. (Level I)
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SRS is recommended in combination with chemotherapy to improve overall survival and progression free survival in lung adenocarcinoma patients. (Level II)
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Routine use of cytotoxic chemotherapy alone for brain metastases is not recommended as it has not been shown to increase overall survival. (Level I)
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Treatment Options

It is recommended that whole brain radiation therapy can be added to stereotactic radiosurgery to improve local and distant control keeping in mind the potential for worsened neurocognitive outcomes and that there is unlikely to be a significant impact on overall survival. (Level II)
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The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume <7 cc. (Level III)
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In patients with 2 to 3 brain metastases not amenable to surgery, the addition of stereotactic radiosurgery to whole brain radiation therapy is not recommended to improve survival beyond that obtained with whole brain radiation therapy alone. (Level I)
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In patients with multiple brain metastases, tumor resection is recommended in patients with lesions inducing symptoms from mass effect that can be reached without inducing new neurological deficit and who have control of their cancer outside the nervous system. (Level III)
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Emerging and Investigational Therapies

There is insufficient evidence to make a recommendation regarding the routine use of existing local therapies, such as interstitial chemotherapy, brachytherapy, or other local modalities, aside from their use in approved clinical trials. ()
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There is insufficient evidence to make a recommendation regarding the use of immune therapy for brain metastases. ()
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The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.There is insufficient evidence to make recommendations regarding: the use of epidermal growth factor receptor inhibitors erlotinib and gefitinib in patients with brain metastasis due to nonsmall cell lung cancerthe use of BRAF inhibitors dabrafenib and vemurafenib in the treatment of patients with brain metastases due to metastatic melanomathe use of HER2 agents trastuzumab and lapatinib to treat patients with brain metastases due to metastatic breast cancerthe use of vascular endothelial growth factor agents bevacizumab, sunitinib, and sorafenib in the treatment of patients with solid tumor brain metastases. (Level I)
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Whole Brain Radiation Therapy

A standard WBRT dose/fractionation schedule (ie, 30 Gy in 10 fractions or a biological equivalent dose [BED] of 39 Gy10) is recommended as altered dose/fractionation schedules do not result in significant differences in median survival or local control. (Level I)
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Due to concerns regarding neurocognitive effects, higher dose per fraction schedules (such as 20 Gy in 5 fractions) are recommended only for patients with poor performance status or short predicted survival. (Level III)
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WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases. (Level III)
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There is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. Molecular status may have an impact on the decision to delay WBRT in subgroups of patients, but there is not sufficient data to make a more definitive recommendation. ()
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Due to neurocognitive toxicity, local therapy (surgery or SRS) without WBRT is recommended for patients with ≤4 brain metastases amenable to local therapy in terms of size and location. (Level II)
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Given the association of neurocognitive toxicity with increasing total dose and dose per fraction of WBRT, WBRT doses exceeding 30 Gy given in 10 fractions, or similar biologically equivalent doses, are not recommended, except in patients with poor performance status or short predicted survival. (Level II)
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If prophylactic cranial irradiation (PCI) is given to prevent brain metastases for small cell lung cancer, the recommended WBRT dose/fractionation regimen is 25 Gy in 10 fractions, and because this can be associated with neurocognitive decline, patients should be told of this risk at the same time they are counseled about the possible survival benefits. (Level II)
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Patients having WBRT (given for either existing brain metastases or as PCI) should be offered 6 mo of memantine to potentially delay, lessen, or prevent the associated neurocognitive toxicity. (Level III)
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WBRT is not recommended in WHO performance status 0 to 2 patients with up to 4 brain metastases because, compared to surgical resection or radiosurgery alone, the addition of WBRT improves intracranial progression-free survival but not overall survival. (Level II)
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In WHO performance status 0 to 2 patients with up to 4 brain metastases where the goal is minimizing neurocognitive toxicity, as opposed to maximizing progression-free survival and overall survival, local therapy (surgery or radiosurgery) without WBRT is recommended. (Level II)
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Compared to surgical resection or radiosurgery alone, the addition of WBRT is not recommended for patients with more than 4 brain metastases unless the metastases' volume exceeds 7 cc, or there are more than 15 metastases, or the size or location of the metastases are not amenable to surgical resection or radiosurgery. (Level III)
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Steroids

STEROID THERAPY VERSUS NO STEROID THERAPY

Asymptomatic brain metastases patients without mass effect
Insufficient evidence exists to make a treatment recommendation for this clinical scenario. Brain metastases patients with mild symptoms related to mass effect. ()
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Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4 to 8 mg/d of dexamethasone be considered.Brain metastases patients with moderate to severe symptoms related to mass effect. (Level III)
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Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/d or more be considered. (Level III)
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Choice of steroid

If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. (Level III)
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Duration of Corticosteroid Administration
Corticosteroids, if given, should be tapered as rapidly as possible but no faster than clinically tolerated, based upon an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy. Given the very limited number of studies (2) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. (Level III)
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Recommendation Grading

Overview

Title

Treatment of Adults with Metastic Brain Tumors

Authoring Organization

Endorsing Organization

Publication Month/Year

March 1, 2019

Last Updated Month/Year

August 10, 2022

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Male, Adult

Health Care Settings

Ambulatory, Emergency care, Hospital, Operating and recovery room

Intended Users

Physician, nurse, nurse practitioner, physician assistant

Scope

Management, Treatment

Keywords

chemotherapy, Surgical resection, Metastatic brain tumors, whole brain radiation therapy, Prophylactic Anticonvulsants

Methodology

Number of Source Documents
44
Literature Search Start Date
October 1, 2008
Literature Search End Date
December 31, 2015
Description of External Review Process
The completed systematic review was then distributed to the Joint Guidelines Committee (JGC) of the American Association of Neurological Surgeons (AANS) and CNS for consideration of endorsement by the CNS Executive Committee and the AANS Board of Directors. JGC reviewers were permitted to critique the content and methodology used to create this systematic review. Any concerns of the JGC were addressed by the Task Force, and the document was resubmitted to the JGC for endorsement.
Specialties Involved
Neurological Surgery, Neurology
Description of Systematic Review
CNS/AANS has an established methodology. The grading of recommendations is unique to their specialty.
List of Questions
Refer to the full text.
Description of Study Criteria
Each Section had unique inclusion and exclusion criteria that yield citations. Nine Sections are included. Eligibility Criteria 1. Peer-reviewed publications. 2. Patients with newly diagnosed and recurrent brain metastases who have had surgery. 3. Each study had >5 or more subjects. 4. Patients <18 years of age. Studies with mixed adult and child populations were included if the adult cohorts could be isolated and analyzed separately. 5. Publications in English. 6. Excluded radiosensitive tumor histologies (small cell lung cancer, lymphoma, and multiple myeloma).
Description of Search Strategy
The following electronic databases were searched from January 1, 2008 to December 31, 2015: PubMed and Ovid Medline, using relevant MeSH and non-MeSH terms, including: “Metastasis”, “Metastases”, “Metastatic”, “Metastasize”, “Surgery”, “Surgical”, “Operative”, “Resect”, “Brain”, and “Brain Neoplasm.” See Appendix A for the complete search strategies.
Description of Study Selection
The search criteria were developed and abstract review was performed by two independent 80 reviewers. Citations were independently reviewed and included if they met the a priori criteria 81 for relevance. No discrepancies in study eligibility were noted. Corresponding full-text PDFs 82 were obtained for all citations meeting the criteria, and were reviewed. Data were extracted by 83 the first reviewer and verified by another, all of which were compiled into evidence tables. The 84 tables and data were reviewed by all of the authors. Articles that did not meet the selection 85 criteria were removed.
Description of Evidence Analysis Methods
Information was compiled by that subgroup and then distributed to the entire group for review until a final consensus by means of group discussion, voting, and approval was achieved. The task force used voting among its members to approve the final recommendations, language, and strength of recommendations. The voting was used to ensure that the language of each recommendation accurately reflected the evidence and the strength of the evidence. All the recommendations in this review were approved following the first round of voting, and no further discussion was needed to finalize the recommendations described below. The voting technique is referred to as the nominal group technique, as described in an article by Murphy et al. During the course of editing and finalization of the document, changes were made to allow recommendations to conform to the rules of evidence and language as described above. When this occurred, the changes were reviewed and approved by the group.
Description of Evidence Grading
The quality of evidence was rated using an evidence hierarchy developed by the Joint Guidelines Committee for each of the 4 different study types (ie, therapeutic, diagnostic, prognostic, and clinical assessment). The strength of evidence of each article that underwent full text review was graded according to the criteria established by the AANS/CNS JGC. The class of evidence (i.e., Class I, II, or III) assigned to each article was determined after review of the sample size, study design, follow-up, and outcome measures (refer to Table 1 in the original guideline).
Description of Recommendation Grading
The strength of evidence of each article that underwent full text review was graded according to the criteria established by the AANS/CNS JGC. The class of evidence (i.e., Class I, II, or III) assigned to each article was determined after review of the sample size, study design, follow-up, and outcome measures. The strength of clinical recommendations (i.e., Level I, II, or III) was then linked to the level of evidence included to support the recommendation.
Description of Funding Source
These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons and the Tumor Section of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.
Company/Author Disclosures
The Brain Metastases Guideline Update Task Force members were required to report all possible conflicts of interest (COIs) prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee, including potential COIs that are unrelated to the topic of the guideline. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination. The CNS Guidelines Committee and Guideline Task Force Chair are given latitude to approve nominations of task force members with possible conflicts and address this by restricting the writing and reviewing privileges of that person to topics unrelated to the possible COIs.
Percentage of Authors Reporting COI
100