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Target Population: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma (GBM) QUESTION : For adult patients with newly diagnosed GBM does testing for Isocitrate Dehydrogenase 1 or 2 (IDH 1/2) mutations afford benefit beyond standard histopathology in providing accurate classification and outcome prognostication? Level III IDH 1/2 mutational status by immunohistochemistry (IHC) and/or sequencing is suggested for classification and prognostic information. Level III Non-canonical IDH 1/2 mutations are very rare in patients aged 55 or older and universal testing of variant mutations by sequence analysis is not suggested for this age range., Question: For adult patients with lower grade infiltrating astrocytomas (WHO grades II and III) can the IDH-wildtype status designation supersede histopathology to predict prognosis and biologic relevance to eventual behavior as a GBM? Level III The designation of infiltrating astrocytomas (WHO grades II and III) as IDH-wildtype is not suggested as sufficient for a higher grade designation alone. Level III It is suggested that IDH-wildtype WHO grades II and III astrocytomas be tested for molecular-genetic alterations typical of IDH-wildtype GBM such as EGFR amplification, gain of chromosome 7/loss of chromosome 10 and TERT-p mutation to substantiate prediction of behavior similar to IDH-wildtype glioblastoma. Level III It is suggested that a diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO grade IV be rendered for infiltrating astrocytomas that lack histologic criteria of GBM but harbors molecular-genetic alterations of IDH-wildtype glioblastoma., Question: For adult patients with newly diagnosed infiltrating glioma arising in the midline does testing for H3-K27M mutations provide information beyond that gained by histopathology for accurate classification and outcome prognostication? Level III It is suggested that infiltrating gliomas arising in midline anatomic locations be tested for the H3-K27M mutation as they tend to exhibit WHO grade IV behavior even if they lack histologic criteria for glioblastoma.

Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. QUESTION 1 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the addition of radiation therapy (RT) more beneficial than management without RT in improving survival?, Recommendations: Level I: Radiation therapy (RT) is recommended for the treatment of newly diagnosed malignant glioblastoma in adults. QUESTION 2 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the RT regimen of 60 Gy given in 2 Gy daily fractions more beneficial than alternative regimens in providing survival benefit while minimizing toxicity?, Recommendations: Level I: Treatment schemes should include dosage of up to 60 Gy given in 2 Gy daily fractions that includes the enhancing area. QUESTION 3 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is a tailored target volume superior to regional RT for reduction of radiation-induced toxicity while maintaining efficacy?, Recommendation: Level II: It is recommended that radiation therapy planning include 1-2 cm margin around the radiographically T1 weighted contrast-enhancing tumor volume or the T2 weighted abnormality on MRI. Level III: Recalculation of the radiation volume during RT treatment may be necessary to reduce the radiated volume of normal brain since the volume of surgical defect will change during the long period of RT. QUESTION 4 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, does the addition of RT of the subventricular zone to standard tumor volume treatment improve tumor control and overall survival?, Recommendation: No recommendation can be formulated as there is contradictory evidence in favor of and against intentional radiation of the subventricular zone (SVZ) QUESTION 5 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does the addition of RT to surgical intervention improve disease control and overall survival?, Recommendation: Level I: Radiation therapy is recommended for treatment of elderly and frail patients with newly diagnosed glioblastoma to improve overall survival. QUESTION 6 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does modification of RT dose and fractionation scheme from standard regimens decrease toxicity and improve disease control and survival?, Recommendation: Level II: Short RT treatment schemes are recommended in frail and elderly patients as compared to conventional 60 Gy given in 2 daily fractions because overall survival is not different while RT risk profile is better for the short RT scheme. Level II: The 40.05 Gy dose given in 15 fractions or 25 Gy dose given in 5 fractions or 34 Gy dose given in 10 fractions should be considered as appropriate doses for Short RT treatments in elderly and/or frail patients. QUESTION 7 : In adult patients with newly diagnosed glioblastoma is there advantage to delaying the initiation of RT instead of starting it 2 weeks after surgical intervention in decreasing radiation-induced toxicity and improving disease control and survival?, Recommendation: Level III: It is suggested that RT for patients with newly diagnosed GBM starts within 6 weeks of surgical intervention as compared to later times. There is insufficient evidence to recommend the optimal specific post-operative day within the 6 weeks interval to start RT for adult patients with newly diagnosed glioblastoma that have undergone surgical resection. QUESTION 8 : In adult patients with newly diagnosed supratentorial glioblastoma is Image-Modulated RT (IMRT) or similar techniques as effective as standard regional RT in providing tumor control and improve survival?, Recommendation: Level III: There is no evidence that IMRT is a better RT delivering modality when compared to conventional RT in improving overall survival in adult patients with newly diagnosed glioblastoma. Hence, IMRT should not be preferred over the Conventional RT delivery modality. QUESTION 9 : In adult patients with newly diagnosed glioblastoma does the use of radiosensitizers with RT improve the efficacy of RT as determined by disease control and overall survival?, Recommendation: Level III: Iododeoxyuridine is not recommended to be used as radiosensitizer during RT treatment for patients with newly diagnosed GBM QUESTION 10 : In adult patients with newly diagnosed glioblastoma is the use of Ultrafractionated RT superior to standard fractionation regimens in improving disease control and survival?, Recommendation: There is insufficient evidence to formulate a recommendation regarding the use of ultrafractionated RT schemes and patient population that could benefit from it. QUESTION 11 : In patients with poor prognosis with newly diagnosed glioblastoma is hypofractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival?, Recommendation: Level I: Hypofractionated RT schemes may be used for patients with poor prognosis and limited survival without compromising response. There is insufficient evidence in the literature for us to be able to recommend the optimal hypofractionated RT scheme that will confer longest overall survival and/or confer the same overall survival with less toxicities and shorter treatment time. QUESTION 12 : In adult patients with newly diagnosed glioblastoma is the addition of brachytherapy to standard fractionated RT indicated to improve disease control and survival?, Recommendation: Level I: Brachytherapy as a boost to external beam RT has not been shown to be beneficial and is not recommended in the routine management of patients with newly diagnosed GBM. QUESTION 13 : In elderly patients (> 65 year old) with newly diagnosed glioblastoma under what circumstances is accelerated hyperfractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival?, Recommendation: Level III: Accelerated Hyperfractionated RT with a total RT dose of 45 Gy or 48 Gy has been shown to shorten the treatment time without detriment in survival when compared to conventional external beam RT and should be considered as an option for treatment of elderly patients with newly diagnosed GBM. QUESTION 14 : In adult patients with newly diagnosed glioblastoma is the addition of Stereotactic Radiosurgery (SRS) boost to conventional standard fractionated RT indicated to improve disease control and survival?, Recommendation: Level I: Stereotactic Radiosurgery boost to external beam RT has not been shown to be beneficial and is not recommended in patients undergoing routine management of newly diagnosed malignant glioma.

Target Population: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven glioblastoma (GBM)., Question: What are the optimal imaging techniques to be used in the management of a suspected glioblastoma (GBM), specifically: which imaging sequences are critical for most accurately identifying or diagnosing a GBM and distinguishing this tumor from other tumor types?, Recommendations: Critical Imaging for the Identification and Diagnosis of Glioblastoma Level II: In patients with a suspected GBM, it is recommended that the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted, FLAIR and pre- and post-gadolinium contrast enhanced T1 weighted imaging. The addition of diffusion and perfusion weighted MR imaging can assist in the assessment of suspected GBM for the purposes of distinguishing GBM from other tumor types. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage and also can be useful for subjects who are unable to undergo MR imaging. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. Improvement of diagnostic specificity with the addition of non-anatomic (physiologic imaging) to anatomic imaging Level II: One blinded prospective study and a significant number of case series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected GBM, for the purposes of distinguishing GBM from other tumor types (e.g., primary CNS lymphoma or metastases). Level III: It is suggested that magnetic resonance spectroscopy (MRS) and nuclear medicine imaging (PET 18F-FDG and 11C-MET) be used to provide additional support for the diagnosis of GBM.

Question: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma?, Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma., Recommendation: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect., Question: Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?)., Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma., Recommendation: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM., Question: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma?, Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma., Recommendation: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol., Question: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma?, Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma., Recommendation: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.

Target Population: These recommendations apply to adults with newly diagnosed or suspected glioblastoma., Question: What is the effect of extent of surgical resection on patient outcome in the initial management of adult patients with suspected newly diagnosed glioblastoma?, Recommendation: Level II: Maximal cytoreductive surgery is recommended in adult patients with suspected newly diagnosed supratentorial glioblastoma with gross total resection defined as removal of contrast enhancing tumor. Level III: Biopsy, subtotal resection, or gross total resection is suggested depending on medical comorbidities, functional status, and location of tumor if maximal resection may cause significant neurologic deficit., Question: What is the role of cytoreductive surgery in adults with newly diagnosed bi-frontal "butterfly" glioblastoma?, Recommendation: Level III: Resection of newly diagnosed bi-frontal "butterfly" glioblastoma is suggested to improve overall survival over biopsy alone., Question: What is the goal of cytoreductive surgery in elderly adult patients with newly diagnosed glioblastoma?, Recommendation: Level III: Elderly patients (> 65 years) show survival benefit with gross total resection and it is suggested they undergo cytoreductive surgery., Question: What is the role of advanced intraoperative guidance techniques in cytoreductive surgery in adults with newly diagnosed glioblastoma?, Recommendation: Level III: The use of intraoperative guidance adjuncts such as intraoperative MRI (iMRI) or 5-aminolevulinic acid (5-ALA) are suggested to maximize extent of resection in newly diagnosed glioblastoma. There is insufficient evidence to make a suggestion on the use of fluorescein, indocyanine green, or intraoperative ultrasound.

Target Population: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma., Imaging: Question What imaging modalities are in development that may be able to provide improvements in diagnosis, and therapeutic guidance for individuals with newly diagnosed glioblastoma?, Recommendation: Level III: It is suggested that techniques utilizing magnetic resonance imaging for diffusion weighted imaging, and to measure cerebral blood and magnetic spectroscopic resonance imaging of N-acetyl aspartate, choline and the choline to N-acetyl aspartate index to assist in diagnosis and treatment planning in patients with newly diagnosed or suspected glioblastoma., Surgery: Question What new surgical techniques can be used to provide improved tumor definition and resectability to yield better tumor control and prognosis for individuals with newly diagnosed glioblastoma?, Recommendations: Level II: The use of 5-aminolevulinic acid is recommended to improve extent of tumor resection in patients with newly diagnosed glioblastoma. Level II: The use of 5-aminolevulinic acid is recommended to improve median survival and 2 year survival in newly diagnosed glioblastoma patients with clinical characteristics suggesting poor prognosis. Level III: It is suggested that, when available, patients be enrolled in properly designed clinical trials assessing the value of diffusion tensor imaging in improving the safety of patients with newly diagnosed glioblastoma undergoing surgery., Neuropathology: Question What new pathology techniques and measurement of biomarkers in tumor tissue can be used to provide improved diagnostic ability, and determination of therapeutic responsiveness and prognosis for patients with newly diagnosed glioblastomas?, Recommendations: Level II: Assessment of tumor MGMT promoter methylation status is recommended as a significant predictor of a longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level II: Measurement of tumor expression of neuron-glia-2, neurofilament protein, glutamine synthetase and phosphorylated STAT3 is recommended as a predictor of overall survival in patients with newly diagnosed with glioblastoma. Level III: Assessment of tumor IDH1 mutation status is suggested as a predictor of longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level III: Evaluation of tumor expression of Phosphorylated Mitogen-Activated Protein Kinase protein, EGFR protein, and Insulin-like Growth Factor-Binding Protein-3 is suggested as a predictor of overall survival in patients with newly diagnosed with glioblastoma., Radiation: Question What radiation therapy techniques are in development that may be used to provide improved tumor control and prognosis for individuals with newly diagnosed glioblastomas?, Recommendations: Level III: It is suggested that patients with newly diagnosed glioblastoma undergo pretreatment radio-labeled amino acid tracer positron emission tomography to assess areas at risk for tumor recurrence to assist in radiation treatment planning. Level III: It is suggested that, when available, patients be with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of radiation dose escalation, altered fractionation, or new radiation delivery techniques., Chemotherapy: Question What emerging chemotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?, Recommendation: Level III: As no emerging chemotherapeutic agents or techniques were identified in this review that improved tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of chemotherapy., Molecular and Targeted Therapy: Question What new targeted therapy agents are available to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?, Recommendation: Level III: As no new molecular and targeted therapies have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of molecular and targeted therapies IMMUNOTHERAPY: Question What emerging immunotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?, Recommendation: Level III: As no immunotherapeutic agents have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of immunologically-based therapies., Novel Therapies: Question What novel therapies or techniques are in development to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?, Recommendations: Level II: The use of tumor-treating fields is recommended for patients with newly diagnosed glioblastoma who have undergone surgical debulking and completed concurrent chemoradiation without progression of disease at the time of tumor-treating field therapy initiation. Level II: It is suggested that, when available, enrollment in properly designed studies of vector containing herpes simplex thymidine kinase gene and prodrug therapies be considered in patients with newly diagnosed glioblastoma.

Target Population: These recommendations apply to adult patients newly diagnosed with multiple (more than 1) brain metastases., Question 1: In what circumstances should whole brain radiation therapy be recommended to improve tumor control and survival in patients with multiple brain metastases?, Recommendation: Level 2: 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., Question 2: In what circumstances should stereotactic radiosurgery be recommended to improve tumor control and survival in patients with multiple brain metastases?, Recommendations: Level 1: 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 3: 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., Question 3: In what circumstances should surgery be recommended to improve tumor control and survival in patients with multiple brain metastases?, Recommendation: Level 3: 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.The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;6., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Question: What evidence is available regarding emerging and investigational treatment options for metastatic brain tumors?, Target Population: Adult patients with brain metastases., Interstitial Modalities: 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., Immune Modulators: There is insufficient evidence to make a recommendation regarding the use of immune therapy for brain metastases., Molecular Targeted Agents: Level 1: 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.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;9., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Target Population: These recommendations apply to adult patients with new or recurrent solitary or multiple brain metastases from solid tumors as detailed in each section., Question 1: Should patients with newly diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities?, Recommendations: Level 3: 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 3: 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., Question 2: What is the role of SRS after open surgical resection of brain metastasis?, Recommendation: Level 3: After open surgical resection of a solitary brain metastasis, SRS should be used to decrease local recurrence rates., Question 3: What is the role of SRS alone in the management of patients with 1 to 4 brain metastases?, Recommendations: Level 3: For patients with solitary brain metastasis, SRS should be given to decrease the risk of local progression. Level 3: 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., Question 4: What is the role of SRS alone in the management of patients with more than 4 brain metastases?, Recommendation: Level 3: 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. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;4., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;2) for the target population of each recommendation listed below.  SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)?, Recommendations: Level 1: Surgery + 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 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits.  SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities?, Recommendations: Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT.  SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection?, Recommendations: Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS.  SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence?, Recommendation: Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases., Question B: Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence?, Recommendation: Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;2., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Question: Do steroids improve neurological symptoms and/or quality of life in patients with metastatic brain tumors compared to supportive care only or other treatment options? If steroids are given, what dose should be used?, Target Population: These recommendations apply to adults diagnosed with brain metastases., Recommendations: STEROID THERAPY VERSUS NO STEROID THERAPYAsymptomatic brain metastases patients without mass effectInsufficient evidence exists to make a treatment recommendation for this clinical scenario.Brain metastases patients with mild symptoms related to mass effect Level 3: 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 3: 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., Choice of Steroid: Level 3: If corticosteroids are given, dexamethasone is the best drug choice given the available evidence.Duration of Corticosteroid Administration Level 3: 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.The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;7., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Question 1: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT) for the treatment of their brain metastases?, Target Population: This recommendation applies to adult patients with newly diagnosed brain metastases amenable to both chemotherapy and radiation treatment., Recommendations: Level 1: Routine use of chemotherapy following WBRT for brain metastases is not recommended. Level 3: Routine use of WBRT plus temozolomide is recommended as a treatment for patients with triple negative breast cancer., Question 2: Should patients with brain metastases receive chemotherapy in addition to stereotactic radiosurgery (SRS) for the treatment of their brain metastases?, Recommendations: Level 1: Routine use of chemotherapy following SRS is not recommended. Level 2: SRS is recommended in combination with chemotherapy to improve overall survival and progression free survival in lung adenocarcinoma patients., Question 3: Should patients with brain metastases receive chemotherapy alone?, Recommendation: Level 1: Routine use of cytotoxic chemotherapy alone for brain metastases is not recommended as it has not been shown to increase overall survival.Please see the full-text version of this guideline (https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;5) for the target population of each recommendation., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Target Population: Adult patients (older than 18 yr of age) with newly diagnosed brain metastases., Question: If whole brain radiation therapy (WBRT) is used, is there an optimal dose/fractionation schedule?, Recommendations: Level 1:  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 3: 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 3: WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases., Question: What impact does tumor histopathology or molecular status have on the decision to use WBRT, the dose fractionation scheme to be utilized, and its outcomes?, Recommendations: 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., Question: Separate from survival outcomes, what are the neurocognitive consequences of WBRT, and what steps can be taken to minimize them?, Recommendations: Level 2: 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 2:  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 2: 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 3: 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., Question: Does the addition of WBRT after surgical resection or radiosurgery improve progression-free or overall survival outcomes when compared to surgical resection or radiosurgery alone?, Recommendations: Level 2: 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 2: 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 3: 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.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter&#95;3., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Appropriate imaging modalities for screening, staging, and surveillance of patients with suspected and documented metastatic disease to bone include (99m)Tc bone scanning, MRI, CT, radiography, and 2-[(18)F]fluoro-2-deoxyglucose-PET. Clinical scenarios reviewed include asymptomatic stage 1 breast carcinoma, symptomatic stage 2 breast carcinoma, abnormal bone scan results with breast carcinoma, pathologic fracture with known metastatic breast carcinoma, asymptomatic well-differentiated and poorly differentiated prostate carcinoma, vertebral fracture with history of malignancy, non-small-cell lung carcinoma staging, symptomatic multiple myeloma, osteosarcoma staging and surveillance, and suspected bone metastasis in a pregnant patient. No single imaging modality is consistently best for the assessment of metastatic bone disease across all tumor types and clinical situations. In some cases, no imaging is indicated. The recommendations contained herein are the result of evidence-based consensus by the ACR Appropriateness Criteria((R)) Expert Panel on Musculoskeletal Radiology.

Question: What evidence is available regarding the use of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or chemotherapy for the treatment of recurrent/progressive brain metastases?, Target Population: This recommendation applies to adults with recurrent/progressive brain metastases who have previously been treated with WBRT, surgical resection and/or radiosurgery. Recurrent/progressive brain metastases are defined as metastases that recur/progress anywhere in the brain (original and/or non-original sites) after initial therapy., Recommendation: Level 3 Since there is insufficient evidence to make definitive treatment recommendations in patients with recurrent/progressive brain metastases, treatment should be individualized based on a patient's functional status, extent of disease, volume/number of metastases, recurrence or progression at original versus non-original site, previous treatment and type of primary cancer, and enrollment in clinical trials is encouraged. In this context, the following can be recommended depending on a patient's specific condition: no further treatment (supportive care), re-irradiation (either WBRT and/or SRS), surgical excision or, to a lesser extent, chemotherapy. Question If WBRT is used in the setting of recurrent/progressive brain metastases, what impact does tumor histopathology have on treatment outcomes? No studies were identified that met the eligibility criteria for this question.

Target Population: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain., Recommendation: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.

Question: Should patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? Target population These recommendations apply to adults with newly diagnosed solid brain metastases amenable to SRS; lesions amenable to SRS are typically defined as measuring less than 3 cm in maximum diameter and producing minimal (less than 1 cm of midline shift) mass effect. Recommendations SRS plus WBRT vs. WBRT alone Level 1 Single-dose SRS along with WBRT leads to significantly longer patient survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS > or = 70.Level 1 Single-dose SRS along with WBRT is superior in terms of local tumor control and maintaining functional status when compared to WBRT alone for patients with 1-4 metastatic brain tumors who have a KPS > or =70.Level 2 Single-dose SRS along with WBRT may lead to significantly longer patient survival than WBRT alone for patients with 2-3 metastatic brain tumors.Level 3 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS<70 [corrected].Level 4 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS < 70. SRS plus WBRT vs. SRS alone Level 2 Single-dose SRS alone may provide an equivalent survival advantage for patients with brain metastases compared with WBRT + single-dose SRS. There is conflicting class I and II evidence regarding the risk of both local and distant recurrence when SRS is used in isolation, and class I evidence demonstrates a lower risk of distant recurrence with WBRT; thus, regular careful surveillance is warranted for patients treated with SRS alone in order to provide early identification of local and distant recurrences so that salvage therapy can be initiated at the soonest possible time. Surgical Resection plus WBRT vs. SRS +/- WBRT Level 2 Surgical resection plus WBRT, vs. SRS plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3: Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. SRS alone vs. WBRT alone Level 3 While both single-dose SRS and WBRT are effective for treating patients with brain metastases, single-dose SRS alone appears to be superior to WBRT alone for patients with up to three metastatic brain tumors in terms of patient survival advantage.

Question: Do steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? Comparisons include: (1) steroid therapy versus none. (2) comparison of different doses of steroid therapy., Target Population: These recommendations apply to adults diagnosed with brain metastases., Recommendations: 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 Level 3 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 4-8 mg/day of dexamethasone be considered. Brain metastases patients with moderate to severe symptoms related to mass effect Level 3 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/day or more be considered. Choice of Steroid Level 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. Duration of Corticosteroid Administration Level 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period, or longer in symptomatic patients, 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 (two) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. Please see "Discussion" and "Summary" section for additional details.

The movement to create guidelines for management of medical maladies has been gaining strength for quality, academic, financial and political purposes over the past two decades. This applies to neurological diseases, too. Evidence-based guidelines created in a multidisciplinary fashion using predetermined criteria for grading scientific data and translating this to similarly ranked recommendations is a valuable approach to meeting this goal. The following is a summary of the methods used for, and the results of, an evidence-based guideline for the management of newly diagnosed glioblastoma. In addition to outlining recommendations by discipline, it also addresses how concerns and conflicts were addressed in their development and provides comment on future directions in management of this situation that may improve outcome. It is important that clinicians directly experienced in patient management take the lead in creation of guidelines related to the diseases they deal with, as these clinicians are clearly the most suited to being able to arrive at a meaningful and useful product.