CNS Cancers
Gliomas, glioblastoma, meningioma, medulloblastoma, and CNS lymphoma
DefinitionClick to collapse
Central nervous system (CNS) cancers encompass a heterogeneous group of neoplasms arising within the brain, spinal cord, meninges, and related structures. The NCCN Guidelines for CNS Cancers (Version 2.2026) focus on management of adult CNS cancers including glioma (WHO grade 1, oligodendroglioma [IDH-mutant, 1p19q codeleted], IDH-mutant astrocytoma, glioblastoma), intracranial and spinal ependymomas, medulloblastoma, primary CNS lymphomas, meningiomas, primary spinal cord tumors, brain metastases, leptomeningeal metastases, and metastatic spine tumors [1,2]. The WHO 2021 Classification of Tumors of the Central Nervous System reclassified adult diffuse gliomas into three principal molecular subtypes: IDH-mutant astrocytoma, oligodendroglioma (IDH-mutant, 1p19q codeleted), and glioblastoma (IDH-wildtype) [6]. Primary brain tumors are derived from glial cells (astrocytes, oligodendrocytes, ependymal cells), neuronal or glioneuronal elements, or meningeal arachnoid cap cells. Brain metastases are the most common intracranial tumors in adults, occurring up to 10 times more frequently than primary brain tumors [443-445]. CNS tumors are associated with symptoms including seizures, fatigue, psychiatric disorders, impaired mobility, neurocognitive dysfunction, difficulty speaking, short-term memory problems, and complications such as intracerebral edema, endocrinopathies, and venous thromboembolism that can seriously impact quality of life [2].
EpidemiologyClick to collapse
SubtypesClick to collapse
Circumscribed Glioma (WHO Grade 1)
Non-invasive, generally surgically curable low-grade gliomas including pilocytic astrocytoma (PA), subependymal giant cell astrocytoma (SEGA), ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), and pleomorphic xanthoastrocytoma (PXA). These tumors range from the very uncommon, noninvasive, and surgically curable pilocytic astrocytomas to glioblastoma, the most common malignant brain tumor in adults [2].
Oligodendroglioma, WHO Grade 2 (IDH1/2-mutant, 1p19q codeleted)
Diffusely infiltrative gliomas defined by the co-occurrence of IDH1/2 mutation and whole-arm 1p/19q codeletion. Radiographically, these tumors appear well demarcated, occasionally contain calcifications, and do not often enhance with contrast. In histology, the typical 'fried egg' appearance is evident as a fixation artifact in paraffin [MS-9]. Survival rates tend to be better in oligodendrogliomas than in other gliomas.
Oligodendroglioma, WHO Grade 3 (IDH1/2-mutant, 1p19q codeleted)
Higher-grade counterpart of grade 2 oligodendrogliomas with the same defining molecular features (IDH mutation and 1p/19q codeletion) but with more aggressive histopathology. Conventionally treated with similar radiation doses as WHO grade 3 and 4 astrocytomas but generally at lower dose per fraction (1.8 Gy/fraction vs. 2.0 Gy/fraction) to decrease risk of late side effects [MS-13].
IDH-Mutant Astrocytoma, WHO Grade 2
Diffusely infiltrative astrocytomas defined by IDH1/2 mutation WITHOUT 1p/19q codeletion, and WITHOUT the histopathologic features of glioblastoma (necrosis and/or microvascular proliferation). These tumors have a more favorable prognosis than IDH-wildtype glioblastomas but generally progress faster than grade 2 oligodendrogliomas [MS-9].
IDH-Mutant Astrocytoma, WHO Grade 3
Higher-grade IDH-mutant astrocytomas without the molecular hallmarks of glioblastoma. Strict histopathologic criteria do not currently exist for definitively diagnosing a WHO grade 2 versus a WHO grade 3 IDH-mutated astrocytoma [GLIO-5 footnotes]. Some panel members feel that it may be reasonable to try treating patients with newly diagnosed IDH1/2-mutated grade 3 astrocytoma upfront with an IDH inhibitor in certain circumstances.
IDH-Mutant Astrocytoma, WHO Grade 4
Diffusely infiltrative astrocytomas with IDH1/2 mutation that have either: (1) traditional grade 4 histologic features (necrosis and/or microvascular proliferation), OR (2) homozygous deletion in CDKN2A/B without necrosis/MVP. These are now distinguished from IDH-wildtype glioblastoma, as they have better clinical outcomes [6,23,30-33].
Glioblastoma (IDH-Wildtype)
The most common malignant brain tumor in adults, characterized by IDH1/2 wild-type status. The term 'glioblastoma' is now reserved exclusively for IDH-wildtype gliomas. Some IDH-wildtype gliomas may lack histologic features of glioblastoma but have molecular hallmarks including: IDH1/2 wild-type; EGFR gene amplification; gain of chromosome 7 and loss of chromosome 10; and/or TERT promoter mutation [22,24]. Median survival remains poor despite aggressive multimodal therapy.
High-Grade Glioma: Other
Includes WHO grade 3 PXA, high-grade astrocytoma with piloid features (HGAP), and H3-mutated high-grade glioma. These are relatively rare subtypes that require molecular testing to guide treatment decisions. Treatment recommendations follow general high-grade glioma pathways with consideration of specific molecular markers.
Intracranial and Spinal Ependymoma
Ependymal tumors arising from ependymal cells lining the ventricular system and spinal canal. In adults, ependymomas occur more often in the spinal canal than in the intracranial compartment. These tumors can cause hydrocephalus, increased intracranial pressure, mimic brainstem lesions, and cause cranial nerve palsies [216,217]. Posterior fossa ependymomas are categorized as two groups: A (PFA) and B (PFB), with PFA more aggressive [24,218,224].
Sellar Tumors (Pituitary Adenomas and Craniopharyngiomas)
Tumors arising in the sellar region including pituitary adenomas (functioning and non-functioning), craniopharyngiomas (papillary and adamantinomatous), pituitary carcinomas, and other sellar masses. Papillary craniopharyngiomas are driven by BRAF V600E mutations. Treatment approaches vary widely based on tumor type, hormone secretion status, and clinical presentation.
Adult Medulloblastoma
WHO grade 4 embryonal tumors predominantly arising from the cerebellum. Although most common in children, they also occur in adults, comprising 1% of CNS tumors in adults [260]. Adult medulloblastoma is genetically distinct from pediatric medulloblastoma with differing prognostic markers. Tumors can be classified into WNT-activated, SHH-activated (TP53-mutant and TP53-wildtype), and non-WNT/non-SHH subgroups [6,259,262].
Primary CNS Lymphoma (PCNSL)
An aggressive form of non-Hodgkin lymphoma developing within the brain, spinal cord, eye, or leptomeninges without evidence of systemic involvement. Pathologically, PCNSL is an angiocentric neoplasm composed of dense monoclonal proliferation of lymphocytes, usually diffuse large B cells, with more than 90% being activated B-cell-like (ABC) subtype [306,307]. Brain parenchyma is involved in more than 90% of patients and disease is multifocal in more than 50% of cases.
Primary Spinal Cord Tumors
Histologically diverse set of tumors representing 2%–4% of all primary CNS tumors [388]. Extramedullary lesions (most commonly benign meningiomas) account for 70%–80% of spinal cord tumors [389]. Astrocytomas (more prevalent in children) and ependymomas (more prevalent in adults) are the most common intramedullary tumors. Since 70% are low-grade and slow-growing, patients often suffer pain for months to years before diagnosis [388].
Meningiomas
Extra-axial CNS tumors arising from arachnoid cap cells in the meninges. Most often discovered in middle-to-late adult life with a female predominance. Radiographic features include dural-based, homogeneously contrast-enhancing mass with dural tail and CSF cleft. Histologically graded as WHO grade 1 (benign, 92%), grade 2 (atypical, 6%), or grade 3 (malignant/anaplastic, 2%) [408,409].
Limited Brain Metastases
Brain metastases for which SRS represents an effective alternative to WBRT, with more cognitive protection. The definition of 'limited' in terms of number of metastases or total intracranial disease volume is evolving and may depend on the specific clinical situation [Yamamoto M, et al. Lancet Oncol 2014;15:387-395 and Aizer AA, et al. JAMA 2026]. Primary lung cancers are the most common source [446], and melanoma has the highest rates of brain metastases among patients with metastatic disease [447,448].
Extensive Brain Metastases
Brain metastases that do not fit the definition of 'limited brain metastases.' Management generally involves WBRT (with hippocampal avoidance and memantine if eligible) or SRS in selected patients with good performance status and low overall tumor volume. The optimal treatment strategy is highly individualized.
Leptomeningeal Metastases
Malignant cells' multifocal seeding of the leptomeninges. Known as leptomeningeal carcinomatosis when originating from solid tumors, lymphomatous meningitis for lymphoma, and leukemic meningitis for leukemia. Occurs in approximately 5% of cancer patients [579]. Most cases arise from breast cancers, lung cancers, and melanoma [580,581]. Median survival is typically 2–4 months [580,581].
Metastatic Spine Tumors
Bone metastases involving the spinal column, the most frequently affected site of bony metastases. Spinal metastases primarily arise from breast, lung, prostate, and renal cancers [611,612]. Extradural lesions account for about 95% of spinal tumors, mostly in the thoracic region. Spinal cord compression affects 5%–10% of all cancer patients with more than 20,000 cases diagnosed annually in the United States [613].
NF2-Related Schwannomatosis (NF2-SWN)
An autosomal dominant tumor predisposition syndrome caused by mutations in the NF2 gene (merlin gene) on chromosome 22q12. Characterized by development of multiple CNS tumors including bilateral vestibular schwannomas (VS), multiple meningiomas, ependymomas, and schwannomas. The condition results in significant morbidity from hearing loss, neurologic deficits, and the challenges of managing multiple tumor types.
Molecular PathogenesisClick to collapse
Risk FactorsClick to collapse
Ionizing radiation exposure
Prior cranial radiation therapy is a well-established risk factor for development of secondary CNS tumors, including meningiomas and gliomas. Radiation therapy for prior cancer is the most consistently identified risk factor for meningiomas. NF2-SWN patients have increased lifetime risk of CNS malignancy (~6%) in irradiated patients [16].
Age
Risk of CNS tumors increases with age, particularly for glioblastoma and meningiomas. Older adults have higher incidence of glioblastoma and less improvement in survival outcomes [2]. Gliomas are less common before age 30 (except pilocytic astrocytomas in children). IDH mutation is associated with younger age at diagnosis.
Genetic syndromes
NF2 (neurofibromatosis type 2): bilateral vestibular schwannomas, multiple meningiomas, ependymomas. Li-Fraumeni syndrome (TP53 germline mutations): predisposition to various CNS tumors including gliomas. Tuberous sclerosis complex: SEGAs. VHL syndrome: hemangioblastomas. Lynch syndrome: DNA mismatch repair deficient glioblastomas. Gorlin syndrome (PTCH1): medulloblastoma (SHH subtype). Turcot syndrome (APC mutations): medulloblastoma (WNT subtype) [BRAIN-F].
Immunosuppression
HIV/AIDS and iatrogenic immunosuppression (post-transplant) increase risk of PCNSL. PCNSL occurs in about 7%–15% of patients with post-transplant lymphoproliferative disorders [309-312]. AIDS-related PCNSL has a distinct clinical course with worse prognosis [303].
Male sex (for PCNSL)
Higher incidence of primary CNS lymphoma in males than females in immunocompetent patients [301].
Epstein-Barr virus (EBV) infection
Strongly associated with PCNSL in immunocompromised patients (HIV/AIDS and post-transplant). EBV-positive PCNSL is virtually restricted to immunosuppressed individuals.
Clinical FeaturesClick to collapse
Typical Presentation
CNS tumors present with highly variable symptoms depending on tumor type, location, grade, and rate of growth. Primary brain tumors such as gliomas, medulloblastomas, and CNS lymphomas typically present with focal neurologic deficits, seizures, headache from increased intracranial pressure, cognitive or personality changes, and signs of increased intracranial pressure (papilledema, nausea/vomiting, altered mental status). Brain metastases may be found incidentally on screening MRI without any symptoms, or present similarly with focal neurologic deficits and increased intracranial pressure [MS-45]. Leptomeningeal metastases present with cranial nerve palsies, spinal cord symptoms, or hydrocephalus signs [MS-47]. Meningiomas are often incidental findings on imaging, but may present with seizures (27%) or focal neurologic symptoms related to location and mass effect [MS-34]. Spinal cord tumors present with progressive pain (often worse at night for intramedullary lesions), motor weakness, sensory loss, and late autonomic dysfunction [MS-32]. Sellar tumors (pituitary adenomas) present with hormonal syndromes or visual field defects from optic chiasm compression [SELLAR-1]. NF2-related schwannomatosis presents with bilateral vestibular schwannomas causing progressive hearing loss, as well as multiple meningiomas, ependymomas, and schwannomas throughout the neuraxis [BRAIN-G]. In a retrospective review of 248 immunocompetent patients with PCNSL, 43% had mental status changes, 33% showed signs of elevated intracranial pressure, 14% had seizures, and 4% suffered visual symptoms at diagnosis [MS-308].
Symptoms
Seizures
Common presenting symptom for low-grade gliomas (81%), particularly oligodendrogliomas. Also occur in 14% of PCNSL and 27% of meningiomas. May be the sole presenting complaint in slowly growing tumors.
Headache
Occurs with increased intracranial pressure from mass effect or hydrocephalus. May be worse in the morning, exacerbated by Valsalva maneuver. Persistent progressive headaches in adults are an alarming symptom.
Focal neurologic deficits
Hemiparesis, aphasia, visual field deficits, cranial nerve palsies depending on tumor location. Progressive motor weakness occurs in half of primary spinal cord tumor patients. Cranial nerve palsies may indicate leptomeningeal disease or skull base tumors.
Cognitive and personality changes
Mental status changes, memory loss, executive dysfunction, and personality changes are common with frontal or temporal lobe tumors. Up to 90% of individuals with supratentorial brain tumors experience some degree of neurocognitive dysfunction [MS-19-21]. In PCNSL, 43% present with mental status changes.
Hearing loss
Unilateral or bilateral progressive hearing loss is the hallmark of vestibular schwannomas. In NF2-SWN, bilateral VS causes progressive hearing loss; treatment with bevacizumab results in hearing improvement in 36% of patients [BRAIN-G]. Sudden sensorineural hearing loss may occur.
Visual disturbances
Visual field deficits from optic pathway compression by pituitary adenomas or craniopharyngiomas. Ocular involvement in PCNSL occurs independently in 10%-20% of patients, presenting as blurred vision or floaters. Pituitary adenomas can cause bitemporal hemianopsia.
Motor weakness and sensory loss
Progressive motor weakness occurs in half of primary spinal cord tumor patients. Spinal cord compression from metastatic spine tumors presents with progressive radicular pain followed by motor weakness, sensory loss, and bowel/bladder dysfunction.
Pain
Three classic types: local pain (constant, deep aching improving with steroids), mechanical pain (varies with movement, indicates instability), and radicular pain (sharp/stabbing from nerve root compression). Pain worsening at night is classic for intramedullary lesions.
Gait instability and ataxia
Cerebellar tumors (medulloblastoma, posterior fossa metastases) cause truncal and limb ataxia, dysmetria, and gait instability. Posterior fossa ependymomas can cause neck stiffness and head tilt.
Signs
Papilledema
Elevated intracranial pressure from mass lesions, hydrocephalus, or diffuse disease. Found on fundoscopic examination.
Motor deficits
Upper motor neuron signs (hyperreflexia, Babinski sign, spasticity) from cortical or corticospinal tract compression. Spinal cord compression may show motor weakness, hyperreflexia below the level of compression.
Cranial nerve palsies
May indicate skull base tumor, leptomeningeal metastases, or nerve sheath tumors. Cranial nerve VIII dysfunction (hearing loss, tinnitus, vestibular symptoms) is hallmark of vestibular schwannomas. New cranial nerve palsies in the context of known cancer suggest leptomeningeal disease.
Cerebellar signs
Intention tremor, dysdiadochokinesia, nystagmus, gait ataxia with posterior fossa tumors.
Sensory deficits
Sensory level on examination may help localize spinal cord compression. Stocking-glove sensory loss is excluded from abnormal examination for spinal cord compression assessment.
Endocrine dysfunction
Hypopituitarism, hyperprolactinemia, Cushing disease, acromegaly, diabetes insipidus from sellar/parasellar tumors. Endocrinopathies are common in brain tumor patients and may be affected by steroid use, RT, and surgery.
Red FlagsClick to collapse
New-onset seizure in an adult without prior history, especially with focal neurologic symptoms
Progressive headache with papilledema, nausea, or vomiting suggesting increased intracranial pressure
Acute or rapidly progressive focal neurologic deficits (hemiparesis, aphasia, visual loss) suggesting mass effect, hemorrhage, or herniation
Signs of spinal cord compression: progressive weakness, sensory level, bowel/bladder dysfunction — spinal cord compression is a medical emergency requiring intervention within 24 hours [MS-54]
Rapid cognitive decline or acute altered mental status suggesting hydrocephalus, leptomeningeal disease, or tumor hemorrhage
New cranial nerve palsies in a patient with known cancer, suggesting leptomeningeal metastases
Acute severe back pain with new neurologic deficits in a cancer patient, requiring urgent spine MRI [MS-54]
Sudden visual loss or bitemporal hemianopsia suggesting pituitary tumor with acute apoplexy
Bilateral vestibular schwannomas identified on imaging, indicating NF2-SWN and requiring comprehensive workup [NF2-SWN-1]
Pituitary adenoma with acute deterioration suggesting apoplexy (hemorrhage or infarction)
Any new or worsening neurologic symptoms in a patient with known cancer and brain metastases, suggesting progression, hemorrhage, or leptomeningeal spread
Tumor bleeding (hemorrhagic conversion): acute sudden-onset severe headache with neurologic deterioration, particularly with melanoma, renal cell carcinoma, or choriocarcinoma metastases
InvestigationsClick to collapse
Diagnostic
Brain MRI with and without gadolinium contrast
Standard of care imaging method for all CNS neoplasms, providing superior soft tissue contrast for detection and characterization. Required at diagnosis, pre-treatment baseline, and post-treatment surveillance [BRAIN-A, MS-2]
Spine MRI with gadolinium contrast
Required for staging of medulloblastoma, ependymomas, PCNSL, and leptomeningeal metastases. Must be performed before lumbar puncture to avoid false-positive imaging artifacts. Should be delayed 2-3 weeks postoperatively to avoid artifacts [BRAIN-A, MS-24]
CT head without contrast
Alternative when MRI contraindicated; shows calcifications in meningiomas (25%) and ependymomas, bone changes, acute hemorrhage, and hydrocephalus [BRAIN-A, MS-34]
Stereotactic or open biopsy
Required for histopathologic diagnosis when surgery not feasible. Strongly recommended as the primary procedure for PCNSL diagnosis [PCNS-1]. Stereotactic biopsy is preferred over resection for PCNSL to minimize invasiveness [MS-318]. Frozen section analysis helps guide intraoperative decision-making [BRAIN-B]
Surgical resection (gross total resection or maximal safe resection)
Primary therapeutic and diagnostic modality for gliomas, ependymomas, meningiomas, medulloblastoma, and spinal cord tumors. Goals include maximal safe resection, symptom relief, and adequate tissue for pathology [BRAIN-B, MS-4]. Extent of resection should be documented with postoperative MRI within 48 hours.
Contrast-enhanced CT chest/abdomen/pelvis
Systemic workup for brain metastases when primary unknown; staging evaluation for PCNSL to exclude systemic involvement [MS-45, PCNS-2]
Whole body FDG-PET/CT
Considered for staging of brain metastases when primary unknown; for PCNSL staging to evaluate systemic involvement [PCNS-2]. Whole-body PET/CT may be considered for patients with brain metastases of unknown origin.
Cerebrospinal fluid (CSF) analysis
Essential for staging medulloblastoma (cytology, cell count), ependymoma (dissemination assessment), PCNSL (diagnostic adjunct when tissue biopsy not feasible), and leptomeningeal metastases (cytology positive for tumor cells). Must be done after spine MRI; delayed 2 weeks post-surgery to avoid false-positive cytology [MS-24, PCNS-1]. CSF analysis should include flow cytometry, cytology, cell count, PCR or NGS of MYD88, and possibly IgH gene rearrangement for PCNSL [PCNS-1]. When available, CSF-tDNA testing can increase sensitivity [BRAIN-E]
Full ophthalmologic exam including slit-lamp examination
Required for PCNSL evaluation to detect vitreoretinal involvement which occurs independently in 10%-20% of patients [PCNS-2, MS-30]. Diagnostic vitrectomy may be performed for primary vitreoretinal lymphoma.
Lumbar puncture for CSF flow study
Indicated before intrathecal chemotherapy in leptomeningeal metastases if CSF flow blockage suspected. Flow abnormalities require radiation correction before intrathecal therapy [LEPT-2]
HIV blood test
Required for PCNSL evaluation; both prognosis and treatment differ in HIV-related PCNSL. HIV-positive patients should receive antiretroviral therapy with cancer treatment [PCNS-2, MS-30]
Bone marrow biopsy
Category 2B option for PCNSL staging if clinical suspicion of bone marrow involvement [PCNS-2]. May also be considered in metastatic workup of brain metastases from unknown primary.
Staging
Brain and spine MRI (complete neuraxis imaging)
Required for staging medulloblastoma, ependymoma, PCNSL, and leptomeningeal metastases. Shows extent of local disease, multifocal disease, and CSF dissemination along the neuraxis [AMED-2, EPEN-2, PCNS-2, LEPT-1]
CT or PET/CT chest/abdomen/pelvis
Systemic staging for brain metastases to identify primary tumor and assess systemic disease burden [LTD-1, MU-1]. For PCNSL, contrast-enhanced body CT or PET/CT required to rule out systemic involvement [PCNS-2]
PET-MRI brain scan
Added as follow-up imaging for meningiomas every 3-6 months per updated recommendations [BRAIN-A]. SSTR PET/CT or PET/MRI may help distinguish meningioma from dural metastases and improve radiation planning [BRAIN-A].
Biomarkers
IDH1/2 mutation testing
Required for workup of ALL gliomas per WHO 2021 classification. IDH1 R132H most common mutation, detected by IHC; sequencing required for non-canonical mutations. IDH mutations define WHO grade 2-4 astrocytomas and oligodendrogliomas, and distinguish them from glioblastoma (IDH wild-type) [BRAIN-E, MS-4-5]
1p/19q codeletion testing
Essential for diagnosis of oligodendroglioma. A tumor should only be diagnosed as oligodendroglioma if it contains both IDH1/2 mutation AND 1p/19q codeletion [BRAIN-E, MS-7]. Detectable by array-based genomic copy number testing (preferable) or FISH.
MGMT promoter methylation testing
Essential for high-grade gliomas (grade 3 and 4). Predictive biomarker for response to alkylating chemotherapy. MGMT promoter methylated tumors respond better to temozolomide. Methods include methylation-specific PCR (most validated), pyrosequencing (possibly best prognostic stratifier), and droplet-digital PCR [BRAIN-E, MS-6, MS-33-35]
ATRX mutation testing
Required for glioma workup. ATRX mutations are strongly associated with IDH mutations and nearly always mutually exclusive with 1p/19q codeletion. Loss of nuclear ATRX immunostaining indicates mutation, supporting astrocytoma over oligodendroglioma diagnosis [BRAIN-E, MS-5]
TERT promoter mutation testing
Recommended for glioma workup. Nearly always present in IDH wild-type glioblastomas and IDH-mutant 1p/19q codeleted oligodendrogliomas. Combined with IDH and 1p/19q status, helps classify gliomas into molecular subtypes with distinct prognoses [BRAIN-E, MS-5-6]
BRAF mutation/fusion testing
Clinically indicated for low-grade gliomas where BRAF-targeted therapy may be appropriate. BRAF V600E found in 60%-80% of PXA, 30% of DNETs, 20% of gangliogliomas, 5% of pilocytic astrocytomas [BRAIN-E, MS-6]. BRAF fusions found in pilocytic astrocytomas. May guide treatment with dabrafenib/trametinib, vemurafenib/cobimetinib, or tovorafenib.
H3-3A and HIST1H3B mutation testing
Recommended in appropriate clinical context for diffuse midline gliomas (H3K27M) and hemispheric gliomas (H3G34). H3K27M-mutant diffuse midline gliomas are WHO grade 4 with poor prognosis. CSF-tDNA testing should be considered for diagnosis and monitoring [BRAIN-E, MS-5]
Multi-gene panel testing (MGPT)
Preferred approach for pathologic workup of CNS tumors, screening for multiple diagnostic and prognostic mutations in one test. May identify BRAF V600E or NTRK fusions that could guide targeted therapy [BRAIN-E, MS-4].
NTRK1/2/3 gene fusion testing
Tumor-agnostic biomarker; patients with NTRK fusion-positive solid tumors may respond to TRK inhibitors (larotrectinib, entrectinib, repotrectinib) including for brain metastases [BRAIN-A, BRAIN METS-A]
MSI-H/dMMR or TMB-H testing
Tumor-agnostic markers; pembrolizumab is a category 2B preferred option for MSI-H/dMMR or TMB-H tumors with isolated brain metastases [BRAIN METS-A]
PD-L1 expression testing
Relevant for NSCLC brain metastases; pembrolizumab recommended for PD-L1 TPS >=1%, nivolumab for TPS >=1% [BRAIN METS-A]
KRAS G12C testing
Relevant for NSCLC brain metastases; adagrasib and sotorasib have activity [BRAIN METS-A]
ALK rearrangement testing
Essential for NSCLC; second- and third-generation ALK inhibitors (brigatinib, lorlatinib, alectinib, ceritinib) have excellent CNS activity for brain metastases [BRAIN METS-A, MS-42]
EGFR mutation testing
Essential for NSCLC; osimertinib has excellent CNS penetration. Also relevant for leptomeningeal metastases [BRAIN METS-A, LEPT-A]
ROS1 rearrangement testing
Relevant for NSCLC; crizotinib, repotrectinib, and taletrectinib have CNS activity [BRAIN METS-A]
BRAF V600 mutation testing (melanoma)
Essential for melanoma brain metastases; dabrafenib/trametinib, vemurafenib/cobimetinib have CNS activity [BRAIN METS-A, MS-40-41]
HER2 status testing (breast cancer)
Essential for breast cancer brain metastases; HER2-directed therapies including tucatinib/trastuzumab/capecitabine have CNS activity [BRAIN METS-A, MS-44]
MYD88 PCR or NGS testing (CSF)
For PCNSL diagnosis; PCR or NGS assays of MYD88 in CSF can help establish diagnosis when tissue biopsy not feasible [PCNS-1, MS-30]
CSF tumor-derived DNA (tDNA) testing
When available, CSF-tDNA testing can be considered with CSF cytology to increase sensitivity of tumor cell detection and assessment of residual disease after surgery or induction therapy [BRAIN-E, LEPT-1]. For H3K27-altered tumors, CSF-tDNA testing should be further considered.
Temozolomide mutational signature testing
Recommended for recurrent glioblastoma, particularly MGMT-promoter methylated recurrent GBMs. This signature renders the recurrent GBM resistant to further temozolomide [BRAIN-E]
DNA mismatch repair protein testing (IHC and NGS)
Recommended for newly diagnosed glioblastoma with TMB-H to identify hypermutated/DNA replication repair deficient subtype. May predict benefit from immune checkpoint blockade. Patients should undergo germline testing for Lynch syndrome [BRAIN-E]
Genomic methylation profiling
For ependymoma: genomic methylation profiling is recommended for differentiation of PFA and PFB ependymomas [BRAIN-E]. For meningioma: may screen for genomic copy number variations; validated internally. For gliomas: genome-wide CpG methylation profiling is a powerful classification tool [BRAIN-E, MS-4]
ZFTA and YAP1 gene fusion testing (ependymoma)
ZFTA gene fusions are found in supratentorial ependymomas with more aggressive behavior. YAP1 fusions have better prognosis. Testing recommended in appropriate clinical context [BRAIN-E, MS-21]
MYCN gene amplification testing (ependymoma)
MYCN-amplified spinal ependymoma is an aggressive subtype now codified as SP-EPN-MYCN in WHO classification [BRAIN-E, MS-222-223]
Medulloblastoma molecular subtyping (WNT, SHH, Group 3/4)
Referred to academic centers with expertise. WNT-activated tumors have markedly better prognosis. SHH-activated with TP53 mutation has worse prognosis. DNA methylation arrays or IHC panel (beta-catenin, GAB1, YAP1) recommended [BRAIN-E, MS-263]
Meningioma copy number profiling
Any validated assay measuring copy number variation across the entire genome. FISH not recommended (insufficient coverage). Homozygous CDKN2A/B loss or TERT promoter mutation justifies WHO grade 3 [BRAIN-E, MS-409]
StagingClick to collapse
CNS tumors do not use AJCC TNM staging. Gliomas, ependymomas, medulloblastoma, and meningiomas are classified by WHO histologic and molecular grade (2021 WHO Classification of Tumors of the CNS). Brain metastases are classified as 'limited' versus 'extensive' based on treatability with SRS versus WBRT. Leptomeningeal metastases are stratified by risk (good vs. poor) rather than anatomic stage. Metastatic spine tumors are classified by anatomic location (extradural, intradural-extramedullary, intradural-intramedullary) and presence of spinal cord compression.
T Categories
| Stage | Description |
|---|---|
| Not applicable | CNS primary tumors do not use T staging. Tumors are classified by WHO histologic and molecular grade (Grade 1-4) and integrated molecular diagnosis per WHO 2021 classification. |
N Categories
| Stage | Description |
|---|---|
| Not applicable | CNS primary tumors do not use N staging. Nodal disease is not applicable to primary brain tumors. For brain metastases, extent of disease is classified as limited vs. extensive. |
M Categories
| Stage | Description |
|---|---|
| Not applicable for primary CNS tumors | Primary CNS tumors are staged by WHO grade, not M stage. Medulloblastoma uses modified Chang staging (M0 = no metastasis, M1 = CSF cytology positive, M2 = intracranial metastases beyond primary, M3 = spinal drop metastases, M4 = extraneural metastases). Leptomeningeal metastases represent disseminated disease within the CNS. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| WHO Grade 1 — Circumscribed Gliomas | Pilocytic astrocytoma, subependymal giant cell astrocytoma (SEGA), ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET). Noninvasive, surgically curable [GLIO-1, MS-7-8] | Generally indolent, curable with surgery alone. SEGA associated with tuberous sclerosis complex. | Excellent (>90% for pilocytic astrocytoma) | Curative |
| WHO Grade 2 — Oligodendroglioma (IDH-mutant, 1p19q codeleted) | IDH1/2-mutant with 1p/19q whole-arm codeletion. Non-enhancing or minimally enhancing on MRI [GLIO-2, MS-9] | Relatively favorable prognosis among diffuse gliomas. Responds to RT and alkylating chemotherapy. 1p/19q codeletion and IDH mutation both confer favorable prognosis [MS-8, MS-13-14] | ~80%-90% with combined modality treatment | Potentially long-term disease control; observation possible after GTR |
| WHO Grade 2 — IDH-mutant Astrocytoma | IDH1/2-mutant without 1p/19q codeletion. No ATRX loss excluded. No CDKN2A/B homozygous deletion [GLIO-4, MS-9-10] | Intermediate prognosis between oligodendroglioma and glioblastoma. Progresses faster than grade 2 oligodendroglioma. IDH mutation confers favorable prognosis [MS-8-9] | ~70%-80% | Long-term disease control; observation possible after GTR in select cases |
| WHO Grade 3 — Oligodendroglioma (IDH-mutant, 1p19q codeleted) | Higher-grade oligodendroglioma with IDH mutation and 1p/19q codeletion [GLIO-3, MS-14-15] | Better prognosis than other grade 3-4 gliomas. Significant survival benefit from RT + PCV (EORTC 26951: OS not reached in RT+PCV vs 112 months RT alone in 1p19q codeleted subgroup) [MS-161-162]. RTOG 9402: doubling of median OS with PCV in 1p19q codeleted tumors (14.7 vs 7.3 years) [MS-163-164] | ~70%-80% with RT + PCV | Long-term disease control with RT + PCV |
| WHO Grade 3 — IDH-mutant Astrocytoma | IDH1/2-mutant astrocytoma, grade 3 by histology [GLIO-5, MS-15-16] | CATNON trial showed benefit of adjuvant TMZ in IDH-mutant anaplastic gliomas (HR 0.48, P < .0001) [MS-167]. RT + adjuvant TMZ is preferred. | ~56% with RT + TMZ (CATNON 5-year data) | Long-term disease control |
| WHO Grade 4 — IDH-mutant Astrocytoma | IDH1/2-mutant astrocytoma with necrosis/microvascular proliferation OR CDKN2A/B homozygous deletion, regardless of classic histologic features [GLIO-6, MS-6, MS-23] | Prognosis better than IDH wild-type glioblastoma. CATNON trial benefit from adjuvant TMZ extrapolated. RT + concurrent and adjuvant TMZ is preferred [MS-140, MS-167] | ~40%-50% with RT + TMZ | Long-term disease control |
| Glioblastoma, IDH1/2 Wild-Type (WHO Grade 4) | Diffusely infiltrative astrocytoma with IDH wild-type status AND at least one of: necrosis, microvascular proliferation, EGFR amplification, gain of chr7/loss of chr10, or TERT promoter mutation [GLIO-10-11, MS-6, MS-22] | Most common malignant brain tumor in adults. Very poor prognosis. Median OS 14.6 months with RT + TMZ (EORTC-NCIC) [MS-160]. MGMT promoter methylation is both prognostic and predictive for TMZ benefit. Alternating electric field therapy improves survival in good PS patients [MS-178-179] | ~10% at 5 years with RT + TMZ | Prolong survival; not curative |
| Glioblastoma (Age >70) | IDH wild-type glioblastoma in patients older than 70 [GLIO-11, MS-16-17] | Hypofractionated RT + concurrent and adjuvant TMZ preferred for MGMT-methylated tumors. Hypofractionated RT alone is a category 2B option. TMZ alone may be reasonable for MGMT-methylated tumors in elderly who prefer to delay radiation [MS-54-55, MS-141] | <5% | Palliative; prolong survival |
| Ependymoma — Posterior Fossa Type A (PFA) | Posterior fossa ependymoma with loss of H3K27 trimethylation by IHC, confirmed by genomic methylation profiling [EPEN-2, MS-21, BRAIN-E] | More aggressive behavior than PFB subtype. Standard RT recommended regardless of extent of resection for intracranial PFA ependymomas [EPEN-2] | ~60%-70% | Long-term disease control with RT |
| Medulloblastoma — Standard Risk | No evidence of metastasis, small-volume residual disease (<1.5 cm2), classic or desmoplastic histology [AMED-2] | WNT-activated subtype has best prognosis. Molecular profiling recommended to inform prognosis [AMED-2, MS-259] | ~85%-90% in children; variable in adults | Long-term disease control |
| Medulloblastoma — High Risk | Unresectable tumor, residual >1.5 cm2, disseminated disease, or large cell histology [AMED-2] | Requires neuraxis irradiation and systemic therapy. SHH-activated TP53-mutant has particularly poor prognosis [MS-269] | ~60%-70% in children | Long-term disease control with aggressive multimodality |
| Primary CNS Lymphoma | Aggressive non-Hodgkin lymphoma within brain, spine, CSF, or leptomeninges without systemic involvement [PCNS-1, MS-301-305] | High-dose methotrexate-based regimens are standard. Complete response to chemotherapy ranges 42%-61% with OS 14-55 months [MS-320-323]. High-dose chemotherapy with stem cell rescue feasible for fitter patients. Approximately 50% of initial complete responders eventually relapse [MS-328] | 30%-40% with high-dose methotrexate-based therapy | Curative potential; long-term disease control |
| Meningioma — WHO Grade 1 | Benign meningioma; 92% of all meningiomas [MS-409] | 10-year PFS 75% after GTR, 39% after STR [MS-418]. Often curable with complete resection. | >95% with GTR | Curative with GTR; observation for small asymptomatic |
| Meningioma — WHO Grade 2 (Atypical) | Atypical meningioma; 6% of all meningiomas [MS-409]. Concomitant loss of 22q and 1p sufficient for grade 2 [BRAIN-E] | Higher recurrence risk (20%-41%) even after GTR [MS-419-420]. Postoperative RT recommended for incomplete resection; may be considered after GTR [MENI-1] | ~60%-80% | Long-term disease control |
| Meningioma — WHO Grade 3 (Malignant/Anaplastic) | Malignant meningioma; 2% of all meningiomas. Homozygous CDKN2A/B loss or TERT promoter mutation justifies grade 3 [BRAIN-E, MS-409] | Highest recurrence risk (56%-63%) [MS-421]. Adjuvant RT recommended regardless of extent of resection [MENI-1]. Postoperative RT 59.4-60 Gy in 1.8-2.0 Gy fractions [BRAIN-C] | ~50%-60% | Long-term disease control |
| Brain Metastases — Limited | Patients for whom SRS is an effective alternative to WBRT with more cognitive protection. Definition evolving based on number of metastases and intracranial disease volume [LTD-1, MS-467] | SRS is preferred treatment. Cognitive preservation superior to WBRT [MS-464-465]. Multiple lesions with low total volume may still be candidates for SRS [MS-467-471] | Highly variable by primary tumor type and systemic disease status | Local control; systemic disease control |
| Brain Metastases — Extensive | Metastases not fitting definition of 'limited' — too numerous or too large for SRS, or widespread disease [MU-1, MS-46-47] | WBRT with or without HA + memantine is primary treatment. SRS may be considered in select patients. Systemic therapy may be appropriate [MU-1] | Generally poor; highly variable by primary | Palliative; symptom control |
| Leptomeningeal Metastases — Good Risk | KPS >=60, no major neurologic deficits, minimal systemic disease, reasonable systemic treatment options [LEPT-1, MS-48] | Chemotherapy (systemic or intrathecal) recommended. May also receive RT to symptomatic sites. Median survival typically 2-4 months but may be extended [MS-47-48, MS-580-581] | <5% | Palliative; improve/stabilize symptoms; prolong survival |
| Leptomeningeal Metastases — Poor Risk | KPS <60, multiple serious neurologic deficits, extensive systemic disease with few options, bulky CNS disease, encephalopathy [LEPT-1, MS-48] | Palliative/supportive care. RT to symptomatic sites for temporary improvement [LEPT-2] | <1% | Palliative/supportive care |
Staging Pearls
- CNS tumors do not use AJCC TNM staging; WHO grade and integrated molecular diagnosis are the primary classification systems per WHO 2021 [MS-3-6]
- For gliomas, the combination of IDH status, 1p/19q codeletion, and TERT promoter mutation divides gliomas into three major molecular subtypes with distinct prognoses: oligodendroglioma (IDH+1p/19q+) > astrocytoma (IDH+1p/19q-) > glioblastoma (IDH wild-type) [MS-8-10]
- IDH mutation in a grade 2-3 glioma indicates at least a grade 2 diffusely infiltrative glioma; true grade 1 non-infiltrative gliomas do not have IDH mutations [BRAIN-E, MS-22]
- Glioblastoma is now reserved exclusively for IDH wild-type tumors with traditional histologic features or molecular hallmarks of glioblastoma [MS-6, MS-22-23]
- The term 'oligoastrocytoma' should no longer be used; molecular testing resolves morphologically ambiguous tumors into astrocytomas or oligodendrogliomas [BRAIN-E, MS-17, MS-25]
- For brain metastases, total volume of intracranial disease and rate of developing new metastases may be more important prognostic factors than number of discrete lesions [MS-468-471]
- Modified Chang staging is used for medulloblastoma, not standard CNS tumor grading [AMED-2, MS-298-299]
- For ependymomas, posterior fossa type A (PFA) and type B (PFB) distinction by methylation profiling is critical for prognosis and treatment planning [BRAIN-E, EPEN-2, MS-21]
- CDKN2A/B homozygous deletion is now sufficient for grade 4 designation in IDH-mutant astrocytoma even without classic histologic features of glioblastoma [BRAIN-E, MS-6, MS-30-33]
- For PCNSL, a positive CSF cytology in solid tumors is virtually always diagnostic, but CSF cytology has approximately 50% sensitivity with first lumbar puncture, up to 90% after repeated analyses [MS-585-586]
- Pseudoprogression occurs in the first 3 months or longer after RT, more often in MGMT-methylated tumors, and must be distinguished from true tumor progression [MS-144, MS-200-201]
- Spinal cord compression is a medical emergency; intervention should be implemented immediately to prevent irreversible neurologic damage. Paraplegia for over 24 hours is a strong relative contraindication to surgery [MS-613-615, MS-617]
- For NF2-SWN, the diagnosis is confirmed by bilateral vestibular schwannomas OR 2 major criteria OR 1 major + 2 minor criteria [NF2-SWN-1, BRAIN-G]
Management PrinciplesClick to collapse
The management of primary and metastatic central nervous system (CNS) tumors requires a highly individualized, multidisciplinary approach due to the heterogeneity of tumor types, locations, and patient factors. Treatment goals vary from curative intent (e.g., for low-grade circumscribed gliomas) to prolonging survival and maintaining quality of life (e.g., for glioblastoma or leptomeningeal metastases). A multidisciplinary tumor board, ideally comprising neurosurgeons, radiation oncologists, neuro-oncologists, neuropathologists, neuro-radiologists, and allied health services (physical, occupational, speech therapy; neuropsychology; social work), is strongly recommended for all patients [BRAIN-D 1-6]. Clinical trial participation is encouraged whenever possible for all patients, as standard treatments for many CNS tumors remain suboptimal [BRAIN-D].
Curative
Patients with newly diagnosed low-grade circumscribed gliomas (e.g., pilocytic astrocytoma, ganglioglioma) following gross total resection.
Observation with serial imaging is standard after complete resection. No adjuvant therapy is indicated [GLIO-1].
Adjuvant Disease Control
Patients with newly diagnosed diffuse gliomas (WHO grade 2-4) after maximal safe resection.
Risk-stratified adjuvant therapy, combining radiation therapy (RT) with and/or without chemotherapy, is recommended based on histology, molecular markers (IDH, 1p/19q, MGMT), patient age, and performance status [GLIO-2 to GLIO-6, GLIO-10].
Palliative/Best Supportive Care
Patients with poor performance status (e.g., KPS <60), recurrent/refractory disease with limited options, or those who decline active treatment.
Focus on symptom management, including corticosteroids for edema, antiepileptics for seizures, pain control, and psychosocial support. Palliative radiation or single-agent systemic therapy may be considered [BRAIN-D, GLIO-11, GLIO-13].
The NCCN panel strongly recommends multidisciplinary discussion for all patients with newly diagnosed or recurrent/progressive gliomas (any grade). Similarly, if treatment with an IDH inhibitor is being considered for a patient with newly diagnosed oligodendroglioma or astrocytoma, multidisciplinary discussion or referral to a brain tumor center is recommended [GLIO-2A footnote e]. For rare tumors like ependymoma or medulloblastoma, management should begin with consultation at a center of neuro-oncologic expertise [EPEN-1, AMED-1].
Performance status (PS), often assessed by Karnofsky Performance Status (KPS) or ECOG score, critically influences treatment decisions. Patients with good PS (KPS ≥60 or ECOG 0-1) are generally candidates for more aggressive, multimodal therapy. Patients with poor PS (KPS <60) may receive hypofractionated RT, single-modality systemic therapy, or best supportive care. For example, in newly diagnosed glioblastoma, standard concurrent RT/temozolomide is recommended for KPS ≥70, while hypofractionated RT ± temozolomide or temozolomide alone (if MGMT methylated) is preferred for patients >70 years or those with poor PS [GLIO-10, GLIO-11].
Management PathwaysClick to collapse
Branching: Tumor location and resectability, Patient age and symptoms
Branching: Performance status (KPS), Residual disease status, Patient preference for upfront treatment
Branching: Age, Performance status (KPS), MGMT promoter methylation status
Branching: Extent of resection, Evidence of metastasis (brain/spine/CSF), Posterior fossa type A (PFA) status
Branching: Risk stratification (standard vs. high), Extent of resection, Metastatic status
Branching: Performance status, Suitability for high-dose methotrexate, Ocular involvement
Branching: Extent of resection, Tumor grade
Branching: Number/volume of metastases, Systemic disease status, Performance status
Branching: Performance status, Systemic disease burden, CSF cytology
Branching: Laterality, Hearing status, Tumor size and symptoms
Pretreatment EvaluationClick to collapse
Imaging
Pathology
Functional and Laboratory
Multidisciplinary Consultation
SurgeryClick to collapse
Surgery is both diagnostic and therapeutic. The primary goals are: 1) to obtain sufficient tissue for accurate histopathologic and molecular diagnosis, 2) to achieve maximal safe resection to improve survival and local control, 3) to relieve mass effect and symptoms (e.g., seizures, increased intracranial pressure), and 4) to reduce tumor burden to enhance the efficacy of adjuvant therapies [BRAIN-B].
Maximal safe resection is recommended whenever feasible, guided by preoperative MRI and intraoperative adjuncts (neuronavigation, intraoperative MRI, awake mapping, fluorescence-guided surgery) [BRAIN-B].
For diffuse gliomas, supramarginal resection (including T2/FLAIR abnormalities) is suggested for IDH-mutant tumors [BRAIN-B footnote 1].
For ependymoma, gross total resection is a strong prognostic factor; re-resection should be considered if initial resection is incomplete [EPEN-1].
For PCNSL, stereotactic biopsy is preferred over resection, as maximal resection does not improve survival [PCNS-1].
Postoperative MRI within 48 hours (brain) and 2-3 weeks (spine) is required to assess extent of resection [BRAIN-B].
Tissue should be reviewed by an experienced neuropathologist with molecular testing [BRAIN-E].
Procedures
Gross total resection (GTR)
Stereotactic biopsy
Laser interstitial thermal therapy (LITT)
Carmustine wafer implantation
Radiation TherapyClick to collapse
RT is a cornerstone of treatment for many primary and metastatic CNS tumors. It is used adjuvantly after surgery, as definitive therapy, and in the recurrent setting. The goal is to maximize tumor control while minimizing toxicity to surrounding normal brain or spinal cord [BRAIN-C].
Principles
- Treatment planning should be based on pre- and postoperative MRI, with the target volume defined by the gross tumor volume (GTV) and appropriate clinical target volume (CTV) margins [BRAIN-C].
- Conformal techniques (3D-CRT, IMRT, VMAT, proton therapy) are recommended to spare critical structures [BRAIN-C].
- For diffuse gliomas, tumor volumes are defined using T2/FLAIR and contrast-enhanced T1 sequences [BRAIN-C].
- For brain metastases, SRS is preferred for limited disease to preserve cognition. WBRT is reserved for diffuse disease or poor prognosis [BRAIN-C].
- Hypofractionated RT is appropriate for elderly or frail patients [BRAIN-C].
- Reirradiation is feasible in select cases, with careful attention to cumulative doses and interval from prior RT [BRAIN-C].
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Standard fractionated RT for gliomas | 54-60 Gy | 1.8-2.0 Gy | 30-33 | Daily, 5 days/week | Adjuvant treatment for WHO grade 2-4 gliomas [BRAIN-C]. |
| Hypofractionated RT for elderly/frail | 40.05 Gy | 2.67 Gy | 15 | Daily, 5 days/week | Glioblastoma in elderly or poor PS patients [BRAIN-C]. |
| SRS for brain metastases | 15-24 Gy | Single fraction | 1 | Single session | Limited brain metastases (≤4-5 lesions) [BRAIN-C]. |
| WBRT for brain metastases | 30 Gy | 3.0 Gy | 10 | Daily, 5 days/week | Diffuse brain metastases or poor prognosis [BRAIN-C]. |
| Craniospinal RT for medulloblastoma/ependymoma | 23.4-36 Gy (CSI) + 54-55.8 Gy (boost) | 1.8 Gy | 13-20 (CSI) + 30-31 (boost) | Daily, 5 days/week | Medulloblastoma or ependymoma with metastatic disease [BRAIN-C]. |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Adjuvant RT for glioblastoma | 60 Gy in 30 fractions or 59.4 Gy in 33 fractions | Temozolomide 75 mg/m2 daily during RT | Newly diagnosed glioblastoma, KPS ≥60 [BRAIN-C]. | EORTC-NCIC trial [142] | Fatigue, alopecia, cognitive effects, edema, nausea [BRAIN-C]. |
| SRS for brain metastases | 18-24 Gy single fraction or 24-30 Gy in 3-5 fractions | None | Limited brain metastases [BRAIN-C]. | JLGK0901 [467] | Radionecrosis, edema, headache [BRAIN-C]. |
| HA-WBRT + memantine | 30 Gy in 10 fractions | Memantine 20 mg daily during and 6 months after RT | Brain metastases not within 5 mm of hippocampi, KPS ≥70, life expectancy ≥4 months [BRAIN-C]. | NRG-CC001 [495] | Cognitive decline (reduced with memantine), fatigue [BRAIN-C]. |
| Reirradiation for recurrent glioblastoma | 35 Gy in 10 fractions (fractionated SRT) or SRS (15-18 Gy) | Consider bevacizumab to reduce neurotoxicity | Recurrent glioblastoma, especially if new lesion outside prior field or geometrically favorable [BRAIN-C]. | RTOG 1205 [11] | Increased risk of radionecrosis [BRAIN-C]. |
Systemic TherapyClick to collapse
Systemic therapy for CNS tumors includes alkylating agents, targeted therapies, immunotherapies, and intrathecal treatments. Blood-brain barrier penetration is a key consideration. Treatment is often based on histology and molecular markers [BRAIN-D, GLIO-A].
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Response Assessment in Neuro-Oncology (RANO)
Timing
Post-treatment MRI brain within 24-48 hours for surgical extent assessment. Follow-up MRI at 2-8 weeks after RT completion, then every 2-4 months for 3 years, then every 3-6 months indefinitely for high-grade gliomas [BRAIN-A]. For low-grade gliomas, intervals may be longer (every 3-6 months initially) [BRAIN-A].
Response Logic
-
Pseudoprogression (treatment-related increase in enhancement/edema) can mimic tumor progression, especially in the first 3-6 months after RT or with concurrent temozolomide. It is more common in MGMT-methylated glioblastoma [200, 201].
-
If progression is suspected, consider advanced imaging (MR perfusion, spectroscopy, PET) or biopsy to confirm true progression vs. treatment effect [BRAIN-D].
-
For leptomeningeal metastases, response is assessed by CSF cytology (conversion to negative) and clinical/neuroimaging improvement [LEPT-3].
-
For brain metastases, response is assessed by RECIST criteria on MRI [BRAIN-A].
Imaging Recommendations
-
MRI brain with and without contrast is the standard for follow-up [BRAIN-A].
-
For ependymoma: MRI brain/spine every 3-4 months for 1 year, then every 4-6 months for year 2, then every 6-12 months for 5-10 years [EPEN-4].
-
For medulloblastoma: Brain MRI every 2-3 months for 2 years; then every 6-12 months for 5-10 years [AMED-3].
-
For meningiomas: Postoperative MRI within 48 hours; then WHO grade 1/2: MRI at 1, 3, 6 months, then every 6-12 months for 5 years; WHO grade 3: MRI every 2-4 months for 3 years, then every 3-6 months [BRAIN-A].
Biopsy Or Salvage Logic
-
Biopsy should be considered when imaging suggests progression but treatment effect is possible, to confirm recurrence and assess for transformation (e.g., low-grade to high-grade glioma) [GLIO-7, GLIO-13].
-
For recurrent brain metastases, if recurrence is suspected after SRS, advanced imaging or biopsy is recommended before considering further radiation [BRAIN-C].
-
Salvage options depend on prior therapy and may include re-resection, reirradiation, systemic therapy, or clinical trial [GLIO-13, LTD-3, MU-2].
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Glioblastoma: Brain MRI every 2-3 months for 3 years, then every 2-4 months indefinitely
- IDH-mutant astrocytoma grade 4: Brain MRI 2-8 weeks after standard RT, then every 2-4 months for 3 years, then every 3-6 months indefinitely
- Lower-grade gliomas (grade 2 oligodendroglioma/astrocytoma): After RT and chemotherapy, at least every 6-9 months until progression; after surgery only, every 3-4 months until progression
- Oligodendroglioma grade 3: After RT and chemotherapy, at least every 6-9 months until progression
- Ependymoma: Imaging of tumor site every 3-4 months for 1 year, then every 4-6 months for year 2, then every 6-12 months for 5-10 years, then as clinically indicated
- Medulloblastoma: Brain MRI every 2-3 months for 2 years, then every 6-12 months for 5-10 years, then every 1-2 years or as clinically indicated
- Primary CNS lymphoma: Brain MRI every 3 months until year 2, then every 6 months until 5 years, then annually indefinitely
- Meningiomas grade 1-2: Brain MRI at 1, 3, and 6 months, then every 6-12 months for 5 years, then every 1-3 years as clinically indicated
- Meningiomas grade 3: Brain MRI every 2-4 months for 3 years, then every 3-6 months
- Limited brain metastases: Brain MRI every 2-3 months for 1-2 years, then every 4-6 months indefinitely
- Extensive brain metastases: Brain MRI every 2-3 months for 1-2 years, then every 4-6 months indefinitely
- Leptomeningeal metastases: Neuroimaging every 2-3 months until year 2, every 6 months until 5 years, then annually indefinitely
- Metastatic spine tumors: Spine MRI/CT 1-3 months after treatment, then every 3-4 months for 1 year, then as clinically indicated
Imaging Strategy
- MRI is the standard imaging modality for all CNS tumor surveillance
- Brain MRI with and without IV gadolinium-based contrast is recommended for most CNS tumors
- Spine MRI when clinically indicated or for staging purposes
- Postoperative brain MRI within 48 hours for gliomas and other brain tumors to determine extent of resection
- Spine MRI should be delayed by at least 2-3 weeks post surgery to avoid artifacts
- Consider PET-MRI every 3-6 months for meningiomas
- Amino acid PET/CT or PET/MRI may be used for equivocal cases to differentiate treatment effects from tumor recurrence
- MR perfusion, MR spectroscopy, and FDG-PET may help differentiate pseudoprogression/radiation necrosis from true progression
- Brain MRI should be obtained as early as possible if patient experiences change in seizures, new/worsening neurologic signs, or new/higher dose steroid requirements
Laboratory Monitoring
- CBC and metabolic panel: monitor regularly during systemic therapy, particularly with temozolomide and PCV regimens
- CSF analysis: indicated when clinical concern for meningeal dissemination
- For primary CNS lymphoma: CBC, comprehensive metabolic panel, LDH test, HIV status
- For leptomeningeal metastases: CSF cytology via lumbar puncture; sensitivity approximately 50% with first LP, up to 90% with repeated analyses
- CSF flow scan if concerns about CSF flow blockage before intrathecal therapy
- Hepatitis B testing before rituximab therapy due to risk of reactivation
Supportive Follow Up
- Regular neurocognitive assessment; neuropsychological evaluation when indicated
- Endocrine function monitoring, especially for patients who received cranial RT
- Seizure control assessment and medication management
- Quality of life assessment
- Psychiatric symptom screening for depression and anxiety
- Audiologic evaluation for NF2-SWN patients
- Ophthalmologic exams for NF2-SWN and PCNSL patients with ocular involvement
- Vocal fold evaluation prior to VS surgery for NF2-SWN patients
- Health maintenance and survivorship care
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Brain edema and mass effect | Corticosteroid therapy with careful monitoring; lowest dose for shortest time; patients with extensive mass effect should receive steroids for at least 24 hours before RT; consider H2 blockers or PPI for high GI risk patients |
| Seizures | Seizure prophylaxis NOT recommended as routine in asymptomatic patients; reasonable to consider perioperatively; avoid enzyme-inducing antiepileptic drugs (phenytoin, phenobarbital, carbamazepine); prefer non-EIAEDs (levetiracetam, topiramate, valproic acid, lacosamide) |
| Pseudoprogression | Occurs in first 3 months or longer after completion of RT; more often in MGMT promoter methylated tumors; biopsy, MR spectroscopy, MR perfusion, or brain PET/CT can differentiate from true progression |
| Radiation necrosis | Tends to be detected between 6 and 24 months following RT treatment; consider bevacizumab if symptoms do not resolve with corticosteroids; consider hyperbaric oxygen; consider LITT |
| Hydrocephalus | VP shunt placement if needed; neurosurgical evaluation |
| Spinal cord compression | Medical emergency; steroids (minimum 4 mg dexamethasone every 6 hours); decompressive surgery followed by RT is preferred (category 1); primary RT for radiosensitive tumors |
| Endocrinopathies | Common in brain tumor patients; evaluate hypothalamic-pituitary-adrenal axis, thyroid, and gonad function; long-term monitoring of hypothalamic-pituitary and adrenal axis may be considered for patients who received prior RT |
| Neurocognitive dysfunction | Up to 90% of individuals with supratentorial brain tumors experience some degree; neuropsychological evaluation is gold standard; consider neuropsychological evaluation as needed based on physician assessment |
| Cranial nerve palsies | Depends on location and cause; surgical evaluation for structural lesions |
| Hearing loss (NF2-related) | Multidisciplinary care including otologists; bevacizumab results in hearing improvement in 36% of NF2-SWN patients; CI or ABI may be considered; auditory rehabilitation |
| Leptomeningeal disease | Prognosis-dependent treatment; CSF analysis; systemic therapy, intra-CSF therapy, and/or RT as appropriate |
Supportive CareClick to collapse
Supportive care is integral to comprehensive management of CNS cancers. The NCCN panel emphasizes that throughout treatment, the patient's quality of life should remain the highest priority and guide clinical decision-making. The multidisciplinary team approach is essential, incorporating neuro-oncology, surgery, radiation, radiology, neuropsychology, rehabilitation medicine, palliative care, and psychosocial support services. Management of complications such as seizures, edema, neurocognitive dysfunction, endocrinopathies, venous thromboembolism, fatigue, and psychiatric disease requires systematic attention.
Nutritional assessment and support should be integrated into comprehensive care. Patients with brain tumors may experience difficulty with oral intake due to neurologic deficits, treatment side effects, or medication effects. Nutritional supplementation and dietary counseling should be provided as needed. Multidisciplinary nutritional support teams should be involved for patients with significant nutritional compromise.
Standard antiemetic protocols should be used based on the emetogenic potential of specific systemic therapy regimens. Corticosteroids used for cerebral edema may have some antiemetic properties. Specific antiemetic guidelines for chemotherapy-induced nausea and vomiting should be followed per institutional protocols.
Granulocyte colony-stimulating factor (GCSF) should be considered for patients experiencing significant myelosuppression, particularly those receiving PCV chemotherapy for low-grade gliomas. In EORTC 26951, 70% of patients in the RT followed by PCV arm did not complete the planned six cycles of treatment due to toxicity. Dose modifications and growth factor support should be individualized based on patient tolerance.
Venous thromboembolism is common in brain tumor patients. Treatment with direct oral anticoagulants is appropriate for brain cancer patients unless there is active bleeding or history of recent bleeding (recommend consultation with neurosurgeon). Referral to the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease for detailed management.
Pain management should be integrated into comprehensive care from diagnosis through survivorship. Pain may be due to tumor mass effect, treatment-related effects, or neuropathic causes. For metastatic spine tumors, three types of pain are classically defined: local pain (deep aching, improves with steroids), mechanical back pain (varies with movement/position, attributed to structural instability), and radicular pain (sharp/stabbing from nerve root compression). Multimodal pain management including pharmacologic and interventional approaches should be utilized.
Depression and anxiety are common in neuro-oncology patients, greater than simple sadness or anxiety associated with tumor diagnosis. These symptoms respond to psychotropic medications. Physical exercise can help reduce anxiety and improve mood. All oncology providers should inquire about psychiatric symptoms in follow-up visits. Refer to the NCCN Guidelines for Distress Management including NCCN Distress Thermometer. Communication between patient's healthcare team members regarding treatment response is important.
Oral care is important for patients receiving systemic therapy, particularly those on temozolomide who may develop stomatitis. Dental evaluation and maintenance should be recommended prior to initiation of systemic therapy. Oral care protocols should be implemented during treatment.
PrognosisClick to collapse
Prognosis for CNS cancers is highly variable depending on tumor type, histologic grade, molecular features, patient age, and performance status. Glioblastoma, the most common malignant primary brain tumor in adults, has a 5-year survival rate around 6%, with higher rates among younger age groups. WHO grade 2-3 gliomas generally have better outcomes, particularly those with favorable molecular profiles. Brain metastases prognosis depends on primary tumor type, number and volume of metastases, patient performance status, and extracranial disease control. Primary CNS lymphoma prognosis has improved with treatment advances. Meningiomas, most of which are WHO grade 1, generally have favorable outcomes with surgical resection. Ependymomas and medulloblastomas in adults are rare but have distinct prognostic profiles based on molecular subtyping.
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Oligodendroglioma, WHO Grade 2 (IDH-mutant, 1p19q codeleted) | Significantly improved compared to other gliomas | Favorable prognosis conferred by both IDH mutation and 1p/19q codeletion; patients may remain progression-free for many years after gross total resection |
| Oligodendroglioma, WHO Grade 3 (IDH-mutant, 1p19q codeleted) | Significantly better than other high-grade gliomas | In EORTC 26951, OS not reached in the RT+PCV group vs 112 months in the RT group for 1p/19q codeleted subgroup |
| IDH-Mutant Astrocytoma, WHO Grade 2 | Better than IDH wild-type glioblastoma | Prognosis is intermediate between oligodendroglioma and glioblastoma; IDH mutation confers favorable prognosis |
| IDH-Mutant Astrocytoma, WHO Grade 4 | Better than IDH wild-type glioblastoma | Despite grade 4 histologic features, these tumors still have better prognosis than IDH wild-type glioblastomas |
| Glioblastoma (IDH wild-type) | Around 6% | Median OS 14.6 months with RT+TMZ (EORTC-NCIC); 5-year survival 10% with RT+TMZ vs 2% with RT alone |
| Glioblastoma in older adults (>70 years) | Poorer than younger adults | Hypofractionated RT+TMZ: median OS 9.3 months vs 7.6 months RT alone; MGMT-methylated tumors benefit most |
| Primary CNS Lymphoma | Improved over recent decades | Complete response to chemotherapy ranges 42%-61%; OS ranges 14-55 months |
| Ependymoma | Generally favorable with complete resection | 10-year survival rates over 50% after RT; local recurrence is primary pattern of failure |
| Meningioma, WHO Grade 1 | Excellent after gross total resection | 10-year PFS 75% after GTR; short-term recurrence rates 1%-16% |
| Meningioma, WHO Grade 2 | Variable | 10-year PFS drops to 39% with STR; short-term recurrence rates 20%-41% |
| Meningioma, WHO Grade 3 | Poor | Short-term recurrence rates 56%-63% |
| Brain metastases, limited | Variable by primary tumor | SRS preferred for limited disease; local and distant brain control are primary concerns |
Prognostic Factors
- IDH1/2 mutation status: favorable prognostic marker for OS in grade 2-3 gliomas
- 1p/19q codeletion: confers favorable prognosis and predictive of response to alkylating systemic therapy with or without RT
- MGMT promoter methylation: strong prognostic biomarker and predictive for benefit from temozolomide in high-grade gliomas
- ATRX mutation: associated with IDH mutations; loss of ATRX immunostaining suggests astrocytoma
- TERT promoter mutation: associated with reduced OS in IDH wild-type gliomas
- H3K27M mutation: associated with very poor prognosis regardless of histologic appearance
- Extent of resection: GTR associated with decreased mortality and lower risk of progression in low-grade gliomas
- Karnofsky Performance Status: KPS ≥60 vs <60 determines treatment intensity
- Age: older age associated with worse prognosis in glioblastoma
- CDKN2A/B homozygous deletion: associated with grade 4 status in IDH-mutant astrocytomas
- Medulloblastoma molecular subtype: WNT-activated associated with markedly better prognosis
- Meningioma grade and extent of resection: Simpson classification correlates with recurrence
- Brain metastasis volume and rate of developing new metastases: more important than number for prognosis
Follow UpClick to collapse
Post Curative Treatment
After curative-intent treatment for primary brain tumors, patients should be followed with serial brain MRI scans and clinical assessment. For glioblastoma: brain MRI 2-8 weeks after standard RT, then every 2-4 months for 3 years, then every 3-6 months indefinitely. For IDH-mutant astrocytoma WHO grade 4: same schedule. For lower-grade gliomas: monitoring frequency depends on molecular subtype and treatment received. Early scans (first 3 months) may show pseudoprogression and should not automatically trigger change in therapy. After brain metastases treatment: brain MRI every 2-3 months for 1-2 years, then every 4-6 months indefinitely.
Surveillance Rationale
Surveillance imaging serves multiple purposes: 1) Early detection of tumor recurrence to enable timely intervention; 2) Monitoring for treatment effects including pseudoprogression (common in first 3 months post-RT, particularly in MGMT-methylated tumors) and radiation necrosis (typically 6-24 months post-RT); 3) Assessment of response to systemic therapy; 4) Titration of corticosteroid doses based on extent of mass effect and brain edema. The treating provider should have flexibility to determine appropriate imaging frequency based on individual patient circumstances.
Late Effects Screening
- Neurocognitive assessment: neuropsychological evaluation as needed; cognitive deterioration is a sensitive indicator of tumor progression
- Endocrine monitoring: long-term monitoring of hypothalamic-pituitary-adrenal axis (ACTH stimulation test), thyroid function, gonad function
- Seizure management: long-term anti-epileptic medication management; periodic assessment of seizure control
- Functional status: ongoing assessment of performance status, ADLs, and quality of life
- Radiation necrosis monitoring: serial MRIs to distinguish from tumor progression
- Secondary malignancy screening: particularly relevant for NF2-SWN patients who received radiation (~6% lifetime risk)
- Dental health: monitoring for oral complications of treatment
- Psychosocial screening: depression, anxiety, cognitive changes
- Bone health: monitoring for osteoporosis in patients on chronic steroids
Recurrence Patterns
Recurrence patterns vary by tumor type: Glioblastoma typically recurs locally within the prior radiation field; however, 20-30% may recur at distant sites. Low-grade gliomas may transform to higher-grade gliomas over time, with approximately half undergoing anaplastic transformation within 5 years. Brain metastases may recur locally at treated sites or develop as new distant lesions. Primary CNS lymphoma recurrence occurs in about half of patients who initially achieved complete response. Meningioma recurrence depends on grade and extent of resection (Simpson classification).
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| EORTC-NCIC | Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma | 2005 | 573 | RT (60 Gy) + concurrent daily TMZ (75 mg/m2) + adjuvant TMZ (150-200 mg/m2, 5/28 days × 6 cycles) | RT alone (60 Gy) | Newly diagnosed glioblastoma, age ≤70, WHO PS ≤2 | Overall survival | Median OS 14.6 vs 12.1 months (P=.001); 2-year survival 26.5% vs 10.4% | 5-year survival 10% vs 2% | Established RT+TMZ as standard of care for newly diagnosed glioblastoma | N Engl J Med |
| RTOG 9802 | Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma | 2012/2016 | 251 | RT (54 Gy) + 6 cycles PCV | RT alone (54 Gy) | Supratentorial WHO grade 2 gliomas with risk factors (STR or age ≥40 years) | Overall survival | Median OS 13.3 vs 7.8 years (P=.02); 10-year survival 62% vs 41% | Significant improvement in PFS; subgroup analysis showed benefit primarily in IDH-mutant tumors | Category 1 recommendation for RT+PCV in high-risk low-grade glioma | J Clin Oncol / N Engl J Med |
| EF-14 | Tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone for glioblastoma | 2017 | 695 | Standard RT+TMZ followed by TMZ + alternating electric field therapy | Standard RT+TMZ followed by TMZ alone | Newly diagnosed glioblastoma, KPS ≥70 | Overall survival | Median OS 20.9 vs 16.0 months (HR 0.63; P<.001) | Median PFS 6.7 vs 4.0 months (HR 0.63; P<.001); no increased seizure frequency | Category 1 recommendation for alternating electric field therapy with TMZ for newly diagnosed glioblastoma | JAMA |
| NRG-CC001 | Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases | 2020 | 518 | HA-WBRT + memantine | Standard WBRT + memantine | Brain metastases not within 5 mm of hippocampi, KPS ≥70, life expectancy ≥4 months | Cognitive failure (HVLT-R) at 6 months | Risk of cognitive failure significantly lower with HA-WBRT (HR 0.76; 95% CI 0.60-0.98; P=.03) | No significant survival differences | HA-WBRT + memantine preferred over standard WBRT for eligible patients | J Clin Oncol |
| HER2CLIMB | Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer | 2020 | 612 | Tucatinib + trastuzumab + capecitabine | Placebo + trastuzumab + capecitabine | HER2-positive metastatic breast cancer previously treated with ≥1 HER2-directed regimen | PFS | Median PFS 7.8 vs 5.4 months (HR 0.54); OS HR 0.73; P=.001 | In patients with brain metastases: CNS PFS HR 0.36 (P<.00001); OS HR 0.49 (P=.004) | Category 1 recommendation for tucatinib-based regimen for HER2-positive breast cancer with brain metastases | N Engl J Med |
| INDIGO | Phase 3 study of vorasidenib versus placebo in grade 2 IDH1/2-mutant glioma | 2023 | 331 | Vorasidenib (dual IDH1/IDH2 inhibitor) | Placebo | Residual or recurrent grade 2 IDH1/2-mutant glioma (after surgery, no prior treatment) | Progression-free survival | Median PFS 27.7 vs 11.1 months (HR 0.39; P<.001) | Overall survival data not yet available | Category 1 recommendation for vorasidenib in residual/measurable disease after surgery for grade 2 IDH-mutant glioma | N Engl J Med |
| EORTC 26951 | Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma | 2006/2013 | 368 | RT (59.4 Gy) + 6 cycles adjuvant PCV | RT alone | Anaplastic oligodendroglioma or oligoastrocytoma | Overall survival | Median OS 42.3 vs 30.6 months (HR 0.75; P=.018) | In 1p/19q codeleted subgroup: OS not reached vs 112 months (HR 0.56; 95% CI 0.31-1.03) | Category 1 recommendation for RT + adjuvant PCV for WHO grade 3 oligodendroglioma | J Clin Oncol |
| Perry et al | Short-course radiation plus temozolomide in elderly patients with glioblastoma | 2017 | 562 | Hypofractionated RT (40 Gy/15 fractions) + concurrent and adjuvant TMZ | Hypofractionated RT alone | Glioblastoma, age ≥65, KPS ≥50 | Overall survival | Median OS 9.3 vs 7.6 months (HR 0.67; P<.001) | PFS 5.3 vs 3.9 months (HR 0.50; P<.001); greatest benefit in MGMT-methylated tumors | Hypofractionated RT+TMZ preferred for elderly glioblastoma patients | N Engl J Med |
| CheckMate 204 | Combined nivolumab and ipilimumab in melanoma metastatic to the brain | 2018/2021 | 101 | Nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W × 4, then nivolumab 240 mg Q2W | None (single-arm) | Melanoma with active, untreated brain metastases | Intracranial ORR | Intracranial ORR 57.4%; CR 33%; 36-month PFS 54.1%, OS 71.9% | 58% of responses lasted >2 years; limited response in symptomatic disease | Category 1 recommendation for ipilimumab + nivolumab for melanoma brain metastases | N Engl J Med / Lancet Oncol |
| FLAURA | Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer | 2018 | 556 | Osimertinib | Gefitinib or erlotinib | Previously untreated EGFR-sensitizing mutation-positive NSCLC | Progression-free survival | Median PFS 18.9 vs 10.2 months (HR 0.46; P<.001); OS 38.6 vs 31.8 months (HR 0.80; P=.046) | CNS ORR 91% vs 68% (P=.066) in patients with measurable CNS lesions | Preferred first-line treatment for EGFR-mutated NSCLC including patients with brain metastases | N Engl J Med |
| IELSG32 | Chemoimmunotherapy with MATRix regimen in patients with primary CNS lymphoma | 2016 | 219 | Methotrexate, cytarabine, thiotepa, rituximab (MATRix) | Methotrexate + cytarabine; methotrexate + cytarabine + rituximab | Newly diagnosed PCNSL | Complete response rate | CR rate 49% (95% CI 38%-60%) with MATRix vs 30% (21%-42%) and 23% (14%-31%) for other regimens | Median PFS 12.4 months; 2-year PFS 46% | MATRix regimen established as preferred induction therapy for PCNSL | Lancet Haematol |
| COMBI-MB | Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma brain metastases | 2017 | 125 | Dabrafenib 150 mg BID + trametinib 2 mg QD | None (single-arm, multicohort) | Melanoma with BRAF V600-mutant brain metastases | Intracranial ORR | Intracranial ORR 58% (Cohort A: asymptomatic, untreated), 56% (Cohort B: asymptomatic, previously treated), 59% (Cohort C: symptomatic) | Clinical benefit and acceptable toxicity across cohorts | Dabrafenib/trametinib is preferred for BRAF V600-mutant melanoma brain metastases | Lancet Oncol |
| CROWN | First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer | 2020 | 296 | Lorlatinib | Crizotinib | Previously untreated ALK-positive advanced NSCLC | Progression-free survival | Median PFS not reached vs 9.3 months (HR 0.19; P<.001) | In patients with brain metastases (n=78): complete CNS response 61% vs 15% with lorlatinib vs crizotinib | Lorlatinib preferred for ALK-positive NSCLC, particularly with brain metastases | N Engl J Med |
| SCORAD | Effect of single-fraction vs multifraction radiotherapy on ambulatory status among patients with spinal canal compression | 2019 | 342 | Single-fraction 8 Gy | Multifraction 20 Gy in 5 fractions | Metastatic cancer with spinal cord or cauda equina compression | Ambulatory status at 8 weeks | Single-fraction 8 Gy did not meet criteria for noninferiority for ambulatory status | Similar efficacy with different fractionation schedules | Multifraction schedules preferred for spinal cord compression in general, though single-fraction may be appropriate for selected patients | JAMA |
Clinical PearlsClick to collapse
- Pearl 1: MGMT promoter methylation status is both prognostic and predictive for benefit from alkylating chemotherapy (temozolomide) in high-grade gliomas. Patients with MGMT-methylated tumors derive greater benefit from temozolomide-based regimens.
- Pearl 2: Molecular testing is now integral to diagnosis and treatment planning for gliomas. IDH1/2 mutation testing, 1p/19q codeletion, ATRX, TERT promoter, and MGMT methylation should be standard. The presence of an IDH mutation indicates at least a grade 2 diffusely infiltrative glioma.
- Pearl 3: For patients with low-grade glioma (grade 2 oligodendroglioma or astrocytoma), RTOG 9802 demonstrated that RT followed by 6 cycles of PCV significantly improved median OS (13.3 vs 7.8 years; P=.02) compared to RT alone. This is a category 1 recommendation for high-risk patients.
- Pearl 4: Maximum safe resection is recommended for brain tumors whenever possible. For low-grade gliomas, GTR is associated with decreased mortality and lower risk of disease progression. Postoperative MRI should be performed within 48 hours to document extent of resection.
- Pearl 5: SRS is generally preferred over WBRT for limited brain metastases due to superior cognitive preservation and comparable survival. Routine addition of WBRT to SRS is not recommended due to increased cognitive toxicity without OS benefit.
- Pearl 6: Hippocampal avoidance with WBRT plus memantine is the preferred WBRT approach for patients with favorable prognosis (life expectancy ≥4 months, no metastases within 5 mm of hippocampi) based on the NRG-CC001 trial demonstrating significantly lower cognitive failure risk.
- Pearl 7: For primary CNS lymphoma, high-dose methotrexate-based regimens are the standard induction therapy. Steroids should be withheld prior to biopsy if possible, as they are cytolytic and can significantly decrease tumor enhancement and affect histologic appearance.
- Pearl 8: Pseudoprogression occurs in the first 3 months or longer after completion of RT and can be distinguished from true progression using MR spectroscopy, MR perfusion, PET/CT, or tissue sampling. It occurs more often in patients whose tumors are MGMT promoter methylated.
Special SituationsClick to collapse
Glioblastoma in older adults (>70 years) with MGMT-methylated tumor
HIV-positive patients with primary CNS lymphoma
Brain metastases from EGFR-mutated NSCLC
Brain metastases from HER2-positive breast cancer
Brain metastases from BRAF V600-mutant melanoma
Brain metastases from ALK-rearranged NSCLC
Patients with NF2-related schwannomatosis and vestibular schwannomas
Glioblastoma with de novo DNA replication repair deficiency
Recurrent or progressive WHO grade 3/4 glioma amenable to reirradiation
Meningioma with progression despite surgery and RT
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers
NCCN Guidelines for Cancer in People with HIV
NCCN Guidelines for Distress Management
NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease
NCCN Guidelines for Survivorship
NCCN Guidelines for Palliative Care
NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate
NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections
WHO Classification of Tumours of the Central Nervous System (5th Edition)
Joint guidelines on clinical use of PET imaging in brain tumor patients
Protective FactorsClick to collapse
- MGMT promoter methylation status (predictive of better response to temozolomide-based therapy in glioblastoma, not a causal protective factor but improves treatment outcomes)
- IDH1/2 mutation status (associated with relatively favorable prognosis in grade 2–3 gliomas and better survival across treatment modalities)