Brain and CNS tumors

Overview

• Epidemiology (US 2025): ~26,000 primary brain cancer cases, ~19,000 deaths. Metastatic tumors represent the majority of all CNS tumors.
• Distribution of primary tumors: roughly one third meningiomas, one third gliomas (~60% of which are glioblastoma), one third others.
• Most common brain tumors (adults): metastases > meningioma > pituitary > glioblastoma > schwannoma. Most common primary malignant brain cancer is glioblastoma.
• Children: primary CNS tumors are the most common solid cancer; gliomas (especially pilocytic astrocytoma) predominate; medulloblastoma is the most common embryonal/malignant CNS tumor (ependymoma also common).
• Risk factors: ionizing radiation; immunodeficiency (HIV) for CNS lymphoma; male > female; risk increases with age; White > Black.
• Germline predisposition: astrocytomas (Li-Fraumeni TP53, NF1, tuberous sclerosis TSC1/TSC2, Lynch); medulloblastoma (Li-Fraumeni TP53, basal cell nevus/Gorlin PTCH1, FAP APC); hemangioblastoma (VHL).

• MRI is more sensitive than CT. Contrast enhancement indicates blood-brain barrier disruption and increases with grade. Ring enhancement is characteristic of glioblastoma (central necrosis); low-grade tumors may also enhance.
• Tissue diagnosis is required for most CNS tumors (diffuse gliomas, PCNSL) but not all; typical meningioma, vestibular schwannoma, and NF1 optic pathway glioma may be managed on imaging; brainstem gliomas may not be biopsy candidates because of operative risk. Grade 1 has the lowest proliferative potential; grade 4 shows increased mitotic activity, necrosis, and microvascular proliferation.

WHO 2021 molecular classification

• Molecular markers are now integral to diagnosis. The 2021 WHO classification of adult diffuse gliomas defines three categories:
  • Oligodendroglioma: IDH-mutant AND 1p/19q codeleted. Best prognosis (5-yr OS ~70 to 90%, mOS ~12 to 18 yr with RT plus PCV); best response to RT and chemo. Grade 2 or 3 only (grade 4 does not exist for oligodendroglioma). Must be both IDH-mutant and 1p/19q codeleted.
  • Astrocytoma: IDH-mutant, NO 1p/19q codeletion. Intermediate, grade-dependent prognosis (grade 2 median OS >10 yr, 5-yr OS well above 50%; grade 3 intermediate; grade 4 substantially worse); grades 2, 3, or 4.
  • Glioblastoma: IDH-wildtype, grade 4. Poor prognosis (5-yr OS ~5%), less chemo-responsive. There is no IDH-mutant glioblastoma: all glioblastomas are IDH-wildtype. A grade 4 IDH-mutant tumor is instead a WHO grade 4 astrocytoma.

Glioblastoma (IDH-wildtype, grade 4)

• Most common primary CNS cancer in adults. Grade 4 histology: high cellularity, nuclear pleomorphism, frequent mitoses, necrosis, and neovascularization. Diagnosable even without grade 4 histology if TERT promoter mutation, EGFR amplification, or +7/-10 is present.
• Median OS ~12 to 15 mo with standard treatment (18 to 20 mo in selected good-performance-status patients). MGMT-methylated vs unmethylated: ~18.2 vs 12.2 mo.
• Surgery: gross total resection (removal of all contrast-enhancing tissue) improves outcome, but true complete resection is impossible and all patients have residual disease requiring further treatment.
• Radiation: postoperative involved-field RT 60 Gy in 30 fractions is standard (WBRT improved OS over supportive care, ~35 vs 14.5 weeks historically). Hypofractionated RT (40 Gy in 15 fractions over 3 weeks) equals standard RT in the elderly.
• Stupp protocol (EORTC-NCIC, N = 573, ages 18 to 70; NEJM 2005): maximal safe resection → concurrent RT (60 Gy/30 fr) + temozolomide 75 mg/m²/day → adjuvant temozolomide (cycle 1 150 mg/m², cycles 2 to 6 200 mg/m², days 1 to 5 of a 28-day cycle × 6). mOS 14.6 vs 12.1 mo (HR 0.63); 2-yr OS 27% vs 11%; 5-yr OS 10% vs 2%. Alternative temozolomide schedules are not more effective.
• Lomustine + temozolomide (CeTeG/NOA-09, N = 141, MGMT-methylated): during and after RT; mOS 48.1 vs 31.4 mo (HR 0.60, 95% CI 0.35 to 1.03; stratified log-rank p=0.0492, met primary OS endpoint) with more grade 3 to 4 hematologic toxicity and nausea. A good option in younger, fit patients with MGMT-methylated disease.
• Elderly (≥65 yr): hypofractionated RT 40 Gy/15 fr. Good PS: add concurrent and adjuvant temozolomide (Perry NEJM 2017: OS 9.3 vs 7.6 mo, HR 0.67; MGMT-methylated subgroup 13.5 vs 7.7 mo, HR 0.53). Poor PS: MGMT-unmethylated → short-course RT alone; MGMT-methylated → temozolomide alone (phase 3 supported).
• Tumor-treating fields (TTFields, Optune): low-intensity alternating electric fields that disrupt mitosis, FDA-approved (1) first-line as maintenance with temozolomide after chemo-RT, and (2) second-line recurrent GBM as monotherapy. EF-14 (N = 695): mOS 20.9 vs 16.0 mo (unblinded, no sham; QoL and gross cognition comparable).
• Bevacizumab + temozolomide/RT: first-line, no OS benefit (mixed PFS signal); some worsening of neurocognition and QoL and more AEs (VTE, HTN).
• Recurrence: consider radiographic pseudoprogression before switching therapy, especially in MGMT-methylated patients (among patients with lesion enlargement on the first post-RT MRI, pseudoprogression was ~91% of methylated vs ~41% of unmethylated cases; post-RT changes ~3 mo after RT; no imaging reliably distinguishes it; repeat biopsy often inconclusive). Options: second resection if resectable; bevacizumab OR lomustine after RT/temozolomide failure. Bevacizumab + lomustine and bevacizumab + irinotecan did NOT improve OS and add toxicity. Bevacizumab has no proven OS benefit but reduces edema and spares steroids (delay surgery ≥6 weeks; watch bleeding, bowel perforation, VTE, HTN, nephrotic syndrome). TTFields is approved but has no OS benefit vs chemotherapy at recurrence (similar OS, fewer AEs, better QoL). Offer hospice.
• Rare targetable subsets: BRAF V600E+ GBM (dabrafenib + trametinib); NTRK fusion (larotrectinib, entrectinib). CAR-T, vaccines, and IO remain investigational and disappointing to date in GBM.

Astrocytoma, IDH-mutant

• The 2021 WHO groups all IDH-mutant diffuse astrocytic tumors as a single type, graded 2, 3, or 4 (the older terms diffuse astrocytoma, anaplastic astrocytoma, and IDH-mutant GBM are retired).
  • Grade 2: infiltrative growth, mild atypia, few or no mitoses; high propensity to transform.
  • Grade 3 (formerly anaplastic): increased cellularity and mitotic activity.
  • Grade 4: microvascular proliferation and/or necrosis, OR CDKN2A/B homozygous deletion (which makes it grade 4 even without grade 4 histology).
• Surgery: maximal safe resection of the T2/FLAIR-defined tumor, including the non-enhancing component (enhancement alone does not define the tumor). Small, asymptomatic grade 2 tumors: upfront surgery vs watchful waiting.
• Radiation: adjuvant RT improves OS in grade 3 (and likely grade 2). Immediate vs delayed (at-progression) RT improved PFS (5.3 vs 3.4 yr) but not OS (7.4 vs 7.2 yr), so in grade 2 IDH-mutant astrocytoma with minimal symptoms, well-controlled seizures, gross total resection, and young age, RT may be deferred. RTOG 9802 (RT then PCV) showed minimal long-term neurotoxicity.
• Chemotherapy:
  • Grade 3: adjuvant temozolomide after RT is standard. CATNON (EORTC 26053): concurrent temozolomide gave no OS benefit, but adjuvant temozolomide improved OS (HR 0.64), with the benefit confined to IDH-mutant tumors.
  • Grade 2: for low-risk (<40 yr, gross total resection), observation is preferred (RTOG 9802 paradigm). When RT is indicated, add chemo (PCV or temozolomide); RTOG 9802 OS benefit was with PCV; temozolomide is often chosen for lower toxicity. Grade 4 IDH-mutant astrocytoma is treated like GBM (Stupp).
• Vorasidenib (Voranigo), brain-penetrant mutant IDH1/2 inhibitor (INDIGO, Mellinghoff NEJM 2023, PMID 37272516): mPFS 27.7 vs 11.1 mo; delays time to next intervention. FDA approved Aug 2024 for grade 2 IDH-mutant astrocytoma or oligodendroglioma after surgery. Toxicity: transaminitis (≥grade 3 ~10%), nausea, fatigue. Low-risk grade 2 (<40 yr, gross total resection) may be observed OR given vorasidenib.
• Recurrence: repeat surgery (debulking or to distinguish progression from treatment effect), re-treatment with temozolomide or nitrosourea, bevacizumab for symptomatic high-grade recurrence, repeat RT.

Oligodendroglioma (IDH-mutant AND 1p/19q codeleted)

• Rare (~8% of gliomas), favorable prognosis, chemosensitive. Presents with mass effect or seizures. IDH mutation plus 1p/19q codeletion are required for diagnosis.
• Histology: rounded nuclei with clear perinuclear halos (fried-egg pattern) and capillary networks (chicken-wire vessels). CT frequently shows calcification. Mixed oligoastrocytomas are reclassified by molecular findings (oligodendroglioma if 1p/19q codeleted; astrocytoma if not, ATRX-mutant). Grade 4 does not exist for oligodendroglioma.
• Surgery: maximal safe resection of the T2/FLAIR-defined tumor (many oligodendrogliomas do not enhance); small/asymptomatic tumors, upfront surgery vs watchful waiting (controversial).
• Grade 3: surgical debulking → RT + PCV is standard.
  • RTOG 9402 (PCV before RT vs RT alone): mOS 14.7 vs 7.3 yr in IDH-mutant/1p19q codeleted; 5.5 vs 3.3 yr in IDH-mutant noncodeleted (whole noncodeleted subgroup had no benefit: 2.6 vs 2.7 yr).
  • EORTC 26951 (PCV after RT vs RT): OS benefit in the whole population (42.3 vs 30.6 mo, HR 0.75), most pronounced in 1p/19q codeleted tumors.
• Grade 2: surgery → RT + chemo. Temozolomide is an alternative chemo backbone. The CODEL trial (RT then PCV vs RT + temozolomide then adjuvant temozolomide, grades 2 and 3) is ongoing. Vorasidenib is an option for grade 2 after surgery (INDIGO, above).

Grade 1 astrocytomas

• Rare, good prognosis, well-circumscribed, in children and young adults. Two types:
  • Pilocytic astrocytoma: cerebellum (~40%) then supratentorial (~35%); ~66% harbor a 7q34 tandem duplication producing the unique BRAF-KIAA1549 fusion. Imaging: cystic with a contrast-enhancing mural nodule. Potentially curable with complete resection.
  • Subependymal giant cell astrocytoma (SEGA): periventricular; ~10% of tuberous sclerosis patients. Surgery if symptomatic (ventricular enlargement); stable asymptomatic: serial MRI surveillance; growing asymptomatic: surgery or mTOR inhibitor (everolimus).
• Even after incomplete resection these remain indolent; RT is usually deferred until significant progression. For progressive or unresectable pediatric pilocytic (low-grade) astrocytoma, carboplatin/vincristine or vinblastine can control disease and defer RT.

Diffuse midline / histone-mutated glioma (H3 K27M-altered)

• Diffuse midline glioma, H3 K27-altered (grade 4) arises at midline sites including the pons (DIPG), but not all DIPG are H3 K27-altered; diffuse hemispheric glioma, H3 G34-mutant (grade 4) is more common in adolescents and young adults. Molecular profile differs from GBM and IDH-mutant tumors.
• Dordaviprone (Modeyso, formerly ONC201), a DRD2 antagonist and ClpP allosteric activator. Integrated 50-patient analysis across 5 trials: ORR 22%, meaningful median duration of response. FDA accelerated approval Aug 6, 2025 for recurrent H3 K27M-mutant diffuse midline glioma in adults and children ≥1 yr, the first targeted therapy for this entity; continued approval is contingent on the confirmatory ACTION trial.

Ependymal tumors

• Arise from the ependymal lining of the ventricles or the spinal central canal. Location: posterior fossa in children, spinal cord in adults. The 2021 WHO divides them by compartment (supratentorial, posterior fossa, spinal); supratentorial ZFTA (RELA) fusion carries a poorer prognosis. Myxopapillary ependymoma and subependymoma are separate types regardless of location.
• Treatment: maximal safe complete resection; adjuvant RT for grade 3 regardless of resection extent, for incompletely resected grade 2, and for disseminated disease; most pediatric intracranial ependymomas get postoperative focal RT even after GTR. May respond to platinum-based chemo, but no randomized trial guides management.

Medulloblastoma

• Most common in children; develops in the posterior fossa (cerebellar hemispheres or vermis, may involve the fourth ventricle), causing obstructive hydrocephalus (headache, nausea, vomiting, gait instability, diplopia, dysarthria).
• Molecular subtypes (2016 = 2021 WHO): WNT-activated (best prognosis, ~90% long-term OS); SHH-activated (intermediate); group 3 (MYC-amplified, worst) and group 4 (intermediate).
• Treatment: surgery → craniospinal RT with a boost to the posterior fossa can be curative. Post-RT chemo is standard in children because it lowers the total RT dose needed for the developing CNS. In adults there is no prospective evidence of chemo benefit after full-dose craniospinal RT (weekly vincristine during RT is poorly tolerated in adults); other adjuvant options are cisplatin/cyclophosphamide/vincristine or cisplatin/lomustine/vincristine.
• Poor prognostic features: residual tumor, positive CSF cytology, leptomeningeal disease on MRI. 5-yr EFS >80% in average-risk; contemporary high-risk/metastatic cohorts ~60 to 70%, varying by molecular subgroup.
• Other: vismodegib (SHH pathway) for recurrent SHH-type; high-dose chemo with autologous stem-cell transplant may prolong OS in selected patients.

Meningioma

• Most common primary brain tumor; female predominant; usually benign (grade 1); originates from the dura. Classic MRI: uniform dural contrast enhancement with clear separation from brain parenchyma (dural tail).
• WHO grade 1: asymptomatic/incidental → observation (about two thirds never become symptomatic). Symptomatic or mass effect → surgery (feasible at olfactory groove, anterior sagittal sinus, posterior fossa); RT for sites difficult to resect (sphenoid, parasagittal, orbital, tentorial, clival).
• WHO grade 2 (atypical) or grade 3 (anaplastic): grade 3 gets surgery + RT (external-beam or stereotactic radiosurgery); grade 2 gets RT for subtotal resection or recurrence, but after GTR observation vs RT is individualized (RCTs ongoing); limited role for chemo.
• Refractory: bevacizumab, sunitinib, hydroxyurea (modest). NF2, AKT1, and SMO mutations are emerging targets.

Primary CNS lymphoma (PCNSL)

• Non-Hodgkin lymphoma confined to the CNS without systemic disease; >95% diffuse large B-cell (nongerminal-center subtype); ~2 to 3% of brain tumors; male > female, median age ~67. Most patients are immunocompetent, but immunodeficiency (transplant, congenital, HIV) markedly raises risk; EBV-driven in the immunocompromised. Often a single periventricular irregular lesion.
• Avoid corticosteroids before biopsy if PCNSL is suspected (steroids can make the lesion vanish and the biopsy nondiagnostic), unless mass effect causes serious, immediate complications. Biopsy (stereotactic or CSF sampling) is mandatory.
• Staging workup: slit-lamp/funduscopic eye exam (ocular involvement in ~25%, does not change treatment), spine MRI, PET/CT or CT chest/abdomen/pelvis, lumbar puncture (with CSF flow cytometry) if safe, HIV testing, testicular exam in men; bone marrow involvement is uncommon (role of biopsy controversial).
• Induction: high-dose methotrexate-based regimens (3.5 to 8 g/m²), up to 8 cycles:
  • MTR (methotrexate 8 g/m², temozolomide, rituximab; Alliance 50202): ORR 77%, CR 66%, 2-yr PFS 57%.
  • R-MPV (rituximab, methotrexate 3.5 g/m², procarbazine, vincristine): ORR ~80%.
  • MATRix (methotrexate 3.5 g/m², cytarabine 2 g/m² q12h × 4, thiotepa 30 mg/m², rituximab): ORR 87%, CR 49%, 7-yr OS 56%.
  • Not a high-dose-methotrexate candidate: temozolomide +/- rituximab, high-dose cytarabine, or WBRT (conventional low-dose methotrexate is not adequate).
  • Intrathecal methotrexate has no role in induction, even with CSF dissemination (IV methotrexate >3 g/m² achieves adequate CSF levels; Ommaya carries infection risk).
• Consolidation (for induction responders): high-dose chemo with autologous stem-cell transplant (best for young, fit patients; thiotepa-based), non-myeloablative chemo (etoposide + cytarabine, EA), or WBRT (cognitive toxicity in older patients). CALGB 51101: consolidative HDC-ASCT vs EA, PFS favored HDC-ASCT (median 6 vs 2.4 yr, primary endpoint), 3-yr OS 83% vs 72% (no significant OS difference shown); EA hematologic toxicity is substantial. No clear survival difference among the three approaches.
• Relapsed/refractory: re-induction with high-dose methotrexate if relapse >12 mo, or salvage ASCT; also ibrutinib, lenalidomide, temozolomide, pemetrexed, rituximab, possibly PD-1 inhibitors, and WBRT (higher neurotoxicity).

Brain metastases

• Result from hematogenous spread, most common at the gray-white junction where vessels narrow (~80% hemispheric, ~15% cerebellum, ~5% brainstem). Most common primaries: lung > breast > melanoma > colorectal > kidney.
• Surgery: single, accessible, large lesions with edema/mass effect, for rapid symptom and local control.
• Radiation:
  • SRS can treat up to ~10 metastases; local control ~80 to 90%. Limits: no tissue diagnosis, cannot relieve mass effect, lesions generally <3 to 4 cm, and can cause post-SRS edema.
  • WBRT for high intracranial burden of brain metastases, but adjunctive WBRT after local therapy does not improve OS and worsens QoL/neurocognition. Surgery or SRS → WBRT lowers intracranial progression (48% vs 78%) and neurologic death but does not change OS. Surgery → SRS to the resection cavity improves 1-yr local control (72% vs 43%) without OS change.
  • Hippocampal-avoidance WBRT plus memantine reduces cognitive decline (RTOG 0614 showed memantine delayed time to cognitive decline; hippocampal sparing further helps).
• CNS-active systemic therapy is increasingly used; classic chemo has a limited role because of poor BBB penetration (though curative in CNS lymphoma and germ-cell tumors).

• Prophylactic antiepileptics are not recommended routinely (no benefit without a seizure history, and none proven in the postcraniotomy setting; if started perioperatively, discontinue after a few weeks). Start antiseizure therapy after a tumor-related seizure; individualize duration (supervised withdrawal possible in selected seizure-free patients with resected/stable tumors).
• Dexamethasone for symptomatic edema (note possible negative neurocognitive impact).

Leptomeningeal disease

• Most common with breast, lung, and melanoma; median OS ~4 to 6 weeks if untreated; treated patients commonly survive several months, longer in actionable molecular subsets. Tumor cells disseminate through CSF flow, producing cranial neuropathies, radiculopathy, raised ICP/hydrocephalus (headache, nausea, vomiting), and encephalopathy.
• Diagnosis: CSF shows mildly elevated protein, pleocytosis, possibly low glucose (may be negative; sensitivity of cytology improves with repeated LPs). MRI shows diffuse or nodular leptomeningeal enhancement or hydrocephalus without a mass.
• Treatment: corticosteroids and analgesics (limited, temporary), focal RT for bulky or symptomatic sites (WBRT only for extensive symptomatic disease, no OS benefit), ventriculoperitoneal shunt for refractory symptomatic hydrocephalus, and CNS-active systemic agents. If CSF flow is obstructed, tumor deposits reduce drug delivery and increase intrathecal toxicity, so give RT to restore flow before intrathecal chemo (methotrexate, cytarabine via Ommaya or repeated LP) when flow is normal.

Cerebral edema, seizures, and VTE

• Cerebral edema: dexamethasone is preferred (minimal mineralocorticoid activity, long half-life). Bevacizumab can control severe edema, including radiation-necrosis edema.
• Seizures: avoid CYP450-inducing agents (phenytoin, phenobarbital, carbamazepine reduce chemo exposure) and CYP450 inhibitors (valproate raises chemo toxicity). Preferred non-interacting agents: levetiracetam, lacosamide, zonisamide, lamotrigine, pregabalin (topiramate is a weak, dose-dependent CYP3A4 inducer at 200 mg/day or more, so less ideal). No benefit to prophylaxis without a seizure history; after a seizure, continue long term, with supervised withdrawal possible in selected seizure-free patients with resected or stable tumors.
• Venous thromboembolism: occurs in ~20 to 30% of primary CNS cancer patients. Anticoagulation increases intracranial hemorrhage risk in primary brain tumors (~12.5% vs ~4.4% without); still often indicated for VTE, with LMWH or DOACs preferred. Low-molecular-weight heparin is generally more effective than warfarin; limited data on DOACs and direct thrombin inhibitors.

Pediatric / AYA note

• Pilocytic astrocytoma: benign, posterior fossa, BRAF fusion; surgery often curative.
• NF1: optic pathway glioma; selumetinib (MEK inhibitor) for inoperable plexiform neurofibroma. NF2: bilateral vestibular schwannomas.
• Tovorafenib (Ojemda), type II RAF inhibitor active against BRAF V600 and BRAF fusion/rearrangement. FIREFLY-1 (Kilburn Nat Med 2024): ORR 51%, median duration of response 13.8 mo in relapsed/refractory BRAF-altered pediatric low-grade glioma. FDA Apr 23, 2024 for pediatric LGG ≥6 mo with BRAF fusion/rearrangement or V600 mutation with relapsed or refractory disease, the first systemic therapy approved for pediatric LGG with BRAF fusions.

High-yield CNS pearls

• GBM Stupp: RT + concurrent then adjuvant temozolomide × 6, plus optional TTFields (EF-14, mOS 20.9 vs 16.0 mo).
• MGMT methylated = best temozolomide response and better prognosis.
• IDH-mutant = better prognosis; vorasidenib for grade 2 IDH-mutant glioma after surgery (INDIGO, FDA Aug 2024, mPFS 27.7 vs 11.1 mo).
• 1p/19q codeletion defines oligodendroglioma; grade 3 gets RT + PCV (RTOG 9402).
• CATNON: adjuvant temozolomide (not concurrent) benefits grade 3 astrocytoma.
• CDKN2A/B homozygous deletion makes an IDH-mutant astrocytoma grade 4.
• Medulloblastoma: WNT best, group 3 (MYC) worst; craniospinal RT plus chemo.
• PCNSL: avoid steroids before biopsy; high-dose methotrexate + rituximab induction, then ASCT or WBRT; no role for intrathecal methotrexate in induction.
• Brain metastases: SRS for up to ~10 lesions; hippocampal-avoidance WBRT + memantine reduces cognitive decline; CNS-active systemic agents matter.
• Dordaviprone (Modeyso): FDA Aug 6, 2025 for recurrent H3 K27M+ diffuse midline glioma, first targeted therapy for this entity.
• Seizure prophylaxis is not indicated without a prior seizure; prefer non-enzyme-inducing agents; LMWH or a DOAC for VTE.