Glioblastoma and other Primary Brain Malignancies in Adults. A Review

Abstract

Importance:

Malignant primary brain tumors cause over 15,000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100,000 individuals and increases with age. Five-year survival is about 67%.

Observations:

Malignant brain tumors include glioblastoma (49%), other gliomas with infiltration in the central nervous system (CNS) parenchyma (about 30%), primary CNS lymphoma (7%), and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20–50%), neurocognitive impairment (30–40%), and focal neurologic deficits (10–40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival compared to radiotherapy alone (2-year survival: 27.2% versus 10.9%; 5-year survival: 9.8% versus 1.9%)(HR 0.6, 95% CI 0.5–0.7; p<0.001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without versus with the combination of procarbazine, lomustine, and vincristine was 13.6% versus 37.1% (n=80; HR 0.60; 95% CI 0.35–1.03; p=0.06) in the EORTC 26951 trial and 14.9% versus 37% in the RTOG 9402 trial (n=125; HR 0.61; 95% CI 0.40–0.94; p=0.02). Treatment of primary CNS lymphoma includes high-dose methotrexate containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, non-myeloablative chemotherapy regimens, or whole brain radiation.

Conclusions and Relevance:

The incidence of primary malignant brain tumors is about 7 per 100,000 individuals and approximately 49% of brain tumors are glioblastomas. Most patients die from progressive disease. First line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.

INTRODUCTION

Approximately 85,000 individuals in the United States are diagnosed with a primary brain tumor each year, of which approximately 29% are malignant ¹. Approximately 80–85% of malignant brain tumors in adults are gliomas which diffusely infiltrate the brain parenchyma. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), which provides the international standard for the classification of brain and spinal cord tumors, refers to this group of tumors as “adult-type diffuse gliomas” ². The incidence of glioblastoma, the most common malignant primary brain tumor in adults, increases after the age of 40 and peaks in adults aged 75–84 ^1,3. Lower-grade diffuse gliomas usually afflict patients under the age of 50 and are further classified into molecular subtypes, astrocytoma and oligodendroglioma^4,5. Less common malignant brain tumors in adults include primary central nervous system lymphoma (PCNSL) and malignant forms of meningiomas, ependymomas, and other rare brain tumor types ¹. PCNSL is a rare variant of non-Hodgkin lymphoma that presents in the brain, eyes, or leptomeningeal space without evidence of extracranial disease. The incidence of PCNSL is about 0.5 per 100,000 individuals, and the incidence is rising in patients older than 60 years ^6,7. About 5 % of meningiomas, the most common primary CNS tumor in adults, are WHO grade 2 (atypical) and 1–2 % are WHO grade 3 (malignant/anaplastic) ^1,8. Ependymomas are rare CNS tumors which arise in the supratentorial brain, posterior fossa, and spine. The incidence is about 0.2–0.4 per 100,000 individuals and as a proportion of all primary brain cancers, they are more common in children. Ependymomas are classified according to a combination of histopathological and molecular features as well as anatomic site and range in growth speed from benign to malignant ^1,9. This review summarizes current evidence regarding diagnosis and treatment of primary malignant brain tumors in adults.

METHODS

Two literature searches of PubMed, restricted to English-language articles published within the last 10 years, were performed on June 11, 2022 and updated on December 10, 2022, using MeSH keywords “glioma”, “glioblastoma”, “malignant meningioma”, and “primary CNS lymphoma”. Articles with MeSH keyword “pediatric” were excluded. The search was limited to clinical trials, meta-analyses, and systematic reviews. 3,592 articles were retrieved. Additional articles were identified by the authors based on their knowledge of literature before 2012 and from review of citations in retrieved articles. 110 articles were included for this review, consisting of 48 clinical trials, 19 meta-analyses or reviews, 11 guideline or consensus papers, 14 retrospective studies, 4 epidemiologic studies, 3 case-control studies, 2 prospective cohort studies, 1 editorial, and 8 other original research studies.

DISCUSSION AND OBSERVATIONS

Epidemiology

Fewer than 5% of adults with a malignant brain tumor report a family history of brain tumors or have a cancer pre-disposition syndrome ^10,11. However, the contribution of heritability to brain tumor formation is likely higher, based on germline sequencing ¹² and Genome-Wide Complex Trait Analysis ¹³. Prior exposure to ionizing radiation to the CNS, usually during treatment for another cancer such as childhood leukemia, is a risk factor for brain tumors ¹⁴. Exposure to low-frequency electromagnetic fields is not an established risk factor ¹⁵. There is not high-quality evidence demonstrating an association between cell phone use and brain tumor formation ^11,16. An update to the UK Million Women Study, a prospective study of 776,156 women, reported adjusted relative risks for ever vs never cellular telephone use of 0.97 (95% CI 0.90–1.04) for all brain tumors; there was no increased risk for glioma, meningioma, pituitary tumors, or acoustic neuroma ¹⁷. A history of atopic conditions, such as asthma or eczema ¹⁸, and a history of varicella-zoster virus infection ¹⁹ are associated with lower glioma risk. Immunodeficiency, including Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), is a risk factor for the development of PCNSL ²⁰.

Clinical Presentation

Headache occurs in nearly 50% of patients with newly diagnosed brain tumor ²¹. Patients with rapidly growing tumors may develop increased intracranial pressure (ICP) and present with nausea, vomiting, or fatigue. Physical examination may reveal papilledema. Transient increases in ICP can cause episodic loss of consciousness (so-called “plateau waves”) and may be mistaken for seizures. Patients may develop focal neurologic deficits related to the location of the tumor (Figure 1). For example, tumors affecting the frontal lobes (24%)¹ may cause lack of initiative and difficulties with processing information and responding appropriately to the environment. Tumors in the dominant hemisphere may present with speech difficulty while non-dominant tumors may have more subtle symptoms of spatial distortion and constructional apraxia. Anosognosia, defined as inability to recognize one’s deficits, may contribute to delayed symptom reporting. Cranial neuropathies due to leptomeningeal dissemination of disease or increased ICP can present with ocular palsies, hearing loss, or dysphagia. Symptoms may arise over weeks to months. Up to 74% of patients with lower-grade gliomas present with seizures ²² but tumors can be present for years before symptoms occur or can be discovered incidentally. PCNSL preferentially affects deep matter structures and many patients (~40%) exhibit behavioral or cognitive changes. Patients with PCNSL who have involvement of the vitreoretinal space (~25%) may present with blurred vision or floaters. Slit lamp examination should be performed in all patients with suspected PCNSL and vitreoretinal biopsy may be diagnostic ⁷.

Figure 1. Symptoms of Malignant Brain Tumors related to the location of the tumor.

Highlighted in this image are symptoms that are related to the location of the tumor. In addition, patients with primary brain malignancies may experience generalized fatigue, seizures, and symptoms related to increased intracranial pressure, such as headache, nausea, vomiting, or papilledema.

Diagnosis

Contrast-enhanced magnetic resonance imaging (MRI) of the brain is the imaging modality of choice when a brain tumor is suspected, ideally using a standardized brain tumor imaging protocol ²³. Glioblastomas typically show contrast-enhancement on T1-weighted sequence, central necrosis, T2-weighted/fluid-attenuated inversion recovery (T2/FLAIR) hyperintense cerebral edema, and signs of mass effect. Lower-grade gliomas are often hypointense on T1-weighted imaging and hyperintense on T2/FLAIR. PCNSL may be multifocal and demonstrate homogeneous enhancement and diffusion restriction on diffusion-weighted imaging. Meningiomas typically demonstrate homogeneous contrast enhancement and adjacent dural thickening (Figure 2).

Figure 2. Imaging Features of Malignant Brain Tumors.

Representative MRIs from patients with glioblastoma, IDH-mutant low grade glioma, PCNSL, and malignant meningioma. Images include T1-weighted pre- and post-gadolinium and T2-weighted FLAIR. White arrows indicate vasogenic edema apparent on T2/FLAIR. Black arrow indicates ring-enhancement reflective of central necrosis often seen in glioblastoma. Yellow arrow indicates the dural attachment (“dural tail”) common with meningiomas.

Tumor tissue is required to establish the diagnosis. Patients with imaging findings suggestive of a brain malignancy should be referred to a center with advanced neurosurgical techniques ²⁴. Procedures are typically performed under general anesthesia and patients are observed in the hospital for several days following the procedure to monitor for complications. Preservation of neurologic function, also referred to as “maximal safe surgical resection”, is a priority and patients may undergo awake craniotomies during which repetitive neurologic assessments guide the resection. When tumor resection is not feasible, a tumor biopsy should be performed.

Accurate grading of CNS tumors is important for estimating patient prognosis and requires integration of histological features and molecular abnormalities ² (Figure 3). For instance, astrocytomas with mutations in the genes Isocitrate dehydrogenase (IDH) 1 (GenBank Accession O75874) or 2 (GenBank Accession P48735) and homozygous loss of the genes Cyclin-dependent kinase inhibitor 2A (GenBank Accession P42771) and B (GenBank Accession P42772) (CDKN2A/B) are considered grade 4 even if they lack histological features of a grade 4 tumor ². Molecular testing is also required to identify glioma subtypes that are characterized by specific molecular alterations, such “diffuse midline glioma, H3 K27-altered” or “diffuse hemispheric glioma, H3 G34-mutant”. Molecular testing can also help select the most appropriate treatment. For example, O⁶-methylguanine-DNA-methyltransferase (MGMT) (GenBank Accession P16455) promoter methylation is characteristic of glioblastomas which are more likely to respond to alkylating agents such as temozolomide²⁵. Many centers are shifting toward comprehensive DNA sequencing and methylation profiling to classify brain tumors ^26,27 and referral to a cancer center should be considered for detailed molecular analysis and treatment planning.

Figure 3. Integration of histological features and molecular alterations in the revised WHO Classification of Tumors of the Central Nervous System (CNS). Shown are examples for the most common “adult-type” diffuse gliomas.

^a This figure does not include pediatric-type diffuse high-grade gliomas which can present in adults. ^b Immunohistochemistry (IHC) with a highly sensitive and specific monoclonal antibody that recognizes the IDH1-R132H mutant protein is widely used. The IDH1-R132H mutation accounts for about 90% of all IDH1 and IDH2 mutations in supratentorial adult-type diffuse glioma. Testing for non–IDH1-R132H mutations uses DNA sequence analysis and is necessary when IHC for IDH1-R132H is negative. ^c IDH-wildtype glioblastomas lack mutations in IDH1 and IDH2. Absence of immunoreactivity for IDH1 R132H is sufficient to diagnose IDH-wildtype glioblastoma in patients aged 55 and older with histologically classic glioblastoma. ^d NEC: Not Elsewhere Classifiable. NEC designation indicates that appropriate diagnostic testing has been performed and results do not allow for an alternative diagnosis per World Health Organization criteria. Further molecular work up should exclude the presence of genetic findings that are associated with “pediatric-type” diffuse gliomas and circumscribed astrocytic gliomas.

Systemic cancer staging is generally not required because the most common primary brain malignancies do not spread beyond the CNS. Notable exceptions include patients with CNS lymphoma, who require a systemic work up to differentiate PCNSL from secondary CNS involvement, and patients with ependymomas who require craniospinal MRI and cerebrospinal fluid (CSF) cytology following surgery to assess for leptomeningeal dissemination.

Treatment of Symptoms and Complications

Seizures occur in as many as 75% of patients with glioma ²⁸. Older anti-epileptic drugs, such as phenobarbital, carbamazepine or phenytoin, stimulate the synthesis of hepatic cytochrome P450 enzymes and can affect the metabolism of concomitant drugs. Non-enzyme inducing antiepileptic agents, such as levetiracetam, lacosamide, or clobazam, are preferred due to fewer drug-drug interactions and improved side effect profiles ²⁹. Tumor-directed treatments may reduce the risk of seizure recurrence ³⁰. For patients who never had a seizure, routine anti-convulsant prophylaxis is not recommended ²⁹. The use of anti-epileptic drugs peri-operatively is common, but evidence for this practice is scant ²⁹.

Cerebral edema is treated with corticosteroids ³¹. Dexamethasone is preferred due to its low mineralocorticoid activity and long half-life. For severe neurologic symptoms, such as gait impairment or altered consciousness, a bolus of dexamethasone 10mg may be administered followed by 16mg/day. Mild to moderate symptoms, such as headache or sensory deficits, can be managed with dexamethasone 4–8mg/day without a loading dose. Once or twice a day dosing is typically sufficient ³². The lowest dose required for symptom control should be administered ³¹ and tapering off corticosteroids should be attempted as soon as appropriate. A slow taper (e.g., dose reduction every 3–4 days) is recommended to identify the minimal steroid dose required to control neurologic symptoms and to reduce the risk of adrenal insufficiency. Patients receiving the equivalent of prednisone 20mg daily for more than a month (i.e., approximately dexamethasone 3mg daily) should receive prophylaxis for Pneumocystis pneumonia (PJP) ³³ (Table 1). Trimethoprim/sulfamethoxazole prophylaxis reduces incidence of PJP in non-HIV immunocompromised individuals by approximately 85%, from 6.2% to 0.2% (RR 0.15, 95% CI 0.04–0.62) ³³. Gastrointestinal prophylaxis with a proton pump inhibitor is recommended for patients on daily dexamethasone doses above 8mg, in peri-operative settings, and in patients treated with anticoagulation, non-steroidal inflammatory drugs, or in patients with a history of peptic ulcer disease. Myopathy is a common complication of corticosteroid use in patients with brain tumors. Patients with steroid induced myopathy may complain of difficulty arising from a seated position and climbing stairs. Symptoms may resolve after steroid discontinuation. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), can improve cerebral edema in patients with brain tumors who are did not respond to steroids or who are intolerant to steroids ^31,34,.

Table 1.

Management of medical complications of glioblastoma and other primary malignant brain tumors in adults

Treatment	Treatment of cerebral edema		Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) (patients on dexamethasone ≥3 mg daily for ≥ 1 month)				Treatment of venous thromboembolism
	Dexamethasone	Bevacizumab	Sulfamethoxazole-trimethoprim (preferred)	Dapsone	Atovaquone	Pentamidine	Enoxaparin	Edoxaban	Rivaroxaban	Apixaban
Dosage Form	Oral tablet, solution, or IV	IV	Oral tablet	Oral tablet	Oral suspension	Inhaled or IV	Subcutaneous	Oral tablet	Oral tablet, suspension	Oral tablet
Dose	Severe symptoms: bolus 10mg, then 16mg/day in divided doses; mild-moderate symptoms: 4–8mg/day	10 mg/kg every two weeks	DS (TMP 160mg, SMX 800mg) three times a week OR SS (TMP 80 mg, SMX 40 mg) once daily	50mg twice a day OR 100mg daily	1500mg daily	300mg inhaled monthly OR 4 mg/kg IV (max 300 mg) monthly	1mg/kg every 12 hours OR 1.5mg/kg daily	*Following 5 days UFH or LMWH >60 kg: 60mg daily ≤60 kg: 30 mg daily	15mg twice daily for 21 days, then 20mg daily	10mg twice daily for 7 days, then 5mg twice daily
Mechanism of Action	Long-acting corticosteroid, decreases inflammatory mediators, reverses vascular permeability	VEGF inhibition	Interference with bacterial folic acid synthesis	PABA antagonist	Inhibits mitochondrial electron transport	Inhibits topoisomerase enzymes, interferes with functions of DNA/RNA, phospholipids, and protein synthesis	Binds and potentiates antithrombin	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Adverse effects°	Hyperglycemia, psychiatric/behavioral disturbance, fluid retention, weight gain, gastritis, myopathy, increased infection risk Adverse effects are dose dependent and increase with prolonged exposure	Hypertension(19–42%), hemorrhage (0.4–7%), proteinuria (5–20%), arterial thromboembolism (5%), deep venous thrombosis (6–9%), posterior reversible encephalopathy syndrome (0.5%)	Rash, urticaria, nausea/vomiting, Hepatotoxicity, thrombocytopenia, hyponatremia. Frequencies not reported.	Methemoglobinemia, hemolytic anemia, hepatotoxicity, dermatologic toxicity. Frequencies not reported.	Rash (6.3–39%), diarrhea (3.2–42%), nausea (4.1–26%), headache (16–28%), erythema multiforme, hepatotoxicity	Decreased appetite (50%), leukopenia (10.4%), nephrotoxicity (45%), bronchospasm (15%), cough (38–62.7%), fatigue (65.7%)	Hemorrhage (4–13%), hepatotoxicity (5.9–6.1%), anemia (<16%), thrombocytopenia (<3%)	Hemorrhage, major (1.4–6.1%), hepatotoxicity (4.8–7.8%)	Hemorrhage (13.4–36.2%), gastroenteritis (12.5%), angioedema	Major bleeding (0.1–2.13%), hepatotoxicity, <1%
Comments	Patients should be maintained on lowest dose possible for shortest amount of time feasible. Add PJP prophylaxis (see below) if continuing ≥3 mg dexamethasone for ≥ 1 month	May be used for treatment of recurrent glioma or management of edema Hold at least 4 weeks before and after any surgical procedures	Not to be used in patients with sulfa allergy	Check for G6PD deficiency prior to prescribing			In patients with kidney injury, anti-factor Xa levels may be used to monitor effects. Dose adjustment required for patients with CrCl< 30 mL/minute	Dose adjustment required for patients with CrCl ≤ 50 mL/minute	Dose adjustment required for patients with CrCl CrCl ≤ 50 mL/minute

°Adverse effects obtained from IBM Micromedex database and are meant to represent most frequent/most serious adverse effects. Lists are not all-inclusive.

CrCl: creatinine clearance; DS: double strength; G6PD: glucose-6-phosphate dehydrogenase; IV: intravenously; PABA: para-aminobenzoic acid; PJP: pneumocystis pneumonia, SMX: sulfamethoxazole; SS: single strength; TMP: trimethoprim; VEGF: vascular endothelial growth factor

Venous thromboembolism (VTE) occurs in up to 30% of patients with glioma and CNS lymphoma ^35,36, often shortly following diagnostic surgery ³⁷. Hospitalized neurosurgical patients should receive prophylactic low-molecular weight or unfractionated heparin, ideally beginning 24 hours after surgery ³⁸. There are no data to support maintenance of VTE prophylaxis after hospital discharge ³⁹ and there are also only few prospective data to guide the treatment of VTE in patients with brain tumors. The risk of intracranial bleeding may increase with the use of anticoagulants, but these data are not definitive ^39,40 and anticoagulation is generally recommended given the significant mortality associated with untreated VTE. Many neuro-oncologists favor low-molecular weight heparin (LMWH) over vitamin K antagonists, mostly based on extrapolation of findings from studies with few patients with brain tumors ⁴¹. Direct oral anticoagulants (DOACs) have been shown to be non-inferior to LMWH in a general cancer population ^42,43 and may also be appropriate for patients with brain tumors with VTE ^44–46. In a single-institution retrospective cohort study of patients with glioblastoma and VTE treated with either DOAC or LMWH (n=121), rates of clinically significant intracerebral hemorrhage at 30 days and six months favored the DOAC group (30 days: 0% vs 9%, p=0.11; 6 months: 0% vs 24%, p=0.01) ⁴⁴. Systemic anticoagulation for VTE should be continued for at least three to six months, but in patients with brain malignancies it may be appropriate to continue anticoagulation indefinitely. Placement of an inferior venous cava filter can be considered when systemic anticoagulation is considered unsafe, but inferior vena cava filters are associated with a 30% rate of recurrent VTE ⁴⁷.

Patients with malignant brain tumors experience neurocognitive decline, decreased mobility, fatigue, depression, seizures, and reduced sexual wellness. Symptom management is an important part of treatment and early referral to palliative medicine should be considered ⁴⁸. Patients should receive fertility counseling prior to treatment including information about egg or sperm preservation.

Treatment of Glioblastoma

Glioblastoma is the most common malignant primary brain tumor and has a median survival of less than two years ^49,50. Glioblastomas are more common in non-Hispanic Caucasians than other ethnic groups and there is a slight male predominance ¹. Patient participation in clinical trials should be considered whenever possible given the limited number of effective standard therapies for glioblastoma.

Surgical removal of all contrast-enhancing tumor, also referred to as “gross total resection”, is associated with improved progression-free (PFS) and overall survival (OS) ^51,52. Use of 5-aminolevulinic acid (ALA), an optical imaging agent, aids in the visualization of malignant tissue during surgery and improved rates of gross total resection and six month PFS ⁵³. Within 3–6 weeks after surgery, patients should receive radiation (60 Gy, typically given over six weeks in 30 fractions of 2 Gy) with concurrent administration of the oral alkylating agent temozolomide. Temozolomide should be resumed four weeks after completion of radiation, typically for five consecutive days every 28-days for a total of six monthly cycles ^{49, 54}. In a clinical trial of 573 participants, this regimen improved survival compared to radiation alone (14.6 mo vs 12.1 mo, HR 0.63, 95% CI 0.52–0.75; p<0.001) ⁴⁹. Patients with epigenetic silencing of the DNA-repair protein MGMT in tumor tissue (n=92) benefited the most from temozolomide, with a median OS of 21.7 months (95% CI 17.4–30.4) compared to 15.3 months (95% CI 13.0–20.9) with radiation alone (p=0.01) ⁵⁵. Health-related quality of life was similar in patients treated with radiation alone compared to radiation with temozolomide ⁵⁶. Another clinical trial randomized 562 patients aged 65 and older to either short-course radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with temozolomide and demonstrated improved OS with combination therapy (9.3 mo vs 7.6 mo, HR 0.67, 95% CI 0.56–0.80; p<0.001) ⁵⁷. In patients unlikely to tolerate the combination of chemotherapy and radiation, treatment with either radiation alone (if MGMT unmethylated) or temozolomide alone (if MGMT methylated) should be considered ^58,59 (Table 2). The addition of tumor treating fields, alternating low-intensity electric fields delivered via transducer arrays on the shaved scalp and connected to a portable device, to maintenance temozolomide improved OS in a clinical trial of 695 participants from 16.0 months to 20.9 months (HR, 0.63, 95% CI 0.53–0.76, p<0.001) ⁵⁰.

Table 2.

First-line treatment of adult-type diffuse glioma-

Diagnosis	Grade	Treatment Options	Radiation dose	Chemotherapy	Efficacy rates	Adverse effects*
Glioblastoma, IDH-wildtype ⱡ	4	RT/ temozolomide followed by temozolomide ± tumor-treating fields	60 Gy in 30 fractions	Concurrent temozolomide: 75 mg/m2 orally once a day during RT Adjuvant temozolomide 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, 6 cycles Tumor-treating fields: > 18 hours per day for two years or until second progression	Median OS 14.6 months for patients treated with RT and temozolomide vs 12.1 months for RT alone (HR 0.63, 95% CI, 0.52–0.75; p<0.001) 49. Addition of tumor treating fields associated with median OS 20.5 months vs 15.6 months without (HR 0.64, 99.4% CI, 0.42–0.98; p=0.01) 50.	Grade 3/4 toxicities: hematologic (16%) 49
Glioblastoma, IDH-wildtypeⱡ in patients not appropriate for above regimen (elderly/frail/poor KPS)	4	Short-course RT ± temozolomide followed by temozolomide	40 Gy in 15 fractions	Concurrent temozolomide: 75 mg/m2 orally once a day during RT Adjuvant temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, up to 12 cycles	In patients ≥ 65 years considered not suitable for full dose RT, addition of temozolomide to 40 Gy RT improved median OS from 7.6 to 9.3 months (HR 0.67, 95% CI, 0.56–0.80; p<0.001) 57	Grade 3/4 toxicities: anemia (3/270), leukopenia (19/270), lymphopenia (73/270), neutropenia (22/266), thrombocytopenia (30/270) 57.
		Short-course RT alone (MGMT unmethylated)	40 Gy in 15 fractions OR 25 Gy in 5 fractions		In patients ≥ 70 years with KPS ≥ 70, RT improved median OS from 16.9 weeks to 29.1 weeks (HR 0.47, 95% CI, 0.29–0.76; p=0.01105. For patients ≥ 60 years old and KPS ≥ 50, there was no difference in survival with standard RT (60 Gy) (OS 5.1 mo) or short-course (40 Gy) (OS 5.6 mo). HR 0.89, 95% CI, 0.59–1.36; p=0.57) 58. For patients ≥ 50 with KPS 50–70 or ≥ 65 KPS 80–100, there was no difference in survival with 25 Gy RT (7.9 mo) and 40 Gy RT (6.4 mo); p=0.99106	No grade ≥ 3 acute toxicities 106
		Temozolomide alone (MGMT methylated)		Temozolomide 100mg/m2 days 1–7 of 1 week on, 1 week off cycles. Dose increases or decreased in 25 mg/m2 steps based on tolerability. 6 months OR 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, up to 12 cycles	In patients ≥ 65 years and KPS ≥ 60 with MGMT promoter methylation, treatment with temozolomide alone yielded median OS 18.4 months vs RT alone at 9.6 months (HR 0.44, 95% CI, 0.27–0.70(; p<0.001). This was a non-inferiority trial 107	Grade 3/4 toxicities: neutropenia (16/195), lymphopenia (46/195), thrombocytopenia (14/195), liver enzyme elevation (35/195), thromboembolic event (24/195), fatigue (24/195) 107
		Best supportive care
Astrocytoma, IDH- mutant, non-codeleted	2	RT followed by temozolomide	54 Gy in 30 fractions	Temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycles, 12 cycles	No efficacy data available specific to this patient population. Use of temozolomide regimen extrapolated from astrocytoma grade 3 literature.	Grade 3/4 hematologic toxicity 15%, grade 3/4 aminotransferase elevation 1% 80,108.
		RT followed by procarbazine/lomustine/ vincristine		Procarbazine 60mg/m2 orally once daily days 8–21, lomustine 110 mg/m2 orally once on day 1, vincristine 1.4 mg/m2 IV (maximum 2mg) IV once daily days 8, 29. 8-week cycle, 6 cycles	At a median follow-up of 9 years, median OS was 4.3 yr for patients treated with RT alone vs. 11.4 yr for patients treated with RT and procarbazine/lomustine/vincristine (HR 0.38; p=0.01) 78.	Grade 3/4 toxicities included fatigue (8/125), weight loss (4/125), hematologic toxicity (64/125), nausea/vomiting (7/125), hepatic toxicity (3/125) 77
		Observation°
	3	RT followed by temozolomide	59.4 Gy in 33 fractions	Temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycles, 12 cycles	In patients with astrocytoma grade 3, OS 82.3 months with RT and temozolomide vs 46.9 months RT alone (HR 0.64, 95% CI 0.52–0.79; p<0.001) 80.	Grade 3/4 toxicities: hematologic 15%, aminotransferase elevation 1% 80,108.
	4	RT ± temozolomide followed by temozolomide	60 Gy in 30 fractions	Concurrent temozolomide: 75 mg/m2 orally once a day during RT Adjuvant temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, 6–12 cycles	No efficacy data available specific to this patient population. Use of temozolomide regimen extrapolated from astrocytoma grade 3 and glioblastoma literature.	Grade 3/4 toxicities: hematologic (16%) 49, transaminitis (2%) 80
Oligodendroglioma, IDH-mutant, codeleted	2	RT followed by procarbazine/lomustine/ vincristine	54 Gy in 30 fractions	Procarbazine 60mg/m2 orally once daily days 8–21, lomustine 110 mg/m2 orally once on day 1, vincristine 1.4 mg/m2 IV (maximum 2mg) IV once daily days 8, 29. 8-week cycle, 6 cycles	At a median follow-u of 9 years, median OS was 13.9 for patients treated with RT alone vs. not reached for patients treated with RT and procarbazine/lomustine/vincristine (HR 0.21; p=0.03) 78.	Grade 3/4 toxicities included fatigue (8/125), weight loss (4/125), hematologic toxicity (64/125), nausea/vomiting (7/125), hepatic toxicity (3/125)
		RT ± temozolomide followed by temozolomide		Concurrent temozolomide: 75 mg/m2 orally once a day until RT completed Adjuvant temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, up to 12 cycles	No prospective efficacy data available specific to this patient population. Use of temozolomide regimen extrapolated from astrocytoma and glioblastoma literature.	Grade 3/4 toxicities included hematologic toxicity (16%) 49, transaminitis (2%) 80
		Observation°
	3	RT followed by procarbazine/lomustine/ vincristine	59.4 Gy in 33 fractions	Procarbazine 60mg/m2 orally once daily days 8–21, lomustine 110 mg/m2 orally once on day 1, vincristine 1.4 mg/m2 IV (maximum 2mg) IV once daily days 8, 29. 8-week cycle, 6 cycles	Median OS 9.3 years RT alone vs 14.2 years RT + procarbazine/lomustine/vincristine (HR 0.60; 95% CI, 0.35 to 1.03; p=0.06) 79	Grade 3/4 hematologic toxicity (74/161), nausea (9/161), vomiting (10/161), neuropathy (3/161), allergic skin reactions (2/161) 109.
		Procarbazine/lomustine/ vincristine (intensified) followed by RT		Procarbazine 75 mg/m2 orally once daily days 8–21, lomustine 130 mg/m2 orally once on day 1, vincristine 1.4 mg/m2 IV (no maximum) on days 8, 29. 6-week cycles, 4 cycles	Median OS 7.3 years RT alone vs 13.2 years RT + procarbazine/lomustine/vincristine (HR 0.61; 95% CI, 0.4 to 0.94; p=0.02) 79	Grade 3/4 toxicities: hematologic toxicity (80/144), neurologic toxicity (cognitive or mood change, peripheral or autonomic neuropathy) (19/144), nausea/vomiting (13/144), hepatic toxicity (6/144), dermatologic toxicity (6/144) 110
		RT ± temozolomide followed by temozolomide		Concurrent temozolomide: 75 mg/m2 orally once a day until RT completed Adjuvant temozolomide: 150–200mg/m2 orally once a day, days 1–5 of 28-day cycle, up to 12 cycles	No efficacy data available specific to this patient population. Use of temozolomide regimen extrapolated from astrocytoma and glioblastoma literature.	Grade 3/4 toxicities: hematologic (16%) 49, transaminitis (2%) 80

^*Adverse effects as reported in corresponding clinical trial(s). Additional important adverse effects include: procarbazine: hypertensive crisis as result of monoamine oxidase inhibition (frequency not reported), rash, abdominal pain, constipation, diarrhea, nausea, vomiting, myelosuppression, hepatotoxicity; lomustine: nausea, vomiting, myelosuppression, hepatoxicity, pulmonary toxicity; vincristine: alopecia, neuropathy including autonomic neuropathy, hyponatremia, constipation, myelosuppression, ototoxicity, bronchospasm; temozolomide: constipation (18–22%), nausea (36–49%), vomiting (20–29%), myelosuppression including neutropenia (8%), thrombocytopenia (4–8%), hepatotoxicity. Frequencies included when reported.

°Consider for patients with favorable prognostic factors: gross total resection, minimal neurologic deficits, age <40

^ⱡTreatment of IDH-wildtype tumors that do not meet molecular or histological criteria for glioblastoma is not well-defined. Generally, recommendations for IDH mutated glioma can be followed.

IV: intravenously; KPS: Karnofsky Performance Status; mo: months; OS: overall survival; PFS: progression-free survival; RT: radiation therapy; yr: years

Glioblastoma recurrence is inevitable, with a median PFS of approximately 7 months ^49,50. Many patients undergo a second tumor resection and additional chemotherapy with nitrosoureas or temozolomide. Bevacizumab is widely used in the U.S. to control symptoms from vasogenic edema ³. A recent randomized trial (n=182) reported improvement in 6-month PFS (54.3% vs 29.1% p=0.01) with re-irradiation in combination with bevacizumab, compared to bevacizumab alone, but there was no difference in OS (10.1 mo vs 9.7 mo, HR 0.98; 80% CI 0.79–1.23, one-sided p=0.46) ⁶⁰.

Many new drugs have not proven effective in late-stage clinical trials, highlighting gaps in early clinical drug development ⁶¹. Unlike other intracranial tumors, which respond to small molecule inhibitors of oncogenic signaling pathways, such everolimus ⁶², selumetinib ⁶³, vemurafenib ^64,65, ibrutinib ^66,, or belzutifan ⁶⁷, glioblastomas have been largely unresponsive to molecularly targeted therapy. Antibodies targeting the immune checkpoint inhibitor programmed death-1 (PD-1), such as pembrolizumab or nivolumab, also did not improve overall survival in Phase 3 trials ^{68, 69} despite altering the tumor microenvironment ^{70, 71}. Current efforts aim to generate antitumor immunity through intratumoral injection of genetically engineered herpes simplex virus type 1 ⁷², adenovirus ⁷³, or poliovirus ⁷⁴.

Treatment of IDH-mutant Astrocytoma and Oligodendroglioma

IDH-mutant gliomas comprise approximately 70–80% of histologically low-grade gliomas, commonly occur in patients under the age of 50, and generally respond better to treatment than IDH-wildtype gliomas ^{4,5, 75}. Oligodendrogliomas are defined as gliomas with a mutation in IDH and an unbalanced translocation between chromosomes 1 and 19 (“1p/19q-codel”); they are graded on a scale of 2–3, based upon histological features such as mitotic activity and presence of microvascular proliferation or necrosis. IDH-mutant gliomas without 1p/19q codeletion (“1p/19q-non-codel”) are astrocytomas and graded on a scale of 2 to 4 based on a combination of histological features and molecular markers (Figure 3).

Maximal safe surgical resection represents a critical first step in the treatment of IDH-mutant glioma, with more extensive resections being associated with improved OS ⁷⁶. A “watch and wait” approach with regular MRI surveillance may be appropriate for younger patients with a WHO grade 2 IDH-mutant glioma and no neurologic symptoms related to the tumor, with the goal to delay treatment-associated side effects (e.g., fatigue, short-term memory loss). Post hoc analysis of the cooperative group NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9802 ⁷⁷ showed that patients with “high-risk” IDH-mutant WHO grade 2 glioma (i.e., patients aged 40 and older or with subtotal resections) benefited from the addition of procarbazine, lomustine, and vincristine (PCV) to radiotherapy (IDH-mutant 1p/19q codel [n=37]: OS 13.9 yr [RT] vs not-reached [RT+PCV], HR, 0.21; p=0.03); IDH-mutant 1p/19q non-codel [n=43]: OS 4.3 yr [RT] vs 11.4 yr [RT+PCV], HR 0.38; p=0.01) ⁷⁸. Long-term survival analysis from the European Organization for the Research and Treatment of Cancer (EORTC) 26951 and RTOG 9402 trials showed that adding PCV to radiotherapy lengthened OS compared to radiation alone as first line therapy for anaplastic oligodendroglial tumors (EORTC 26951 [n=80]: OS 14.2 yr vs 9.3 yr, HR 0.60, 95% CI 0.35–1.03; p=0.06; RTOG 9402 [n=125]: OS 13.2 yr vs 7.3 yr, HR 0.61, 95% CI 0.4–0.94; p=0.02) ⁷⁹. Both EORTC 26951 and RTOG 9402 studies demonstrated a PFS of >30% at 20 years in patients with 1p/19q codeletion, indicating that durable disease control was feasible with this regimen. PCV also improved OS for patients with IDH-mutant tumors without 1p/19q codel ⁷⁹, consistent with the results from RTOG 9802. Temozolomide is an acceptable alternative to PCV ³¹. The Phase 3 Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma (CATNON Intergroup Trial) showed that OS was improved with the use of adjuvant temozolomide (median OS 82.3 mo vs 46.9 mo, HR 0.64, 95% CI 0.52–0.79; p<0.001) when compared to patients who did not receive temozolomide after radiation ⁸⁰. It is currently unknown whether radiation with temozolomide or radiation with PCV are more effective in treating patients with newly diagnosed 1p/19q codel glioma.

Progress has been made in delineating the pathobiology of IDH-mutant glioma since the first report of IDH mutations in glioma ⁸¹. Production of the metabolite 2-hydroxyglutarate (2HG) by the mutant IDH enzyme and subsequent accumulation of 2HG in tumor tissue inhibits α-ketoglutarate-dependent enzymes, eliciting profound effects on DNA methylation, gene expression, cellular differentiation state, and the tumor microenvironment ⁷⁵. Small molecule inhibitors of the mutant IDH enzyme have shown preliminary activity against IDH-mutant lower grade gliomas ^82,83 and an IDH1(R132H)-specific peptide vaccine induced specific therapeutic T helper cell responses ⁸⁴.

Treatment of Primary Central Nervous System Lymphoma

PCNSL is a rare hematologic malignancy confined to the brain, spinal cord, leptomeningeal or vitreoretinal space. The annual incidence is 0.4 per 100,000 but incidence rises with age to 4 per 100,000 in patients over 70 years ⁶. Immunodeficiency is a known risk factor, but PCNSL also affects immunocompetent patients. Presenting neurologic symptoms develop over the course of weeks to months and may be reversed with treatment. Unlike other brain tumors discussed in this review, PCNSL is highly sensitive to chemotherapy and radiation, and the goal of treatment is cure although approximately 33% to 60% of patients will relapse⁸⁵.

The diagnosis of PCNSL is made with tumor biopsy. The association of more extensive tumor resection with improved survival remains controversial. High-dose intravenous methotrexate (HD-MTX), administered at a dose between 3–8 g/m² in at least 4–8 infusions, is the most effective therapy and is included in several combination chemotherapy regimens for PCNSL. A randomized phase 2 trial of 79 patients with PCNSL showed a poorer radiographic response to HD-MTX alone (40%) than HD-MTX plus cytarabine (69%)(p=0.01) ⁸⁶. Other drug combinations include rituximab-methotrexate-procarbazine-vincristine (R-MPV), methotrexate-temozolomide-rituximab (MTR), methotrexate-cytarabine-thiotepa-rituximab (MATRix), and rituximab-methotrexate-carmustine-etoposide-prednisone (R-MBVP) ⁷. Because of high response rates, typically consisting of >80–90% radiographic response, MTX-based therapy is first-line even in older, frail patients and those with difficulty performing activities of daily living due to symptoms. To reduce relapse rates, patients receive consolidation therapy with either myeloablative thiotepa (alkylating therapy)-based conditioning followed by autologous stem cell transplant (ASCT), non-myeloablative chemotherapy (for example with etoposide/cytarabine), or whole brain radiation therapy ^{87, 88, 89}. Delayed neurotoxicity, presenting with gait imbalance and impaired cognition, affects approximately 60% of patients treated with radiation ⁸⁵. Approximately 36–62% of patients relapse following initial responses to first-line therapy, usually within the first two years after treatment ⁸⁶. Retreatment with HD-MTX is appropriate for patients who initially responded to HD-MTX based induction therapy. High-dose combination therapy followed by ASCT, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, thalidomide derivatives (lenalidomide, pomalidomide) or clinical trials should be considered for patients with relapsed or refractory disease ⁷.

Treatment of Malignant Meningiomas

Meningiomas are the most common primary CNS tumor in adults¹ however, more than 90% are benign (WHO 1) ⁸ and either require no intervention or are curable with surgery or focal radiation. Approximately 5% are WHO grade 2 (atypical), and 1–2 % are WHO grade 3 (malignant/anaplastic) ⁸. Several molecular alterations (e.g., TERT promoter mutation, CDKN2A/B deletion, loss of trimethylation of lysine 27 of histone 3) are associated with worse prognosis and more complex genomic or integrated molecular-morphologic scores outperform traditional histopathological WHO grading in their ability to predict outcome ⁹⁰. Meningiomas are more common in women (incidence approximately 12.76 per 100,000 in women vs 5.79 per 100,000 in men) ¹ and may be associated with underlying cancer predisposition syndrome such as neurofibromatosis 2.

Meningiomas that are small (<3 cm), asymptomatic, and lack peritumoral edema can be monitored radiographically. A typical surveillance schedule is repeat MRI at 3, 6, and 12 months after diagnosis, every 6–12 months for 5 years, then every 1–3 years ³¹. In a meta-analysis of 2130 patients with incidental meningioma and a follow-up of 49.5 months, 1040 (50.7%) were initially observed without intervention. Of these, 220 were recommended for intervention, either resection or stereotactic radiosurgery, a precise and focal form of radiation, during the follow up period, most for radiographic progression ⁹¹. Asymptomatic meningiomas that require intervention but are not amenable to surgery due to location may be treated with stereotactic radiosurgery. Stereotactic radiosurgery resulted in stable tumor size in 98.2% of treated patients and tumor regression (defined as ≥25% decrease in area compared to baseline) in 35.5% of a matched cohort of skull-based meningioma patients (n=110) ⁹².

Symptoms of meningiomas are generally related to their location. Meningiomas that are large, rapidly enlarging, symptomatic, associated with edema, or appear to be infiltrating the parenchyma should be resected. Total resection is an independent positive prognostic factor for progression-free and overall survival and should be attempted ⁹³. Adjuvant fractionated radiation therapy is recommended for all grade 3 and incompletely resected grade 2 meningiomas ³¹. In the event of recurrence (50–90% of grade 2 and 3 meninigomas) ^93,94, further resection or radiation therapy may be considered. Anti-angiogenic agents, such as bevacizumab and sunitinib, and the Focal Adhesion Kinase inhibitor GSK2256098 showed antitumor activity in small single group or retrospective studies ^95–98. A small percentage of atypical or malignant meningiomas may have increased expression of PD-L1, increased tumor mutational burden, or deficiencies in mismatch repair. Responses to immunotherapy have been described in these settings ^99,100.

Treatment of Malignant Ependymomas

Ependymomas are a heterogenous group of tumors arising from the ependymal lining of the brain. These tumors differ in their biology according to patient age, tumor location, histology, and molecular features. Because malignant ependymomas are rare, few clinical trials of therapies for malignant ependymomas exist. Further, nine distinct ependymoma subgroups were identified recently and it is unclear whether current treatments apply across the nine subgroups ^101,102. Surgery is a first-line treatment for intracranial ependymomas and gross total resection is associated with improved survival ¹⁰³. Post-operative radiation is recommended for WHO grade 3 tumors and incompletely resected grade 2 tumors ³¹. Intracranial ependymomas in adults with spinal or CSF dissemination should be treated with craniospinal radiation. Chemotherapy is reserved for recurrence after local treatment options (re-operation, re-irradiation). Retrospectivecohort studies in pediatric and adult ependymoma patients did not demonstrate survival benefit with chemotherapy¹⁰¹ but temozolomide, etoposide, and bevacizumab may benefit a subset of patients ⁹.

Prognosis

The five-year survival following diagnosis of a malignant brain tumor is approximately 67%. Older patients have poorer survival than younger patients. Survival rates by age are approximately 71.5% for patients age 15–39 years and 21% for patients 40 years and older ¹. The median OS for patients with IDH-wildtype glioblastoma is 12–21 months and only about 7% survive five years. ^49,50. Patients with IDH-mutant 1p/19q non-codel tumors have a median OS of 7–8 years ^78,80, whereas patients with 1p/19q-codel oligodendrogliomas have a median OS of 13–14 years after chemoradiation ^78,79. Recurrence rates of malignant meningiomas are 50–90% with a five-year OS of 20–50% ^93,94. The 10-year OS of patients with ependymal tumors is about 80%, but prognosis depends on patient age and tumor grade, tumor location, and site-specific molecular genetics ¹⁰¹. PCNSL is potentially curable with chemotherapy and 10-year survival for PCNSL is about 30% ^1,104.

LIMITATIONS

This review has some limitations. First, this was not a systematic review. Second, the quality of included studies was not assessed. Third, some relevant reports may have been missed. Fourth, the review is limited by quality of the evidence. Fifth, this review did not discuss the following tumor types: pediatric-type diffuse gliomas (such as histone-mutant gliomas) which can present in adults; astrocytic gliomas, glioneuronal tumors, and neuronal tumors, which are relatively rare and occur more frequently in children and young adults; or primary brain tumors in patients with HIV/AIDS.

CONCLUSION

The incidence of primary malignant brain tumors is about 7 per 100,000 individuals and approximately 49% of brain tumors are glioblastomas. Most patients die from progressive disease. First line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.

BOX.

Commonly Asked Questions

When Should a Headache Prompt Evaluation for Brain Tumor?

Headaches with the following associated symptoms are concerning for the possibility of a brain tumor and warrant prompt evaluation. These symptoms include acute, severe headaches that represent a change from prior headache pattern, new headaches in older adults or children, headaches that are positional or worsen with exertion, and headaches associated with any new neurologic symptoms.

What Causes Brain Tumors?

Exposure to ionizing radiation, such as from prior treatment for another cancer, is the only known environmental risk factor for brain tumor development. Immunodeficiency is a risk factor for the development of primary central nervous system lymphoma. There is no clear link between brain tumor development and power lines, electronic devices, or cellular telephone use. Most brain tumors are not hereditary.

What Is the Prognosis of a Malignant Primary Brain Tumor?

Most malignant brain tumors are not curable, and the goal of treatment is disease control and symptom management. Prognosis varies based on histology, grade, and molecular markers. Glioblastoma has the worst prognosis with overall survival of approximately 15 months. Lower-grade gliomas, particularly oligodendrogliomas with 1p/19q codeletion, may be controlled for decades.