What is the appropriate diagnosis and treatment plan for a patient with glioma?

Glioma: Diagnosis and Treatment Approach

The diagnosis and treatment of glioma requires histological confirmation through maximal safe surgical resection, followed by molecular characterization (IDH mutation status, 1p/19q codeletion, MGMT promoter methylation) to guide subsequent therapy with radiotherapy and alkylating agent chemotherapy tailored to the specific molecular subtype. 1

Diagnostic Workup

Imaging

• MRI with contrast is the standard diagnostic modality for initial evaluation and should include T1-weighted, T2-weighted, FLAIR sequences, and gadolinium enhancement 1
• Obtain baseline MRI within 24-48 hours post-surgery to distinguish residual tumor from postoperative changes 1, 2
• CT imaging has no role in initial glioma evaluation and should be avoided due to unnecessary radiation exposure 3
• Amino acid PET (using tracers like [11C-methyl]-l-methionine or O-(2-[18F]-fluoroethyl)-l-tyrosine) may help distinguish tumor from treatment effects but is not standard practice 1

Tissue Diagnosis

• All patients should undergo maximal safe surgical resection when technically feasible, as extent of resection is both diagnostic and prognostic 1
• Biopsy is indicated only when resection would cause unacceptable neurological morbidity or in patients with poor performance status 1
• Histological classification must follow WHO 2021 criteria with integrated molecular diagnostics 1

Essential Molecular Testing

• IDH mutation status (IDH1/IDH2) - fundamental for classification and prognosis 1
• 1p/19q codeletion status - defines oligodendroglioma subtype with better prognosis and chemosensitivity 1
• MGMT promoter methylation - predicts benefit from temozolomide in glioblastoma 1, 4
• CDKN2A/B homozygous deletion - adverse prognostic marker in IDH-mutant gliomas 1

Treatment by Molecular Subtype

IDH-mutant, 1p/19q-codeleted Oligodendroglioma (WHO Grade 2)

• Surgery is primary treatment; watch-and-wait is justified after gross total resection, particularly in patients <40 years without neurological deficits beyond epilepsy 1
• When adjuvant therapy is needed: radiotherapy (60 Gy in 30 fractions) followed by PCV chemotherapy (procarbazine, lomustine, vincristine) is standard of care 1
• Chemotherapy alone remains investigational but may reduce late cognitive deficits in select cases 1

IDH-mutant, 1p/19q-codeleted Oligodendroglioma (WHO Grade 3)

• Radiotherapy followed by PCV chemotherapy approximately doubles overall survival based on two large RCTs 1
• Watch-and-wait after gross total resection may be considered in patients <40 years without homozygous CDKN2A/B deletion and no neurological deficits 1
• Standard regimen: 60 Gy radiotherapy in 2 Gy fractions, followed by 6 cycles of PCV 1

IDH-mutant Astrocytoma (WHO Grade 3)

• Radiotherapy (60 Gy) followed by adjuvant temozolomide improves outcome in non-codeleted IDH-mutant astrocytoma 5
• Temozolomide dosing: 150-200 mg/m² days 1-5 of each 28-day cycle for 6 cycles 5

Glioblastoma (IDH-wild-type, WHO Grade 4)

• Standard of care is maximal safe resection followed by concurrent chemoradiotherapy with temozolomide, then adjuvant temozolomide 1, 4

Concomitant phase: 4

• Temozolomide 75 mg/m² daily for 42 days during focal radiotherapy (60 Gy in 30 fractions)
• PCP prophylaxis is mandatory during concomitant therapy and should continue until lymphocyte recovery to ≤Grade 1 4
• Monitor CBC weekly; interrupt if ANC <1.5 × 10⁹/L or platelets <100 × 10⁹/L 4

Maintenance phase: 4

• Begin 4 weeks after completing chemoradiotherapy
• Cycle 1: 150 mg/m² days 1-5 of 28-day cycle
• Cycles 2-6: escalate to 200 mg/m² if ANC ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, and non-hematologic toxicity ≤Grade 2 4

MGMT methylation status predicts temozolomide benefit but should not exclude patients from standard therapy 1

Carmustine Wafers

• Implantation into resection cavity provides modest OS benefit in newly diagnosed high-grade gliomas and recurrent glioblastoma 1
• Benefit is marginal and not statistically significant when WHO grade 3 tumors (mostly IDH-mutant) are excluded 1

Bevacizumab

• Approved for recurrent glioblastoma in USA, Canada, and Switzerland but no overall survival benefit has been demonstrated 1
• Not approved in European Union 1

Monitoring and Follow-up

Imaging Schedule

• Watch-and-wait without histological verification requires MRI every 2-3 months due to risk of underestimating malignancy grade 1
• After completing therapy: MRI every 2-6 months depending on histology, using RANO criteria for response assessment 1, 2
• Obtain MRI 3-4 weeks after radiotherapy completion to establish new baseline 1
• For suspected progression, repeat MRI in 4-8 weeks to confirm true progression versus pseudoprogression 1

Critical Pitfall: Pseudoprogression

• Contrast enhancement 4-8 weeks post-radiotherapy may represent pseudoprogression, not true progression 1, 2
• Most common in first 3 months after chemoradiotherapy or immunotherapy but can occur later 1
• Confirm with repeat MRI 4 weeks later before changing treatment 1, 2
• Perfusion MRI and amino acid PET help distinguish pseudoprogression from true progression 1
• Biopsy is not definitive as viable tumor cells are regularly detected even in pseudoprogression 1

Clinical Monitoring

• Complete neurological examination at each visit 2
• Monitor seizure activity and antiepileptic drug levels 2
• Taper corticosteroids as rapidly as possible to minimize myopathy, hyperglycemia, opportunistic infections, and psychiatric complications 2
• Surveillance for venous thromboembolism, which occurs frequently with residual/recurrent tumor 2

Chemotherapy Toxicity Monitoring

Temozolomide

• Main dose-limiting toxicity is thrombocytopenia and myelosuppression occurring 2-3 weeks after dosing 1
• Monitor CBC weekly during concomitant phase, before each maintenance cycle 4
• Monitor hepatic function regularly 1, 4

Nitrosoureas (Lomustine, Carmustine in PCV)

• Cause delayed (4-6 weeks) and cumulative leukopenia/thrombocytopenia unlike temozolomide's early toxicity 1
• May necessitate dose reductions, interruptions, or discontinuation 1
• Pulmonary fibrosis risk mainly with carmustine, rare with lomustine 1

Long-term Considerations

• Alkylating agents can induce hypermutator phenotype associated with more malignant transformation, particularly concerning in IDH-mutant gliomas with longer life expectancy 1
• This risk must be weighed against demonstrated survival benefits in RCTs 1

Supportive Care

Mandatory Elements

• Patients should be offered counseling by specialized psychologists, nurses, and palliative care specialists as gliomas are non-curable diseases 1
• Assess need for occupational, speech, and physical therapy 1
• Provide counseling for social support 1

Thromboembolism Prophylaxis

• Prophylactic low-molecular weight heparin and compression stockings recommended perioperatively 1
• Therapeutic anticoagulation can be prescribed 4-5 days post-surgery for thromboembolic complications without undue hemorrhagic risk 1

Antiepileptic Management

• First-line treatment should be monotherapy 1
• Consider drug interactions with chemotherapy, particularly enzyme-inducing effects 1

Special Populations

Elderly or Poor Performance Status

• Shorter hypofractionated radiotherapy regimens (e.g., 40 Gy in 15 fractions) are appropriate 1
• Radiotherapy (50 Gy in 28 fractions of 1.8 Gy) superior to best supportive care alone in patients >70 years 1

Pediatric Optic Nerve Glioma

• Newly diagnosed cases should be managed by observation with serial ophthalmologic and MRI evaluations 3
• Perform ophthalmologic examination focusing on visual acuity, visual fields, color vision, optic nerve appearance 3
• Screen for and aggressively treat refractive amblyopia, which accounts for majority of vision loss 3
• Baseline MRI and repeat every 3-6 months until stability confirmed 3
• When intervention required, chemotherapy (carboplatin/vincristine) is preferred initial treatment 3
• Avoid radiation therapy due to malignant transformation risk, particularly in NF1 patients 3
• Never biopsy solely for diagnosis as natural history is often indolent and intervention risks vision loss 3