What are the guidelines for treating a patient with a cerebral tumor?

Guidelines for Cerebral Tumors

Initial Diagnostic Approach

The diagnosis of cerebral tumors requires gadolinium-enhanced MRI as the standard imaging modality, followed by tissue diagnosis through biopsy or surgical resection to establish both histopathological and molecular characteristics. 1

Imaging Requirements

• MRI with gadolinium contrast is mandatory for initial evaluation, using T1-weighted (with and without contrast), T2-weighted, and FLAIR sequences 2, 3
• Obtain imaging in three dimensions using standardized technique for treatment planning 2
• Advanced imaging (perfusion MRI, MR spectroscopy, amino acid PET) should be considered when distinguishing tumor progression from treatment-related changes 1
• CT scanning is inferior to MRI and should be reserved for patients unable to undergo MRI 2

Molecular Characterization

• Molecular testing is mandatory and should include: MGMT promoter methylation status, IDH mutations, and 1p/19q co-deletions 4, 2
• These molecular markers provide critical diagnostic and prognostic information that guides treatment selection 4, 2

Primary Brain Tumors (Gliomas)

Newly Diagnosed Glioblastoma

For newly diagnosed glioblastoma, maximal safe surgical resection followed by concurrent temozolomide (75 mg/m² daily) with radiotherapy (60 Gy in 2 Gy fractions), then adjuvant temozolomide (150-200 mg/m² for 5 days every 28 days for 6 cycles) is the standard of care. 1, 5, 6

Surgical Management

• Attempt maximal tumor resection without compromising neurological function 1, 4
• Use 5-aminolevulinic acid (5-ALA) fluorescence guidance during surgery to improve complete resection rates and progression-free survival 4
• When safe resection is not feasible, perform stereotactic or open biopsy for tissue diagnosis 1, 4

Radiation Therapy

• Deliver 60 Gy in 2 Gy fractions over 6 weeks as standard fractionation 1, 2
• Clinical target volume (CTV) should include 20 mm margin around gross tumor volume, which may be reduced based on tumor characteristics 2
• For elderly patients (>65 years), use hypofractionated radiotherapy (e.g., 40 Gy in 15 fractions) instead of standard fractionation 4

Chemotherapy

• Concomitant phase: Temozolomide 75 mg/m² daily for 42 days during radiotherapy 5, 6
• Adjuvant phase: Start 4 weeks after completing radiotherapy at 150 mg/m² for Days 1-5 of 28-day cycle; increase to 200 mg/m² if tolerated, continue for 6 cycles 5
• MGMT promoter methylation predicts better response to temozolomide 1, 4

Anaplastic Gliomas

For anaplastic astrocytomas and oligodendrogliomas, surgical resection followed by radiotherapy is standard, with chemotherapy added based on molecular features. 1

• For anaplastic oligodendrogliomas with 1p/19q co-deletion: Radiotherapy plus PCV chemotherapy (procarbazine, lomustine, vincristine) significantly improves survival compared to radiotherapy alone 6
• Initial temozolomide dose: 150 mg/m² once daily for 5 consecutive days per 28-day cycle for refractory anaplastic astrocytoma 5

Brain Metastases

Resectable Single or Limited Metastases (1-3 lesions)

For resectable brain metastases with good systemic disease control, surgical resection followed by stereotactic radiosurgery (SRS) is preferred over whole-brain radiotherapy (WBRT) to preserve neurocognitive function. 1

Treatment Algorithm by Number of Lesions

• Single resectable metastasis: Surgical resection followed by WBRT (Category 1) OR SRS + WBRT (Category 1) OR SRS alone (Category 2A) 1
• 1-3 metastases, newly diagnosed with stable systemic disease:
  • Resectable: Surgery followed by SRS preferred 1
  • Unresectable: SRS and/or WBRT 1
• Lesion size considerations: Smaller lesions (<2 cm), deep, asymptomatic → consider SRS; larger lesions (>2 cm), symptomatic → surgery preferred 1

Multiple Metastases (>3 lesions)

For patients with more than 3 brain metastases, treatment depends on systemic disease status and prognosis. 1

• Favorable prognosis (<10 metastases, controlled extracranial disease, expected survival >3 months): SRS/stereotactic radiotherapy (SRT) OR systemic pharmacotherapy 1
• Unfavorable prognosis (>10 metastases, uncontrolled extracranial disease, expected survival <3 months): WBRT ± boost if no previous prophylactic cranial irradiation (PCI), OR systemic pharmacotherapy, OR palliative care 1
• Disseminated systemic disease with poor treatment options: WBRT, consider chemotherapy (Category 2B) 1

Special Populations

• Small-cell lung cancer: WBRT ± boost if no previous PCI, OR systemic pharmacotherapy 1
• Melanoma: Surgery followed by SRS/SRT, OR SRS/SRT alone, OR surgery followed by systemic pharmacotherapy, OR systemic pharmacotherapy alone 1
• Chemosensitive tumors (lymphoma, germ cell, myeloma): Consider primary chemotherapy in absence of clinical myelopathy 1

Recurrent Disease

Recurrent Glioblastoma

For recurrent glioblastoma, repeat cytoreductive surgery should be considered in selected patients with symptomatic circumscribed relapses diagnosed at least 6 months after initial surgery, good performance status, and possibility of gross total resection. 7

Systemic Therapy Options

• Lomustine is the standard chemotherapy option with confirmed single-agent efficacy 7
• Bevacizumab provides high response rates with steroid-sparing effect, though overall survival benefit is uncertain 7
• Bevacizumab plus lomustine may improve progression-free survival but does not improve overall survival and increases severe adverse events 7
• Temozolomide rechallenge may be considered in MGMT-methylated tumors with prolonged interval since initial temozolomide 7

Targeted Therapies for Molecular Alterations

• BRAF V600E-mutated tumors: Dabrafenib/trametinib or vemurafenib 7
• TRK fusion-positive tumors: Larotrectinib or entrectinib 7
• Hypermutant tumors: Nivolumab or pembrolizumab 7
• ALK rearrangement-positive tumors: Lorlatinib or alectinib 7

Re-irradiation

• May be considered for selected patients with small recurrent tumors using brachytherapy or stereotactic radiotherapy, though benefit remains uncertain 7

Recurrent Brain Metastases

Treatment options for recurrent brain metastases are determined by performance status, neurological function, type of CNS progression, and prior treatment. 1

• Surgery followed by SRS/SRT 1
• SRS/SRT alone 1
• Systemic pharmacotherapy 1
• WBRT if not previously administered 1
• Palliative surgery for large metastases, particularly in posterior fossa 1

Supportive Care and Monitoring

Corticosteroids

• Use the lowest effective dose for the shortest duration to control raised intracranial pressure 1, 4
• Minimum dose: Dexamethasone 4 mg every 6 hours, though doses may vary (10-100 mg) for spinal cord compression 1
• Taper as early as possible to minimize complications 1, 4
• Prophylactic corticosteroids should not be prescribed routinely 2

Pneumocystis Pneumonia Prophylaxis

• PCP prophylaxis with trimethoprim-sulfamethoxazole is required for all patients receiving concomitant temozolomide and radiotherapy for 42 days 5
• Consider prophylaxis in patients on steroids for more than a few weeks with additional immunosuppressive therapy 1

Seizure Management

• Anticonvulsants should only be administered to patients with history of seizures; prophylactic use is not recommended 1
• Use non-enzyme-inducing agents (levetiracetam, lamotrigine, lacosamide) to avoid drug-drug interactions 1
• Avoid phenytoin, carbamazepine, or valproic acid 1

Hematologic Monitoring

• Monitor complete blood counts prior to each treatment cycle 5
• Geriatric patients and women have higher risk of myelosuppression 5
• Watch for myelodysplastic syndrome and secondary malignancies including myeloid leukemia 5

Hepatotoxicity Monitoring

• Perform liver function tests at baseline, midway through first cycle, prior to each subsequent cycle, and 2-4 weeks after last dose 5

Follow-up Schedule

• Brain MRI every 2-3 months or at any instance of suspected neurological progression 1
• Neurological examination every 2-3 months using standardized procedures 1
• Neurocognitive function and ability to consent should be regularly assessed 1
• Use RANO criteria for response assessment in clinical practice 1

Thromboprophylaxis

• Primary thromboprophylaxis with low-molecular-weight heparin (LMWH) or unfractionated heparin should be considered in hospitalized patients or those confined to bed 1

Palliative Care

Palliative and best supportive care should be offered to patients with poor performance status, large or multifocal lesions, inability to consent to treatment, or when aggressive therapy is unlikely to provide meaningful survival benefit. 7

• Recommended palliative regimens: Oral etoposide, bevacizumab, or nitrosoureas (lomustine or carmustine) 7
• Bevacizumab is superior to steroids for treatment of radionecrosis after SRT 1

Clinical Trial Participation

Enrollment in clinical trials is strongly recommended whenever possible for patients with brain tumors, particularly recurrent disease. 1, 7

• Consider phase 0 or preoperative clinical trials before resection when available 7
• Molecular testing may determine eligibility for targeted therapy trials 7