What is the optimal management approach for a patient with a brain tumor?

Brain Tumor Management

Primary Management Approach

All patients with suspected brain tumors should be immediately transferred to a specialized neurosurgical center for multidisciplinary evaluation by neurosurgeons, radiation oncologists, medical oncologists, neurologists, and neuroradiologists. 1

---

Diagnostic Workup

Imaging

• MRI with gadolinium enhancement is the mandatory diagnostic modality for both initial diagnosis and follow-up of brain tumors 1, 2, 3
• Obtain postoperative MRI within 24-72 hours after surgery to document extent of residual disease 1
• For brain metastases specifically, MRI is superior to CT due to higher sensitivity in detecting multiple lesions 4

Tissue Diagnosis

• Histological confirmation is mandatory before initiating adjuvant therapy unless the patient has prohibitive surgical risk 1, 2
• Review by an experienced neuropathologist is essential, as diagnosis may be difficult without sufficient tumor tissue 1
• Molecular testing should be performed on all specimens to guide systemic therapy decisions 5, 2, 6

---

Treatment Algorithm by Tumor Type

PRIMARY MALIGNANT GLIOMAS (Glioblastoma, Anaplastic Astrocytoma)

Surgical Management

Maximal safe surgical resection should be performed when technically feasible with low risk of permanent functional deterioration 1, 2

Proceed with optimal resection EXCEPT in patients with: 1, 2

• High physiological age (>70 years)
• Multiple comorbidities
• Poor performance status (Karnofsky <70)
• Tumors in eloquent/functional brain regions
• Multifocal or centrally located lesions

If optimal resection is not possible, obtain stereotactic or open biopsy for histological diagnosis 1

Postoperative Treatment for Glioblastoma

Standard regimen (Stupp protocol): 2, 7, 3

1. Concurrent phase: Radiotherapy 60 Gy in 30 fractions PLUS temozolomide 75 mg/m² daily for 42 days (maximum 49 days), starting first day of RT
2. Adjuvant phase: Temozolomide 150-200 mg/m² on days 1-5 of every 28-day cycle for 6 cycles, starting 4 weeks after RT completion

Critical requirement: PCP prophylaxis is mandatory during concurrent temozolomide and radiotherapy, regardless of lymphocyte count, and must continue until lymphocyte recovery to ≤Grade 1 7

Monitoring requirements: 2, 7

• Complete blood counts before each cycle, on Day 22 of each cycle, and throughout treatment
• Liver function tests at baseline, midway through first cycle, and before each subsequent cycle

Treatment must begin within one month of surgery 1, 2

This regimen improved median survival by 2.5 months with hazard ratio 0.63 (95% CI 0.52-0.75, P<0.0001), increasing 2-year survival from 10.9% to 27.2% and 5-year survival from 1.9% to 9.8% 7, 3

Postoperative Treatment for Anaplastic Astrocytoma

Radiotherapy 60 Gy is standard 1

Chemotherapy options: 1, 2

• Mono-drug chemotherapy with nitrosourea (BCNU), OR
• PCV (procarbazine, lomustine, vincristine), OR
• Temozolomide

Postoperative Treatment for Oligodendroglioma/Anaplastic Oligodendroglioma

Radiotherapy is standard (45-54 Gy, preferably 50-54 Gy) 1

PCV chemotherapy has proven efficacy, particularly in tumors with 1p/19q codeletion 1, 2, 3

• 1p/19q codeletion is a favorable prognostic factor for survival and treatment response 1
• Probable 20-year survival with PCV plus radiotherapy was 37% vs 14% with radiotherapy alone (HR 0.60-0.61) 3

Timing of chemotherapy (neoadjuvant vs adjuvant vs at recurrence) remains undefined 1

In selected patients (large unresectable tumors, elderly, complete response to neoadjuvant chemotherapy), radiotherapy may be deferred 1

Recurrent High-Grade Glioma

No standard treatment exists; five therapeutic options should be considered: 1, 2

1. Repeat cytoreductive surgery (for symptomatic circumscribed relapses with good performance status and possibility of gross total resection)
2. Systemic chemotherapy (lomustine/CCNU is standard with confirmed efficacy; alternatives include temozolomide rechallenge, bevacizumab, nitrosoureas)
3. Local chemotherapy (carmustine implants)
4. Second-line radiotherapy (brachytherapy, stereotactic radiotherapy)
5. Palliative care without anticancer treatment

Avoid re-operation within 6 months of initial surgery due to high risk of pseudoprogression 2

Consider pseudoprogression if MRI changes occur within 6-9 months after radiotherapy 2

---

LOW-GRADE GLIOMAS (Grade 2 Astrocytoma, Oligodendroglioma)

Risk Stratification

Poor prognostic factors include: 1

• Age >35-40 years
• Low Karnofsky score
• Intracranial hypertension or functional deficit
• Uncontrolled epilepsy
• Large or rapidly increasing tumor volume
• Localization in functional zones
• Involvement of deep structures
• Contrast enhancement on MRI

Treatment Algorithm

If optimal resection is possible: 1

• With ≥1 poor prognostic factor: Perform surgical resection
• Without poor prognostic factors: Options include surgical resection OR surveillance with or without biopsy

If optimal resection is NOT possible: 1

• With ≥1 poor prognostic factor: Options include partial resection, partial resection + radiotherapy, radiotherapy alone (after histological confirmation), or chemotherapy (after histological confirmation)
• Without poor prognostic factors: Options include surveillance with or without biopsy, partial resection, partial resection + radiotherapy, or biopsy + radiotherapy

When radiotherapy is indicated, deliver 45-54 Gy (preferably 50-54 Gy) 1

---

BRAIN METASTASES

Initial Management

Dexamethasone is first-line treatment for symptomatic brain metastases: 4

• 4-8 mg/day for moderate symptoms
• Up to 16 mg/day for severe symptoms with marked mass effect

Treatment Selection Based on Number of Metastases and Performance Status

For 1-4 unresected brain metastases with good performance status: 1, 4

Stereotactic radiosurgery (SRS) alone is preferred over whole brain radiotherapy (WBRT) to reduce cognitive side effects 1, 4, 6

• Local control rates of 75-95% can be achieved with SRS 1
• SRS delivers high-dose radiation to target with rapid dose decline outside target volume 1

Surgery is indicated for: 1, 4

• Large tumors with mass effect
• Diagnostic uncertainty
• Symptoms refractory to steroids
• Bulky metastases
• Solitary brain metastases

For resected brain metastases (1-2 lesions): 4

• SRS to surgical cavity should be performed within 4 weeks of surgery (as early as 2 weeks post-op) 6
• Surgical resection plus radiotherapy reduces local recurrence from 52% to 20% and increases survival from 15 to 40 weeks compared to radiation alone 1

En bloc tumor resection is preferred over piecemeal resection to decrease risk of leptomeningeal disease 5

For multiple brain metastases or when SRS is not feasible: 4

• WBRT should be considered
• If WBRT is used, offer memantine and hippocampal avoidance to patients with no hippocampal lesions and ≥4 months expected survival 4

Systemic Therapy for Brain Metastases

Systemic therapy selection depends on primary tumor type and molecular characteristics: 5, 4, 6

For EGFR-mutant NSCLC brain metastases:

• EGFR tyrosine kinase inhibitors (TKIs) plus radiation therapy improve overall survival, progression-free survival, and intracranial PFS 5

For ALK-positive NSCLC:

• Alectinib delays intracranial tumor progression 5

For BRAFV600E-positive melanoma brain metastases:

• Dabrafenib plus trametinib improves local tumor control 5
• Immunotherapy added to BRAF inhibitors improves CNS control 5

For patients without targetable mutations:

• Concurrent immune checkpoint blockade plus chemotherapy is preferable for those who can tolerate it 6
• Single-agent immune checkpoint blockade is alternative for patients who cannot tolerate chemotherapy 6

Systemic therapy should continue during radiation therapy, with radiation occurring between cycles 6

---

Supportive Care Management

Cerebral Edema

Dexamethasone 4-8 mg/day for moderate symptoms, up to 16 mg/day for severe symptoms 5, 4

Consider gastric protection in patients receiving high-dose corticosteroids or those with risk factors for ulcers 1

Seizure Management

For patients with previous seizures: 1

• Anticonvulsant treatment should be continued perioperatively and postoperatively

For patients without seizures: 1, 4

• Perioperative anticonvulsant treatment is optional
• Do NOT use prophylactic anti-seizure medications
• When required, prefer agents that don't impact hepatic metabolizing enzymes to avoid drug interactions with chemotherapy 1, 4

First-line treatment should be single-drug therapy 1

Thromboembolism Prevention

Prophylactic low-molecular weight heparin and compression stockings are recommended perioperatively 1

After 4-5 days post-surgery, therapeutic anticoagulation can be prescribed for thromboembolic complications without undue hemorrhagic risk 1

Radiation Necrosis

First-line treatment is glucocorticoids 4

If unsuccessful, consider: 4

• Neurosurgical resection
• Laser interstitial thermal therapy (LITT)
• Bevacizumab

Neurocognitive Decline

Consider acetylcholinesterase-inhibiting medication and cognitive rehabilitation 4

---

Follow-up and Monitoring

Patients should undergo neurological assessment and neuroimaging (MRI) every 3 months 5

For brain metastases, MRI of brain 1 month after SRS, then every 3 months thereafter 6

Early postoperative MRI (≤48 hours) should be obtained as baseline for monitoring disease progression 5

---

Critical Pitfalls to Avoid

• Never delay postoperative treatment beyond one month 1, 2
• Never omit PCP prophylaxis during concurrent temozolomide and radiotherapy 2, 7
• Never perform re-operation within 6 months of initial surgery without considering pseudoprogression 2
• Never use prophylactic anticonvulsants in patients without seizure history 4
• Never use enzyme-inducing anticonvulsants that may potentiate chemotherapy toxicity 1
• Surgical wounds must heal (10 days to 3 weeks) before starting radiation or chemotherapy, which may favor SRS over surgery in some cases 1
• Anti-angiogenesis agents like bevacizumab may interfere with wound healing 1