What is the recommended management approach for high-grade glioma when biopsy is not possible?

Management of High-Grade Glioma When Biopsy is Not Possible

When biopsy is not feasible for high-grade glioma, proceed directly with empiric radiotherapy (60 Gy in 1.8-2 Gy fractions) with or without concurrent temozolomide, based on clinical and imaging findings alone. 1

Clinical Context for Non-Biopsy Management

The 2003 British Journal of Cancer guidelines explicitly state that biopsy is not mandatory in rare situations where optimal cancer treatment plans are not feasible due to: 1

• High physiological age
• Multiple co-morbidities
• Poor performance status (low Karnofsky score)
• Centrally localized lesions
• Multifocal disease

In these specific circumstances, palliative treatment with radiotherapy or chemotherapy can be offered, tailored to the individual patient. 1

Treatment Algorithm Without Histological Confirmation

Step 1: Confirm Imaging Diagnosis

• MRI with contrast demonstrating features consistent with high-grade glioma (infiltrative mass, heterogeneous enhancement, restricted diffusion, vasogenic edema) 1
• Assess for classic radiographic patterns that strongly suggest glioblastoma or anaplastic glioma 1

Step 2: Initiate Radiotherapy as Primary Treatment

First-line external-beam radiotherapy should be offered since it has been shown to improve survival (Level of Evidence: A): 1

• Total dose: 60 Gy 1
• Fractionation: 1.8 to 2 Gy per fraction per day 1
• Focal RT includes the tumor bed with a 2- to 3-cm margin 1, 2
• Treatment should be started within one month of diagnosis 1

Step 3: Consider Concurrent Temozolomide

For patients with reasonable performance status (Karnofsky ≥70) and age <70 years, add concurrent temozolomide during radiotherapy: 1, 2

• Dose: 75 mg/m² daily for 42 days during the entire RT course 2
• Continue up to 49 days if blood counts remain adequate (ANC ≥1.5 x 10⁹/L, platelets ≥100 x 10⁹/L) 2
• PCP prophylaxis is required during concurrent treatment 2

Step 4: Maintenance Chemotherapy (If Concurrent TMZ Given)

Four weeks after completing RT, administer maintenance temozolomide for 6 cycles: 2

• Cycle 1: 150 mg/m² daily for 5 days every 28 days 2
• Cycles 2-6: Escalate to 200 mg/m² if tolerated (ANC ≥1.5 x 10⁹/L, platelets ≥100 x 10⁹/L, non-hematologic toxicity ≤Grade 2) 2

Alternative Chemotherapy Options Without Histology

If temozolomide is not used or contraindicated, nitrosourea-based chemotherapy can be offered: 1

• Mono-drug chemotherapy with BCNU (carmustine) 1
• This can be combined with radiotherapy (Level of Evidence: B1) 1

Critical Supportive Care Measures

Thromboembolism Prophylaxis

Surveillance, prevention and treatment for thromboembolism should be performed, as this occurs frequently in glioma patients: 1

• Prophylactic low-molecular weight heparin and compression stockings are recommended perioperatively (Level of Evidence: B2) 1

Corticosteroid Management

Steroids are not necessary in patients without increased intracranial pressure and absence of neurological deficits: 1

• No need for prolonged steroid therapy after tumor resection or prophylaxis during radiotherapy 1

Antiepileptic Therapy

Antiepileptic therapy is indicated only in patients presenting with an initial seizure: 1

• Prophylactic antiepileptic therapy is not needed 1
• Prefer third-generation agents (levetiracetam, lamotrigine, pregabalin) over first-generation drugs that induce hepatic metabolism 1

Important Caveats and Pitfalls

Limitation of Non-Histological Approach

• Without tissue diagnosis, you cannot determine molecular markers (MGMT methylation, IDH mutation, 1p/19q codeletion) that have prognostic and predictive value 1
• MGMT promoter methylation predicts benefit from alkylating chemotherapy in glioblastoma 1
• This means you are treating empirically without ability to stratify therapy based on molecular profile 1

Performance Status Considerations

• Clinical trials that established radiotherapy benefit excluded patients with poor prognostic factors (low Karnofsky score, advanced age, large/multifocal tumors) 1
• For elderly patients (>70 years) with good performance status, no randomized data exist for the TMZ/RT regimen 1

Monitoring Without Histology

• Obtain complete blood count weekly during concurrent TMZ/RT 2
• MRI within 24-48 hours after any intervention as baseline 3
• Clinical and/or radiological deterioration in the 2 months after radiotherapy should be interpreted with caution and not automatically considered treatment failure (may represent pseudoprogression) 3

When to Reconsider Biopsy

• If the patient's clinical condition improves with steroids or supportive care, reassess whether biopsy has become feasible 1
• In experienced hands, stereotactic biopsy has >95% diagnostic yield even in challenging locations 1
• Open biopsies may yield more tissue for molecular analyses compared with stereotactic biopsies 1

Evidence Quality Assessment

The most recent guideline addressing this specific scenario is the 2014 ESMO guideline 1, which builds upon the 2003 British Journal of Cancer recommendations 1. The 2010 ESMO guideline 1 established the TMZ/RT standard based on Level I evidence. However, all these guidelines were written in the context where biopsy is strongly preferred, and the non-biopsy approach represents a compromise for patients where tissue diagnosis is truly impossible. 1

The FDA labeling for temozolomide 2 is based on histologically confirmed glioblastoma, so using it without tissue confirmation represents off-label application of the dosing paradigm to a radiographically presumed diagnosis.