# Glioblastoma and High-Grade Gliomas: Current Standard and Emerging Therapies

## Introduction

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Despite multimodal therapy, median survival remains approximately 15 months. This lecture covers the current standard of care, molecular prognostication, and emerging therapeutic strategies.

## Epidemiology and Molecular Biology

GBM has an incidence of approximately 3.2 per 100,000 with a median age at diagnosis of 65 years and a male predominance (1.6:1). GBM, IDH-wildtype accounts for more than 90% of glioblastomas; IDH-mutant grade 4 astrocytoma is a distinct entity with a better prognosis. Key molecular features of IDH-wildtype GBM include TERT promoter mutation, EGFR amplification, and chromosome +7/-10 changes. MGMT promoter methylation is present in approximately 40% of GBM and predicts benefit from temozolomide therapy.

### Molecular Prognostic Markers

MGMT methylation is the strongest predictive biomarker: it silences a DNA repair gene, enhancing temozolomide efficacy. IDH mutation defines a separate, better-prognosis entity (IDH-mutant astrocytoma grade 4). TERT promoter mutation is found in approximately 80% of IDH-wildtype GBM. CDKN2A/B homozygous deletion now defines grade 4 in IDH-mutant astrocytomas.

## Standard of Care: The Stupp Protocol

### Maximal Safe Resection

Extent of resection correlates with survival, and gross total resection should be achieved when safely possible. Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) improves completeness of resection. Postoperative MRI within 48 hours assesses residual tumor.

### Concurrent Chemoradiation

Radiation therapy delivers 60 Gy in 30 fractions over 6 weeks to the tumor bed plus margin. Concurrent temozolomide at 75 mg/m2 is given daily during radiation. Temozolomide is an oral alkylating agent requiring weekly CBC monitoring due to the risk of lymphopenia and myelosuppression. PJP prophylaxis with trimethoprim-sulfamethoxazole is given during concurrent chemoradiation.

### Adjuvant Temozolomide

Six cycles of adjuvant temozolomide are given at 150-200 mg/m2 for 5 days every 28 days (some protocols extend to 12 cycles if tolerated). The survival benefit is greatest in patients with MGMT promoter methylation. CBC is monitored before each cycle, with treatment held if ANC falls below 1500 or platelets below 100,000.

### Tumor Treating Fields (TTFields)

The Optune device delivers alternating electric fields (200 kHz) to the scalp via adhesive arrays. Added to adjuvant temozolomide, TTFields improved median overall survival from 16 to 20.9 months in the EF-14 trial. The device requires shaving the head and wearing the arrays for 18 or more hours per day. Side effects are limited to scalp irritation with no systemic toxicity. Patient adherence and quality of life are practical considerations.

## Management in Elderly and Frail Patients

| Patient Population | MGMT Status | Recommended Approach | Evidence |
|---|---|---|---|
| Fit (KPS ≥70, age <70) | Any | Stupp protocol (60 Gy + TMZ + adjuvant TMZ + TTFields) | Stupp 2005; EF-14 |
| Elderly (>70) or KPS <70 | Methylated | Hypofractionated RT + TMZ, or TMZ monotherapy | Nordic, NOA-08 |
| Elderly (>70) or KPS <70 | Unmethylated | Radiation alone (hypofractionated) | Nordic, NOA-08 |
| Poor performance (KPS <50) | Any | Best supportive care; individualized | — |

For patients over 70 or with KPS below 70, hypofractionated radiation (40 Gy in 15 fractions) with concurrent/adjuvant temozolomide is an option. In MGMT-methylated elderly patients, temozolomide monotherapy is reasonable (Nordic trial, NOA-08 trial). In MGMT-unmethylated patients, radiation alone is preferred because temozolomide adds toxicity without significant benefit. Treatment should be individualized based on functional status, comorbidities, and patient goals.

## Recurrent Glioblastoma

### Diagnosis of Recurrence

Serial MRI every 2-3 months is standard; increasing enhancement or new lesions suggest recurrence. Pseudoprogression is a treatment-related enhancement increase within 3 months of chemoradiation that is more common with MGMT methylation; it should be managed with observation and repeat imaging. Pseudoresponse refers to decreased enhancement after bevacizumab due to normalized vasculature without true tumor response. Advanced imaging (perfusion, PET with amino acid tracers) helps distinguish true recurrence from treatment effects.

### Treatment Options at Recurrence

Re-resection should be considered if the tumor is surgically accessible and the patient has good functional status. Bevacizumab, an anti-VEGF monoclonal antibody, improves progression-free survival and reduces steroid dependence but provides no overall survival benefit (EORTC 26101). Lomustine (CCNU) is an alkylating agent used alone or with bevacizumab. Re-irradiation with stereotactic radiosurgery or hypofractionated radiation is an option for focal recurrence. Clinical trials should be offered to all eligible patients.

## Emerging Therapies

### Immunotherapy

Checkpoint inhibitors (nivolumab, pembrolizumab) have shown limited efficacy in unselected GBM due to the immunosuppressive tumor microenvironment and low mutational burden. Vaccine-based approaches including rindopepimut (EGFRvIII vaccine) did not meet their primary endpoint; personalized neoantigen vaccines are under investigation. CAR-T cell therapy targeting EGFRvIII, IL13Ralpha2, and GD2 is in early-phase trials demonstrating feasibility.

### Targeted Therapies

IDH inhibitors (vorasidenib) are FDA-approved for IDH-mutant grade 2-3 gliomas based on the INDIGO trial but are not applicable to IDH-wildtype GBM. EGFR-targeted agents have shown limited success despite frequent EGFR alterations. PDGFRA, CDK4/6, and PI3K/mTOR pathway inhibitors are under investigation.

### Novel Approaches

Convection-enhanced delivery allows direct administration of therapeutic agents to the tumor. Oncolytic viruses (DNX-2401, PVSRIPO) are being studied. Focused ultrasound can open the blood-brain barrier for enhanced drug delivery.

## Clinical Pearls

MGMT promoter methylation is the strongest predictive biomarker for temozolomide benefit in GBM. Pseudoprogression occurs in up to 30% of patients within 3 months of completing chemoradiation and should not be confused with true recurrence. The Stupp protocol (maximal resection, concurrent chemoradiation, adjuvant temozolomide with TTFields) remains the standard of care for fit patients with newly diagnosed GBM. All patients with recurrent GBM should be considered for clinical trials.

## References
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
- Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306-2316.
- Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
- Wen PY, Weller M, Lee EQ, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review. Neuro Oncol. 2020;22(8):1073-1113.