Overview of Brain Cancer Treatment
Primary brain tumors, particularly glioblastoma multiforme (GBM), represent some of the most challenging malignancies in oncology. Despite aggressive multimodal therapy including surgery, radiation, and chemotherapy, prognosis remains poor with median survival of approximately 15 months for newly diagnosed GBM. Treatment options are limited compared to other solid tumors due to the blood-brain barrier and the critical nature of brain tissue.
Brain Tumor Classification & Treatment Paradigms
Glioblastoma (WHO Grade IV) - Most aggressive primary brain tumor
- Standard of care: Maximal safe resection followed by radiation with concurrent and adjuvant temozolomide (Stupp protocol)
- Tumor treating fields (Optune) for newly diagnosed GBM
- Bevacizumab for recurrent disease
- Investigational: Immunotherapy, targeted therapies for EGFR, IDH mutations
Anaplastic Astrocytoma (WHO Grade III)
- Surgery followed by radiation and chemotherapy
- PCV (procarbazine, lomustine, vincristine) for 1p/19q co-deleted tumors
- Temozolomide as alternative
Lower-Grade Gliomas (WHO Grade II)
- Observation vs. early intervention based on molecular markers
- IDH-mutant status predicts better prognosis
- Radiation and chemotherapy for high-risk features
Epidemiology & Impact
Primary brain and central nervous system tumors affect approximately 25,000 adults annually in the United States, with glioblastoma (GBM) representing approximately 50% of all malignant brain tumors. Glioblastoma has a median age at diagnosis of 65 years and a striking male predominance (1.6:1 ratio). Overall 5-year survival for malignant brain tumors is approximately 36%, but for glioblastoma specifically, median survival is only 14-16 months with standard treatment and 5-year survival is less than 7%. The only well-established environmental risk factor is ionizing radiation; unlike many cancers, no association with smoking, diet, or cell phone use has been confirmed in large epidemiological studies. Lower-grade gliomas (WHO Grade 2-3) have a more favorable prognosis, with median survival ranging from 5 to 15 years depending on molecular subtype. The blood-brain barrier represents a fundamental challenge in treatment, limiting drug delivery and contributing to treatment resistance.
Molecular Biology & Biomarkers
The 2021 WHO Classification of CNS Tumors fundamentally reorganized brain tumor classification by integrating molecular markers alongside histology. Three molecular markers are now essential for adult glioma diagnosis: IDH mutation status, 1p/19q co-deletion, and MGMT promoter methylation. IDH-mutant gliomas have significantly better prognosis than IDH-wildtype tumors regardless of histological grade. The 1p/19q co-deletion defines oligodendrogliomas and predicts chemosensitivity. MGMT promoter methylation, present in approximately 40% of glioblastomas, impairs DNA repair and strongly predicts benefit from temozolomide. Additional molecular markers including TERT promoter mutations, CDKN2A/B homozygous deletion, EGFR amplification, and chromosome 7 gain/10 loss help refine diagnosis and prognosis. Pediatric-type gliomas are now recognized as molecularly distinct entities, with BRAF alterations (fusions and V600E mutations) and histone mutations (H3K27M in diffuse midline gliomas) driving a separate classification system.
Evolving Treatment Landscape
The standard of care for newly diagnosed glioblastoma — maximal safe resection followed by the Stupp protocol (concurrent temozolomide and radiation, then adjuvant temozolomide) — has remained essentially unchanged since 2005 and represents one of oncology's most challenging unmet needs. Tumor treating fields (TTFields/Optune) added to maintenance temozolomide improved median survival by approximately 5 months in the EF-14 trial. Bevacizumab is FDA-approved for recurrent GBM but did not improve overall survival in the first-line AVAglio and RTOG 0825 trials. Checkpoint immunotherapy has been largely unsuccessful in GBM, likely due to the immunosuppressive tumor microenvironment and low mutational burden. For IDH-mutant gliomas, the INDIGO trial demonstrated that vorasidenib (a brain-penetrant dual IDH1/IDH2 inhibitor) significantly improved progression-free survival in grade 2 gliomas, representing the first targeted therapy advance in lower-grade gliomas. Active research areas include novel immunotherapy approaches (vaccines, CAR-T cells, oncolytic viruses), convection-enhanced delivery to bypass the blood-brain barrier, and combination strategies targeting the tumor microenvironment.
Approved Brain Cancer Therapies
Approved Indications (US/FDA)
Treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment; Treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.
Dosing Schedule
Newly Diagnosed GBM - Concomitant Phase: 75 mg/m² orally once daily for 42 days with focal radiotherapy (60 Gy in 30 fractions)
Maintenance Phase: 150 mg/m² once daily for 5 days, followed by 23 days without treatment (28-day cycle). Increase to 200 mg/m² for cycles 2-6 if tolerated
Refractory Anaplastic Astrocytoma: 150 mg/m² once daily for 5 consecutive days per 28-day cycle. May increase to 200 mg/m² if no toxicity after first cycle
Cycle Length
28-day cycles for maintenance therapy (5 days on, 23 days off)
Clinical Evidence
The landmark EORTC-NCIC trial (Stupp protocol) demonstrated improved median overall survival from 12.1 to 14.6 months and 2-year survival from 10% to 26% when temozolomide was added to radiotherapy. MGMT promoter methylation predicts enhanced benefit with median OS exceeding 21 months in methylated tumors.
Approved Indications (US/FDA)
Treatment of glioblastoma with progressive disease following prior therapy as a single agent (accelerated approval based on improvement in objective response rate).
Dosing Schedule
10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity
Cycle Length
Every 2 weeks (14-day cycles)
Clinical Evidence
Approval based on two single-arm studies showing objective response rates of 26-28% in recurrent GBM. While bevacizumab improves progression-free survival and reduces corticosteroid requirements, randomized trials (AVAglio, RTOG 0825) failed to demonstrate overall survival benefit in newly diagnosed GBM. Primary utility is in managing symptoms and reducing cerebral edema in recurrent disease.
Approved Indications (US/FDA)
Adjunct to surgery and radiation in patients with newly diagnosed high-grade malignant glioma; Adjunct to surgery in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated.
Dosing Schedule
Up to 8 wafers (each containing 7.7 mg carmustine) placed in the resection cavity at the time of surgery. Wafers dissolve over 2-3 weeks, delivering local chemotherapy directly to tumor bed.
Clinical Evidence
Gliadel wafers provide local delivery of carmustine, an alkylating agent, directly to the tumor resection cavity. Studies show modest survival benefit of approximately 2-3 months in newly diagnosed high-grade gliomas when combined with surgery and radiation. Main advantage is local drug delivery without systemic toxicity, though complications include CSF leak, infection, and impaired wound healing.
Approved Indications (US/FDA)
Treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with temozolomide; Treatment of adult patients with recurrent glioblastoma following confirmed radiographic progression in the supratentorial brain after receiving chemotherapy.
Treatment Schedule
Transducer arrays applied to shaved scalp, delivering alternating electric fields at 200 kHz. Worn continuously for at least 18 hours per day. Arrays replaced every 3-4 days. Treatment continued until disease progression.
Clinical Evidence
The EF-14 trial demonstrated that adding TTFields to maintenance temozolomide improved median overall survival from 16.0 to 20.9 months (HR 0.63, p<0.001) and 5-year survival from 5% to 13% in newly diagnosed GBM. Compliance is critical - patients wearing device ≥75% of time had median OS of 24.9 months. Main side effect is scalp irritation. Device uses low-intensity alternating electric fields to disrupt cancer cell division.
Approved Indications (US/FDA)
Treatment of brain tumors (both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures); Secondary therapy in Hodgkin's disease.
Dosing Schedule
130 mg/m² orally as a single dose every 6 weeks. Dose adjustments based on nadir blood counts from prior cycle. Commonly used in PCV regimen (procarbazine, lomustine, vincristine) for anaplastic oligodendrogliomas.
Cycle Length
42 days (6 weeks) - delayed myelosuppression is dose-limiting
Clinical Evidence
Lomustine is a nitrosourea alkylating agent with good CNS penetration. It remains important therapy for anaplastic oligodendrogliomas with 1p/19q co-deletion, where the PCV regimen has demonstrated survival benefit. Also used as salvage therapy in recurrent GBM, though efficacy is limited. Main toxicities include cumulative myelosuppression, pulmonary fibrosis with prolonged use, and secondary malignancies.
Approved Indications (US/FDA)
Treatment of adult and pediatric patients 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, who require initial intervention following at least one prior therapy except surgery.
Dosing Schedule
40 mg orally once daily with or without food until disease progression or unacceptable toxicity. First oral targeted therapy specifically for IDH-mutant gliomas.
Mechanism of Action
Vorasidenib is a first-in-class dual inhibitor of mutant IDH1 and IDH2 enzymes. IDH mutations are present in approximately 70% of grade 2 gliomas and lead to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which promotes tumorigenesis. By inhibiting mutant IDH, vorasidenib reduces 2-HG levels and slows tumor growth.
Clinical Evidence
The phase 3 INDIGO trial demonstrated that vorasidenib significantly improved progression-free survival compared to placebo in patients with residual or recurrent grade 2 IDH-mutant gliomas after surgery (median PFS 27.7 vs 11.1 months, HR 0.39). This represents the first targeted therapy to show benefit specifically in IDH-mutant lower-grade gliomas. Common adverse events include elevated liver enzymes, fatigue, and headache.