Residency · Residency · Neurosurgery

High-Grade Gliomas: Surgical and Adjuvant Therapy

Overview

High-grade gliomas (HGGs) include WHO grade 3 and 4 astrocytic and oligodendroglial tumors. Glioblastoma (GBM), IDH-wildtype, is the most common and aggressive primary brain malignancy in adults, with a median survival of 14-16 months despite multimodal therapy. Maximal safe resection followed by concurrent chemoradiation (the Stupp protocol) remains the standard of care. Emerging therapies including tumor-treating fields, immunotherapy, and targeted molecular agents continue to reshape the treatment landscape.

Epidemiology

GBM accounts for approximately 50% of all malignant primary brain tumors, with an annual incidence of 3-4 per 100,000 population. It peaks in the 6th to 7th decade of life, with a median age at diagnosis around 65 years, and shows a male predominance of roughly 1.6 to 1. Ionizing radiation is the only established environmental risk factor, though rare hereditary syndromes such as Li-Fraumeni, Turcot, and NF1 also confer increased risk.

Classification (WHO 2021)

Glioblastoma, IDH-Wildtype (Grade 4)

The 2021 WHO classification requires diffuse astrocytic morphology combined with IDH-wildtype status and at least one of the following molecular or histologic features: microvascular proliferation, necrosis, TERT promoter mutation, EGFR amplification, or +7/-10 chromosome copy number changes. MGMT promoter methylation is present in approximately 40% of GBMs and serves as the strongest predictor of response to temozolomide.

Astrocytoma, IDH-Mutant, Grade 3 or 4

These tumors carry an IDH mutation but display anaplastic features such as mitoses, microvascular proliferation, or necrosis. Grade 4 IDH-mutant astrocytoma (formerly called "secondary GBM") has a significantly better prognosis than IDH-wildtype GBM. Notably, homozygous CDKN2A/B deletion upgrades the tumor to grade 4 regardless of histologic features.

Oligodendroglioma, IDH-Mutant, 1p/19q-Codeleted, Grade 3

Anaplastic oligodendroglioma is defined by the presence of mitotic activity, microvascular proliferation, or necrosis in the context of IDH mutation and 1p/19q codeletion. It carries a better prognosis than astrocytic HGGs and is notably chemosensitive, responding to PCV or temozolomide regimens.

Clinical Presentation

Unlike low-grade gliomas, HGGs present with rapid onset of symptoms over days to weeks. Patients may develop focal neurological deficits such as hemiparesis, aphasia, or visual field cuts depending on tumor location. Headache with or without signs of raised intracranial pressure is common, and seizures are the first presentation in 20-40% of cases. Cognitive decline and personality change are frequently observed. GBM may also present with acute hemorrhage that can mimic a stroke.

Imaging

MRI Characteristics of GBM

On T1-weighted imaging with gadolinium, GBM typically appears as an irregular ring-enhancing mass with central necrosis. T2/FLAIR sequences reveal extensive perilesional hyperintensity representing both edema and infiltrating tumor. Diffusion-weighted imaging shows restricted diffusion at the enhancing rim, reflecting high cellularity, while MR perfusion demonstrates elevated relative cerebral blood volume at the same location. MR spectroscopy reveals an elevated choline-to-NAA ratio along with lactate and lipid peaks. Multifocal or "butterfly" GBM crossing the corpus callosum indicates contralateral spread.

Differential Diagnosis on Imaging

Brain abscess is distinguished by central (not peripheral) diffusion restriction on DWI. Metastases tend to appear at the gray-white junction and are often multifocal. Lymphoma typically shows homogeneous enhancement in a periventricular location with restricted diffusion throughout the lesion. Tumefactive demyelination can be identified by its incomplete ring enhancement with the characteristic open-ring sign.

<image> Axial MRI of a left temporal glioblastoma on T1 post-gadolinium showing an irregular ring-enhancing lesion with central necrosis, surrounding vasogenic edema on the FLAIR sequence, and restricted diffusion at the enhancing rim on DWI/ADC maps. A comparison panel shows MR perfusion with elevated rCBV at the enhancing margin. Radiological teaching illustration with labeled sequences and characteristic features annotated. </image>

Surgical Management

Goals of Surgery

The goals of surgery in HGG are to obtain tissue for histological and molecular diagnosis, achieve maximal safe resection to reduce tumor burden, relieve mass effect and improve neurological function, and reduce corticosteroid dependence.

Extent of Resection

Gross total resection of the enhancing tumor is the surgical target. Lacroix et al. (2001) demonstrated that greater than 98% extent of resection was associated with survival benefit, and Sanai et al. (2011) showed a stepwise survival benefit with increasing extent of resection, even starting from 78%. Supramaximal resection, which extends beyond the enhancing margin into the FLAIR abnormality, has been associated with further survival benefit in selected studies. Residual non-enhancing tumor on FLAIR is increasingly recognized as a prognostic factor. Assessment of extent of resection requires postoperative MRI within 24-48 hours.

Surgical Adjuncts

5-ALA (aminolevulinic acid) fluorescence is FDA-approved for HGG and preferentially accumulates in high-grade tumor cells, fluorescing under blue-violet light. The Stummer et al. (2006) study showed that it significantly improves gross total resection rates. Intraoperative MRI provides real-time assessment of residual tumor. Awake craniotomy is employed for tumors in or near eloquent cortex. Intraoperative neurophysiologic monitoring with motor evoked potentials, somatosensory evoked potentials, and direct cortical or subcortical stimulation further reduces the risk of iatrogenic deficits. Neuronavigation integrated with DTI tractography assists in white matter tract preservation, and intraoperative ultrasound can rapidly identify residual tumor.

Biopsy Indications

Stereotactic needle biopsy is reserved for deep-seated or brainstem tumors not amenable to resection, multifocal disease, patients with poor performance status precluding craniotomy, or when diagnostic uncertainty exists (such as differentiating lymphoma, infection, or demyelination). Stereotactic biopsy achieves a diagnostic yield exceeding 95% with a complication rate of only 1-3%.

Adjuvant Therapy

The Stupp Protocol (Standard of Care)

The landmark EORTC 26981/NCIC CE.3 trial (Stupp et al., 2005) established the standard of care: concurrent temozolomide at 75 mg/m2 daily with fractionated radiation therapy (60 Gy in 30 fractions), followed by adjuvant temozolomide at 150-200 mg/m2 on days 1-5 of a 28-day cycle for 6 cycles. This regimen improved median overall survival to 14.6 months compared with 12.1 months for radiation alone, and five-year overall survival reached 9.8% versus 1.9%. MGMT-methylated tumors derive the greatest benefit, with a median overall survival of 21.7 months compared with 15.3 months for unmethylated tumors.

Radiation Therapy

The standard regimen is 60 Gy in 30 fractions (2 Gy per fraction) directed at the enhancing tumor plus a 2 cm margin. Hypofractionated radiation (40 Gy in 15 fractions) is non-inferior for elderly patients over 65 with poor performance status, as demonstrated by Perry et al. (2017), who also showed that concurrent temozolomide with hypofractionated RT in the elderly improved overall survival compared with hypofractionated RT alone.

Tumor-Treating Fields (TTFields)

The Optune device delivers alternating electric fields at 200 kHz via transducer arrays on the shaved scalp. The EF-14 trial (Stupp et al., 2017) demonstrated that TTFields plus maintenance temozolomide improved median overall survival to 20.9 months compared with 16.0 months for temozolomide alone. The device requires at least 18 hours per day of use for benefit and is FDA-approved for newly diagnosed GBM after completion of concurrent chemoradiation.

Bevacizumab (Anti-VEGF)

The AVAglio and RTOG 0825 trials showed that adding bevacizumab to standard chemoradiation improved progression-free survival but did not improve overall survival in newly diagnosed GBM. Bevacizumab is FDA-approved for recurrent GBM based on imaging response and clinical improvement. It effectively reduces edema and corticosteroid dependence, though pseudoresponse must be considered when interpreting imaging.

Management of Recurrence

At recurrence, re-resection should be considered if the tumor is surgically accessible, the patient has good performance status, and a prolonged interval has elapsed since initial surgery. Bevacizumab is the most commonly used salvage agent, improving progression-free survival and reducing edema. CCNU (lomustine) serves as an alternative second-line chemotherapy. Re-irradiation with stereotactic radiosurgery or fractionated stereotactic RT is an option for focal recurrences. Clinical trials should always be considered, and tumor-treating fields may be used if not employed in the first-line setting.

Pseudoprogression versus true progression is an important distinction. Pseudoprogression typically occurs within 3 months of completing chemoradiation. Continued treatment through suspected pseudoprogression is advised, and advanced imaging modalities such as perfusion MRI and PET may help distinguish the two entities.

<image> Diagram illustrating the standard treatment algorithm for newly diagnosed glioblastoma: maximal safe resection followed by the Stupp protocol (6 weeks of concurrent temozolomide with 60 Gy radiation therapy, then 6 cycles of adjuvant temozolomide). The addition of tumor-treating fields during adjuvant temozolomide is shown. A decision branch at recurrence shows options including re-resection, bevacizumab, re-irradiation, and clinical trials. Clean flowchart with timeline markers. </image>

Emerging Therapies

Immunotherapy approaches include checkpoint inhibitors (though CheckMate 143 with nivolumab was negative in recurrent GBM), dendritic cell vaccines such as DCVax-L, CAR-T cells, and oncolytic viruses. Targeted therapies are advancing rapidly, with IDH inhibitors like vorasidenib showing promise for IDH-mutant gliomas in the INDIGO trial, and BRAF/MEK inhibitors benefiting BRAF-mutated tumors. Convection-enhanced delivery enables direct intratumoral delivery of therapeutic agents. Laser interstitial thermal therapy (LITT) provides an option for deep-seated or recurrent tumors not amenable to open resection. Carmustine wafers (Gliadel) placed at the time of resection provide modest survival benefit through intraoperative radiation.

Prognostic Factors

The strongest predictors of outcome in HGG include MGMT promoter methylation (the strongest predictor of temozolomide response), IDH mutation status (IDH-mutant grade 4 astrocytoma carries a median OS of approximately 3-5 years versus about 15 months for IDH-wildtype GBM), patient age, performance status (KPS of 70 or greater is required for the Stupp protocol, while KPS below 60 carries very poor prognosis), extent of resection, and tumor location. Recursive partitioning analysis and MGMT-based models guide prognostication in clinical practice.

<image> Intraoperative view under blue-violet light during 5-ALA fluorescence-guided resection of a glioblastoma. The tumor fluoresces bright pink-violet against the non-fluorescent surrounding brain parenchyma. A small area of residual fluorescence at the deep margin is visible. The standard white-light view of the same operative field is shown in a comparison panel. Neurosurgical operative illustration with annotations. </image>

Clinical Pearls

Postoperative MRI must be obtained within 24-48 hours because delayed imaging cannot distinguish residual tumor from postoperative enhancement. 5-ALA fluorescence significantly improves gross total resection rates in HGG and should be considered standard for GBM resection. MGMT methylation testing is essential; in elderly patients with unmethylated MGMT, temozolomide alone provides minimal benefit, and consideration should be given to radiation alone or best supportive care. Pseudoprogression occurs in up to 30% of patients after chemoradiation, particularly those with MGMT-methylated tumors, so premature abandonment of effective therapy should be avoided. Dexamethasone should be tapered as aggressively as possible because chronic steroids impair immune function, may reduce treatment efficacy, and cause significant morbidity. Seizure prophylaxis is not recommended for patients who have not had seizures per AAN practice parameters, though levetiracetam is preferred if treatment is needed. DVT prophylaxis is critical given the high thrombotic risk in GBM patients; mechanical prophylaxis should begin intraoperatively and pharmacologic anticoagulation within 24-48 hours postoperatively.

References

• Stupp R, et al. "Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma." NEJM. 2005;352(10):987-996.
• Stupp R, et al. "Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients with Glioblastoma (EF-14)." JAMA. 2017;318(23):2306-2316.
• Stummer W, et al. "Fluorescence-Guided Surgery with 5-Aminolevulinic Acid for Resection of Malignant Glioma (ALA-Glioma Study)." Lancet Oncol. 2006;7(5):392-401.
• Perry JR, et al. "Short-Course Radiation Plus Temozolomide in Elderly Patients with Glioblastoma." NEJM. 2017;376(11):1027-1037.
• Louis DN, et al. "The 2021 WHO Classification of Tumors of the Central Nervous System." Neuro-Oncology. 2021;23(8):1231-1251.

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