Clinical manifestations

Presentation and course

Glioblastoma, IDH wildtype, is an aggressive tumor with a median age at diagnosis of 68 to 70 years (41). Presenting symptoms vary depending on tumor location and may also present with signs of increased intracranial pressure. Glioblastoma, IDH wildtype, are less likely to present with seizures (18% to 34%) when compared to IDH mutant tumors (59% to 74%), which may be related to the excitatory potential of D-2-hydroxygluterate, the metabolic product of the mutated IDH enzyme gene (11). Glioblastoma IDH wildtype are more likely to present with cognitive impairment in memory and processing speed as well as visuospatial, language, and executive function hypothesized to be secondary to rate of growth (55).

Prognosis and complications

Prognosis for glioblastoma, IDH wildtype, is poor with median survival of 15 to 21 months. Known key prognostic factors include age at diagnosis, functional status, extent of resection, and MGMT promoter methylation status (52; 48; 36). These are discussed in further detail below.

Clinical vignette

Vignette 1. A 53-year-old right-handed male with history of well controlled hypertension and diabetes presented with 2 weeks dizziness, headaches, and falls. His examination was notable for mild left facial weakness, and MRI revealed a large right temporal enhancing mass with midline shift and herniation. He underwent gross total resection of the right temporal mass with pathology consistent with glioblastoma, IDH wildtype, CNS WHO grade 4, and MGMT promoter methylated. Postoperatively, he had mild left-sided weakness and went on to receive fractionated radiation with concurrent temozolomide followed by six cycles of adjuvant temozolomide. He continued stable and free of disease progression at examination 27 months after diagnosis.

Vignette 2. A 68-year-old right-handed male with history of hypertension presented with a week of right focal motor seizure without loss of consciousness. MRI revealed a minimally enhancing, infiltrative mass in the left cingulate. After his seizures were controlled, he underwent gross total resection of the left cingulate mass with histopathology assessment consistent with high-grade astrocytoma without presence of microvascular proliferation or necrosis. However, given his age and the lack of IDH mutation on immunohistochemistry, subsequent sequencing identified amplification of EGFR, which is one of the hallmark molecular features of glioblastoma, IDH wildtype, CNS WHO grade 4. He went on to receive radiation and concurrent temozolomide.

These two clinical vignettes highlight the heterogeneity of neurologic symptoms and radiologic findings of glioblastoma and importance of thorough pathologic review, including sequencing in cases with high clinical suspicion of glioblastoma.

Biological basis

Etiology and pathogenesis

Stem-like cells within the CNS are hypothesized to be cells of origin of glioblastoma, IDH wildtype (01). Several genetic risk factors for gliomas are now known, including rare mutations confined to specific families and more common inherited variants in independent genetic loci (45; 23; 35). Known single gene disorders include, but are not limited to, Lynch and Li-Fraumeni syndromes as well as neurofibromatosis and tuberous sclerosis, which all predispose to glioma formations (23).

Exposure to ionizing radiation, particularly in childhood, remains the strongest environmental risk factor for diffuse glioma (07).

Glioblastoma, IDH wildtype, is a heterogeneous tumor at the cellular level with multiple alterations in numerous pathways. Commonly altered genes and molecular profiles include amplification of EGFR, TERT promotor mutation, and gain of chromosome 7 and loss of chromosome 10 (loss of PTEN) (54).

Data from The Cancer Genome Atlas (TCGA) identified numerous mutations within key pathways of (1) receptor kinases (EGFR, PDGFRA), RAS (NF1), and PI3K (PTEN) dysregulating cell proliferation; (2) p53 signaling pathway (CDKN2A, MDM2/4) activation of the oncogene; and (3) RB signaling pathway (CDK4, CDKN2A/B, RB) resulting in inappropriate progression through the cell cycle (09).

Additional molecular testing for BRAF V600E mutations and NTRK fusions should be considered given potential clinical trial and therapeutic clinical implications (14; 57). Epithelioid glioblastomas (a histologic description not codified in the current WHO classification system) show a high percentage of BRAF V600 mutations (27; 34).

For a more detailed glioblastoma IDH wildtype neuropathology review, please see Overview of neuropathology updates for infiltrating gliomas.

Epidemiology

Glioblastoma accounts for 49.1% of malignant non-metastatic brain tumors and 15% of all CNS tumors in adults (41; 31). The incidence of glioblastoma, IDH wildtype, increases with age and peaks between 75 and 84 years of age, with a median age at diagnosis of 68 to 70 years (41). There is a higher incidence in men than in women and in non-Hispanic white compared to Hispanic white and black individuals (41).

Although the incidence of glioblastoma is low compared to several other malignancies, glioblastoma is associated with considerable morbidity and mortality.

Differential diagnosis

Confusing conditions

Diagnostic workup

Contrast-enhanced MRI is the standard for identification of mass lesion in the brain. The majority of glioblastomas, IDH wildtype, are T2-weighed hyperintense and T1-weighed hypointense lesions with heterogenous contrast enhancement often associated with significant edema secondary to their high vascularity and disruption of the blood-brain barrier (39; 46). However, contrast-enhancement is not an absolute surrogate for tumor histology, with some glioblastoma lacking contrast enhancement and several low-grade gliomas avidly contrast-enhancing (46). Glioblastomas may be a single radiographic lesion, multicentric, or multifocal, and particular attention should be given to evaluate for additional, distant areas of T2/FLAIR hyperintensity that may not enhance but may be additional sites of disease, especially if these lesions appear expansile (03). Depending on patient history, radiologic differential diagnosis, etc., CT of chest, abdomen, and pelvis could be considered for evaluation of systemic cancer (02). In routine practice this is often unnecessary.

Histopathologic criteria for glioblastoma include the presence of microvascular proliferation and necrosis (29). WHO revised the classification of CNS tumors in 2016, and again in 2021, to incorporate molecular markers into histopathology for an integrated diagnosis (30; 08). Assessment of IDH status is imperative for an accurate classification of the tumor. An immunohistochemical stain for IDH 1 (R132H) mutant protein, which accounts for approximately 85% of IDH mutations in adult-type diffuse gliomas, is available for clinical use. If a non-canonical IDH mutation is suspected, next-generation sequencing should be performed to screen for the absence of an IDH mutation.

Molecular testing should be considered to assess for potential targetable mutations and to evaluate for the hallmark molecular alterations (EGFR amplification, the combined gain of chromosome 7 and loss of chromosome 10, or TERT promoter mutation) that are consistent with a diagnosis of glioblastoma, IDH wildtype, CNS WHO grade 4, and share a survival experience similar to glioblastoma (08). This is often done by a broad next-generation sequencing panel. DNA methylation signatures are also increasingly being used to subclassify brain tumors, with fewer technical limitations (10; 22). There is often greater value in extensive next generation sequencing than in the performance of numerous immunohistochemical stains, which utilize tissue and do not help refine the diagnosis nor guide management.

Though not incorporated into the revised WHO 2021 brain tumor classification system, the DNA repair enzyme 6-0-methylguanine-DNA methyltransferase (MGMT) is an important prognostic and predictive biomarker in glioblastoma, IDH wildtype. Functionally, MGMT allows repair of DNA damage caused by alkylating chemotherapy, such as temozolomide discussed in detail below (19). However, sensitivity to temozolomide is increased when MGMT is silenced via promoter methylation (59). MGMT is methylated in approximately 40% of glioblastoma, IDH wildtype, and is not only a predictor of response to temozolomide but is also a prognostic marker (05; 06; 21) and is particularly helpful in treatment decisions in the elderly as discussed below.

Management

Surgery. Maximum resection of area of contrast enhancement is associated with prolonged survival in glioblastoma (33; 44; 47). Postoperative residual enhancement is also inversely associated with improved outcomes in glioblastoma (16). For tumors in eloquent areas, use of intraoperative stimulation mapping significantly decreases risk of severe delayed neurologic deficits and have both been shown to increase extent of resection for glioblastoma (15).

Consideration should be given for referral to high volume center given complexity of treatment, particularly resection, and opportunities for clinical trial (including surgically based trial) participation.

Radiation and chemotherapy. Due to the infiltrative nature of glioblastoma, maximum resection is not considered curative. Since 2005, fractionated radiation to 60 Gy in approximately 30 fractions with concurrent and adjuvant temozolomide has been the standard of care (49; 50). Adding the alkylating agent, temozolomide, to fractionated radiation improved overall survival by almost 3 months. Temozolomide is given concomitant with radiation at 75 mg/m² followed by adjuvant treatment at 150 to 200 mg/m² on days 1 to 5 of a 28-day cycle, typically for six cycles. Data from the GEINO trial of randomizing patients to either 6 or 12 months of adjuvant temozolomide demonstrated no significant differences 6-month progression-free survival, progression-free survival, or overall survival, demonstrating there is no significant benefit in unselected populations for 12 months of adjuvant temozolomide (04). The limited number of patients in this trial makes it underpowered to detect subtle differences in outcomes between the two arms.

In the CeTeG/NOA-09 trial, temozolomide was combined with another alkylating agent, lomustine (CCNU), in the upfront setting in patients with MGMT methylated glioblastoma. Results from the relatively small phase 3 study demonstrated survival improvement; marked toxicity was also seen (24; 54) (56). Additional investigation in a larger trial, NCT05095376, is currently ongoing.

The published results from the DCVax®-L trial (NCT00045968) showed improved overall survival in the vaccine group when compared to a composite historical control (28). However, it did not demonstrate an improvement in survival in the investigational arm compared to the control arm.

Use of anti-angiogenic agents, such as bevacizumab, in unselected, newly diagnosed glioblastoma has shown no improvement in overall survival in two phase 3 trials (12; 20). Additionally, randomized controlled, double blinded trials of checkpoint inhibition with nivolumab in combination with radiation and temozolomide in either MGMT methylated or unmethylated in newly diagnosed glioblastoma failed to demonstrate improvement in overall survival above standard of care (40). Though immunotherapy is being heavily investigated in clinical trials, there is, as yet, no evidence for efficacy in unselected patients with glioblastoma.

Tumor-treating fields. Tumor-treating fields were first approved in 2011 in the recurrent setting of glioblastoma (53) and then approved in 2015 for use in newly diagnosed glioblastoma in conjunction with adjuvant temozolomide after completion of radiation and concurrent chemotherapy (50; 51). Results from the phase 3 EF-14 study demonstrated an improvement in overall survival of nearly 5 months with the addition of tumor-treating fields to temozolomide; they are now incorporated into the NCCN guidelines (37). Tumor-treating fields consist of a set of arrays, directly applied to the scalp, which deliver two relatively perpendicular alternating electrical fields of low voltage and moderate frequency, tuned to a frequency to disrupt mitotic activity of glioblastoma cells (25; 26; 18).

Palliative care. Glioblastoma, IDH wildtype, is a terminal illness and falls under the guidelines from the NCCN (38) and ASCO (American Society of Clinical Oncology) (17) for early intervention with palliative care.

Recurrent disease. There is no standard of care for treatment at recurrence. Whenever feasible, consideration should be given to enrollment in a clinical trial. FDA-approved treatments are limited and include bevacizumab with or without concurrent cytotoxic chemotherapy, such as lomustine. However, additional resection, re-irradiation, re-challenge with temozolomide, targeted agents, and immunotherapy may be considered in the correct clinical scenario.

Prophylaxis. Pneumocystis pneumonia prophylaxis with trimethoprim-sulfamethoxazole during temozolomide treatment should be considered in patients with other risk factors for opportunistic infections (long-term steroid use and significant lymphopenia), but in otherwise immunologically healthy patients, the risk may outweigh the benefits (13).

Outcomes

Median overall survival continues to be around 15 to 21 months (51; 36), and less than 10% to 15% of patients survive 5 years after diagnosis (48; 51). Prognostic factors include age and performance status at diagnosis, extent of resection, and MGMT promoter methylation status.

Nomograms have been created to help estimate prognosis based on specific patient characteristics. One of these nomograms can be found via this link: npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/(42).

Special considerations

Many glioblastoma, IDH wildtype, patients are diagnosed in their 70s and 80s (36). However, many clinical trials that defined the standard of care for these patients excluded patients older than 70 years of age, leaving a gap in optimal treatment for this large subset of patients (52). Given the toxicities of fully fractionated radiation and the overall worse outcomes in elderly patients, several trials investigated alternate dosing of radiation and chemotherapy (32; 58; 43). Hypofractionated radiation to 40 Gy in 15 fractions and temozolomide should be considered in patients older than 65 years at diagnosis (43; 60). Furthermore, treatment with only radiotherapy should be considered in elderly patients or those with poor functional status with MGMT unmethylated tumors (32; 58). Although these approaches are largely pragmatic, there may be biological underpinnings requiring further exploration as to why they may be beneficial (24).

Pregnancy

Temozolomide is mutagenic and is contraindicated during pregnancy. Extensive caution is taken when considering the role of radiation therapy in pregnancy. Breastfeeding is also contraindicated with temozolomide therapy. It is unknown what the effects of tumor-treating fields may be in the setting of pregnancy. Similar contraindications are noted with agents utilized in the treatment of recurrent or progressive glioblastoma. Patients with glioblastoma, IDH wildtype, should strongly consider evaluation by a high-risk obstetrician. Furthermore, it is important to discuss options for fertility preservation in patients of reproductive age prior to initiating treatment.

Anesthesia

Precautions with anesthesia are the same as for any intracranial surgery.