Molecular/genetic characterization has taken on greater importance in the classification of adult gliomas and in diagnostic and treatment decision-making. “These tumors are now grouped and predicated more on molecular features rather than histopathologic criteria,” said L. Burt Nabors, MD, Director, Division of Neuro-Oncology, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, in a presentation during the 2023 National Comprehensive Cancer Network (NCCN) Annual Conference.
Standard treatment modalities for glioma include surgery, radiation, and chemotherapy. With these treatments, median overall survival (OS) from the time of glioblastoma diagnosis is 17 months, which decreases to 9 months for elderly patients (aged >65 years) with the disease.
Among diffuse gliomas, the molecular criteria for an adult-type diffuse glioblastoma (World Health Organization [WHO] grade 4) are IDH wild type and at least 1 of the following:
Treatment recommendations for IDH wild-type glioblastoma include consideration of enrollment in a clinical trial for newly diagnosed patients, radiation therapy, and concurrent chemotherapy with temozolomide (Temodar), according to the most recent NCCN Clinical Practice Guidelines: Central Nervous System Cancers (Version 1.2023) for the management of glioblastoma.1 Often, these patients are placed on steroids by neurosurgeons perioperatively, said Dr Nabors. Dexamethasone is the most frequently used steroid. It has an extremely long half-life of 36 hours, permitting once-daily or twice-daily administration, but it is associated with toxicities over the long term.
Patients with IDH wild-type glioblastoma may also be placed on perioperative anticonvulsants. “Our philosophy is that if they have not had a seizure, we will take them off seizure medication,” he said. “If they have had a seizure, I will tell patients that they need to stay on an anticonvulsant for the rest of their life.”
“Determining MGMT promoter methylation status is important,” Dr Nabors continued. “This gives us an idea of sensitivity to temozolomide. If the MGMT gene promoter is active, then the protein product, methyltransferase, is created, and that renders the tumor resistant to the effect of temozolomide. If it is methylated, then the MGMT DNA repair gene is not present, and so the tumor is very sensitive to alkylating agents.” MGMT promoter status is incorporated into the NCCN Guidelines Version 1.2023 for the management of glioblastoma.1
IDH-mutant tumors with necrosis and/or microvascular proliferation (MVP) point to a WHO grade 4 astrocytoma. A homozygous deletion of the CDKN2A/B gene without necrosis or MVP also confirms a WHO grade 4 astrocytoma. If CDKN2A/B is intact, elevated mitoses are indicative of astrocytoma, WHO grade 3. Without elevated mitoses, the diagnosis is astrocytoma, WHO grade 2.
Clinical trials are important for patients diagnosed with IDH-mutated astrocytoma, WHO grade 4, which is often a younger patient population for whom treatment data are limited. Median OS in this group (2.5-3.5 years) is superior to that in patients with glioblastoma, WHO grade 4 (median, 14-16 months), Dr Nabors noted.
IDH-mutant WHO grade 2 and grade 3 gliomas (astrocytomas or oligodendrogliomas) are a heterogeneous group of malignancies with varying clinical behavior. Seizures at presentation and no additional deficits are good prognostic signs. Poor prognostic signs include tumor diameter >5 cm and the presence of contrast enhancement.
Radiation alone is not adequate for high-risk, IDH-mutant, low-grade glioma (WHO grade 2). Radiation therapy followed by chemotherapy (procarbazine, lomustine, and vincristine [PCV]) in patients with high-risk, low-grade glioma results in better progression-free survival and OS compared with radiation alone. There is no advantage to giving concurrent temozolomide with radiation in IDH-mutant astrocytoma, WHO grade 3.
“The advantage [to temozolomide] exists only after radiation,” Dr Nabors noted. In this subset (IDH-mutant), the recommendation is radiation followed by 12 months of adjuvant temozolomide irrespective of MGMT status.
A diffuse glioma with IDH mutation and codeletion 1p/19q is considered a WHO grade 3 oligodendroglioma if it has elevated mitoses, necrosis, and/or MVP (without mitoses, necrosis, and/or MVP, it is considered WHO grade 2). According to the most recent NCCN Guidelines, the mainstay of treatment for a patient with WHO grade 3 oligodendroglioma and good performance status is consideration of a clinical trial.1 Otherwise, the NCCN Guidelines call for standard radiation therapy and neoadjuvant or adjuvant PCV (or standard radiation with concurrent and adjuvant temozolomide, or standard radiation and adjuvant temozolomide). For those with poor performance status (Karnofsky performance score <60), hypofractionated radiation is preferred with or without concurrent and/or adjuvant temozolomide, or temozolomide, or palliative/best supportive care, Dr Nabors said.
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