Refining the Management of Recurrent Glioblastoma

Andrew N. Wilner, MD


June 04, 2018

While attending the 2018 American Academy of Neurology meeting in Los Angeles, California, Medscape contributor Andrew N. Wilner, MD, interviewed University of Tennessee neuro-oncologist and assistant professor of neurology Sushma Bellamkonda, MD, about her research on the treatment of recurrent glioblastoma.

Wilner: You and your colleagues conducted a retrospective review[1] of about 250 patients who had recurrent glioblastoma, and you found that those with MGMT methylation seemed to have better treatment outcomes. Tell us about that.

Bellamkonda: Patients with MGMT-methylated glioblastoma have been noted to do better. MGMT methylation in tumors seems to predict how well the patients will respond to chemotherapy. When you look at all of the studies, those patients tend to have better overall survival. Thus, the presence of MGMT methylation has a predictive as well as a prognostic element.

Even though the World Health Organization restructured the classification of glioblastomas, it did not include MGMT in the classification.[2] Nonetheless, it may be worthwhile to check for MGMT in patients with glioblastoma because it will help you to prognosticate and also help you decide which treatment will help the patient the most.

Wilner: So, some tumors have this methylated MGMT and some don't?

Bellamkonda: That's right.

Wilner: Is it standard practice to test for this when a patient presents with a glioblastoma?

Bellamkonda: In the larger centers, most if not all tumors are tested for MGMT. Testing also depends on how much tissue you have from the surgery; I believe that a volume of 1 cm3 of tissue is required for MGMT, so it depends on whether the sample is from a biopsy or a resection. If you have enough tissue, it is beneficial to the patient to check for MGMT because if the patient is methylated, they respond better to chemotherapy such as temozolomide. In our study, we also found that these patients seemed to respond well to the monoclonal antibody bevacizumab.

Bevacizumab is directed against the VEGF-A, a vascular endothelial growth factor, and it prevents the interaction between VEGF and the VEGF receptors.

The one classic feature of glioblastoma is angiogenesis, which helps in the pathologic diagnosis. If the tumor has angiogenesis, it is most likely to be a glioblastoma. You should also see a kind of necrosis on the slide. Bevacizumab inhibits the angiogenesis; it essentially bleeds the tumor and deprives the tumor of its blood supply.

When they first tried bevacizumab in patients, they saw that it produced a very good response radiologically and clinically. So everyone was excited about it because we didn't have expertise with recurrent glioblastomas and we didn't have a standard of treatment. When patients had a good response clinically and radiologically with bevacizumab, the US Food and Drug Administration (FDA) gave it expedited approval, even without any phase 3 trials. But then a phase 3 trial was conducted and they found that bevacizumab did not improve overall survival.[3] It improves progression-free survival, but not overall survival. Also, if a tumor progresses on bevacizumab, it is unlikely to respond to other chemotherapies. Some research says that maybe salvage radiation may help,[4,5] but more work needs to be done.

Wilner: I want to get back to MGMT. What is MGMT, exactly?

Bellamkonda: MGMT is methylguanine methyltransferase. It's a DNA repair enzyme. The standard therapy for newly diagnosed glioblastoma involves two protocols, one with chemotherapy with temozolomide and one with radiation therapy. Temozolomide is an alkylating chemotherapy. It goes in and acts as an alkyl group to the guanine portion of the DNA, thus causing some damage to the DNA. The glioblastoma cells contain the DNA repair enzyme MGMT. MGMT goes in and removes that alkyl group, which renders the cells resistant to chemotherapy.

If the MGMT enzyme is methylated, that means the repair enzyme is silenced. Thus, the chemotherapy will be more effective in killing the cells if that enzyme is methylated. That's why checking the MGMT is important, especially when the patient is sick and elderly. If the patient has methylated MGMT, he will get more benefit from temozolomide, and so it helps you decide which way to go.

Wilner: Is MGMT methylation a rare phenomenon?

Bellamkonda: It's not rare but I would say that lower-grade tumors are more likely to be MGMT methylated and have IDH mutations than a glioblastoma.

Wilner: That was IDH?

Bellamkonda: The IDH mutation has been integrated into the new WHO classification.[2] IDH is isocitrate dehydrogenase, an enzyme in the Krebs cycle. When this is mutated, it results in the formation of a metabolite, which is a kind of one-off that only steps in during the glioma genesis. On the basis of our studies, we found that tumors that are IDH mutated are more likely to be MGMT methylated, and those tumors end up responding better to treatment.[1]

Wilner: So the IDH mutation and MGMT methylation tend to go together.

Bellamkonda: Yes, but there are always exceptions to this.

Wilner: Are there any ongoing trials that will delve a bit deeper into this and work out some better prognosis?

Bellamkonda: I don't know off the top of my head whether there are trials looking into this. From a practical, clinical standpoint, if the patient responds to treatment similar to one who has an MGMT-methylated tumor, and the patient doesn't have an MGMT test done, we believe that it is more likely that the MGMT must be methylated. If the patient doesn't have enough tissue, or insurance doesn't cover it—they don't cover MGMT testing in most cases—then we believe that if the tumor is IDH mutated, it is more likely to be MGMT methylated as well.

Wilner: It sounds as though to get the highest quality of care, if you have a patient with a glioblastoma, you would want them to be at a large center where a more personalized and detailed genotyping of the tumor could be done to guide therapy. Is that correct?

Bellamkonda: Yes. In a smaller center, all of these tests, if they are done, will be sent out for analysis, which will cost more. In a larger center that has a brain tumor program, the tests may be done in-house, which can help with the cost. It also would be better to get treatment in a larger center with a multidisciplinary tumor board that can get together and make a decision about the testing and treatment.


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