Promising Glioma Therapy Options

Today we are discussing glioma therapy options with Dr. James Perry, MD, FRCPC, a neuro-oncologist at the Sunnybrook Health Sciences Centre in Toronto, Canada who specializes in the care of patients with central nervous system cancers.

-Interviewed by Anna Azvolinsky

Cancer Network: Can you talk about the difference between gliomas and glioblastomas? Do both types of brain tumors tend to be malignant when they are found and what are the differences in prognosis for these two tumor types?

Dr. Perry: I’d be very happy to and thank you for the opportunity to communicate with this great audience. One thing that is not well appreciated is that glioma represents a family of tumors and in the recent World Health classification of brain tumors in 2016, there were no less than 36 different subtypes of glioma identified based on histology and various biomarkers.

Glioma refers to a primary brain tumor rather than a metastatic brain cancer and refers to tumors that have started growing within the brain, usually from glial cells. The predominant ones are astrocytes, which [are] for the astrocytomas and they are graded 2–4 with a grade 4 astrocytoma being a glioblastoma (GBM) [which] is by far the most common form of brain tumor.

Gliomas can also come from oligodendrocytes.  Those form oligodendrogliomas which are significantly more favorable in terms of their biological behavior and their prognosis for patients and can have survivorship measured of decades for folks with these tumors that have the most favorable biomarker profiles.

Cancer Network: What are the main initial therapies for malignant gliomas and for glioblastomas?

Dr. Perry: These tumors are usually identified by imaging, usually following a neurological symptom such as a seizure and usually patients are evaluated in a surgical center by a surgeon. Although the imaging appearance can be fairly typical for most of the gliomas, especially, glioblastoma, it is relatively uncommon to begin treatment without tissues through an operation.

Typically patients will have a biopsy or surgical resection. But that said, we’ve learned in the past 5–10 years that so-called maximal resection, meaning removal of as much of a brain tumor as can be done safely within the confines of not causing neurological morbidity, is beneficial to patients. Patients that have an excellent resection tend to tolerate subsequent treatment much better and their overall prognosis is better.

Patients will typically start with a craniotomy and surgical resection and these days the technology has improved quite a bit so a lot of these patients will have pre-op and intra-operative imaging, awake craniotomies or real-time monitoring of neurological condition, and some neuro techniques using fluorescence imaging where pre-operatively, a patient is given a fluorescent compound that actually tags tumor cells because at surgery, especially with lower grade gliomas, it is very difficult to distinguish abnormal cancer tissue from the normal brain and this technique can really help.

Then the tissue sample goes to a pathologist and a name and histology [is given] for the tumor and a grade. The most important thing these days are the biomarkers that not only help classify tumors, but also are predictive of response to certain therapies. Treatment is tailored, as much as it can be, to the particular type of glioma but most patients will go on to receive external beam radiation therapy. Patients with many of the tumor types will receive the radiation combined with the oral, alkylating agent temozolomide.

Cancer Network: You mentioned temozolamide so could you talk about its role in the treatment of these tumor types and subtypes? Are there other chemotherapies that are often used on their own or in conjunction with the radiotherapy?

Dr. Perry: Historically, the field of neuro-oncology, from the perspective of chemotherapy, started with drugs such as carmustine and thereafter, PCV (procarbazine, lomustine and vincristine). PCV was a very commonly adopted strategy until what we call the temozolamide era emerged. Temozolamide was developed in the 1980s and 1990s and the clinical trials started in the late 1990s. [It] is an oral alkylating agent that is much better tolerated than PCV chemotherapies or the nitrosoureas used historically like carmustine.

A real change in the field happened in 2005 with the publication of the so-called Stupp protocol based on our colleague Roger Stupp who led an international trial testing the role of temozolamide chemotherapy given concurrent with radiation and followed by adjuvant or maintenance oral temozolomide. The field shifted at that point because we had not really had a positive clinical trial for decades prior to that, so there was finally a standard drug therapy. From that success in glioblastoma, multiple groups around the world have tested temozolomide in a variety of other glioma subtypes, including anaplastic astrocytoma and oligodendrogliomas.

All of these tend to be quite sensitive to temozolomides, and oligodendrogliomas in particular are one of the most chemo-sensitive human, solid malignancies. One of the downsides of temozolomide is that its activity is very dependent on a DNA repair enzyme, MGMT [O⁶-methylguanine DNA methyltransferase], so patients that have high expression of MGMT don’t do well because the alkylating damage induced by temozolomide is quickly repaired.

About 40% of patients with glioblastoma have random hyper-methylation of the MGMT gene promoter region, effectively shutting off the gene, and diminishing MGMT expression in the tumor cells. Those folks, the 40% or so with this MGMT promoter methylation, have much better prognosis and response. So a sort of hole in our field that remains are the 60% of patients with GBM that don’t harbor the MGMT promoter methylation which is a very easily determined biomarker in the lab and is routinely done these days.

Essentially 60% of patients receive no benefit from the drug and there really is not an effective chemotherapy agent in standard practice at this point for this unmethylated MGMT promoter situation.

Cancer Network: Lastly, are there novel therapies in development or novel combinations for either of these tumor types that are particularly interesting or promising that you could highlight?

Dr. Perry: Sure, the first caveat is that our field is, unfortunately, lagging behind other cancers in that regard. We all went through the era of targeted therapies and the promise of targeted therapies and we’ve seen those evolve. For example, EGFR inhibitors for lung cancer. The issue for us as neuro-oncologists is the presence of the blood brain barrier and the way our clinical trials were designed were insufficient at detecting that the vast majority of these compounds were not brain-penetrant.  We had a huge number of negative phase II and phase III clinical trials testing these approaches. They never had a chance because they were not getting into the brain in sufficient concentrations.

I mention that because we are in the midst of the newest revolution with immunotherapies including oncolytic viruses and vaccine approaches and we are facing the same kinds of challenges compared to other cancer types. What seems to be promising now is the combination of immunotherapy strategies with anti-angiogenic strategies. So, bevacizumab is fully FDA approved and is routinely used for recurrent gliomas, especially glioblastoma, and it has excellent symptomatic effects although has never really been shown to enhance survival. The immunotherapies have been a challenge on their own.

All of the published vaccine trials have not shown much promise and the checkpoint inhibitors, when used as single agents essentially have no activity. When combined, they have some activity but a lot of toxicity. Newer trials that have shown promise have combined those approaches, whether it's vaccine-based, or checkpoint inhibitor based combined with bevacizumab or other experimental anti-VEGF [Vascular endothelial growth factor] treatments. That is one of the major areas of focus for those of us involved in cooperative group and other trials, trying to find the optimal combination approaches and there have been some exciting early results as there always are when you are trying new things and it remains to be seen how things evolve over the next couple of years.

Cancer Network: Thank you so much for joining us today Dr. Perry.

Dr. Perry: Sure, it was a pleasure, thank you.