In the clinical array of brain tumors, glioblastoma is the most difficult to treat, and despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Leading brain tumor experts at the recent 25th Annual Cancer Progress Conference in New York discussed this difficult clinical scenario. The ASCO Post spoke with the chair of the brain tumor session, Minesh P. Mehta, MD, FASTRO, Medical Director of the Maryland Proton Treatment Center at the University of Maryland, Baltimore.
A Lethal Tumor
Please give us a brief natural history of glioblastoma.
Glioblastoma is one of the most malignant neoplasms that affect mankind. It is a relatively uncommon tumor within the wider scope of cancer, but it is one of the most common brain tumors, accounting for almost 20% of all new primary brain tumors.
Its clinical significance rests largely on its lethality, and most patients with glioblastoma will die within the first year of diagnosis. The historic median survival has ranged from 6 to 14 months. It usually presents in the elderly and progresses rapidly. In fact, on computed tomography (CT) scan, we can see a doubling of tumor size within several days.
What are the clinical challenges of such a fast-growing tumor?
Because of such rapid growth within the confines of the skull, it produces considerable edema of the brain. Therefore, we have to manage both the tumor and the consequential mass effect and swelling. The tumor is also highly infiltrative without a well-defined margin that can easily be resected by a neurosurgeon. The tumor we see on a magnetic resonance imaging (MRI) scan is the tip of the iceberg because, even if resected, microscopic infiltrative disease is almost universally present; for most patients with glioblastoma, a total resection is not achievable.
Standard of Care
What are the current management strategies in glioblastoma?
The standard of care is maximal surgical resection followed by combination adjuvant therapy, which is typically 6 weeks of radiation to a total of about a 60-Gy dose in conjunction with the oral alkylating agent temozolomide given every day during the course of radiation therapy. After the 6 weeks of radiation, patients usually stay on maintenance temozolomide for several months, up to a maximum of 12 or so months, depending on how they tolerate the therapy and whether the disease is stable on treatment.
What kind of survival are we seeing after such aggressive management?
Depending on certain patient characteristics, median survival with this standard-of-care approach can range anywhere from 12 to 16 months. We have recognized that a subset of patients appear to do better, especially with this regimen, when we test for the activity of a specific enzyme—O6-alkylguanine-DNA alkyltransferase, known as MGMT.
The test specifically looks at the silencing of MGMT at the epigenetic level. If the enzyme is silenced, the tumor is therefore MGMT-methylated, and the patient will have superior outcome compared with a patient whose tumor does not halt the activity of the MGMT enzyme. So methylation testing has become common practice for many patients with glioblastoma.
Even patients with unmethylated tumors appear to have a modest degree of benefit with the addition of temozolomide. That said, this is a fairly controversial issue, and some in the community contend that the small benefit we see in unmethylated tumors might actually be the result of our failure to detect all patients with methylated tumors.
There is no question that glioblastoma patients with methylated MGMT derive the maximum benefit from combination therapy with temozolomide. However, even in the best of these groups, the median survival is still very poor, and long-term cures are quite uncommon in glioblastoma.
Role of Antiangiogenic Agents
Given the poor prognosis for survival, where do we go from here?
Fortunately, there’s much interest in new therapies. In the past few years, antiangiogenic agents have received a lot of attention, which is not surprising since the tumor induces a substantial degree of neovascularization and secretes a host of proangiogenic factors. In fact, glioblastoma might be the most angiogenic known neoplasm.
Antiangiogenic agents were first used in recurrent glioblastoma with a modest level of activity. On MRI scan, we clearly see a dramatic response. There also appears to be clinical benefit with the reduction of swelling on the brain, and the breakdown of the blood-brain barrier along with the consequential edema all seem to resolve rather quickly.
In short, we have highly symptomatic patients who become functional in a matter of days to weeks after receiving these agents. So there is definitely a place for them in the setting of recurrent symptomatic glioblastoma.
Are we optimistic about seeing durable survival with these agents?
It is still unclear whether antiangiogenic agents produce a genuine, robust response and survival advantage in the recurrent setting. Therefore, the agents were moved upfront to assess survival benefit.
The most widely studied antiangiogenic agent is bevacizumab (Avastin), and earlier this year, two major trials of the drug in glioblastoma were reported in The New England Journal of Medicine—an industry-funded European trial called AVAglio and a National Cancer Institute–funded intergroup trial.1,2 In both trials, the patients were randomly assigned to a backbone of temozolomide and radiation therapy to compare how well they work when given together with or without bevacizumab.
In terms of overall survival, there was no categorical benefit seen in either trial. Some argue that the trials’ crossover design might have taken away from any survival advantage. But if the agent were truly producing a substantial survival benefit, we would have seen that. So even though angiogenic agents clearly have activity in this setting, our ability to convert that activity into meaningful survival prolongation is still not there.
These trials also assessed whether there might be other benefits, such as progression-free survival, which was demonstrated in one of the trials but not the other. The statistical methodology and definitional differences could have influenced why this endpoint was positive in one trial, but not another. But in terms of overall survival, the use of antiangiogenic agents is clearly not a home run.
That said, exploratory work is being conducted to see if there are subsets of patients in whom new agents can be used on other targetable pathways to produce durable responses in glioblastoma. This is a highly heterogeneous tumor, so we need to look at multiple subsets of patients and match those patients with the correct agent.
Other Approaches
What other novel strategies are being looked at?
Traditionally, we have viewed brain tumors as existing in a relatively immune-privileged site, where the penetrability of immune modulators was assumed to be very limited. This concept is now being challenged, and it appears that a number of immune approaches, such as vaccines, could be developed for this tumor.
About 20% to 40% of glioblastomas express a variant form of epidermal growth factor receptor (EGFR). We can use this to develop an anti-EGFR vaccine strategy, and some early phase II trials in this area have already shown promise. We are also looking at immune checkpoint inhibitors that target CTLA-4 activity or PD-1, which could have a role in this disease.
Closing Thoughts
Any last thoughts on this perplexing clinical issue?
It is fair to say that the nihilism once associated with glioblastoma is slowly diminishing because we are beginning to establish strategies that are not necessarily home runs, but singles. Each single is a step closer in identifying subsets of patients who will derive long-term benefits from therapy. We will learn from our failures and enhance our knowledge, which will eventually turn the tide in this disease. ■
Disclosure: Dr. Mehta is a consultant for AbbiVe, BMS, Celldex, Elekta, Merck, Novocure, Novellos, Philips, and Roche; he has received research funding from Novocure; and is on the board of directors, with stock options, for Pharmacyclics.
References
1. Chinot OL, Wick W, Mason W, et al: Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709-722, 2014.
2. Gilbert MR1, Dignam JJ, Armstrong TS, et al: A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699-708, 2014.
