While primary malignant brain tumors account for only 2% of all adult cancers, these deadly neoplasms cause severe cancer-related disability; the 5-year survival rates for brain tumors rank third lowest among all cancers, with those for pancreas and lung cancers being first and second lowest, respectively. However, new developments in molecular biology have led to a better understanding and classification of central nervous system (CNS) tumors, offering the potential for the development of promising new treatments. Internationally regarded brain tumor expert Tracy Batchelor, MD, spoke with The ASCO Post about recent advances and future directions in the treatment of CNS tumors.
Major Advances
What have been the biggest advances in brain tumor treatment over the course of your career?
I would arrange the advances according to surgical, radiation, and medical therapies. Certainly in the surgical setting, the advent of intraoperative magnetic resonance imaging (MRI) has markedly increased our ability to perform complete and much safer resection of various types of CNS tumors.
In radiation, we’ve seen the development of far more precise and controlled conformal techniques, which limits the amount of neurotoxicity that was associated with older radiation delivery techniques. The newer conformal techniques also offer the possibility of limiting the long-term side cognitive and endocrine effects of brain irradiation.
By far, the two biggest advances in medical therapy have been the U.S. Food and Drug Administration approval of temozolomide in 2005 and bevacizumab (Avastin) in 2009, both indicated for glioblastoma—the deadliest of CNS tumors. It’s important to highlight diagnostic and pathologic advances as well. Over the past several years, we’ve seen the expanded use of tumor profiling, which, for instance, has allowed us to divide glioblastoma into more relevant biologic categories. The next WHO classification of CNS tumors will incorporate molecular markers for the first time. Most importantly, this new information will ultimately be the basis for the development of more personalized therapies and better-designed clinical trials.
Clinical Challenges
Please discuss the different clinical challenges involved in managing brain metastases and primary tumors.
Brain metastases are more difficult to treat than most primary brain tumors, because by the time they develop in the brain they are usually the result of advanced, refractory cancer that hasn’t responded to standard treatments. Another challenge is that it is very difficult to deliver some of the newer targeted drugs effective in lung cancer, melanoma and other malignancies to the brain, as these agents have difficulty crossing the blood-brain barrier.
This area is in desperate need of new therapies, but before we get there, we need to have a better scientific understanding of the metastatic process as a whole. Consequently, the treatment options in surgery and radiation for brain metastases haven’t really changed much over the past decade.
Naturally, we still have a lot of work to do in primary brain tumors, but since we’re usually not dealing with the burden of widespread disease in those cases, it becomes a more focused challenge. Recently completed randomized trials have identified new drug combinations (bevacizumab plus lomustine), immunotherapies (rindopepimut) and novel techniques (alternating electrical fields) that may prove to be useful for glioblastoma patients.
CNS Lymphoma
CNS lymphoma has historically been associated with poor survival. Over the past decade, however, we’ve seen some improvement in survival. Please give the readers an update on this issue.
Outcomes for primary CNS diffuse large B-cell lymphoma (PCNSL), > 90% of all cases of primary CNS lymphoma, remain inferior to other extranodual forms of non-Hodgkin lymphoma. This may be due to the fact that > 90% of PCNSL cases consist of the more aggressive activated B-cell–like form. The improvement we’ve seen in PCNSL is due largely to the development of customized chemotherapy regimens that can cross the blood brain barrier and effectively treat the lymphoma. The drug combinations used to treat a non-Hodgkin lymphoma of the body are very different from those used to treat PCNSL. As we’ve gotten better at devising ways that allow our patients to tolerate high-dose therapy, we’re now seeing early evidence suggesting that combining high-dose chemotherapy and bone marrow transplant could be quite effective for this group of patients. Also, investigators are developing treatment regimens for PCNSL that include targeted agents with demonstrated activity against the activated B-cell subtype of diffuse large B-cell lymphoma.
Moreover, we’ve finally reached a point in this rare brain cancer where we are able to conduct cooperative group randomized clinical trials. It’s important to note that when I began in this field, there had only been one published randomized trial that was terminated early because it failed to get proper accrual numbers. Now we have three completed and five ongoing randomized trials. So, for the first time we are truly beginning to develop some evidence-based medical practice data around PCNSL.
Treatment Tolerance
You mentioned that a major step forward in treatment and research came with patients’ ability to tolerate regimens such as high-dose chemotherapy with bone marrow transplantation. Please elaborate on that.
First of all, not every patient is a candidate for transplantation, because many of the older patients are not. But in those patients with adequate organ function who are candidates for bone marrow transplant, we now have much better supportive treatments that allow them to tolerate the toxicities associated with these rather aggressive therapies.
Detection and Diagnosis
Please talk a bit about the challenges involved in detection and diagnosis of brain tumors.
A big challenge in detection is that neurologic symptoms due to a brain tumor have many similarities to other neurologic disorders such as stroke or multiple sclerosis. Given the dearth of symptoms unique to brain tumors, there is no way for early detection unless you use imaging. Since these are relatively rare tumors, there is no rationale to use imaging as a screening tool. Plus, we currently have no curative therapies for the most common primary brain cancers like glioblastoma.
On the other hand, if certain symptoms could possibly be caused by a brain tumor, then we advise a contrast-enhanced brain MRI, which in most cases gives us enough information either to rule a tumor out or make an accurate diagnosis. Because surgical techniques and peri-operative care have improved so much, resection or biopsy of a brain is much safer with far less chance of side effects.
Closing Thoughts
Do you have any closing thoughts on this very difficult oncologic setting that you’ve devoted much of your career to?
In this varied group of CNS malignancies, glioblastoma is where we have the most work to do and the biggest clinical and scientific questions to answer. A promising area is in molecular diagnostics, which enable us to subdivide glioblastomas into specific subtypes, giving us an opportunity to develop more personalized therapeutic approaches and clinical trials. At the same time, by reclassifying an uncommon tumor like glioblastoma into multiple molecular groups, we are creating rare biological tumor subtypes, which makes it more difficult to execute clinical trials.
This highlights the need for those of us in the clinical and research communities to develop and standardize molecular profiling platforms so that we’re all on the same page with regard to the markers we are using to classify tumors. Once we cross that bridge, we need to initiate large cooperative group and intergroup studies so that we have the numbers to adequately investigate these targeted drugs in subtypes of glioblastoma.
Another area of promise in glioblastoma is immunotherapy. We’re anticipating the results of a randomized trial that should be wrapping up fairly soon. There are also some interesting glioblastoma studies underway examining the role of vaccines and checkpoint inhibitors. And, as mentioned, we are still hopeful that combinations of certain antiangiogenic treatments will prove active in glioblastoma. We have a long way to go, but there is also great promise in several areas that didn’t exist a decade ago. ■
Disclosure: Dr. Batchelor reported no potential conflicts of interest.
