We are rapidly enhancing our scientific understanding of the molecular abnormalities that drive these tumors, which will lead to the development of pathway-specific agents that will hopefully increase patient survival.
—Lisa M. DeAngelis, MD
Despite the extremely difficult clinical challenges posed by brain tumors, mortality rates in this disease have decreased somewhat over the past several decades due, in part, to advances in surgical techniques and therapies. The ASCO Post recently discussed contemporary issues in neuro-oncology with Lisa M. DeAngelis, MD, Chair of the Department of Neurology and Co-Executive Director of the Brain Tumor Center at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. Dr. DeAngelis, who was elected to the Institute of Medicine last year, shed light on, among other things, the current state of brain tumor therapies.
Inside the Brain Tumor Center
Please give the readers a glimpse into Sloan-Kettering’s Brain Tumor Center.
It is a virtual multidisciplinary center that encompasses both clinicians and basic investigators from many of Sloan-Kettering’s departments. On the clinical side, it includes neurology, neurosurgery, neuroimaging, neuropathology, and radiation oncology. On the laboratory side, we have translational scientists who work in tandem with our clinicians, as well as basic investigators conducting studies that pertain to brain tumors. So the Brain Tumor Center is truly an aggregate of multiple areas of expertise, all of which are intensely focused on advancing the treatment of brain tumors.
As Executive Co-Director of the Brain Tumor Center, what do your daily duties encompass?
I have a very varied set of responsibilities. I do see patients 1 full day a week and occasionally on our consult service. As Chair of the department, I do a fair amount of administrative work, which also involves educational activities at the resident and fellow levels, and I help junior faculty develop their careers. I do not have a laboratory program, but I am very engaged in our ongoing clinical research projects.
Given the issues with false-positives in other clinical scenarios, where do we stand in brain imaging as it relates to detection?
Brain imaging has undergone a revolution over the past couple of decades. We rely almost exclusively on MRI as our standard neuroimaging modality, and the technology is actually quite good at detecting early abnormalities in the brain, as far as anatomy and localization are concerned. In some scenarios, using advanced imaging tools such as spectroscopy or perfusion techniques, we can actually get an indication of the tumor type or grade. That said, there are no imaging techniques that replace tissue samples for diagnosis.
The challenge in brain imaging comes not so much at the point of diagnosis but rather during the course of treatment. Imaging helps us to interpret disease response and progression and helps us differentiate tumor from the actual effects of treatment. This is important because when tumors are treated effectively, there is residual dead tissue and inflammatory debris in the area where the tumor was. The brain lacks a lymphatic system and lymph nodes to provide drainage, so it takes much longer for some of this material to clear than it would in other parts of the body. It can also incite an inflammatory response leading to edema and causing this remaining debris to look exactly like tumor tissue. This is a big challenge for us.
Another imaging challenge is posed by our increasing use of bevacizumab (Avastin) and other antiangiogenic agents, which interfere with the scan’s ability to outline the tumor definitively using intravenous contrasts. This lack of visual specificity on the scan consequently makes it harder to determine what’s happening clinically with the disease. Thus, most of our imaging
challenges arise during the course of treatment delivery.
You mentioned an increased use of antiangiogenics in brain tumors. Do these agents show promise in gliomas?
Bevacizumab recently received FDA accelerated approval for recurrent glioblastoma. So far, two large randomized phase III trials incorporating bevacizumab into initial therapy have been completed. One, the AVAglio study, predominantly conducted in Europe, has shown significant improvement in progression-free survival when adding bevacizumab to upfront chemoradiation. We are currently waiting for overall survival data and the results from a Radiation Therapy Oncology Group (RTOG) phase III bevacizumab study. These trials will likely define the role of bevacizumab in the treatment of glioblastoma, and antiangiogenic agents still need further study in other grades of glioma.
What’s currently under investigation at your center?
One area of clinical interest is the epidermal growth factor receptor (EGFR) pathway that is upregulated in about 40% of glioblastomas and has been associated with a specific mutation called EGFRvIII, which is seen in about 20% of glioblastoma patients. However, our research has demonstrated that the standard anti-EGFR drugs are not effective in this disease. Recently published work by Dr. Ingo Mellinghoff at MSKCC points to several problems with studies looking at the EGRF pathway, such as not achieving adequate drug level in the brain.1 This suggests that high-dose pulsatile scheduling might be more effective. We are looking at that in clinical trials.
In addition, the anti-EGFR agents—like erlotinib (Tarceva)—that are useful in lung cancer do not bind very well to the specific EGFR conformation that we see in glioblastomas harboring the EGFRvIII mutation. Alternatively, drugs like lapatinib (Tykerb) bind more effectively and if given in a high-dose pulsatile schedule might prove more effective. This will be studied in a trial currently under development by Dr. Mellinghoff.
Growing Array of Clinical Successes
Any last thoughts about your work in this very difficult clinical scenario?
I have been optimistic about making a difference in brain tumors since the beginning of my career, which is one of the reasons I’ve been able to remain focused on my clinical work. This is a particularly exciting time in our understanding of brain tumors and our ability to translate that knowledge into a growing array of clinical successes.
It’s important to note that when I began my career in neuro-oncology, nobody was interested in this field. Brain tumors were considered a terminal disease, and the mindset was that any treatment, even one that conferred survival benefit, would leave the patient compromised by brain-tissue destruction that was irreparable. However, what we’ve learned over the years is that our patients can do remarkably well when we control their disease in ways that are sensitive to quality-of-life issues.
Moreover, we are rapidly enhancing our scientific understanding of the molecular abnormalities that drive these tumors, which will lead to the development of pathway-specific agents that will hopefully increase patient survival. Neuro-oncology is such an exciting field within cancer care, and I hope it will continue to attract enthusiastic young people from our medical schools. ■
Disclosure: Dr. DeAngelis reported no potential conflicts of interest.
1. Vivanco I, Robins HI, Rophie D, et al: Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458-471, 2012.