Despite advances in neuroimaging, the development of focused radiation therapy, and more effective chemotherapy, life expectancy for patients with primary malignant tumors of the brain and spinal cord remains stubbornly low at between 15 and 18 months. However, there are significant advances on the horizon that could improve patients’ quality of life and lead to significant increases in survival rates in the near future, said Steven Brem, MD, Co-Director of the Penn Brain Tumor Center, Professor of Neurosurgery, and Chief of Neurosurgical Oncology in the Department of Neurosurgery at the Hospital of the University of Pennsylvania in Philadelphia.
A student of Dr. Judah Folkman’s at Harvard Medical School, Dr. Brem has been a leader in research in angiosuppressive agents in the treatment of malignant brain tumors and is a cofounder of the Adult Brain Tumor Consortium (ABTC), an initiative of the National Cancer Institute. Dr. Brem has performed more than 3,500 brain tumor surgeries and chaired the National Comprehensive Cancer Network (NCCN) committee that developed guidelines for the treatment of brain tumors.
The ASCO Post talked with Dr. Brem about the causes of this deadly cancer and the major shifts in the care of patients with malignant brain tumors.
Survival Statistics
Survival for high-grade gliomas remains low. Is progress being made in extending overall survival rates?
Patients with malignant gliomas are living longer than ever before and they have better quality of life. Overall survival used to be 9 months, and now the average is 15 to 18 months. It’s not a spectacular improvement, but the trend is unmistakable. And there is a definite subgroup—perhaps 20% of patients—who are living over 3 years, with an occasional long-term survivor. So there are definitely reasons to be hopeful.
The combination of temozolomide chemotherapy and radiation therapy in the upfront setting has proved to be a major benefit to patients. The use of bevacizumab (Avastin) in the treatment of recurrent glioblastomas is exciting and has changed the landscape of neuro-oncology because patients experience a significant increase in progression-free survival and enhancement in quality of life.
Bevacizumab starves the tumor of its blood supply, shrinks the size of the tumor, and decreases brain edema. Its discovery revolutionized neuro-oncology—the previous dogma was that large molecules, such as a monoclonal antibody, would be ineffective in the brain because of the blood-brain barrier. The effectiveness of the molecule provided “proof of principle” that a targeted therapy can be highly effective in the brain. Today, there is great interest in developing additional targeted therapies for brain tumors.
The development of high-quality cancer centers housing integrated teams of highly trained nurses and clinicians following NCCN guidelines (and where patients have access to clinical trials) has also led to increased survival. The intensity of overall medical care at these centers with close attention focused on preventing side effects, such as seizures, deep-vein thrombosis, and infections, have improved patient outcomes. But while historic progress has been made, major challenges remain.
Current Research
What research might lead to improved overall survival in the near future?
There are several areas of research we are pursuing. The field of cancer genomics, including pediatric brain tumors, and the advent of personalized medicine will have a tremendous impact on patient outcomes. Glioblastomas were among the first malignant tumors to be decoded by The Cancer Genome Atlas Research Network. These tumors are known to have four distinct molecular subtypes, and we are studying the pathways that determine the specific malignant behaviors.
The Abramson Cancer Center of the University of Pennsylvania has created a Neuro-Oncology Translational Center of Excellence with high-impact projects underway. For example, my colleagues, including Donald M. O’Rourke, MD, Associate Professor of Neurosurgery, and Carl H. June, MD, Richard W. Vague Professor in Immunotherapy, are working to find more effective immunologic therapies for brain tumors. Dr. June published landmark studies in chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. The Penn Brain Tumor Center is working to develop a protocol using T-cell chimeric antigen receptor technology for patients with glioblastomas.
Furthermore, following the advances of the NIH Human Connectome Project [a 5-year endeavor to link brain connectivity to human behavior], we are deciphering the human connectome by mapping the neural pathways in the brain and incorporating the technology into the operating room. Using advanced mathematical modeling, surgeons can visualize what was formerly invisible to the eye, and even invisible under the microscope—the brain’s “wiring diagram.”
In this way, we can tailor our surgery precisely to the region of the tumor boundary, reducing the risk of neurologic complications, such as cognitive impairment, paralysis, or language deficit. Also, since glioblastoma cells follow the white fiber matter pathways, we can better predict tumor growth and strategically plan therapy using newer mathematical models that provide a roadmap of each tumor.
Management Challenges
Is it possible to manage malignant brain tumors in such a way that long-term survival is possible?
Hopefully, we will be able to control glioblastoma growth so that long-term survival becomes commonplace. Glioblastoma is a wily beast, and while we have been able to tame the beast with safer surgery, radiation, and antiangiogenic therapy, brain tumors are a genetically heterogeneous group. Glioblastomas are particularly intractable because, while they do not metastasize throughout the rest of the body, they can spread throughout the entire brain and, therefore, recurrences are inevitable. The biochemical redundancy of the metabolic pathways enables the cells to escape targeted therapies, and resistant cells can invade the surrounding brain.
Underlying Causes
What is research showing about the causes of malignant brain tumors?
Our current research is investigating the root causes of these tumors. For example, it is well known that as we age, we are more likely to be struck by cancer, and this is particularly true of brain cancer.
At the Moffitt Cancer Center, I was part of a team that looked at the DNA gene expression of over 5,000 patients with 10 major types of malignant tumors, including melanoma and breast, colon, lung, and prostate cancers. We compared the DNA of young patients with older patients to see if there were senescence-associated genes. As individual cells age, they are programmed to become harmless and senescent. However, if these same cells are in an inflammatory environment or have gene mutations, they can “switch” to malignancy, as shown by an independent group led by Judith Campisi, PhD. These findings highlight a possible cause of cancer and may explain the link between age, incidence, and aggressiveness of malignant brain tumors.
Our laboratory is also focused on drug discovery and development of novel peptides aimed at blocking glioma invasion and angiogenesis, as well as the molecular pathways that drive the spread of malignant cells throughout the brain.
Looking Ahead
Do you foresee improvements in survival rates in malignant brain tumors over the next decade?
Yes, absolutely. We will see more progress over the next 10 years than we’ve seen over the past 30 or 40 years because we have all the new tools based on genomics and neuroimaging (based on the emerging field of connectomics, which combines neural imaging and histologic techniques to map the neural connections of the nervous system). There is also a realization now that knowing a cancer cell’s mutational status can inform successful treatment and guide therapy, building on the traditional classification of tumors, based on morphology and location. This is indeed an exciting time for the study and treatment of malignant brain cancer. ■
Disclosure: Dr. Brem reported no potential conflicts of interest.
