There are few diagnoses in medicine as dreaded for patients to receive, and for physicians to give, as brain cancer. Having shared this news countless times with patients, I can say two things with certainty: The responses are as varied as the patients themselves, and after the initial shock, the questions are almost universal: "How long do I have left?" "What do I do next?" and "How can I fight this?"
In medical school, we are taught to master knowledge of the common and the deadly. In the world of brain tumours, the two are one and the same with glioblastoma multiforme, the most common primary brain tumour in adults, and also the most aggressive. The last two decades, however, have seen major advances in imaging, genetics, neurosurgery, and adjuvant therapy that are now reshaping how we understand and treat these tumours. There is reason to believe that the next few years will offer hope to the many patients and families with this disease – a disorder that crosses all social, socioeconomic, educational, racial, and gender lines, and is able to fell even the most heroic among us.
What is glioblastoma multiforme?
Glioblastoma multiforme (GBM) is a primary brain tumour that arises from the support cells of the brain, known as astrocytes. Tumours of astrocytes, known as astrocytomas, come in 4 grades, determined by their appearance and characteristics under a microscope. High-grade astrocytomas contain evidence of increased cell division, new blood vessel growth, and necrotic brain tissue – all suggestive of more aggressive tumour behaviour. GBM represents the highest-grade astrocytoma, Grade 4, and is also the most common of the astrocytomas.
How is glioblastoma currently treated?
Current treatments for GBM can be classified as local and generalized. First line treatment is usually surgery, where the goals are three-fold:
- Remove as much of the tumour as safely possible;
- Obtain tissue for diagnosis and molecular characterization; and
- Relieve pressure on the brain to treat any symptoms, if present – e.g., seizures, etc.
Following surgery, patients undergo treatment with combined chemotherapy and, typically, focused radiation therapy (also referred to as "adjuvant therapy"). Serial MRI scans are performed during the six weeks of prescribed treatment and some patients go on to receive six additional months of chemotherapy, following a discussion with their oncologist. Surgery is sometimes repeated for tumour recurrence, often after careful consideration and discussion with the treating team.
GBM has traditionally been among the most challenging of the brain tumours to treat. The challenges are many, and include:
- The rapid rate with which tumour cells divide and grow;
- The presence of necrosis which makes chemo- and radiation therapy more challenging;
- The inability of potentially helpful chemotherapy treatments to access the tumour due to the blood-brain barrier; and
- The late stage at which the tumour is detected. Often, by the time patients present, their tumour has caused a significant amount of brain irritation and swelling. Tumour cells have often already migrated to remote regions of the brain, beyond what can be seen on imaging.
The last two decades have seen a dramatic increase in our understanding of GBM, and especially in its molecular characteristics. It is becoming clear that not every GBM is alike, and that the genetic characteristics of a tumour can determine not only its behaviour but, more importantly, its response to treatment. This will allow specific treatments to be tailored to specific tumours.
How can focused ultrasound be used for GBM?
Focused Ultrasound (FUS) is an image-guided, less invasive, surgical approach to accessing brain disease. It is a novel technology that harnesses the power of multiple sources of ultrasound energy (sound waves), which can be directed to specific targets within the brain, without damaging or disturbing adjacent tissue. At the focal point, high frequency FUS raises temperatures to the point where tissue is destroyed and a lesion is made. As a result, high frequency FUS has emerged as an important treatment alternative in conditions where generating a lesion may be useful, such as for essential tremor or some of the disabling symptoms of Parkinson's disease. Focused ultrasound technology, however, can be used in many other ways, some of which may be able address the very challenges listed above that make treating brain tumours so difficult. These "mechanisms of action" include:
- Ablation: Using FUS to permanently destroy tumour tissue, particularly in brain regions where open surgery may be too risky.
- Histotripsy: Non-thermal ultrasound shockwaves that mechanically disrupt and destroy tumour cells.
- Enhance radiation therapy through moderate hyperthermia pre-conditioning.
- Enhance delivery of chemotherapy by transiently opening the blood-brain barrier.
- Localized and controlled release of chemotherapy from nanoparticles and microbubbles.
- Enhancing immune response to tumours by facilitating release of tumour antigens.
- Increase cell and drug delivery to tumours by increasing vascular permeability.
- Influence the effect of immunotherapy compounds.
What is the future of GBM treatment?
At no point in history have we known more about glioblastomas than now – how they behave and how they may respond to treatment. Although the diagnosis will always be difficult to say and to hear, there is hope that GBM can be a disease managed chronically, with life expectancy measured in many years, rather than months. Advances will come in many forms, but on the close horizon these will include:
- Better molecular characterization of tumours that will allow clinicians to tailor chemo- and radiation therapy to specific tumour types;
- Immunotherapy treatments that target tumour antigens, to more specifically and effectively kill tumour cells while sparing healthy brain; and
- Adjuvant therapy with focused ultrasound, to facilitate the delivery of chemotherapy across the blood-brain barrier.
While the world mourns the recent loss of Senator McCain, patients and their families can find some solace that his condition sparked increased awareness and support for brain tumor research. Focused ultrasound technology may someday be part of a treatment equation that will result in improved outcomes and better quality of life for glioblastoma patients. Together with the Focused Ultrasound Foundation, we at Sunnybrook are working to make that a reality as soon possible.
Dr. Lipsman is a neurosurgeon and scientist at Sunnybrook Research Institute and Sunnybrook Health Sciences Centre, and an Assistant Professor in the Department of Surgery at the University of Toronto. He is currently the clinical director for Sunnybrook’s Focused Ultrasound Centre.