Written by Head for the Cure Ambassador, Dr. Simon Khagi.
Dr. Khagi is an Assistant Professor of Medicine and Neurosurgery at the University of North Carolina, Director of the UNC Neuro-Oncology Program, and the Director of the UNC Brain Metastases Program.
Everyone approaches the diagnosis of a brain tumor in their own unique way. After being told of their diagnosis, patients with a glioblastoma can have a range of emotions. If they had prior knowledge of their disease before meeting me for the first time, they may have already taken the time to “Google” what this may mean to them. However, each individual glioblastoma can be as different and unique as the patient that is diagnosed with it.
A glioblastoma (GBM) is a cancer. Occasionally, these may be referred to as tumors. However, the word tumor implies a very different biology and can be disingenuous to the actual implications of being diagnosed with a GBM. Many patients may hear the word tumor and think that it can be readily removed given that it’s distinct and separate from the rest of the brain. The biology of a GBM varies greatly from one patient to another, but we know that these cancers are by no means confined to a solitary ball of cells that slowly gets larger. A GBM has the propensity to spread and diffusely infiltrate various parts of the brain. These areas of disease may not be readily apparent on a brain scan.
When patients first present with their symptoms, some form of brain imaging is obtained to determine the cause of their complaints. It may start out with a computer tomography (CT) scan followed by a magnetic resonance imaging (MRI) scan. The diagnosis of a GBM cannot be made based on imaging alone; in fact, many times doctors may need to scan the entire body to rule out the possibility that a brain lesion is not part of a metastatic cancer arising from a different organ. If there are no other areas of disease within the body, the likelihood that the brain lesion represents a GBM is much higher. However, obtaining tissue is key in determining any further course of action.
After being given medications for their symptoms (usually steroids with or without antiseizure medications), patients will likely meet with a neurosurgeon to discuss next steps. Ideally, the neurosurgeon they’re meeting has some expertise in the removal of brain tumors. Depending on the expertise of the surgeon, the location of the disease, and the physical fitness of the patient, either a biopsy or a more extensive resection is performed. Studies have shown that more extensive resections can lead to longer survival for patients with GBM. However, a surgeon, no matter how skilled, can never “get it all” given that, even at diagnosis, the disease has diffusely spread beyond what can be visualized during the surgery.
Making the Diagnosis
After acquiring the tissue sample, a diagnosis can be made by a pathologist. However, that is only the beginning of how we define a GBM. In the past 20 years, there has been an extensive amount of research that has yielded insights into the “genetic drivers” of GBM. These are not the genetics of the patient, but rather of the disease itself. In a way, a GBM is a separate entity from the patient—almost like another person with their own set of genes that is potentiating its own existence. Among the more standard genes that we look at is isocitrate dehydrogenase (IDH), methylguanine methyltransferase (MGMT), and telomerase reverse transcriptase (TERT). Alterations in these genes yield important insights into the potential behavior of the disease, with the MGMT gene alterations predicting either a good or inadequate response to chemotherapy and radiation.
After discharge from the hospital, patients will meet the team that will be taking care of them moving forward. This team is usually comprised of a medical oncologist or a neuro-oncologist, as well as a radiation oncologist. Other members of the team may include a nurse navigator and advanced practice provider (i.e. nurse practitioner or a physician assistant). The initial meeting can be overwhelming, but sets the foundation for how a treatment plan will be formulated. Further genetic testing may be discussed and requested, with these results offering even more insight into the biological behavior of the disease and potential options for novel treatment strategies. It is important to consider the expertise of the team that is taking care of the patient. Clinicians with significant experience in the management of GBM should be a part of the treatment team; particularly, a fellowship-trained neuro-oncologist can provide significant insight regarding novel treatments, management of neurological complications, and clinical trial options.
Centers with Clinical Trials
Clinical trials play an incredibly important role in the management of GBM. Being plugged into a center with clinical trial options at the time of diagnosis is ideal. If that isn’t an option, then having access to a center with clinical trial options at the time of disease recurrence is the next best thing. In the absence of a clinical trial at the time of diagnosis, a patient could be offered chemotherapy combined with radiation. After the completion of this combined course of therapy, maintenance chemotherapy combined with a device called Optune® may also be recommended.
Chemotherapy and Radiation
The role of chemotherapy and radiation in GBM has been established from clinical trials done almost 20 years ago, which showed a survival advantage in those patients who had chemotherapy combined with radiation versus radiation alone. The theorized mechanism of action of chemotherapy and radiation is that, when combined, the two treatments lead to DNA damage in tumor cells. If a tumor cell has damaged DNA, that cell will stop replicating and potentially die. The hope is these treatments kill off enough tumor cells and leave healthy cells alone, which would lead to a prolonged period of survival and minimal side effects for these patients.
Chemotherapy prescribed after this combination form of treatment entails taking it 5 days on and 23 days off. We call this a 28-day cycle and are repeated 6 to 12 times depending on the rationale of the treating physician. This is meant to keep the tumor from dividing; however, tumor cells may not be dying and, instead, are being kept from dividing. The addition of Optune® is also considered.
What is Optune®?
Optune®, otherwise known as tumor treating fields, is a first-of-its-kind device that is applied externally to a shaved scalp. It uses rapidly alternating electromagnetic fields (similar to radio waves) to interfere with the process of cell division. It is meant to only impact those cells that are rapidly dividing (i.e. cancer cells) and leave normal brain cells alone. In a large randomized clinical trial, the combination of Optune® and chemotherapy yielded a survival advantage compared to just chemotherapy alone.
In select patients with glioblastoma who have a poorly functioning MGMT gene (i.e. methylated), there is emerging evidence that the combination of two types of chemotherapy might be more effective than one chemotherapy alone. A study out of Germany evaluated the addition of lomustine (CCNU) and temozolomide (TMZ) with radiation, followed by 42-day cycles of CCNU and TMZ, compared to the standard regimen (described above), and found that the combination prolonged survival significantly. This regimen did not include the use of Optune®. The explanation behind these promising results is that the more chemotherapy a particularly sensitive GBM sees, the better. Of course, tolerance needs to be considered when recommending such a regimen and age plays an important factor in recommending this kind of treatment approach.
Age is a very important factor when considering therapy for GBM. Given that the disease afflicts mainly people over the age of 60, a physician needs to take in to account other medical problems of the patient and their baseline “fitness” (i.e. performance status) when deciding on a course of action. For very frail patients, sometimes the best course of action is a short course of radiation or perhaps chemotherapy alone. In others, an abbreviated (i.e. 3 week) combination can be tolerable, as demonstrated in a recent clinical trial in patients over the age of 65. When treating GBM it is very important to listen to the patient and family, and really understand how they feel about potentially losing some quality of life in pursuit of a minimal amount of quantity of life. Values are important.
Importance of Clinical Trials
Another important aspect of care to consider are clinical trials. The field of neuro-oncology is rapidly evolving and new ways of treating cancer are being tested. Some clinical trials are looking to make radiation even more potent. Other studies are assessing how best to implement immunotherapy by inducing immunological memory through peptide and DNA vaccines. And still others are looking to infect cancer cells with viruses and further stimulate the immune system with medicines that activate a robust response against the virally-infected cancer. There are hundreds of studies that are being run across the country. Any patient who is diagnosed with a GBM, should start the process early in identifying potential studies and inquiring with the center that is running the study about enrollment eligibility. There are lots of caveats to enrollment. Be sure to check out my previous post about clinical trials to understand what to expect and what questions to ask.
Living with a GBM is a journey. Along this journey, I recommend to all my patients that they educate themselves about their disease, treatment options, and potential clinical trials for the future. I consider myself a guide in the process and I hope to empower my patients to make informed decisions about their care, to balance the quality-quantity of life equation, and to be advocates for themselves.