What are the Options for High-Grade Gliomas?
- High-grade gliomas, which include the highly aggressive glioblastoma multiforme (GBM), continue to pose treatment challenges. Despite the continued advances in surgical techniques, chemotherapy, radiation, and tumor treating fields (Optune), the prognosis for patients with high-grade gliomas remains relatively poor.
- Doctors may try to find a clinical trial for patients with very high-grade gliomas or GBM, so the patients can gain access to new and innovative drugs that have not yet been approved by the Food and Drug Administration (FDA).
- If a clinical trial is unavailable, standard treatment for glioblastoma includes maximal safe surgical resection (where as much of the cancer as possible is removed), followed by radiation therapy given together with chemotherapy. Then, additional chemotherapy is given alongside tumor treating fields (Optune).
- Dr. Henry Friedman, Deputy Director of the Preston Robert Tisch Brain Tumor Center at Duke University, tells SurvivorNet that his team takes a “standard of care plus” approach, which involves looking at the molecular composition of the tumor and potentially using drugs off-label.
- It is worth nothing that while the “standard of care plus” approach may be valid and appropriate for a particular patient, there could be insurance implications and it is important to discuss specific safety data to support its use with your oncologist particularly given many of these “novel” drugs used in other conditions may have serious safety concerns.
Often gliomas are split into two broad categories of low grade and high grade gliomas. Low grade gliomas are often less aggressive and can often be treated with less intensive therapy. Meanwhile high grade gliomas tend to have a more aggressive disease course and require multiple types of treatment. This may include surgery, radiation, and chemotherapy, among others.
Read MoreThe Role of Clinical Trials
Clinical trials play an important role in the medical field as whole, helping to continually improve patient care by finding the best possible treatment for each disease. This is especially true with clinical trials in the field of cancer and high-grade gliomas. The results from these clinical trials serve multiple purposes. When trials are found to be positive, it can help to create a new standard-of-care for the treatment of high-grade gliomas — either improving the survival and disease progression from treatment or reducing toxicities from treatment while being equally effective.Additionally, each trial helps to increase understanding of high-grade gliomas and glioblastomas and provide invaluable information that can inform future clinical trials. While clinical trials are important for future research and discovery, there is a lot to improve upon. “There are a lot of barriers to patients participating in clinical trials, but it’s notable to me that less than about 15% of patients with glioblastoma will participate in clinical trials.” Dr. Thompson adds.
What is a Clinical Trial? Understanding the Types
No two clinical trials are the same. Although many trials may sounds similar, each one seeks to ask a unique question in a specific group of patients. They may be testing a new drug, a new procedure, a different mode of radiation, or a new medical device. Trials can ask several questions including how effective treatments are and what the safety and toxicity look like. There a various questions and markers of treatment success and safety that can be analyzed, which again can vary significantly based on each trial. The specific questions asked help to design specifically how the trial is run and how many patients are needed for the trial among other things.
Clinical trials can vary in size and the questions they are asking in a major way. They are also broken down into different phases.
Phase I clinical trials are mostly concerned with determining how safe a drug or therapy is, and what the effective dose of the treatment should be. Although the new treatment has promising data from preclinical testing (often performed in labs), the effectiveness for the patient is unclear. A phase I trial is often smaller and enrolls 20 – 100 patients.
Phase II trials seek to examine the effectiveness of a drug or treatment. There are often 100 or more patients enrolled on phase II trials. These trials are typically randomized where patients are randomly assigned to receive the new treatment versus a placebo or standard of care treatment. Additional safety and toxicity data can be generated as well. If the patients who receive the new therapy are shown to have a benefit the study can move on to a phase III trial.
Phase III trials are often large and performed at multiple centers across the country and even internationally. Often hundreds of patients are enrolled and randomized to the new treatment group or the standard-of-care group. If the results are positive and show a benefit, this new treatment can potentially become the new standard-of-care for treatment or be considered in certain cases.
Current Treatments & Limitations
The standard treatment for glioblastoma includes maximal safe surgical resection (where as much of the cancer as possible is removed), followed by radiation therapy given together with chemotherapy. Following the completion of radiation and chemotherapy together, a more dose intensive chemotherapy is given typically for six cycles over the course of six months while the patient uses tumor treating fields (Optune). The chemotherapy typically used during radiation and in the months following is called Temozolomide.
So in summary the optimal treatment is as follows:
- Surgery
- Radiation and Chemotherapy (Temozolomide) for six weeks
- Temozolomide with Tumor Treating Fields (Optune) for approximately six months
Despite these interventions, only around 10% of patients are alive at five years, with a median survival of approximately two years following diagnosis with most tumors recurring after initial treatment.
Given this data, Dr. Henry Friedman, the Deputy Director of the Preston Robert Tisch Brain Tumor Center at Duke University, tells SurvivorNet that “we always prefer clinical trials and if there is no clinical trial … we use standard of care.” However, he explains that at Duke, the team uses something they refer to as “standard of care plus.”
“We also will look at the molecular composition of the tumor, and let’s say it has a mutation that is seen in other cancers and there are drugs on the market for it. We’ll simply do an off-label use of the drug to treat the tumor with this other agent,” Dr. Friedman explains. “We may not know for sure that it’s going to work, but we’ve got good reason to think it may because it’s targeting the same mutation for which it was approved by the FDA.
“This is a controversial intervention. Almost every program in the country will say clinical trial, standard of care. That’s all she wrote. But we don’t believe in that. We believe that just like in regular non neuro-oncology, oncology for solid tumors, leukemia, whatever, if you’ve got agents that you can identify what therapies you can identify, which may help the outcome, why not use it?”
There are important considerations that are necessary when exploring this approach and you should speak with your oncologist. For example while certain treatments may be valid, the cost may not be covered by insurance or the manufacturer. Additionally safety implications should be discussed at length. There is not safety data to support the use and as such caution should be exercised. Quality if life is a serious factor and many of these drugs used in other conditions can have very real safety issues. Be sure to speak with your oncologist.
Why are High-Grade Gliomas and Glioblastomas So Difficult to Treat?
There are a few reasons these cancers are particularly difficult to treat, including:
- Infiltrative nature: Unlike some other tumors which can have well defined borders, glioblastomas invade surrounding brain tissue, making it impossible to remove all tumor cells surgically without leading to significant neurologic deficits
- Genetic and molecular complexity: Glioblastomas are very heterogeneous, meaning different parts of the tumor can have different genetic mutations and molecular characteristics which makes it difficult to develop a treatment that is effective for all cancer cells. Additionally, GBMs have cancer stem cells, which are classically resistant to many forms of treatment including radiation and chemotherapy
- Blood-brain barrier: The lining of the blood vessels in the brain and spinal cord is an important protective barrier in most circumstances, but when trying to treat a brain tumor it limits the ability of many drugs to reach the tumor. Additionally in the brain tissue itself, the dense network of vessels, cells, and other tissue can make it difficult for drugs to disperse and appropriately reach brain tumors.
Given these challenges in creating effective therapies and the overall poor prognosis for these aggressive brain tumors, there is a critical need for new treatment options. Clinical trials provide a structured way to test the efficacy of new therapies against the current standard of care, and explore questions that lead to new discoveries and improved understanding of high-grade gliomas that can lead to more effective and safer treatments down the road. Without clinical trials, it would be impossible to accurately evaluate the safety and effectiveness of these new approaches in a controlled environment, leaving patients with limited or even harmful treatment options.
Developing Personalized Medicine Approaches
One of the major advancements in cancer research over the past several years has been the shift toward precision medicine — where the treatments are tailored to the specific genetic and molecular characteristics of a patient’s tumor.
Through the work of clinical trials and the data collected, there has been advancements in treatment which maximize effectiveness while limiting toxicity. There have also been important steps made in further personalizing the treatment recommendations in the treatment of high-grade glioma. A recent update from the World Health Organization (WHO) in 2021 made the critical distinction that gliomas need to be classified and treated based on molecular and genetic markers which are closely linked to the behavior of gliomas and overall prognosis.
Specifically, researchers identified several genetic mutations and molecular markers that are common in high-grade gliomas and glioblastomas, such as mutations in IDH in grade 3 gliomas or methylation of the MGMT promoter for glioblastomas. These genetic alterations can influence how a tumor responds to treatment. Clinical trials can help determine which therapies are most effective for patients with specific genetic profiles. These findings were only made possible through the work of clinical trials. Further research will continue to personalize and improve upon treatment recommendations.
Advancing Immunotherapy for Glioblastoma
Immunotherapy, which rallies the body’s immune system to attack cancer cells, has revolutionized the treatment and become standard-of-care for several types of cancer, including melanoma and lung cancer. While there is the potential for immunotherapy to be effective in the treatment of glioblastoma and other high-grade gliomas, these disease pose a unique challenge given their location in the brain, which allows it to evade the normal immune system responses.
Regardless, there have been numerous clinical trials of all stages performed and there continues to be ongoing trials assessing the potential effectiveness. Ongoing immunotherapy research seeks to explore potential effectiveness of checkpoint inhibitors (drugs like pembrolizumab and nivolumab), cancer vaccines, and CAR T-cell therapy.
Although no large clinical trials have demonstrated a significant improvement in outcomes with use of immunotherapy, each trial provides valuable information which allows researches and healthcare providers to further tailor and design clinical trials with the goal to overcome the unique challenges posed by glioblastomas and high-grade gliomas. The hope is that the results from these trials could lead to breakthroughs in the treatment for these cancers.
Exploring Novel Drug Delivery Systems
As stated previously, a big challenge in treating glioblastomas is delivering drugs effectively to the tumor site given several factors including the blood-brain barrier and the diffusion of drugs within the brain tissue. Clinical trials are also seeking to test new drug delivery methods that can bypass or penetrate the blood-brain barrier.
Some clinical trials have investigated various drug delivery methods including convection-enhanced delivery (CED) where drugs are directly infused into the brain tissue surrounding the tumor, nanoparticles which can potentially deliver chemotherapy drugs directly to glioblastoma cells, and drug-loaded wafers which can be implanted in the surgical cavity to deliver chemotherapy directly to the tumor site.
Clinical trials were are necessary to further develop these treatments and ensure they are safe, feasible, and potentially effective for patients with high-grade glioma.
Improving Quality of Life for Patients
While much of the focus in glioblastoma research is on finding treatments that extend survival and slow disease progression, it is important to also consider the quality of life of people undergoing cancer treatment, which can have a significant impact on one’s physical, cognitive, and emotional well-being.
Clinical trials test not only the effectiveness of new therapies, but also how to best deliver treatment and provide supportive therapy that best manages symptoms, reduces the side effects of treatment, and improves quality of life.
Clinical trials are invaluable in the treatment and management of high-grade gliomas. The current treatment guidelines defined as the standard-of-care were shaped by the contributions of countless patients enrolled on a variety of clinical trials and allows physicians to treat patients with high-grade glioma with the best treatment regimens that balance treatment effectiveness and side effects.
Clinical trials continue to be crucial in high-grade gliomas, as the outcomes continue to be less than optimal, leaving plenty of room for further innovation and the development of new drugs, surgical and radiation techniques, and treatment devices that can continue to improve the lives of patients while curing the disease.
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