Selected Podcast
Treatment Strategies for Malignant Gliomas
Ashley Ghiaseddin, M.D., highlights treatment strategies for malignant gliomas. He shares challenges to therapeutic options, the standard approaches to treatment, novel treatment strategies and when it is important to refer to the specialists at UF Health Shands Hospital.
Featuring:
I graduated with a bachelor’s degree in science and business from the University of Notre Dame and completed my medical degree at the University of Toledo. I went on to complete my residency at Indiana University and a neuro-oncology fellowship at Duke University.
I am a member of the Preston A. Wells Jr. Center for Brain Tumor Therapy, where I collaborate with an interdisciplinary team of experts dedicated to delivering patient-centered care and discovering better treatments for brain tumors.
In addition to taking care of patients, I conduct research into novel immunotherapy approaches to treat brain cancer and improve outcomes for patients. I am also interested in population-based studies involving glioblastoma and identifying ways to improve quality of life for patients and caregivers.
I am a leader in the neuro-oncology section of the American Academy of Neurology, and I am a member of the Society for Neuro-Oncology and the American Society of Clinical Oncology.
In my free time, I enjoy spending time with my family, walking, traveling and exploring Florida.
Ashley Ghiaseddin, M.D.
My name is Ashley Ghiaseddin, MD, and I’m a neuro-oncologist and chief of the division of neuro-oncology in UF’s Department of Neurosurgery. I specialize in brain cancer treatment, using targeted methods including chemotherapy, immunotherapy and precision medicine for patients with malignant brain tumors, such as glioblastoma.I graduated with a bachelor’s degree in science and business from the University of Notre Dame and completed my medical degree at the University of Toledo. I went on to complete my residency at Indiana University and a neuro-oncology fellowship at Duke University.
I am a member of the Preston A. Wells Jr. Center for Brain Tumor Therapy, where I collaborate with an interdisciplinary team of experts dedicated to delivering patient-centered care and discovering better treatments for brain tumors.
In addition to taking care of patients, I conduct research into novel immunotherapy approaches to treat brain cancer and improve outcomes for patients. I am also interested in population-based studies involving glioblastoma and identifying ways to improve quality of life for patients and caregivers.
I am a leader in the neuro-oncology section of the American Academy of Neurology, and I am a member of the Society for Neuro-Oncology and the American Society of Clinical Oncology.
In my free time, I enjoy spending time with my family, walking, traveling and exploring Florida.
Transcription:
Melanie Cole: Welcome to UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole, and joining me today is Dr. Ashley Ghiaseddin. He's the chief in the division of Neuro-Oncology at the University of Florida College of Medicine in the Department of Neurosurgery, and he practices at UF Health Shands Hospital. He's here to highlight treatment strategies for malignant gliomas. Dr. Ghiaseddin, it's such a pleasure to have you join us today. I'd like you to start by telling us a little bit about the state of therapies for brain tumors as it has been practiced for the last 20 years or so. How has that evolved?
Dr. Ashley Ghiaseddin: Yeah. Thank you so much for having me, Melanie, and I'm happy to be here today to discuss, treatment therapies in malignant gliomas and where we've been, where we're going, in this, current field and what the environment has been like. I would say that early on, we had been treating, let's say before 2005 patients, who were diagnosed with a malignant glioma, specifically glioblastoma, which is a grade four malignant brain cancer. Patients were treated with surgical resection if they were able to have surgery, followed by radiation therapy. There were several different chemotherapies that were used, but that was not actually a standard of treatment.
It was something that was added and some of those treatments included, nitrous, ureas, such as, lomustine, as well as other options that providers may have given to patients, but really the backbone of treatment with surgical resection and radiation. Then in 2005, temozolomide, which is a DNA al alternating chemotherapy was Really brought on as a standard following a 2005, large study that looked at patients who were treated with radiation, after surgical resection versus the addition of temozolomide to their radiation therapy followed by additional cycles of temozolomide chemotherapy.
That did show a survival benefit. And following that, it really became the standard. Now, the difficult thing has been since 2005. There has been very little development in additional treatments for patients until several years ago the addition of Optune tumor treating fields as a additional option with temozolomide therapy, after they finished chemoradiation has shown a small yet Still important survival benefit for patients. And that is another option that is, offered to patients. Now, in addition to the temozolomide chemotherapy upfront.
Because of that, what you will see much of the time is clinical trial enrollment for patients who have newly diagnosed glioblastomas, as well as in the recurrent setting when the cancer is growing back. So this is always something that we consider for patients if there are clinical trials available. at our institution or around the country. If there are trials available, patients will seek those out. But if we're using just the standard of care and what's been really developed over the past, I'd like to say 17 years, almost since 2005 when chemotherapy, temozolomide was added. We really look at the addition of Optune, a tumor treating field.
Melanie Cole: Well, thank you for that. Then, Doctor, can you please speak a little bit about advances in radiologic imaging that have been instrumental in finding these tumors? And while you're doing that, speak a little bit about the development of complementary technologies such as intraoperative MRI and realtime MRI. Entering the fields of neurosurgery and neuro-oncology?
Dr. Ashley Ghiaseddin: Thank you for asking. So, I'll break it up into two parts. Really when it comes to the radio graphic technology that we've been using for patients, that is something that is continuously being looked at, especially when we think about the advent of artificial intelligence coming into the medical setting, and how we can leverage that, to use for patients as we not only look at their initial, diagnostic imaging, but then also tracking patients on their treatment response surveillance, as well as what to do when we see something that looks concerning for disease progression.
The backbone of radiographic imaging has really been, MRI with contrast. And this is, something that's been used, for quite some time where we look at contrasted imaging for patients because malignant gliomas, specifically glioblastomas, they have a heterogeneous ring enhancement, commonly with a necrotic core that is very classic, for glioblastoma. The differential may include things such as tumor, effective multiple sclerosis, or even abscess, but typically the patient's presentation will be able to kind of lead you into the right direction as to, whether or not this is a primary malignant brain tumor.
In addition, we look at other sequences such as T2 and flare imaging, which will assess not only the area of the tumor, but also the surrounding vasogenic edema, which for a primary malignant brain tumor, is a very large area of edema that surrounds the, diffusely infiltrative tumor. And when we look at other options of imaging, frequently people have looked at ADC mapping, which can, show evidence of dense hyper cellularity. We also look at profusion imaging, which although is not validated for use, often it is employed to look at areas of elevated blood volume, which if that is present, may be suggestive of increased cellularity, which you expect to see with tumors.
So that's another option that's being used for patients. When we look at imaging, PET imaging, which. May be familiar with in, neurodegenerative diseases such as Alzheimer's is also something that is an advanced MRI technique available to assist with both diagnosis as well as, treatment changes for patients. And specifically the amino acid PETs have been really the preferred PET tracer, for patients because of higher specific fDG PET is also employed. however, this is a technology that is, limited because of the amount of availability that we see for patients, in centers across the United States.
But I think in the future you'll see PET potentially employed more. and then I, kind of add The talk on artificial intelligence as something that's going to probably be, utilized much more as we kind of move forward in our radiographic techniques. Specifically, I think looking at volumetric studies, three-dimensional spatial technology to really assess. How these tumors look, not only at diagnosis, but even after, immediate surgical resection and during their treatment, which is after radiation, and also, different chemotherapies that they're receiving. Now the second part of the, question, I think was really discussing what we do in terms of surgical management and how that's improving.
And really you can add the imaging. advances, a part of this talk, which is really, the advent and the use of intraoperative MRI for our surgeons, that when they take the patients back to do a, a surgical resection, we know that the greater the amount of tumor that can be removed, the better outcomes that patients will have obviously you have to consider. That you're not resecting areas of eloquent cortex and really minimizing the amount of neurologic deficit that patients may have. But if you are able to achieve a large, safe maximum resection, we know those patients are gonna have better outcomes. So using intraoperative MRI is a useful way.
To assess immediately, real time, the extent of resection so that surgeons can decide while they're still in the OR whether or not a patient needs to have a larger resection and is it safe. Awake cortical mapping is also a new technique that has been utilized now for several years so that patients are actually awake during the surgery. And the surgeons can actually determine whether or not they're getting closer to eloquent cortex or critical structures where further resection will lead to a deleterious outcome, long term. So these are really being, touted as ways for us to have much better outcomes, larger extent of surgical resection.
In addition, when we think of, several other options, we also talk about, fluorescent dye, which is, five amino acid, which is able to visual. malignant tumor tissue. Really the high grade areas of the tumor will, light up when you give this dye. And this also allows the surgeons to really maximize their extent of resection when they're in the OR.
Melanie Cole: An interesting field that you're in and an exciting time with the advancements as you where just discussing. Dr. Ghiaseddin as the advent of gene therapy in the early nineties, raised real expectations for brain tumor therapies in clinical trials in patients with malignant gliomas. Can you tell us a little bit about some of the challenges now of treating these types of brain tumors and the limitation of clinical trials to find new treat?
Dr. Ashley Ghiaseddin: That's an excellent question. When we think about what makes treatment so difficult for malignant brain tumors and specifically glioblastoma clinical trials to date have really been, selective, to identify the patients that we think will, most appropriate for studies. So we look at things like functional status, the amount of, tumor that still remains after a surgical resection. And these things can actually lead to bias and, have, outcomes, for patients that may not be able to, generalize very well to our, real world population.
There are many reasons why we have to do this, and one of them being, the homogeneity of the population that we're treating, which means that when we look at the patients that are being enrolled in a study, they need to look as similar as possible so that we can be able to ensure that the outcome that we are finding isn't due to, variables that we didn't consider. In addition, when you think about treatment outside of just a clinical trial, you run into issues where these tumors are very resistant to therapy. It is difficult for drugs to cross the blood-brain barrier so that you limit the concentration of drug.
It is difficult for us to measure the amount of drug that's been delivered to those patients. So even if we treat a patient, you cannot be completely sure how much drug is actually getting to the tumor. In addition, radiographic challenges make it difficult when certain therapies like radiation or immunotherapy, which can create inflammation. on imaging, it may be difficult to determine what is treatment effect and what is true tumor progression and this sort of challenge is something that we deal with on an everyday basis.
We know that these tumors are very difficult to control so that their progression-free survival, unfortunately, can be somewhere, between six to nine months. And this is, something that challenges us to always think about what is the next therapy we need to be using. Whether that's another surgical resection or tumor treating fields, chemotherapy, targeted therapy based on the molecular markers of the tumor. It makes you always think on your feet and try to plan ahead for those patients so that you're not behind the eight ball, when you're seeing someone with a, progression and looking to have a quick response in terms of the plan moving forward.
Melanie Cole: Well, thank you for speaking also about the barriers to drug and gene delivery challenges that you have seen with this type of condition. So, I'd like you to speak about some of the more novel treatment strategies that you're looking at now, whether they're novel agents that you're using, the cytotoxic agents biologics, tamoxifen, and please tell us how those treatments for malignant gliomas may differ based on a patient's presentation.
Dr. Ashley Ghiaseddin: I'd like to first talk about some of te new technologies that we are using and then get into, medication advances and options that we're considering, for patients that are novel and really I think where the field hopefully is, moving, in the next several. One of those modalities, I alluded to earlier as being one of the new standards in our newly diagnosed patients. And that's tumor treating fields, optune tumor treating fields use low intensity alternating electric field therapy, which disrupts cell division mitosis for these rapidly dividing cells.
So those are the cancer cells. The nerve or muscle tissue are not stimulated. It's treatment that's delivered, via transducer arrays. It's non evasive. You apply it to the shaved scalp, and this is something that is a local treatment, so not systemic. You don't have, the same sort of systemic complica complications.You don't have the same sort of systemic complications that you see with chemotherapies, where you have to monitor, blood counts closely or be worried about, patients, at risk for opportunistic infections because they're immunosuppress. However, you do have to be concerned for skin irritation.
So there can be inflammation of the scalp, and there's preventive care that one would use, when they're using this sort of device. Another option that I think is novel that. Has been used at our institution as well as other large institutions as something called lit, which is laser interstitial thermal therapy, and that is where Hyperthermic laser ablation, is employed to tumors which can lead to a temporary disruption of the Peritumoral blood-brain barrier. We talked about earlier how the blood-brain barrier can limit the effectiveness of certain chemotherapy due to poor penetration, and this limits the treatment options for brain tumors.
Therefore, laser thermal therapy really attacks recurrent tumors in a way to disrupt blood-brain barrier and opens the door to use of drugs that were previously limited by their inability to cross that blood-brain barrier. You increase your therapeutic options. The immune system is really something that we're trying to harness and use to fight cancer. Now, this has been widely successful in lung cancer as well as melanoma, unfortunately, in brain tumors. We haven't had the same sort of success. However, this is something that we're, looking at more closely.
We've had studies, such as Checkmate 143, which looked at nivolumab, a PD1 inhibitor, that was compared to Bevacizumab monotherapy, which is also known as Avastin. And this was, studied in recurrent glioblastoma. There was no improved overall survival. There were more durable responses noted in nivolumab. However, at this point, When we think about immunotherapy in malignant brain tumors, we really think about this in terms of how we can combine this approach to maybe chemotherapy or small molecule therapy, and really need to pay attention to things such as tumor mutational burden and mismatch repair deficiency or microsatellite instability.
As well as PD-L1 expression on tumor tissue. These may be possible predictive biomarkers and help us determine what patients may benefit when we consider the use of immunotherapy. And then I think when you look at targeted therapy options, you wanna look at the molecular alterations in these tumors and where it makes sense to try to use different biologics and treatments to really, offer a precision medicine for patients. There are several options that have been really considered, and it's based on the molecular target. One of the molecular targets that we look at would be BRAV 600 E mutation.
Although it's not, common in glioblastoma, you can find it. Maybe less than 5% of patients combination treatment with a dual BRAF MEK inhibitor, has been used for patients, and that would be something such as dabrafenib plus trametinib. This is a combination that is successful in melanoma. We also look at EGFR amplification, in patients to see if there is a targeted option for that. specifically EGFR V3 amplification. in certain patients we can use, small molecule inhibitors that target that mutation, and that's been also utilized in non-small cell lung.
And then we know that there are new molecular targets that are being investigated and really identified as potential, therapeutic options. Nearly, every several months we learn about a new option that could be, utilized for patients. one of our more recent developments has been a, VEGF receptor. That also, is a multi tyrosine kinase inhibitor, regorafenib. And there was a trial NCT02926222, which was a randomized phase two study comparing regorafenib with lomustine, in patients who had recurrent glioblastoma.
That is another option that's being used for patients. So although we are. Frustrated at times with the difficulty in treating this tumor. I think we are motivated with the amount of research that has shown different molecular targets for us to really attack and different treatment options for these patients. And I think several ongoing trials I think will be able to identify different molecular therapies for us to use for these patients.
Melanie Cole: Such a fascinating subject, Dr. Ghiaseddin. As we wrap up, looking forward to the next 10 years in the field, what do you feel will be some of the most important areas of research and what else would you like providers to know about precision medicine for brain tumors, malignant gliomas, glioblastomas, and why and when you feel it's important that they refer to the specialists at UF Health Shands?
Dr. Ashley Ghiaseddin: What I want our colleagues, outside of UF to know is although. , it seems like for almost 20 years we've really talked about glioblastoma, malignant brain tumors in terms of surgical resection, radiation, temozolomide, recently using Optum tumor treating fields. There are many new drugs, precision medicine combining with immunotherapy that are coming out. And being, studied in clinical trials as well as utilized really in recurrence at this point, with the advent of next generation sequencing, using Foundation One or Caris, as well as other providers that can really give us a detailed genomic profile of these patients we're able to look at new targeted options for these patients with the hope of improving their survival, controlling the disease.
And as immunotherapy continues to evolve, you will see I think smarter applications of immunotherapy using nanoparticle technology. Combining immunotherapy. So vaccines that may be utilizing nanoparticle technology or RNA technology. And then combining that with a, checkpoint immunotherapy drug. And then, seeing if there molecular targets that we can use, precision medicine, in addition to the immunotherapy, that's where the field is headed. I think you're gonna see much more combinations being used now. We have to be careful and make sure that the combinations are going to still maintain.
Quality of life for patients that they're able to tolerate this and be able to continue doing their activities of daily living. So it certainly is a balancing act, myself and others are very much, committed to ensuring that our patients are not only getting, Improved survival, but also maintaining a, reasonable quality of life so that, the additional time we provide our patients, it's time that they can really spend with their families and loved. Ones and places, specifically, large academic centers like UF Health we are having new clinical trials that are, looking at immunotherapy targeted treat.
But specifically UF Health, we also have been really focused on making sure that we have a multidisciplinary approach to our patients so that they don't just come and see a neuro oncologist. They don't just come and see a neurosurgeon, but they have available options to meet with supportive care specialists, with social workers, with psychologists that are dedicated to treating patients with brain cancers and being able to, provide benefit, and support to not only patients but their caregivers. So research, at our institution not only looks at therapeutics, but also looks at. , the way we support our patients and the way that we improve quality of life.
What are other therapies and modalities we can use, that are not just treatment oriented, but are oriented at improving their functionality. So whether it's psychology, physical therapy, occupational therapy, speech therapy, these are all things that are gonna be extremely important, especially when we think about. Cure for brain cancer, which I hope in my lifetime we will see that. And I think if you do do that, you have to understand that there's going to be a need to really support these patients in survival. And that will be using things like, physical therapy, psychology services and supportive care services that can make sure that, patients live longer and also have quality of life that allows them to go back to their lives.
Melanie Cole: Thank you so much. Dr. Ghiaseddin said that was such an interesting podcast and so informative. Thank you so much for sharing your incredible expertise with us today to learn more about this and. Other healthcare topics at UF Health Shands Hospital, please visit innovation dot uf health.org or to refer your patient and to listen to more podcasts from our experts, you can always visit UFhealth.org/med matters. That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so much for joining us today.
Melanie Cole: Welcome to UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole, and joining me today is Dr. Ashley Ghiaseddin. He's the chief in the division of Neuro-Oncology at the University of Florida College of Medicine in the Department of Neurosurgery, and he practices at UF Health Shands Hospital. He's here to highlight treatment strategies for malignant gliomas. Dr. Ghiaseddin, it's such a pleasure to have you join us today. I'd like you to start by telling us a little bit about the state of therapies for brain tumors as it has been practiced for the last 20 years or so. How has that evolved?
Dr. Ashley Ghiaseddin: Yeah. Thank you so much for having me, Melanie, and I'm happy to be here today to discuss, treatment therapies in malignant gliomas and where we've been, where we're going, in this, current field and what the environment has been like. I would say that early on, we had been treating, let's say before 2005 patients, who were diagnosed with a malignant glioma, specifically glioblastoma, which is a grade four malignant brain cancer. Patients were treated with surgical resection if they were able to have surgery, followed by radiation therapy. There were several different chemotherapies that were used, but that was not actually a standard of treatment.
It was something that was added and some of those treatments included, nitrous, ureas, such as, lomustine, as well as other options that providers may have given to patients, but really the backbone of treatment with surgical resection and radiation. Then in 2005, temozolomide, which is a DNA al alternating chemotherapy was Really brought on as a standard following a 2005, large study that looked at patients who were treated with radiation, after surgical resection versus the addition of temozolomide to their radiation therapy followed by additional cycles of temozolomide chemotherapy.
That did show a survival benefit. And following that, it really became the standard. Now, the difficult thing has been since 2005. There has been very little development in additional treatments for patients until several years ago the addition of Optune tumor treating fields as a additional option with temozolomide therapy, after they finished chemoradiation has shown a small yet Still important survival benefit for patients. And that is another option that is, offered to patients. Now, in addition to the temozolomide chemotherapy upfront.
Because of that, what you will see much of the time is clinical trial enrollment for patients who have newly diagnosed glioblastomas, as well as in the recurrent setting when the cancer is growing back. So this is always something that we consider for patients if there are clinical trials available. at our institution or around the country. If there are trials available, patients will seek those out. But if we're using just the standard of care and what's been really developed over the past, I'd like to say 17 years, almost since 2005 when chemotherapy, temozolomide was added. We really look at the addition of Optune, a tumor treating field.
Melanie Cole: Well, thank you for that. Then, Doctor, can you please speak a little bit about advances in radiologic imaging that have been instrumental in finding these tumors? And while you're doing that, speak a little bit about the development of complementary technologies such as intraoperative MRI and realtime MRI. Entering the fields of neurosurgery and neuro-oncology?
Dr. Ashley Ghiaseddin: Thank you for asking. So, I'll break it up into two parts. Really when it comes to the radio graphic technology that we've been using for patients, that is something that is continuously being looked at, especially when we think about the advent of artificial intelligence coming into the medical setting, and how we can leverage that, to use for patients as we not only look at their initial, diagnostic imaging, but then also tracking patients on their treatment response surveillance, as well as what to do when we see something that looks concerning for disease progression.
The backbone of radiographic imaging has really been, MRI with contrast. And this is, something that's been used, for quite some time where we look at contrasted imaging for patients because malignant gliomas, specifically glioblastomas, they have a heterogeneous ring enhancement, commonly with a necrotic core that is very classic, for glioblastoma. The differential may include things such as tumor, effective multiple sclerosis, or even abscess, but typically the patient's presentation will be able to kind of lead you into the right direction as to, whether or not this is a primary malignant brain tumor.
In addition, we look at other sequences such as T2 and flare imaging, which will assess not only the area of the tumor, but also the surrounding vasogenic edema, which for a primary malignant brain tumor, is a very large area of edema that surrounds the, diffusely infiltrative tumor. And when we look at other options of imaging, frequently people have looked at ADC mapping, which can, show evidence of dense hyper cellularity. We also look at profusion imaging, which although is not validated for use, often it is employed to look at areas of elevated blood volume, which if that is present, may be suggestive of increased cellularity, which you expect to see with tumors.
So that's another option that's being used for patients. When we look at imaging, PET imaging, which. May be familiar with in, neurodegenerative diseases such as Alzheimer's is also something that is an advanced MRI technique available to assist with both diagnosis as well as, treatment changes for patients. And specifically the amino acid PETs have been really the preferred PET tracer, for patients because of higher specific fDG PET is also employed. however, this is a technology that is, limited because of the amount of availability that we see for patients, in centers across the United States.
But I think in the future you'll see PET potentially employed more. and then I, kind of add The talk on artificial intelligence as something that's going to probably be, utilized much more as we kind of move forward in our radiographic techniques. Specifically, I think looking at volumetric studies, three-dimensional spatial technology to really assess. How these tumors look, not only at diagnosis, but even after, immediate surgical resection and during their treatment, which is after radiation, and also, different chemotherapies that they're receiving. Now the second part of the, question, I think was really discussing what we do in terms of surgical management and how that's improving.
And really you can add the imaging. advances, a part of this talk, which is really, the advent and the use of intraoperative MRI for our surgeons, that when they take the patients back to do a, a surgical resection, we know that the greater the amount of tumor that can be removed, the better outcomes that patients will have obviously you have to consider. That you're not resecting areas of eloquent cortex and really minimizing the amount of neurologic deficit that patients may have. But if you are able to achieve a large, safe maximum resection, we know those patients are gonna have better outcomes. So using intraoperative MRI is a useful way.
To assess immediately, real time, the extent of resection so that surgeons can decide while they're still in the OR whether or not a patient needs to have a larger resection and is it safe. Awake cortical mapping is also a new technique that has been utilized now for several years so that patients are actually awake during the surgery. And the surgeons can actually determine whether or not they're getting closer to eloquent cortex or critical structures where further resection will lead to a deleterious outcome, long term. So these are really being, touted as ways for us to have much better outcomes, larger extent of surgical resection.
In addition, when we think of, several other options, we also talk about, fluorescent dye, which is, five amino acid, which is able to visual. malignant tumor tissue. Really the high grade areas of the tumor will, light up when you give this dye. And this also allows the surgeons to really maximize their extent of resection when they're in the OR.
Melanie Cole: An interesting field that you're in and an exciting time with the advancements as you where just discussing. Dr. Ghiaseddin as the advent of gene therapy in the early nineties, raised real expectations for brain tumor therapies in clinical trials in patients with malignant gliomas. Can you tell us a little bit about some of the challenges now of treating these types of brain tumors and the limitation of clinical trials to find new treat?
Dr. Ashley Ghiaseddin: That's an excellent question. When we think about what makes treatment so difficult for malignant brain tumors and specifically glioblastoma clinical trials to date have really been, selective, to identify the patients that we think will, most appropriate for studies. So we look at things like functional status, the amount of, tumor that still remains after a surgical resection. And these things can actually lead to bias and, have, outcomes, for patients that may not be able to, generalize very well to our, real world population.
There are many reasons why we have to do this, and one of them being, the homogeneity of the population that we're treating, which means that when we look at the patients that are being enrolled in a study, they need to look as similar as possible so that we can be able to ensure that the outcome that we are finding isn't due to, variables that we didn't consider. In addition, when you think about treatment outside of just a clinical trial, you run into issues where these tumors are very resistant to therapy. It is difficult for drugs to cross the blood-brain barrier so that you limit the concentration of drug.
It is difficult for us to measure the amount of drug that's been delivered to those patients. So even if we treat a patient, you cannot be completely sure how much drug is actually getting to the tumor. In addition, radiographic challenges make it difficult when certain therapies like radiation or immunotherapy, which can create inflammation. on imaging, it may be difficult to determine what is treatment effect and what is true tumor progression and this sort of challenge is something that we deal with on an everyday basis.
We know that these tumors are very difficult to control so that their progression-free survival, unfortunately, can be somewhere, between six to nine months. And this is, something that challenges us to always think about what is the next therapy we need to be using. Whether that's another surgical resection or tumor treating fields, chemotherapy, targeted therapy based on the molecular markers of the tumor. It makes you always think on your feet and try to plan ahead for those patients so that you're not behind the eight ball, when you're seeing someone with a, progression and looking to have a quick response in terms of the plan moving forward.
Melanie Cole: Well, thank you for speaking also about the barriers to drug and gene delivery challenges that you have seen with this type of condition. So, I'd like you to speak about some of the more novel treatment strategies that you're looking at now, whether they're novel agents that you're using, the cytotoxic agents biologics, tamoxifen, and please tell us how those treatments for malignant gliomas may differ based on a patient's presentation.
Dr. Ashley Ghiaseddin: I'd like to first talk about some of te new technologies that we are using and then get into, medication advances and options that we're considering, for patients that are novel and really I think where the field hopefully is, moving, in the next several. One of those modalities, I alluded to earlier as being one of the new standards in our newly diagnosed patients. And that's tumor treating fields, optune tumor treating fields use low intensity alternating electric field therapy, which disrupts cell division mitosis for these rapidly dividing cells.
So those are the cancer cells. The nerve or muscle tissue are not stimulated. It's treatment that's delivered, via transducer arrays. It's non evasive. You apply it to the shaved scalp, and this is something that is a local treatment, so not systemic. You don't have, the same sort of systemic complica complications.You don't have the same sort of systemic complications that you see with chemotherapies, where you have to monitor, blood counts closely or be worried about, patients, at risk for opportunistic infections because they're immunosuppress. However, you do have to be concerned for skin irritation.
So there can be inflammation of the scalp, and there's preventive care that one would use, when they're using this sort of device. Another option that I think is novel that. Has been used at our institution as well as other large institutions as something called lit, which is laser interstitial thermal therapy, and that is where Hyperthermic laser ablation, is employed to tumors which can lead to a temporary disruption of the Peritumoral blood-brain barrier. We talked about earlier how the blood-brain barrier can limit the effectiveness of certain chemotherapy due to poor penetration, and this limits the treatment options for brain tumors.
Therefore, laser thermal therapy really attacks recurrent tumors in a way to disrupt blood-brain barrier and opens the door to use of drugs that were previously limited by their inability to cross that blood-brain barrier. You increase your therapeutic options. The immune system is really something that we're trying to harness and use to fight cancer. Now, this has been widely successful in lung cancer as well as melanoma, unfortunately, in brain tumors. We haven't had the same sort of success. However, this is something that we're, looking at more closely.
We've had studies, such as Checkmate 143, which looked at nivolumab, a PD1 inhibitor, that was compared to Bevacizumab monotherapy, which is also known as Avastin. And this was, studied in recurrent glioblastoma. There was no improved overall survival. There were more durable responses noted in nivolumab. However, at this point, When we think about immunotherapy in malignant brain tumors, we really think about this in terms of how we can combine this approach to maybe chemotherapy or small molecule therapy, and really need to pay attention to things such as tumor mutational burden and mismatch repair deficiency or microsatellite instability.
As well as PD-L1 expression on tumor tissue. These may be possible predictive biomarkers and help us determine what patients may benefit when we consider the use of immunotherapy. And then I think when you look at targeted therapy options, you wanna look at the molecular alterations in these tumors and where it makes sense to try to use different biologics and treatments to really, offer a precision medicine for patients. There are several options that have been really considered, and it's based on the molecular target. One of the molecular targets that we look at would be BRAV 600 E mutation.
Although it's not, common in glioblastoma, you can find it. Maybe less than 5% of patients combination treatment with a dual BRAF MEK inhibitor, has been used for patients, and that would be something such as dabrafenib plus trametinib. This is a combination that is successful in melanoma. We also look at EGFR amplification, in patients to see if there is a targeted option for that. specifically EGFR V3 amplification. in certain patients we can use, small molecule inhibitors that target that mutation, and that's been also utilized in non-small cell lung.
And then we know that there are new molecular targets that are being investigated and really identified as potential, therapeutic options. Nearly, every several months we learn about a new option that could be, utilized for patients. one of our more recent developments has been a, VEGF receptor. That also, is a multi tyrosine kinase inhibitor, regorafenib. And there was a trial NCT02926222, which was a randomized phase two study comparing regorafenib with lomustine, in patients who had recurrent glioblastoma.
That is another option that's being used for patients. So although we are. Frustrated at times with the difficulty in treating this tumor. I think we are motivated with the amount of research that has shown different molecular targets for us to really attack and different treatment options for these patients. And I think several ongoing trials I think will be able to identify different molecular therapies for us to use for these patients.
Melanie Cole: Such a fascinating subject, Dr. Ghiaseddin. As we wrap up, looking forward to the next 10 years in the field, what do you feel will be some of the most important areas of research and what else would you like providers to know about precision medicine for brain tumors, malignant gliomas, glioblastomas, and why and when you feel it's important that they refer to the specialists at UF Health Shands?
Dr. Ashley Ghiaseddin: What I want our colleagues, outside of UF to know is although. , it seems like for almost 20 years we've really talked about glioblastoma, malignant brain tumors in terms of surgical resection, radiation, temozolomide, recently using Optum tumor treating fields. There are many new drugs, precision medicine combining with immunotherapy that are coming out. And being, studied in clinical trials as well as utilized really in recurrence at this point, with the advent of next generation sequencing, using Foundation One or Caris, as well as other providers that can really give us a detailed genomic profile of these patients we're able to look at new targeted options for these patients with the hope of improving their survival, controlling the disease.
And as immunotherapy continues to evolve, you will see I think smarter applications of immunotherapy using nanoparticle technology. Combining immunotherapy. So vaccines that may be utilizing nanoparticle technology or RNA technology. And then combining that with a, checkpoint immunotherapy drug. And then, seeing if there molecular targets that we can use, precision medicine, in addition to the immunotherapy, that's where the field is headed. I think you're gonna see much more combinations being used now. We have to be careful and make sure that the combinations are going to still maintain.
Quality of life for patients that they're able to tolerate this and be able to continue doing their activities of daily living. So it certainly is a balancing act, myself and others are very much, committed to ensuring that our patients are not only getting, Improved survival, but also maintaining a, reasonable quality of life so that, the additional time we provide our patients, it's time that they can really spend with their families and loved. Ones and places, specifically, large academic centers like UF Health we are having new clinical trials that are, looking at immunotherapy targeted treat.
But specifically UF Health, we also have been really focused on making sure that we have a multidisciplinary approach to our patients so that they don't just come and see a neuro oncologist. They don't just come and see a neurosurgeon, but they have available options to meet with supportive care specialists, with social workers, with psychologists that are dedicated to treating patients with brain cancers and being able to, provide benefit, and support to not only patients but their caregivers. So research, at our institution not only looks at therapeutics, but also looks at. , the way we support our patients and the way that we improve quality of life.
What are other therapies and modalities we can use, that are not just treatment oriented, but are oriented at improving their functionality. So whether it's psychology, physical therapy, occupational therapy, speech therapy, these are all things that are gonna be extremely important, especially when we think about. Cure for brain cancer, which I hope in my lifetime we will see that. And I think if you do do that, you have to understand that there's going to be a need to really support these patients in survival. And that will be using things like, physical therapy, psychology services and supportive care services that can make sure that, patients live longer and also have quality of life that allows them to go back to their lives.
Melanie Cole: Thank you so much. Dr. Ghiaseddin said that was such an interesting podcast and so informative. Thank you so much for sharing your incredible expertise with us today to learn more about this and. Other healthcare topics at UF Health Shands Hospital, please visit innovation dot uf health.org or to refer your patient and to listen to more podcasts from our experts, you can always visit UFhealth.org/med matters. That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so much for joining us today.