Additional Info
- Audio Fileuf_health_shands/ufhs070.mp3
- DoctorsZlotecki, Robert
- Featured SpeakerRobert Zlotecki, MD, PhD
- Guest BioDuring my 15 years at the University of Florida, one of my areas if focus has been the multidisciplinary management of patients with pediatric sarcomas of soft tissue and bone. Currently, I serve as the Medical Director for the UF Department of Radiation Oncology and participate in several national professional societies and committees, including the American Board of Radiology and the Radiologic Society of North America. Clinical research productivity includes 55 peer-reviewed publications and several supporting grants. My clinical practice integrates translational research collaborations with our UF Prostate Disease Center, and also with our medical physics and informatics programs. Direct collaboration with colleagues in the UF Cancer and Genetics Institute connects my PhD training in Pharmacology with the applied radiation biology, to facilitate the translation of laboratory research to clinical application in the delivery of multi-modality integrated cancer therapies. My specific technical interests include the management of metastatic cancers utilizing the technologies of Stereotactic Body Radiotherapy (SBRT) with Image Guidance (IGRT), which employ accelerated hypo-fractionation dose delivery protocols; and the development of emerging mobile and interactive technologies to enable an eMedical infrastructure to facilitate the collection of physician and patient reported quality and satisfaction data related to cancer diagnosis, treatment, and Quality of Life (QoL) outcomes.
- TranscriptionMelanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole. And today we're exploring MRI guided radiation therapy. Joining me is Dr. Robert Zlotecki. He's the Medical Director and a Professor in the Department of Radiation Oncology at the University of Florida College of Medicine. And he practices at UF Health Shand Hospital. Dr. Zlotecki, thank you so much for being with us today. As we start, can you set the table for us a little bit with the evolution of radiotherapy for cancer and help us to understand the role and effectiveness specifically of radiation therapy in the cure and palliation of GI tract cancers?
Robert Zlotecki, MD, PhD (Guest): Very simply, image is everything. And this has been one of the resoundingly advances in not just the delivery of radiotherapy, but the precision delivery of radiotherapy treatment for the cure and sometimes palliation, affective palliation of any malignancy, especially in the GI and genitourinary tracts.
So, the imaging and the corporation of the imaging into the advanced radiotherapy feedback loop, has been one of the biggest things that we have seen and have adopted, and will be bringing forward.
Host: Well, then tell us how this has the potential to preserve and improve patient quality of life factors as these cancers are getting treated.
Dr. Zlotecki: Well, because we can more effectively see our target, we can keep our target radius, our basically low value points to a minimum and keep the high value of bulls eyes on target exactly. And that means a much, much more effective delivery of the cancer therapy, in an efficient manner that reduces the overall number of days sessions, or as we call fractions of therapy for the patient to have to commit to for their course of effective therapy.
So, it's a huge time improvement for the patient. And thus, it's also becoming a huge quality of life improvement, not just from the commitment and the experience, the side measures of investment in the cure of cancer, but also in sparing the risks of side effects, that is without a doubt, a huge focus of the whole treatment. But in this case, we achieve that while also increasing the efficiency of the care overall and the targeting of the effective treatment to the tumor.
Host: Dr. Zlotecki, this is really fascinating technology. So how have you been integrating this into clinical radiotherapy planning and monitoring. Tell us a little bit about what you're doing at UF Health Shands Hospital.
Dr. Zlotecki: At UF Health Shands, we've always had a very close working relationship between the diagnostic radiology and the therapeutic radiology departments, and we've incorporated many of the diagnostic findings and that technique honing in on targets that are identified, directly brought into our treatment planning process.
We have not just adopted the imaging and the imaging technology, but we've also adopted greatly the knowledge base from diagnostics to better identify both the presence of a tumor and the boundaries of a tumor. So bringing that translational knowledge base from the diagnostic and the biometrics fields into the radiotherapy treatment has been a constant process. The latest generation of imaging for cancers of the GI tract that we're focused on today has been the use of MRI guidance and especially the use of advanced sequences that are biomarkers for disease presence and in disease status.
Those include the fusion weighted imaging, an effective, just basically the, the water motion around and about a tumor and surrounding tissues and other factors that will become much more applicable in the future, such as blood oxygen and tissue oxygenation effects. So, we are first adopting the diagnostic imaging technology and incorporating the treatment response markers into our treatment planning process.
Host: So Doctor now, as we look towards what's happening with this technology, how has the added value of real-time physiologic MRI for treatment planning and response, addressing a longstanding challenge for radiation oncologists for mobile tumors, which can often change positions in unpredictable ways? Tell us what you're doing at UF Health Shands Hospital in that regard.
Dr. Zlotecki: So one of the biggest advances in MRI guided radiotherapy is the concept of adaptive therapy, adapting to position, which is really, not that different than what's been enabled in CAT scan based technologies, but adapting to shape and into motion. So we'll be adopting those aspects of technological advantages afforded by MRI, but also by taking advantage of the energy and spectrum of the MRI device and the fact that it is always on and always collecting data, we will be taking the data stream, measuring the fusion weighted image sequences, which is the first foremost biomarker and using that as part of our adaptive response modification on the daily treatments of rectal cancers and other disease sites.
Host: Can you speak about some of the technologic advances that have increased the safety of radiation therapy treatment for other providers that are counseling their patients? This is always a big question.
Dr. Zlotecki: The technology safety is absolutely inherent in everything that we do. The technology is so advanced, just think of it as even the realms of rocket science safety and airline safety. Those are the kinds of things that we strive for and hope to exceed. The practicality of it for patient care delivery in the treatment of GI cancers, centers on concentrating the focus of the radiation on the tumor site, while very importantly, excluding or achieving avoidance of what we call organs at risk. First step is identifying the position of those normal, healthy tissues and organs, and basically accounting for the fact that in the gastrointestinal tract, they're in a constant state of motion. So that is, the short-term and the long-term advances that are being achieved with the real-time active imaging. And not just in any single fraction of radiotherapy, but from fraction to fraction as, the patient's anatomy and physiology adjusts on a daily basis.
And now as the tumor parameters adjust in response to treatment effect of the day before and the day before, we can better optimize the avoidance of normal health of tissues and the treatment volume that is really needed and really required to cure that tumor and do it safely.
Host: As we wrap up Dr. Zlotecki, and again, this is really interesting technology, what would you like other providers to take away from this podcast? What do you feel are the meaningful end points of what you're doing at UF Health Shands Hospital?
Dr. Zlotecki: First and foremost is we're providing an effective deliverable comprehensive path of treatment for patients within a system that will be efficient and effective. We will be able to safely very, very safely reduce a course of radiotherapy treatment from 25 fractions over five weeks to five fractions in one week and do it with safety and efficacy. Not only will it be taking advantage of the most sophisticated, real time imaging surveillance of the patient and patient anatomy during the course of treatment, but will on a day by day basis, will be taking into account in the treatment planning process, the biometric physiologic responses of the tumor as it is day by day, treated and destroyed by the delivery of radiotherapy.
Host: Thank you so much, Doctor for joining us today and sharing your expertise. To refer your patient, or to listen to more podcasts from our experts, you can always visit UFhealth.org/medmatters. That concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. For updates on the latest medical advancements, breakthroughs and research, follow us on your social channels. I'm Melanie Cole. Thanks so much for joining us today. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs069.mp3
- DoctorsHitchcock, Kathryn
- Featured SpeakerKathryn Hitchcock, M.D., PhD
- Guest BioKathryn Hitchcock, MD, PhD, is an assistant professor in the UF Health department of radiation oncology.
Dr. Hitchcock attended the University of Wyoming to earn her bachelor’s degree in chemical engineering. She then pursued further higher education, earning a master’s in mechanical engineering from the University of Maryland and a doctoral degree in biomedical engineering from the University of Cincinnati. She also earned her medical degree at the University of Cincinnati.
Following her education, Dr. Hitchcock completed an internship at UF Health in the department of internal medicine and her residency in the department of radiation oncology. She is board certified with the American Board of Radiology, and a member of the American College of Radiation Oncology, American Society of Therapeutic Radiation Oncology, Florida Society of Clinical Oncology and Radiological Society of North America.
Dr. Hitchcock has clinical experience in all disease sites, and been recognized for her work. She was awarded both the Medical Student and Community Education Award and the Society of Teaching Scholars Outstanding Resident Educator Award among various other recognitions. - TranscriptionAnnouncer: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to join us as we discuss colorectal cancer with Dr. Kathryn Hitchcock. She's an Assistant Professor in the Department of Radiation Oncology at the University of Florida College of Medicine, and she practices at UF Health Shands Hospital. Dr Hitchcock, it's a pleasure to have you join us again. As we're getting into colon cancer and rectal cancer, and your role in these, how have advances in radiologic imaging really significantly augmented your diagnostic and therapeutic capabilities for colon and rectal cancer? Speak about any that have really changed the landscape for you.
Kathryn Hitchcock, MD, PhD (Guest): Hi, Melanie. Thank you so much for having me back again. And it's a great question to start off with because there have been some really amazing changes in imaging that have really transformed the way that we treat these diseases. The two ones that probably have created the greatest change are number one, that it's standard now for every rectal cancer patient to have a MRI of the pelvis that lets us completely understand what organs and what tissues are involved with the primary tumor prior to doing any sort of treatment. And of course, that's a huge advantage, both for radiotherapy, which I do and for the surgery that my colleagues perform, because knowing where the borders of the tumor are, is absolutely essential in being able to cure this curable cancer. And then the other type of imaging that has really transformed how we handle this, these diseases, both colon and rectal cancer, is the combination of PET imaging with MRI of the liver, because it's very difficult to see inside the liver parenchyma with a PET scan in order to understand where metastases are.
You know, not that long ago, if you had metastatic colorectal cancer, that was considered to be the end, we would try to slow things down, maybe with some chemotherapy, but nobody considered you curable. Just within my medical career, which hasn't been terribly long, that has completely changed. And now there are a tremendous number of colorectal cancer patients with oligometastatic disease, meaning, there's just a few metastases either at the time that their primary tumor is discovered or somewhere down the road, we go after those aggressively and we really cure an impressive number of people.
And even in those who we don't cure, we're able to kick the can down the road quite a bit. So, you have asked an astute question and focusing on imaging because without finding those metastases, we aren't able to do that very important trick.
Host: Well, thank you for that. So, next steps, if a rectal cancer is suspected, we're going to concentrate a little bit on that and current treatments, in your area of expertise, Dr. Hitchcock, speak about what you do. If that's suspected, you just gave us a little bit of a background on it. Just expand a little bit more.
Dr. Hitchcock: Okay. So, if somebody suspects that their patient has particularly a rectal cancer, although kind of the first steps are shared in common with a rectal cancer and colon cancer. Really the important things to do up front are of course, a good physical exam and history to try to look at symptoms. But really at that point, there is no substitute for doing a colonoscopy and for getting it done stat because the sooner we diagnose the disease and get moving on it, the better. Of course there are other options out there these days for screening. People can do you know, sampling where they send in a stool sample or do a test for occult blood in the stool, and those are okay for screening, but at the point where you have a suspicion that there might be a colon or rectal cancer present, those really aren't appropriate anymore. You need to get that patient in for colonoscopy, right away. And the things that need to happen during that colonoscopy, of course, they're visualizing the entire rectum and colon and doing biopsies of any areas that are concerning. Our practice as well is if there is an area of concern that we tattoo the wall of the rectum or colon in the place where that concerning lesion is. So that other care providers down the road will have some certainty about where that biopsy came from. Otherwise, they're kind of guessing based on your description. And although our imaging is really good these days, it's still very difficult to achieve concordance between what you see on imaging and what you see when you're doing a colonoscopy.
So that tattooing helps take out some of that uncertainty in location. And then of course, some blood work. A lot of times these patients will present with you know, complaints of rectal bleeding. That's often the thing that brings them to the doctor. So, checking on their blood counts, making sure they're not terribly anemic. It is actually not too uncommon to have a patient present with loss of consciousness because they've had bleeding for a long time. They're embarrassed. They don't know. They assume it's due to hemorrhoids or something like that. They don't come to the doctor. And the first time they see a physician about the problem is because they've passed out and nobody knows why.
So, checking those two things and doing it quickly, is really critical if one of these diseases is suspected. Once that is done, then if those things tend to point toward there being a colon or rectal cancer present, the next very important step is to get high quality imaging and if possible, it's really important not to just send the patients to any old imaging center.
It's really important that it be a place that sees cancer patients pretty regularly because not all MRIs are the same. Not all PET scans are equal. And high quality imaging can save the patient's life. So, in packaging them up and getting them to cancer doctors in a situation that lets them start on treatment as soon as possible. That set of things is just critical.
Host: So interesting. And you've made some great points. Now, are there any recent or ongoing changes in rectal cancer treatment that you'd like to highlight for other physicians? Anything in your field that you'd really like to mention that you see happening or is happening at UF Health Shands Hospital?
Dr. Hitchcock: Yes, a couple of exciting things. And one of them is already in full swing and I think it's a trend that's going across the country now. So, I think people will see this in a lot of places. And that is the use of short course radiotherapy in rectal cancer. In Europe, they've been doing this for years, that the traditional American way to treat rectal cancer was to do radiation maybe before, maybe after surgery.
And it was always something like five weeks of radiotherapy, along with sensitizing chemotherapy. Over time in our practice, at least, we've tried to go entirely to preoperative radiotherapy because it's very difficult to get patients through a full course of chemo, radiation following surgery. And then over the last few years, we've been paying close attention to this European data that says, in fact, that five days of radiotherapy does just as good a job in helping the surgeon create clean borders of resection for rectal cancer and what people were worried about the long-term side effects from treating with higher doses over only five days didn't come to fruition. It turns out patients do just as well after those five intense days as they did after having the radiation spread out over five weeks.
So, in a practice like UF Health Shands Hospital where a proportion of our patients have a long drive in order to get to the hospital for their care. And a lot of folks are working and taking five weeks off of work is really difficult in this context where they really need to keep their health insurance and they need to pay off their medical bills.
Being able to only have them come for five days in a row instead of five days per week for five weeks in a row, is a huge advantage for the patients. They get through radiation very successfully and we keep them moving down the line with chemotherapy and surgery to get a cancer cure. So, here at UF Health Shands Hospital, that's the most exciting and important thing we've done recently.
The number two thing I wanted to highlight is there continues to be a lot of discussion about whether we might be able to treat some rectal cancers without performing surgery. That is something that has been explored probably most throughly down in Brazil. And there's a pretty good literature there. I would say people in north America and Europe in more recent years are starting to look at it a little bit more seriously. It's certainly not standard of care right now. It's something I wouldn't ever do without enrolling a patient in a clinical trial at the moment. But boy, there are a lot of patients where it'd be really nice not to have to take them to a big surgery for this disease.
And a lot of patients would really like that too, especially those for whom it would be necessary to have a colostomy for the rest of their lives if they were to go through surgery.
Host: You've given us some great information and thank you for telling us about the benefit of short course versus long course radiation treatment. That was great. So, now speak a little bit about metastatic colorectal cancer and the current shift in thinking regarding management.
Dr. Hitchcock: Okay. So, I would say that the shift has occurred primarily, probably over the last 10 years. We knew before that, that it was possible to go after metastases when there were just a few of them, when the patient had oligometastatic disease. But I would say people are starting to really get behind this as an idea of something that we should do formally, something that should become part of our standards of practice.
There are many ways that you can treat metastases from colorectal cancer, depending on what tissue they're in. Most often, those are going to appear in the liver. And not infrequently in the lungs. Sometimes they will show up in lymph nodes or other tissues of the body, but those are the two most common places.
So, the combination of the imaging that we talked about and advanced techniques, including stereotactic body radiotherapy, which has an extremely high cure rate, one that approaches is that of surgical resection, if you really look carefully at the literature, as well as some procedures that can be performed by surgeons or by interventional radiology with ablation with either microwave or radio-frequency in order to treat these metastases. Those combination of options, make it so that most patients, even if they're not great surgical candidates can still have their oligometastases treated safely. And it's possible that we will entirely cure their cancer, if we are able to also treat their primary tumor successfully. So, it's a really exciting era where we've gone from a situation where everybody who had metastatic colorectal cancer died of colorectal cancer to a situation where this young person, cause unfortunately, sometimes young folks get colon or rectal cancers, this young person in our office who has metastatic disease at the time that the cancer is discovered, doesn't necessarily have a death sentence. We have things that we can do to try to sustain their life and maybe save their life altogether.
Host: Such an exciting time to be in your field, Dr. Hitchcock, and as we get ready to wrap up. Given everything that you've said and the complexity with these increasingly advanced treatment algorithms that are always adding these new options to your armamentarium of available therapies, speak about the importance of a multidisciplinary approach for these patients. And tell us about your team at UF Health Shands Hospital.
Dr. Hitchcock: Oh a great topic. And one I'll try not to talk too long about, but I sure do like to. Multidisciplinary care for any cancer is important. For these particular cancers, it is really critically important because all three modes of treatment, radiotherapy, surgery and chemotherapy are necessary to the care of these patients. And it's incredibly important that those efforts be coordinated, that information be shared efficiently, and that the team will be on the same sheet of music in deciding how the patient is going to be best managed. Having colleagues who will sit in a multidisciplinary conference and come to a consensus about how to treat each patient is really important.
We certainly do enjoy that privilege here at UF Health Shands Hospital. Everybody on Thursday morning sets their time aside for almost two hours. And we talk about every single colorectal cancer patient who comes to our facility. And in, in fine detail, we work out how we're going to treat them, what the sequence is going to be, who's going to take care of each part and what that results in, is really smooth care. It happens efficiently, the right steps happen at the right time. And it is really a pleasure with our team here. Excellent surgeons. Excellent medical oncologists. And I would like to think that my department is pretty excellent as well.
As well as all of the allied health professionals, physical therapy and all of those folks who are really important to the care of these cancer patients really working together. So, I would encourage anybody who has a patient with colorectal cancer to get them, if not to our facility, then to one like it, where that care is really done on a team basis.
Host: What a great message for referral to UF Health Shands Hospital. Dr. Hitchcock, you're an excellent guest. Thank you so much for joining us today and really sharing your expertise in this exciting time in your field. To refer your patient, or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters.
And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please always remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs067.mp3
- DoctorsPham, Angela
- Featured SpeakerAngela Pham, MD,
- Guest BioAngela Pham, MD, is an assistant professor in the UF Department of Medicine's Division of Gastroenterology, Hepatology & Nutrition. She received her medical degree from Michigan State University College of Human Medicine in East Lansing, Michigan. She completed her internal medicine and pediatric residency at Grand Rapids Medical Education Partners with Michigan State University in Grand Rapids, Michigan. Dr. Pham then went on to complete her gastroenterology fellowship at the University of Florida in Gainesville, Florida.
Dr. Pham is board-certified by the American Board of Internal Medicine in Medicine and the American Board of Pediatrics in General Pediatrics. She is a member of the American College of Physicians, American Academy of Pediatrics and American College of Gastroenterology. Her clinical interest include Crohn disease, gastrointestinal disorders and ulcerative colitis. - TranscriptionThe University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we discuss Project ECHO today with Dr. Angela Pham. She's an Assistant Professor in the Division of Gastroenterology, Hepatology, Nutrition at the University of Florida College of Medicine, and she practices at UF Health Shands Hospital.
Dr. Pham, it's a pleasure to have you join us. So before we get into this whole topic, I'd like you to tell us a little bit about the ECHO model itself, and then tell us what Project ECHO is.
Dr. Angela Pham: So the whole story of Project ECHO dates back all the way to the early 2000s. It was actually initiated by a hepatologist out in Arizona. And it is a rich virtual learning community by which community doctors and doctors from academic centers share knowledge. And what it stands for is Extension for Community Healthcare Outcomes. And it's been used for a variety of different disease processes after it was first used for actually hepatitis C out in Arizona by Dr. Arora.
So I'll tell you a little bit more why I decided to use this model for inflammatory bowel disease. So I am an inflammatory bowel disease specialist, and most of the patients I see that are referred to me suffer from inflammatory bowel disease and have had it for a very long time. And a lot of times, by the time they come to me, their disease course has blossomed to a point where it is much more severe than it needs to be. And my goal in starting the ECHO Project is to democratize knowledge and give access to knowledge and best practice care to community doctors that may not have access to the subspecialists that we have here at University of Florida and, therefore, improve outcomes of inflammatory bowel disease in our community of Central Florida.
Melanie Cole: Wow, what a fascinating topic this is. So tell us a little bit more about how it addresses the gaps in inflammatory bowel disease care to ensure that high quality treatment can be delivered to the underserved and geographically remote regions and how it incorporates those quality metrics to potentially improve patient outcomes. Tell us a little bit about how it works.
Dr. Angela Pham: So a lot of my patients who have inflammatory bowel disease will drive upwards of three hours, sometimes even five to six hours to come see us here in Gainesville. A lot of patients are from the Panhandle, from Southern Georgia, even South Florida. And I will say based on the data that we have, a lot of patients who have inflammatory bowel disease, upwards of 40% or more live in geographically remote isolated locations whereby they don't have access to subspecialty care. And so I would like to make sure that we can move knowledge and not people, so to speak, and give access to subspecialty care to these patients that otherwise wouldn't have access that is so very necessary to put their inflammatory bowel disease into remission.
Melanie Cole: So tell us about the benefits to a physician practice and really how it can be utilized for a physician practice and its patients.
Dr. Angela Pham: So during this whole process, I actually embarked on a journey and went to visit a lot of the referring physicians that send patients to come see me. And I heard clear and loud the fact that a lot of times these physicians don't have access to a lot of the medications that we have. For example, a lot of places don't do infusions the way that we do infusion medications here at University of Florida. And they also don't have access to a pharmacist, a specialized pharmacist, that helps them through the prior authorization and insurance approval process for these very expensive advanced therapy medications. We do have an IBD pharmacist here at University of Florida that helps us with all these medications.
And what I heard from all these physicians was that if they could simply get help with the simple tasks, that their patients would get the help that they need. And it would take just a simple meeting between physicians to hash out what it is that is a barrier to patients getting the care that they need. And rather than have a patient drive back and forth, you know, five to six hours from, you know, their hometown to University of Florida, if the physicians can share knowledge amongst themselves to get the answers that they need, that would greatly benefit the patient, improve outcomes and, ultimately, improve the care and best practices of inflammatory bowel disease.
Melanie Cole: So that's such an interesting model of care, Dr. Pham, and as you're telling us about the benefits to the community and to patients directly, tell us additionally how IBD health liaisons work with these patients as health coaches to help equip them with the skills because doctors don't always and physicians don't always have the time really, or as you said, the resources to work with those patients directly on navigating the healthcare system and managing inflammatory bowel disease, which as you said, can take many medications. I mean, it's certainly a disease situation that needs a lot of management. So speak a little bit about health liaisons and nurse navigators and the people that help along the way.
Dr. Angela Pham: Sure. Absolutely. So as you know, with any chronic condition, the needs are very, very nuanced and not all of these needs can be met by your physician during, you know, a 30-minute to one-hour appointment. And chronic conditions expand beyond the time you spend in clinic with your physician. And so these nuanced needs, I think, are best met by peer mentors or what we have termed health liaisons.
With our model, we have chosen to use health liaisons that have been touched by inflammatory bowel disease themselves. They usually have experience with the illness and so are very well-versed in the care of inflammatory bowel disease from its complications to its medications and the day-to-day life of working and going to school and living with inflammatory bowel disease. And these health liaisons can really help guide a newly diagnosed patient through the navigation of their illness from, you know, scheduling appointments to who do they actually need to see to get the help they need. For instance, if they have joint pain, they need to see a rheumatologist and that's something that's very important to bring up with your gastroenterologist. Or if they have trouble with access to certain medications, how to best collaborate with your insurance company and your doctor's office to make sure that medications are approved expediently. And then also just the administration of medications themselves. A lot of these medications are infused or injected through the skin, and that can be a very new experience for a lot of patients. And so all these little nuances, I think are best met through a peer mentor or a health liaison talking you through the process and helping you get the answers you need outside of just the appointments that you have with your physician. And so I think health liaisons will really pave the way to improving the outcomes for all these patients that don't have health liaisons or a good support network to help them through their disease process. Because sometimes, you know, friends and family don't always completely understand, or they don't have the answers needed and so a health liaison, I think, will fill that gap for patients.
Melanie Cole: Well, I think it's really important to have that sort of multidisciplinary care model. And, as you say, health advocates and health liaisons and family can't always step into that role. What is your goal for the program? Can you speak about the capacity of general gastroenterologists and clinics to empower and safely manage these underserved patients with IBD who always don't receive that subspecialty care? What goals do you have? Where do you see this going in the future?
Dr. Angela Pham: I did want to expand a little bit more on the whole idea of the ECHO Project. What it actually is, is it's a set of didactic series, usually once a month, whereby you collaborate as physicians and basically present patient cases and in real time get answers to questions you may have about patient care. It follows the philosophy of all teach, all learn. And so I think what's really important to realize is that, as gastroenterologists, we all play a different role in patient care and community gastroenterologists have a very, very important role in general GI care, including colon cancer screening and treatment of acid reflux amongst a myriad of other things. And so they are very, very busy with taking care of, you know, the high volume of colonoscopies for colon cancer screening. And so a lot of times, they just don't have the bandwidth to take care of a complex chronic condition such as inflammatory bowel disease. And that's where a place like UF Health Shands Hospital can really step in and help with the subspecialty needs of taking care of inflammatory bowel disease.
And so we hope that with Project ECHO IBD, we can collaborate with our community GI docs to really share knowledge and share all the tricks of the trade necessary to get patients the care that they need without necessarily having to move the patient from place to place, but more just, you know, democratizing knowledge and sharing our best practices amongst one another and creating this rich virtual learning community whereby we can meet on a monthly basis to really get patients the care that they need.
Melanie Cole: As we get ready to wrap up, what a great model you're discussing here today, Dr. Pham, has the ECHO model proven effective and scalable across other disciplines? Where would you see it being useful across the spectrum of the healthcare profession?
Dr. Angela Pham: Absolutely. So what's really interesting is Project ECHO has been used at University of Florida Health Shands Hospital before. So Dr. Michael Haller is a pediatric endocrinologist here at UF Health Shands hospital. And he actually is collaborating with Stanford to use Project ECHO for type 1 diabetes, and they have published several studies that have basically annotated how successful Project ECHO can be. They've improved outcomes in type 1 diabetes in both pediatric and adult patients here and in California.
And so beyond that, outside of the University of Florida, of course, Project ECHO actually has been used in 93% of countries all around the world. And there's over 3000 different Project ECHOs that have been initiated since its advent in the early 2000s. And so it's being used in conditions, such as osteoporosis, end-of-life care, type 1 diabetes, a lot of different mental health conditions, all sorts of different chronic conditions. And so it is very scalable across every different discipline across the board and worldwide.
Melanie Cole: Do you have any final thoughts you'd like to leave other physicians about Project ECHO IBD at the University of Florida College of Medicine and UF Health Shands Hospital.
Dr. Angela Pham: I would just like to let everyone know that I am open to communications to initiate new Project ECHO models across US now that we are a hub. I would like to expand Project ECHO to other GI conditions if possible. And I would really like to build on the whole idea and philosophy of the health liaison and creating a medical home for patients in general beyond Project ECHO. I think health liaisons have a very useful role in any chronic condition, not just, you know, inflammatory bowel disease. And I really encourage anybody out there who is looking at Project ECHO as a viable option for them to reach out to me and I'd be happy to get you started or collaborate in any way.
Melanie Cole: Thank you so much, Dr. Pham. Such an informative topic and what a great initiative. Thank you so much for joining us today. And to refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please also remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs066.mp3
- DoctorsSteigleman, W. Allan
- Featured SpeakerW. Allan Steigleman, MD
- Guest BioW. Allan Steigleman, MD is an Associate Professor in the Department of Ophthalmology at University of Florida College of Medicine.
Learn more about W. Allan Steigleman, MD - TranscriptionThe University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we offer a refractive surgery update on laser surgery for refractive errors of vision. Joining me is Dr. W. Allan Steigleman. He's an Associate Professor in the Department of Ophthalmology at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital.
Dr. Steigleman, it's a pleasure to have you join us today. As we get into this topic, let's set the table as it were. Can you tell us a little bit about refractive errors of the eye in patients? What have we been seeing in the trends? Is this becoming more common? Tell us a little bit about what we're talking about today.
Dr Allan Steigleman: Yeah. Sure. Well, thank you for having me. I appreciate the opportunity. So refractive errors, we categorize them as nearsightedness, farsightedness, and astigmatism. Most patients who have nearsightedness or farsightedness have some degree of astigmatism that goes along with that. It's pretty uncommon to have astigmatism by itself.
We have been seeing an increase worldwide inn the prevalence of myopia or nearsightedness in patients most notably in Southeast Asia and in China. There's been some interesting papers that have come out now since the pandemic, that it seems that more near work and near tasks, you know, folks on their laptops and doing things in indoors, has led to perhaps an increase in the degree of myopia in children more so than in adults. And so that's definitely an area to watch as we move forward.
Melanie Cole (Host): That makes a lot of sense, considering even in these COVID times, but before that certainly with kids. Now, can you tell us a little bit about the role of surgery and how that has evolved for these refractive errors?
Dr Allan Steigleman: Absolutely. So we've been doing corneal refractive surgery. The cornea is the clear window and the front of the eye. We've been doing corneal refractive surgery for over 25 years now with laser-based technologies, including PRK and LASIK. The most recent changes or advances in laser refractive surgery involve using a procedure that's called SMILE. So there's quite an alphabet soup out there of these different laser procedures. But basically what each of them do is to change the shape of the cornea so that it basically mimics the shape of the glasses that someone needs to wear in order to correct the refractive error. So for those of you who have nearsightedness and you take your glasses off and you look at them, you'll see they're a little bit thicker on the edge and a little bit skinnier in the middle. And so what we do with each of these laser technologies is we try to reproduce that same shape. So for nearsightedness, we'll remove tissue in the center of the cornea, so we make it a little bit thinner. And then by default, the periphery gets thicker and that's what helps to create the refractive change to neutralize the glasses that the patient would need.
Melanie Cole (Host): So then can you compare and contrast the most widely used refractive procedures for other providers? Tell them what you're doing at UF Health Shands Hospital that they may not know about. Compare and contrast these for us.
Dr Allan Steigleman: Sure. Well, this is an exciting time in refractive surgery. We have a lot of great options available to us. This technology is, I guess, similar to cell phones. Each year or two, there's new technology, a new capability that comes out. And right now, we're blessed with some of the latest and most modern techniques with excellent outcomes.
A number of papers have been published recently that demonstrate that refractive outcomes in patients with many of these different laser procedures have 20/20 rates greater than 95%, which is just fabulous. The differences between each of these laser technologies, the most commonly being LASIK, PRK, or SMILE now, are actually quite subtle. The majority of the outcomes from each of these laser technologies is a lot more alike than it is different. However, there have been some reports that have been able to tease apart some of these nuances.
For instance, a paper that was just published this past month in one of our leading journals, the Journal of Cataract and Refractive Surgery, demonstrated that when compared in the same patient, so one eye was treated with one laser technology and the other eye in the same patient was treated with a different laser technology, LASIK seemed to be slightly better in certain visual parameters than SMILE was. And this was attributed maybe to some subtle details in how the procedures are centered on the cornea. There's more obviously studies that need to be done in the future to kind of tease some of these out. There's other studies that have been done in the past that compare one laser platform to another. And again, those differences seem to be very subtle. I joke with patients and I say, "Well, the differences between the lasers is essentially the difference between a BMW or Mercedes. They're both excellent, but there are some folks that are entrenched in one camp versus the other."
We do know that there are differences in the healing rates of each of these procedures. So for instance, for LASIK, that seems to be the fastest visual results and the least associated patient discomfort. PRK seems to have the slowest visual recovery and the greatest discomfort. And then, SMILE seems to be somewhere in the middle in most of the report has studies.
Melanie Cole (Host): What a comprehensive explanation. Thank you so much, Dr. Steigleman. Where does physician experience come into play here? Do you have any technical considerations that you would like to offer other providers?
Dr Allan Steigleman: Absolutely. I think the crux of the issue for refractive surgery these days is in patient selection. And that's where I think experience can really matter because it's difficult to know who to treat and who not to treat sometimes. And there are some medical contraindications. Folks who've had a history of other eye pathology. For instance, herpetic eye disease, including herpes simplex or herpes zoster associated with shingles is a reason not to do laser surgery on someone. We used to think that other contraindications were HIV status, diabetes, even certain immune disorders, including collagen vascular disease like lupus, rheumatoid arthritis. Many of us still will not treat patients with concerns for delayed healing or difficulty healing after refractive surgery. However, there's some mounting evidence that patients with comorbidities like HIV or diabetes, as long as they're well controlled and well managed could be suitable candidates for refractive surgery.
There are other eye parameters that may indicate whether a patient is a good candidate or not. That technology is advancing as well. We're able to use imaging technology now to evaluate the cornea preoperatively to decide who may or may not be a good candidate. And we have some exciting technologies that have come along now that allow us not only to look at the front of the cornea, but also the back surface of the cornea. And we can now actually use technology to determine the exact contributions to the thickness of the cornea by each of the separate five layers. And that allows us again to determine who's a good candidate and who may be a poor candidate.
I would also like to mention that I'm very excited about the fact that we recently incorporated some brand new technology in our LASIK practice. We have been able to get the iDesign system from Johnson & Johnson that communicates with our laser. We have the 2.0 software. We're able to use 1,257 little beams of lights actually go inside of an eye, gets reflected off the retina and those little beams of light are then captured, so it creates a customized, essentially a fingerprint for the eye. So instead of the old days of deciding which are better, number one or number two, which many of us are confused when we try to get our new glasses prescription, this is completely customized and passive for the patient. So they just put their face up into a scanner. The scanner evaluates the eye and comes up with this fingerprint-like treatment in order to give the best possible outcomes for the patient. The outcomes using this technology are just fabulous. There are several studies that have published the absolute best visions available with laser technology today, with many of the reports with 20/20 rates more than 98%. What I think is also fabulous about this technology are those patients who are better than 20/20.
So we can now take fully one-third of patients and we can make them able to see better without glasses after LASIK than they could ever see before in their best glasses or contacts. That's just a remarkable position for us to be in now. Really exciting times.
Melanie Cole (Host): Well, you got to my technology question even before I asked it. So that was excellent to cover some of the advancements that have been made that have augmented your diagnostic and therapeutic capabilities. Dr. Steigleman, can you tell us about alternative refractive surgical options when these procedures you've described maybe contraindicated or may not be appropriate?
Dr Allan Steigleman: Yeah, that's a great question. Because given our referral pattern here, we end up actually seeing a number of patients who have been told they're not suitable laser candidates at other laser centers. And so we would agree with that assessment, but we do have a lot of other capabilities available for these patients. We offer an intraocular collamer lens or an ICL. What this is is it's kind of like a small contact lens-related device that we can actually insert into the eye. It's a different type of procedure and involves a trip to the operating room. The lens doesn't come out to clean it. It just stays in the eye. And it can give just astounding refractive results for folks with incredibly thick glasses who are not suitable laser candidates. Now, it takes definitely some extra scrutiny for patient selection and for post-operative care, but the ICL results are just really quite remarkable.
We also can offer refractive lens exchange technologies. And so this is something that's commonly practiced throughout the country and throughout the world. What this is is instead of a patient needing to have essentially cataract surgery, we can do the same sort of technique for someone who's not yet developed a cataract. And our lens technologies these days are quite fantastic. There are a number of lenses available that can behave kind of like bifocals or even trifocal lenses, so that patients can see to read their computer and they can actually see to drive with no glasses these days. So the technology throughout our field is quite remarkable.
Melanie Cole (Host): Well, it certainly is. And as you said at the beginning, what an exciting time to be in your field. Dr. Steigleman, do you have any final thoughts you'd like to leave other providers with? An update or anything that's changed, research studies, your best advice. Wrap it up for us.
Dr Allan Steigleman: Sure. We could spend all day talking about some of the latest studies. Our journals are replete with these comparisons. I think the bottom line is we have great options these days to treat just about every patient who comes in the door. If there's a patient that you're concerned about, or you don't feel comfortable that you can help, I think that we have the capability to help most every patient here. So please send them our way.
Melanie Cole (Host): Thank you so much, Dr. Steigleman, for sharing your expertise with us today. And to refer your patient or to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs068.mp3
- DoctorsCollins, William
- Featured SpeakerWilliam Collins, MD, FACS, FAAP
- Guest BioWilliam Collins, MD, FACS, FAAP, graduated from the University of Miami School of Medicine in Miami, Florida, where he also completed a residency in Otolaryngology – Head & Neck Surgery. Dr. Collins completed a fellowship in Rhinology & Advanced Endoscopic Sinus Surgery at the University of Miami, and then completed a fellowship in Pediatric Otolaryngology at the George Washington University School of Medicine.
Learn more about William Collins, MD - TranscriptionThe University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we discuss pediatric endoscopic sinus surgery with Dr. William Collins. He's the Chief of the Division of Pediatric Otolaryngology at the University of Florida College of Medicine. And he practices at UF Health Shands Hospital. Dr. Collins, it's a pleasure to have you with us. So we've seen really cool improvements in children's health thanks to research from cancer and life expectancy and chronic disease, as well as prevention. Can you tell us a little bit about some of the challenges that face children's health in terms of sinus issues today? What have you been seeing? What are the most common types?
William Collins, MD: Yes. Thank you, Melanie. First of all, I really appreciate the opportunity to chat with you today and to talk about this particular topic that consumes a lot of my clinical practice time. So, the disease burden, particularly the financial burden that pediatric sinusitis impacts on society is significant. It's been estimated the past that several billion dollars a year in doctor's visits, antibiotic costs, things like that, they can really add up for families. So, although it may seem like a sort of bothersome type of condition, it can certainly have a big impact on the quality of life for children and their families.
So, as time has gone along, you know, we have adapted some of the technology that was initially used in the adult population to the pediatric population in management of sinus disease, particularly inflammatory disease like sinusitis in children.
Melanie: Well, thank you for that. So, as we're talking about the clinical indications for pediatric endoscopic sinus surgery, I'd like you to tell us a little bit about endoscopic sinus surgery. What conditions might warrant this? And what types of cases are really typically adequately managed with medications or when is surgery indicated?
William Collins, MD: So first step in evaluation is always making sure you have the diagnosis right. And, you know, probably over the last couple of years, we as a society and certainly as a medical profession have paid a lot more attention to viruses of the respiratory tract than we ever did in the past. So there are a lot of overlapping conditions in children, and it's important to make that proper diagnosis so that you can tailor your treatment to them. Common symptoms such as nasal congestion in kids or runny nose could be indicative of underlying environmental or inhalant allergies. Depending on the nature of the drainage, could be an acute episode of sinusitis or, depending on the time course, could be evidence of a chronic sinusitis. So it's important for the practitioner to make that proper diagnosis because many of these common conditions can be managed medically.
In the children that we have sort of maximized the medical treatment or the term we often use is maximum medical therapy, those are the ones we start looking at surgical options for their sinus disease particularly with their inflammatory sinus disease or sinusitis. So these might be children that have done the full gauntlet of allergy treatment, nasal sprays, anti-histamines, things like Montelukast, Singulair and if they just aren't improving with their symptoms. Those are children that we start to think about surgical therapy as an option for them. And that's probably the most common patient population, is the inflammatory sinus patients.
But there are also expanding indications for endoscopic sinus surgery and kids. For instance, children that are born with congenital anomalies of the nose, such as choanal atresia or if they were to have congenital malformations of the nose, such as an encephalocele, we've now adapted some of that technology to children and can surgically treat those conditions in a much more minimally invasive approach, which results in quicker recovery, shorter hospital stays in these pediatric patients.
Melanie: So then Dr. Collins, what are some of the unique surgical technique differences in pediatric sinus surgery compared to adults? Can you give us a little bit of an overview of the technical aspects and predictors for successful surgery? Any technical considerations you'd like to share with other providers to help them achieve better outcomes with their pediatric patients?
William Collins, MD: Absolutely. So from a technical standpoint, I mean, one of the most obvious considerations is kids are smaller. In the pediatric fields, we like to say, you know, kids are not just little adults. But in this particular instance, their nasal cavities, their nasal passages, the anterior nasal cavity in particular is smaller in children. So we've had to adapt over time to use smaller and smaller instruments to access these surgical fields. You know, another consideration in children as opposed to adults is children are still growing. And there is some concern that there are facial growth centers within the nose that, if disrupted with surgery or trauma, can affect long-term facial growth in children.
So as a general rule, we try to be a little bit more conservative in tissue removal when we're operating in the sinonasal cavities in children compared to adults. You know, another consideration in some of the more advanced or technically complicated endoscopic sinus procedures in kids, for instance, those in which we are looking at maybe tumors of the nasal cavity or that anterior skull base area, the techniques that were originally developed for adults to do what we call endoscopic skull-based surgery have slowly been adapted to children as well. And children are not born with fully developed sinus cavities. They're usually born with the maxillary and ethmoid sinuses developed, but they still enlarge over time and the frontal and sphenoidal sinuses can develop later. So depending on the location of these different lesions, if there is not a well-developed sinus cavity, that can impede our access to those areas. So, a big part of it is just the child's growing and developing sinonasal anatomy that can make the technical access a little bit trickier in the smaller children compared to the adult population.
Melanie: To expand on that just a bit more, Dr. Collins, some of the limitations of performing this type of surgery in the pediatric population, is there any technology or technological advancements or radiologic imaging that you feel are very exciting that can augment your diagnostic and therapeutic capabilities and/or limiting some of them that you feel that there might be something that you wish were available now for these small passages you're working in?
William Collins, MD: Yeah, well, you know, one of the things that we use very frequently in children now is something called image-guided surgery. And this is a method where we can, based on a preoperative CT scan and/or MRI imaging that we can surgically track our instruments at the time of surgery to provide a little more confidence in exactly the anatomic locations that we're reaching. This is particularly useful in more complicated cases. For instance, children that may have, you know, really extensive nasal polyps, which we sometimes see in the cystic fibrosis population where the typical intranasal anatomy is significantly altered.
At an institution, you know, here like UF Health and Shands hospital, we often see the more complicated referrals, revision cases where the native anatomy has been disrupted. So some structures that we would normally use to guide our surgical dissection may not be present. So this type of technology allows us to, you know, as I mentioned, sort of track the tip of our instrument into the different areas within the sinus and nasal cavities to provide a little more extensive removal of tissue, removal of polyps, potentially removal of tumor which can be particularly important when you're talking about trying to get oncologic clearance of a neoplasm within the nose.
Melanie: This is a very interesting topic, Dr. Collins, and you're an excellent educator. Do you have any final thoughts for other providers on what you would like them to know about the importance of the multidisciplinary management for these kids? Any technology or exciting things on the horizon you'd like to mention, and when you feel it's important they refer to the specialists at UF health Shands Hospital?
William Collins, MD: Yeah. You know, we think of evaluation of these children as we do most patients in kind of a stepwise fashion. So again, I can't emphasize enough, it's important to get the diagnosis right. And for many, many of the common diagnoses, there are readily available treatments that will adequately manage the symptoms and the condition in these children, such as, you know, management of allergic rhinitis. But the patients that have been maximized on those therapies and there really isn't any additional medicine that can be offered, it's important for providers to know that there are options that we can use to treat these children.
You know, we were kind of talking mostly about endoscopic sinus surgery, but I wouldn't want to overlook the importance of adenoidectomy, good old fashion removal of the adenoid tissue from the nasopharynx is very effective in children that have chronic sinusitis and the mechanism by which that works is the bacteria hide out. Adenoid tissue serves as a bacterial reservoir. So that is, you know, an additional step before we get to endoscopic sinus surgery in kids. But it is important for people to understand that, as you go through the different steps, there are a lot of different options that we can offer for these patients. And if they're not getting better, and they're not getting better with the usual course of treatment, then you got to start digging a little deeper, you know, maybe that nasal congestion is due to a tumor or perhaps, you know, it's a polyp. And if a child has nasal polyps, you have to start thinking about other co-morbidities such as cystic fibrosis.
You know, again, I think there's a lot of treatment options out there, but it's important for people, you know, to recognize that when all the usual therapies fail to give you adequate improvement, there are still a lot of options available to these patients and their families.
Melanie: Thank you so much, Dr. Collins, for joining us today and sharing your incredible expertise for other providers. And you can visit ufhealth.org/ent or ufhealth.org/oaks. For information on our two locations and to schedule an appointment or to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters.
That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please always remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs065.mp3
- DoctorsWright, Thomas;King, Jay
- Featured SpeakerThomas Wright, MD | Jay King, MD
- Guest BioThomas W. Wright, MD, received his bachelor's degree from Emory University and then attended the University of Florida, where he obtained his medical degree and graduated Alpha Omega Alpha. AOA is a medical honor society representing the highest ideals in medicine. Only the top ten percent of medical students are eligible to be elected to AOA.
Learn more about Thomas Wright, MD
JOSEPH J. KING, III, M.D., earned his medical degree at Drexel University in 2006 before going on to complete his residency in Orthopaedic Surgery at the Drexel University and his Clinical Research Fellowship in Orthopaedic Oncology at the University of Pennsylvania.
Learn more about Jay King, MD - TranscriptionThe University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to join us as we explore computer navigation in shoulder arthroplasty.
Joining me in this panel today is Dr. Thomas Wright. He's a professor in the Department of Orthopedic Surgery and Sports Medicine, and Chief of the Division of Hand and Upper Extremity at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital. And Dr. Jay King, he's an Associate Professor in the Department of Orthopedic Surgery and Sports Medicine and the Division of Hand and Upper Extremity at the University of Florida College of Medicine. He also practices at UF Health Shands Hospital.
Gentlemen, I'm so glad to have you join us today. And this is a really great topic. So Dr. King, I'd like to start with you. Can you just give us a little overview of the indications for shoulder arthroplasty and why you would seek this for patients?
Dr Jay King: Thank you, Melanie. I appreciate the opportunity to talk to you guys today. The indications for shoulder arthoplasty are someone with a painful shoulder that has shoulder arthritis associated with it, which is the cause of their pain. And we seek this for patients and people that have had pain for generally a long time or progressive increase in pain that have tried non-operative management and have not responded to non-operative management and continue to have significant shoulder pain with imaging findings of shoulder arthritis.
Dr Thomas Wright: Jay, let me add that also we use shoulder arthroplasty in patients who have deficient rotator cuffs that are not repairable, that can't be surgically repaired. And there is a specific implant designed to bypass the rotator cuff and manage that particular problem. So that's a little different population.
Dr Jay King: I can add too that the primary indication is that there are also several other indications, including a failed prior fracture surgery, prior fractures, and there's several other indications too, but these are the most common, the ones that Dr. Wright and I mentioned.
Melanie Cole (Host): Well, I'm so glad that you both brought that up because I was going to ask about injuries and where that fits in versus chronic pain and problems. So thank you for clearing that up. And Dr. Wright, would you define a little bit about computer navigation and shoulder arthroplasty? What's the role of robotics for shoulder surgery and how has this evolved over the years? Because it's really an exciting time for this technology.
Dr Thomas Wright: Yes, thanks, Melanie. This came about, and the shoulder's not the first place this has been used, it's certainly been used in the spine, it's been used in the knee and is now being used some in the hip. But it's just starting to be used in the shoulder. And there's a lot of reasons for that. The shoulder is fairly complex. But the reason behind this is that when a surgeon is actually replacing a joint, the shoulder joint, they can't see the orientation or the shoulder blade, which is where we put some of the implant. And therefore, we're kind of guessing. Because this shoulder blade is covered with soft tissues, we can't see it. However, using a CT scan, a CAT scan, which takes slices through the bone, it can then be used, when you marry it with a camera, you can know exactly where you are and you can put the implant in very precisely. And we've been using this for approximately three or four years. I've done a little under 600 cases with the computer navigation.
Melanie Cole (Host): Wow. So Dr. King, tell us about some of those benefits as Dr. Wright just mentioned, the shoulder has such complex movements. Tell us a little bit about the differences compared to traditional instrumentation. Can you compare and contrast these and tell us the benefits, both for the patient, but also for the surgeon?
Dr Jay King: So the biggest issue with placement of shoulder arthroplasties like Dr. Wright mentioned is placement of the socket, the glenoid component. Because you cannot see the shoulder blade, it's difficult to find where the good bone is. This is constantly our problem in shoulder arthroplasty, both for the patients, because if you don't have good fixation, you tend not to have a good outcome and can have complications, and also for the surgeon to make the surgery go faster, which also leads to less complications.
So the ways to do this are just basically by site, that's how we used to do it. We would usually get a preoperative CT scan anyway to look at the bony anatomy and then kind of correlate that in our mind to the patient. Current other ways to do that are specific instrumentation that can be made. So your CTs can be uploaded to a system. There's computer programs that make a little guide that you can use during surgery, mostly that is used to place just the center pin for the glenoid, which can be helpful. And you can also just use preoperative planning, where basically you can put the implants in a computer model and space, and that gives you a little bit more understanding of where to put it during surgery.
But none of those options you can change very easily and are not as accurate as the computer navigation, which basically is able to put the implant right where you planned it. Not only the main fixation of the implant, the center cage, but also the screws and the orientation of the implant as well. That's what the computer navigation allows us to do, which these other things, parts of that, that are unable to be changed during the procedure.
The benefits to the patient would be better placement of the implants and more accurate implant placement, which can lead to hopefully better outcomes and less complications in the long-term.
Melanie Cole (Host): Dr. Wright, this is fascinating. And as Dr. King was just speaking about in those complex movements, evaluate for us the learning curve for other surgeons that are looking to perform computer-navigated shoulder arthroplasty. I mean, it certainly depends upon the individual surgeon's surgical skill and experience, right? But can you give us a little bit of an overview of some of the technical aspects and predictors for successful surgery? What was your learning curve and some of the barriers?
Dr Thomas Wright: Melanie, the learning curve for shoulder replacement is very steep and very long. And the idea behind computer navigation and interoperative navigation is to flatten that curve, make it very short because invariably, with long painful learning curves, there are complications and we want to minimize those.
So in the past, I would say that you probably needed about a hundred of these to get pretty good and without computer navigation. Now, the learning curve with the computer navigation is about five cases. So it's not very long at all. And it allows even inexperienced surgeons, relatively inexperienced surgeons, to do very, very high quality work. It's a big game changer.
Dr Jay King: I would like to add to that too, we actually looked at this in our patients. We did the traditional three-dimensional preoperative planning. We planned all the placement of the glenoid component in a patient. And then when we went to the OR, we used the navigation equipment to see if we didn't have navigation how good we were. And even us, Dr. Wright and I, Dr. Wright has definitely done more cases than I have, but relatively experienced surgeons, in about 40% of the cases, we were significantly off with what we had planned based on that. So, even with all the three-dimensional imaging, without the guidance during surgery, we were still not perfect in placement, and that is with experienced surgeons.
Dr Thomas Wright: Yeah, let me add to that too, Jay, I had a conference earlier today, gave a talk on this and it was not like we weren't very good, we were pretty bad, and that was after me doing several thousand. We still had errors of over plus or minus 12 degrees, which is a lot. So even in experienced hands, our standard deviations as far as implant placement is really tight now. So it's not just the inexperienced surgeon, even the experienced surgeons can be made better. So thank you for adding that.
Melanie Cole (Host): Well, thank you both because this is really fascinating and so helpful for other providers. So Dr. King, speak about some of the current limitations as we've talked about experience and skill and really what comes down to practice as you were both discussing. Speak about some of the limitations that you're recognizing now that you're hoping will get ironed out and some of the future directions for shoulder arthropathy.
Dr Jay King: Our hope for the future is that we build on this computer navigation of the glenoid and we're able to also add to the humeral component placement and humeral component planning, which is already in stages in some systems. The other thing is knowing how we're putting it in and how that affects the ultimate outcomes. That's our big goal. Because if we know if we can put it in a certain way and we can gain extra motion or extra function for patients, that's going to help us in the future place it even better. And now we have a very good way to identify how we're placing it and where to place the implants.
So that's the ultimate goal, to know where the ideal place is and ideally for every patient, almost like patient-specific surgery. If someone needs more motion in one plane, we might know what angles we could put the implants in to try to gain in that motion. That's our ultimate goal in the future, which, honestly, as we do this more and more, we're getting closer and closer to that.
Melanie Cole (Host): Well, you certainly are. And as I've said, it's such an exciting time for this technology. And Dr. Wright, last word to you. Can you give us some thoughts about the future of shoulder arthroplasty and surgeries, and what you would like referring physicians to know about the exciting work that you are doing at UF Health Shands Hospital with computer navigation in shoulder arthroplasty?
Dr Thomas Wright: The first thing, shoulder arthroplasty makes a huge difference in a person's life. When you have pain that's so severe that you can't sleep at night, it's always grinding away at you, and you can take that pain away, which shoulder arthroplasty can do, you can make a tremendous improvement in someone's life. So that's number one.
The future holds, I think what's going to happen is computer navigation will evolve further. We actually may be able with 3D printing make custom implants that fit the person perfectly by just taking the CAT scan, making the implant and be able to navigate it and put it in place. We're currently able to do that actually, but it's very, very expensive. But with time, I think that will come down and that'll make a difference particularly on people who've had multiple failed arthroplasties where there's very little bone to help hold the implant in place.
So this technology is still rapidly evolving. In fact, this afternoon, I got a call in with a French company that we're about to roll out the navigation on the humeral side. So we're really close there. And that's going to add to this whole improvement, I think.
So the bottom line is we want to be able to look a patient in the eye that's miserable, and tell him with the 90 plus percent chance you're going to feel a lot better and you're function is going to improve as well.
Melanie Cole (Host): Wow. Thank you so much, doctors, for joining us today. What a great technology and an amazing time to be in your field. And thank you so much for sharing your expertise and experience with us today.
To refer your patient to Dr. Thomas Wright or to Dr. Jay King or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please always remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs064.mp3
- DoctorsBrisbane, Wayne
- Featured SpeakerWayne Brisbane, MD
- Guest BioWayne Brisbane, MD, is an assistant professor of medicine in the Department of Urology at the University of Florida College of Medicine.
Learn more about Wayne Brisbane, MD - TranscriptionMelanie Cole: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to join us as we explore advanced imaging for prostate cancer. Joining me is Dr. Wayne Brisbane. He's an Assistant Professor in the Department of Urology at the University of Florida College of Medicine. Dr. Brisbane also practices at UF Health Shands Hospital in Gainesville, Florida. Dr. Brisbane, it's a pleasure to have you join us again. I'd like you to start by telling us how advances in radiologic imaging have really augmented your diagnostic and therapeutic capabilities for men with prostate cancer. Any that you want to mention that have really been game changers?
Dr. Wayne Brisbane: Thanks again, Melanie, for having me on. Yeah, there's been a real renaissance in prostate cancer imaging over the last 10 years, but even more in the last two years. And so for many decades, the only imaging modalities we had for diagnosing prostate cancer and imaging prostate cancer were ultrasound, CT and bone scan. So traditionally, men who had an elevated PSA, they'd get an ultrasound-guided biopsy. That ultrasound-guided biopsy would show us the anatomy of the prostate, but couldn't delineate between cancer and benign. And then if cancer was diagnosed, they would sometimes get a CT scan and a bone scan to see if the cancer had spread anywhere in the body. And that paradigm has rapidly shifted.
So currently, we have MRI, so MRI is a multi-parametric MRI, it has multiple phases, that's the multiple parametric portion of it. And the important study that our listeners need to know about is the PROMISE study. This was around 700 men who got an MRI and then were followed by a mapping biopsy. This is about as close as you can get to a prostatectomy and understanding exactly where the tissue is. They also got a TRUS, like a regular templated 12-core biopsy. And in that study, they showed that MRI can triage men showing that, you know, men with a negative MRI, it's a pretty good finding for not having cancer. So that is one thing that's now been incorporated into multiple guidelines. So the NCCN guidelines, it's important for people to know February of 2021 have changed. So now men with a PSA greater than 3 have an indication for an MRI and consideration of biomarkers. And there's multiple biomarkers that are available, the prostate health index, SelectMDx, 4K, ExoDx test. So there's no designation in which one needs to be used, but just using PSA is probably something that's a little antiquated.
The other tests that I think people should be aware of that is absolutely going to change the landscape is a PSMA PET scan. So PSMA PET scans, if there's a protein surface, it's like I guess an enzyme that is overexpressed in prostate cancer and there is a PET radiotracer that binds to this. And there's multiple different ways that companies are using it, but the current one that's commercially available is called DCFPyL, but the easiest way to think about it is just PSMA PET scan. And that has two new indications, both for patients who have biochemical recurrence. So they've been treated and then have a recurrence of disease, common after like a radiation recurrence. So you can find where the cancer is lighting up post-treatment. The other indication, which is a little new, is replacing that CT and bone scan that we usually did for staging, so especially men in high-risk disease or unfavorable intermediate risk disease can get these PSMA scans to see if cancer has spread anywhere else. And so those are two new trials.
The CONDOR trial was the one looking at-- both came out of Australia, looking at men with biochemical recurrence and then the OSPREY trial was looking at the staging in high risk disease. So the final imaging modality that I want to make sure people are aware of that is very new, probably the newest out of all three modalities we're talking about is microultrasound. This is a high-frequency ultrasound that evaluates the prostate. It's only looking at the prostate. It doesn't look at anything else. But it does a very nice job of delineating where tumors are versus where is benign tissue. And so this is the first time where ultrasound's been able to delineate cancer versus benign tissue, and it looks to be very, you know, very accurate. There's definitely some shortfalls in using ultrasound, but it's important that there's this trial that's ongoing called the OPTIMUM study that's going to compare MRI versus microultrasound to identify a prostate cancer on biopsy. So we're going to wait for the trial results to read out.
But three brand new imaging modalities, MRI, which is on guidelines and has been around for, I would say, five to ten years and has really come into its own. And that is, like I said to people with elevated PSA, it's on multiple guidelines, both the NCCN, AUA and I think it's Abdominal Radiology Society recommend using that as a preliminary test and to guide biopsy. PSMA is now on guidelines and just was starting to get approved. And that's for men who have high risk disease prior to treatment and then men with biochemical failure or biochemical recurrence post-treatment and then a brand new ultrasound imaging modality, which is to localize a prostate cancer probably will have some implications for staging of prostate cancer and definitely will be useful for guiding needle biopsies, and that's microultrasound, which will be studied through the OPTIMUM trial, which is currently enrolling.
Melanie Cole: How are you deciding which one of these to use? And what an exciting time in your field, Dr. Brisbane. Really so many things are constantly evolving. And while you're telling us a little bit more, to expand just a little bit more on patient selection for providers that really are looking to use these, how might some of them help to triage men to help patients avoid biopsies and other procedural interventions that could cause side effects?
Dr. Wayne Brisbane: Yeah. So just to give a practical example, so somebody who comes into my clinic who has an elevated PSA, my cut point is going to be 3, which is a little bit lower than what has been kind of traditional. So, basically, I'm starting the screening between 45 and 75 for average risk men and then between 40 and 75 for men of African ancestry, especially if there's, you know, a family history, germline mutations in the family or strong family history. If the PSA is less than 1, kind of screening them between two to four-year intervals. If the PSA's between 1 and 3, I'm screening them at one to two-year intervals. But if the PSA is greater than 3, then I'm going to multiparametric MRI and consideration of a biomarker and I'm using urinary biomarkers, but I don't have a strong preference. There's a lot of really good ones that are out there.
If there's something that's positive on the MRI, so that's a PI-RADS 3 or above, and those PI-RADS are just the risk score that the MRI gets. If the PI-RADS score is 3 or above, we're biopsying that, and I'm using a combination of MRI and microultrasound to guide the biopsy needle. I think it's a very accurate way of going about it. If it is a negative MRI and the PSA density is less than 0.15, that PSA density is important because big prostates produce a lot of PSA. And so as long as if you can evaluate, is it a big prostate that's producing the PSA by dividing their PSA by the prostate volume, you can normalize the PSA values that you're getting and then you can see if the PSA density is less than 0.15 and a negative MRI, that's very protective. Some men who are nervous, I'll offer them a biomarker in addition to that, but that's probably overkill. But regardless, using those MRI plus biomarkers after repeating the PSA to confirm that it's above 3, just trying to decide do men need the biopsy?
And then once imaging has confirmed cancer, let's say it's a high-risk cancer, then I'm using PSMA to stage them rather than a CT and bone scan. And that gives a very accurate assessment of where the cancer is. Is the man going to benefit from local therapy with surgery or radiation? And then God forbid that they fail their primary treatment, we're using PSMA again to see where the cancer may be outside of the prostate.
Melanie Cole: So, where do you see this going as it's evolving just so much and pretty rapidly and our population is growing ever older, so men are living longer? Where do you see some future directions for imaging in prostate cancer? What's new on the horizon that you're looking forward to?
Dr. Wayne Brisbane: Yeah. I think a lot of treatments, especially in localized disease, but also in metastatic disease are going to be altered by our ability to see cancer better. So within the localized disease set, you're going to be able to see where tumors are and where tumors are not using technologies like MRI and microultrasound, and that has several implications. For people undergoing surgery, we're able to tailor the surgery with less damage to the adjacent critical structures, like the neurovascular bundle, the bladder neck, the external sphincter, so that results in surgery with less damage to surrounding tissue and then less side effects.
The same thing goes with radiation. They're able to boost the radiation dose to the actual tumor because they can see where it is next to the benign tissue. And so the recent readout of the FLAME trial where that was done showed that there is an improvement if you boost the actual tumor rather than just giving the same dose to the whole prostate. And that makes sense. And I think with time, we'll actually see that we're able to even reduce the radiation effects to other areas that cause a lot of side effects. So I'm hoping that we'll have more targeted treatment. There's definitely some push also just to treat the tumor as the only thing. So treating the tumor with something called focal therapy, there's multiple different energy sources that have been used, but that's a kind of an extension of what I'm talking about, where you're able to visualize where the tumor is, you treat just the tumor and leave the surrounding structures untreated. There's a long way to go. And I think that there's a lot of research yet to do before we can just get away with treating the tumor in a margin. But I think that it's a very exciting time to be working in prostate cancer.
and then the other flip thing that's very interesting is for many years, we use CT and bone scan to stage people. So we would kind of decide on what their treatments should be initially based on their burden of disease. But PSMA is really going to shift how well we can see a burden of disease. And so we'll kind of rewrite the book as far as how much burden of disease equals what treatments. For example, CT and bone scan used to miss men with small amounts of metastasis. So we're going to start finding men with this period of oligometastatic or a small amount of metastatic disease. And so we kind of have to figure out exactly how to best treat them. So I think it'll be very interesting.
The final thing that I'll say is that some people are also working on taking the PSMA, the linkage, and attaching it to a radioemitter, so like an alpha or beta emitter. And so there's a whole new group of treatments called radiopharmaceuticals that are opening up. And that's going to be in men currently with castration-resistant disease. But I think it'll probably move forward in the metastatic disease space.
Melanie Cole: Wow. So informative, Dr. Brisbane. What a great guest you are. And I hope that you'll join us again to keep updating us as these things evolve. As we said, this is happening pretty rapidly, and there's many exciting advancements in imaging for prostate cancer. Thank you so much.
To refer your patient to Dr. Wayne Brisbane or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please always remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs063.mp3
- DoctorsGhayee, Hans
- Featured SpeakerHans Ghayee, DO
- Guest BioHans Ghayee, DO, is an Associate Professor in the Division of Endocrinology & Metabolism at the University of Florida College of Medicine. Dr. Ghayee practices at UF Health Shands Hospital in Gainesville, Florida.
Learn more about Hans Ghayee, DO - TranscriptionMelanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole. And today we're discussing pheochromocytoma and paraganglioma. Joining me is Dr. Hans Ghayee. He's an Associate Professor in the Division of Endocrinology and Metabolism at the University of Florida College of Medicine. Dr. Ghayee practices at UF Health Shands Hospital. Dr. Ghayee, I'm so glad to have you join us today. Fascinating topic we're discussing today. Can you please define pheochromocytoma and paraganglioma for us and tell us the difference between these two.
Hans Ghayee, DO (Guest): Sure. And thank you so much for having me Melanie. Pheochromocytomas are catecholamine producing tumors that arise from the chromaffin cells of the adrenal medulla, which is the inner most part of the adrenal gland. And there are also pheochromocytomas that are located outside the adrenal gland that we call paragangliomas. Paragangliomas arise from the sympathetic or parasympathetic chain ganglia.
So these tumors can make hormones that can affect our blood pressure, can also affect how our heart functions and as a result, it's really important for those of us that are seeing patients in clinic are thinking about these types of tumors, that a patient could potentially have.
Host: Well, thank you for that Doctor. So who is at risk? Has a genetic component been identified for these?
Dr. Ghayee: Yes. As a matter of fact, that's a great question, Melanie. We've learned in the last several years that there are over 20 genes that have been associated with pheochromocytomas and paragangliomas more than any other endocrine tumor types. So, it's become really important for us to think about a genetic mutation or a genetic driver associated with this disease.
We know about 35 to about 40% could be familial. And it's really critical that if we identify a patient, no matter how old they are, that they get genetic testing done. So, that actually will have an implication in terms of how aggressive a disease that the patient may potentially have. And also it has implications towards their family members in terms of being identified sooner.
Beyond that, with identifying certain genetic mutations that are driving a tumor that a patient could be having, those genetic mutations, could be associated with syndromes that could basically cause other tumors. That's why it's even more important for anybody that is seeing these patients is thinking about this because this is an opportunity to identify those other tumors and have them diagnosed and treated at an earlier stage.
Host: Doctor, I'm so glad that you brought up the importance of other family members being evaluated. So, if you've identified an at-risk patient, you've done your genetic testing. Tell us about any programs that you have that might help family members to receive screening and or medical management.
Dr. Ghayee: Yeah, that's a great question. And we have those opportunities here at UF Health Shands Hospital. So, if that patient's family member is identified with having a driver mutation associated with pheochromocytoma or paraganglioma, those patients would end up seeing us in the endocrinology clinic and we would order certain biochemical studies to identify whether these patients have a pheochromocytoma or paraganglioma. In addition to that, we would be ordering radiographic studies to determine whether they have a tumor that could be involved in this disease process.
Host: So, then Doctor, besides genetic testing, can you discuss evaluation? What's involved in the workup. Are there any biochemical markers you'd like to mention or radiologic imaging that augments your diagnostic and therapeutic capabilities?
Dr. Ghayee: Absolutely. So, in terms of the symptoms that patients may have, the classic triad that most textbooks would talk about is that the patient would have headaches, palpitations or diaphoresis. And it turns out about 25% of these patients actually have this classic triad. We know in the last several years, more and more patients have been discovered because of the fact that they had a CAT scan done for something else, and they were found to have an adrenal pheochromocytoma or a paraganglioma.
And also another group that is now coming into play, are those patients that were found to have a genetic mutation because they were identified as having a tumor or a family member was found to have a tumor. And then they were found to have an at-risk mutation for a pheochromocytoma or a paraganglioma.
So, you can have a patient with a pheochromocytoma or paraganglioma that may have the classic triad of headaches, palpitations, diaphoresis. And even sometimes they might have high blood pressure, but not all of these patients have that. So, that's why it's really important when a patient presents with a adrenal incidentaloma, for example, that we make sure that we do a workup for a pheochromocytoma, because even if they do not have hypertension and they do not have any symptoms, they could still have a pheochromocytoma. So, it's really important that every practitioner understands that and always rules out a pheochromocytoma or paraganglioma. Well, how do we do that biochemically? Well, we check plasma metanephrine levels or a 24-hour urine metanephrine value.
And that's how we are able to determine whether somebody has a pheochromocytoma or a paraganglioma. However rarely, a patient may have a dopamine secreting pheochromocytoma. There had been only 33 case reports published in this, in the last several years, but it's really important that practitioners are aware of that. Also in terms of biochemical testing, there have been some studies that have shown that plasma catecholomines are not a reliable testing method. Instead we should be checking plasma metanephrines. If you're worried about a dopamine secreting tumor, such as a rare pheochromocytoma, that's only making dopamine, then I would check it 24-hour urine for catecholamines.
And this way you will be able to identify some of those patients. Not only that, there are patients that have head and neck tumors that could be paragangliomas. And these tumors may not make any hormones at all. And if they do make hormones, they could just only be dopamine secreting. And so that's where that 24-hour urine for catecholomines becomes really helpful.
Now there's another marker that has shown to be quite helpful that has been discussed in the last several years. It's actually a breakdown product of dopamine called methoxytyramine. So there are opportunities in terms of testing for that. You can test a blood level for methoxytyramine like you were testing plasma metanephrines or normetanephrines.
So just as a reminder, plasma metanephrines and normetanephrines are a breakdown product of epinephrine and norepinephrine. So the same thing methoxytyramine is it's a breakdown product of dopamine. So it could be helpful, especially when we are thinking about somebody having a head and neck paraganglioma, that seems to be non-functional, but you want to do an additional test and that test could be a good test to order.
And another marker that we often think about are chromogranin A level. So chromogranin A levels have traditionally been a good neuroendocrine tumor marker to test, and it is a helpful test to order. But remember, if it's not positive, that does not necessarily mean the patient doesn't have a pheochromocytoma or a paraganglioma.
That's why it's so critical that we order our plasma metanephrines or our 24-hour urine metanephrine value in order to make sure the patient has that right diagnosis, at least biochemically. And then in terms of your question of radiological testing, if somebody has a positive biochemical test, our next step is to do a CAT scan or MRI.
So either test is actually a good test to order for these patients. So, the time that I tend to do an MRI is especially when I'm worried about a patient having a head and neck paraganglioma. That's when it seems like the MRI study might be actually a good test to order, or if the patient is pregnant or if it's a child that we are assessing.
And obviously, if somebody has allergy to a CAT scan contrast agent, then I would order an MRI. Otherwise the CAT scan is a good test to order, and it's also important for healthcare providers to understand that if a CAT scan shows low Hounsfield units, like less than 10, the chances of pheochromocytoma is extremely low.
So what I mean by that, in terms of Hounsfield units is basically a measurement of x-ray attenuation. So, if the Hounsfield units are less than 10, that basically tells us that the adrenal mass is lipid rich and the chances of that lesion being a pheochromocytoma is quite low. So that's what we do in terms of the biochemical testing a 24-hour urine for metanephrines or catacholamines. And we'd like to get plasma metanephrine and also in terms of imaging, we'd like to get a CAT scan or an MRI. If the CAT scan or MRI indicate that the patient has metastatic disease, then we turn to nuclear medicine testing. And generally for nuclear medicine testing, we would like to turn our attention to a gallium 68 dotatate PET scan. That has shown to be a useful imaging modality to look for metastatic lesions.
Especially for those patients that have aggressive and metastatic disease associated with certain mutations such as succinate dehydrogenase type B mutation. Another imaging modality that we may consider is an MIBG scan. And that has actually been around for close to 40 years. However with recent developments in nuclear medicine advances in terms of treatment, this scan has now become an important scan to order, especially if we're thinking of giving high dose MIBG treatment to those with metastatic disease.
Host: Well, then let's speak about treatment for a minute. Dr. Ghayee. What's involved in medical management? And while you're telling us that, how important is relieving symptoms as an important part of this medical care? You can speak even about symptom triggers. But also about the multidisciplinary approach and who is in charge of guiding patients' care, what types of providers are involved?
Dr. Ghayee: That's a great point, Melanie, that you brought up. So treatment for pheochromocytoma and paraganglioma basically is a multidisciplinary approach. It requires an endocrinologist. It requires a hematologist oncologist. It requires a surgeon. It requires a radiation oncologist, even radiologists and pathologists. So it's a big team that's involved in taking care of these patients. And it's also important when there is a team involved, it's not just one person running the show. It's a whole team working together. And at UF Health Shands Hospital, we have an endocrine tumor board where we discuss these patients and we come with a conclusion with the team all in sync so that the patient gets the best care. So, if a lesion is identified to begin with, from imaging, that's when the patient will be considered for surgical evaluation, but before they go for surgery, it's really important that the patient is treated with drugs called alpha blockers. So alpha blockers are really helpful in terms of helping to normalize the blood pressure. And it's really important that not only are we looking at normalizing their blood pressure and heart rate, but also making sure that the patient has enough fluid and they're also taking enough salt.
Because oftentimes many of these patients that have pheochromocytoma or paraganglioma actually are volume depleted and actually need to drink plenty of fluids. And we give them alpha blockers for at least two weeks prior to their surgery. And the other thing we like to do is also monitor their heart rate. So, only after the patient has been on alpha blockers for several days, do we add beta blockers if we need to control a fast heart rate. But we also may add other blood pressure lowering agents as well, such as calcium channel blockers too. Also ACE inhibitors or ARB agents that may be helpful in terms of getting to the goal of lowering their blood pressure to at least less than 130 or over 80 sitting. And a systolic blood pressure about 100 standing. And we'd like to aim for heart rate of 60 to 70 sitting and 70 to 80 standing. So, those are our goals when we're treating our patients. And we also like to warn our patients that when they're starting alpha blockers, that they can actually have hypotension.
And so we ask them to drink plenty of fluids so they can avoid having hypotension as a result of taking the alpha blockers. Because if they have hypotension, then they're less likely to take the medicine because it's such a terrible side effect that people can consider. And as a result, may stop their medicine.
So we don't want that to happen. So it's important that we at least warn our patients, that, our patients can definitely get hypotension and they can feel dizzy while taking this medicine. And so oftentimes we ask them to take it at night so that they're able to tolerate the medicine a little bit better. And again, drink plenty of fluids. I can't emphasize that enough. And also a day before their surgery, we'd like to admit them so they can get IV fluids so that they're volume expanded well.
Host: This is such an interesting podcast, Dr. Ghayee, and as we get ready to wrap up, can you tell us about any ongoing research studies related to pheochromocytoma and paraganglioma and any research that you're doing at UF Health Shands Hospital that other providers may not know about.
Dr. Ghayee: Yes. Thank you for asking that question, Melanie. So, if a patient has a metastatic pheochromocytoma or paraganglioma, it is really important that you have that multidisciplinary team involved and following that patient closely. We have such a program here at UF Health Shands Hospital. So we have our medical oncologist involved. We have our radiation oncologist involved. We have our surgeons involved. And we have our pathologist involved as well as our nuclear medicine doctors and endocrinologists. So, in terms of treatment for metastatic disease, these patients are continued on alpha blockers. And the only FDA approved treatment for metastatic disease is high dose MIBG therapy. That is if their MIBG scan is able to show that they do have lesions and the tumors are picking up the MIBG radionucleotide agent. So, if they do, then we would consider high dose MIBG treatment, but there's also another treatment called peptide related radionuclei therapy, or PRT or high dose dotatate therapy that patients can receive, but that has not been officially approved yet, but certainly that is in clinical trials and we're waiting for approval. Some of the guidelines are suggesting that if the patient has a positive dotatate scan, they may be a candidate for high dose dotatate treatment.
And that would need to be taken on a case by case basis in terms of which patients would get MIBG treatment versus high dose dotatate treatment, or PRT treatment. However, what has been FDA approved so far as of 2018 is high dose MIBG treatment. There are number of tyrosine kinase agent drugs that are under clinical trials right now.
And I think that does provide a lot of hope for many of our patients. However, if a patient has a rapid tumor growth, that's going on in less than a six month period of time, these patients would undergo chemotherapy. Which includes cyclophosphamide, vincristine and dacarbazine or temozolomide as an alternative. But if their tumor growth is slow to moderate, basically it takes over six months for tumors to grow, then those patients would undergo radionucleotide therapy either with a high dose MIBG treatment or with high dose dotatate treatment, depending on that circumstance, the patient has. And then there are some novel targeted therapies. The hypoxia inducible factor two inhibitor are called a HIF-2 inhibitor drugs, these drugs, one was actually approved by the FDA in August of 2021 called belzutifan. This was actually approved for Von Hippel-Lindau related disease. For those patients that may have Von Hippel-Lindau disease that have renal cell carcinoma or central nervous system hemangioblastomas or pancreatic neuroendocrine tumors.
That could be an option as part of a special clinical circumstance for a patient. And obviously it depends on what the patient has, what the driver mutation is. If it's a Von Hippel-Lindau related disease, certainly that could be a possibility for some of those patients. In terms of studies that are going on, more on the translational level. In terms of the research that we're doing at UF Health Shands Hospital, we're looking at what metabolic pathways that malignant pheochromocytomas and paragangliomas could be utilizing. One pathway we identified is the polyamine pathway. So, polyamines are essential cations for a cell. They bind to negatively charged macromolecules and their role is important for cells to function, especially for transcription, translation as well as DNA repairs. So, considering how important polyamines are for a cell's function, we therefore hypothesize that if this pathway is so important, why don't we just target this pathway? So our group was lucky enough to work with a medicinal chemist here at UF Health Shands Hospital, by the name of Dr. Raymond Bergeron, who actually synthesized a polyamine inhibitor, where we were able to test it in the laboratory and show that these inhibitors that he developed actually inhibit these aggressive tumors from growing in the laboratory. And we also were able to see this in an animal model system.
So we are currently in the process of identifying exactly how these inhibitors work in these tumors cells before they move to clinical trials. So, there's a lot of exciting developments that are happening not only in our laboratory, but we are also collaborating with a number of other laboratories around the world to find new treatments for patients that may have metastatic disease.
I think there is a lot of hope on the horizon for these patients, and I can assure anybody who is afflicted with this disease or who has family members that are afflicted with this disease, that there are a lot of people working around the world very hard to see if they can find a good treatment option for them and their loved ones.
Host: Thank you so much, Dr. Ghayee. What a fascinating episode this was, you gave us so much information. Thank you very much for joining us and sharing your incredible expertise for other providers today. To refer your patient or to listen to more podcasts from our experts, please visit UFhealth.org/medmatters. And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs062.mp3
- DoctorsWilson, Christina
- Featured SpeakerChristina Wilson, MD
- Guest BioChristina Wilson, MD, PhD is an Associate Professor of Neurology at the University of Florida College of Medicine. She serves as the Neurology Residency Program Director, Vascular Neurology Fellowship Director, and Associate Chair of Education for the Department of Neurology.
Learn more about Christina Wilson, MD - TranscriptionScott (preroll): The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA category one credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole and I invite you to listen as we examine tenecteplase for treatment of acute ischemic stroke. Joining me is Dr. Christina Wilson. She's an Associate Professor of Neurology at the University of Florida College of Medicine, and she practices at UF Health Shands Hospital. Dr. Wilson, it's a pleasure to have you join us today as alteplase remains the only FDA approved thrombolytic for acute ischemic stroke. Can you tell us a little bit about the history and evolution of thrombolytics for stroke?
Christina Wilson, MD (Guest): Absolutely. And thank you for having me. So as you noted, alteplase is currently our standard of care for the treatment of acute ischemic stroke. We've been using this in clinical practice for just about 25 years now, based on the initial NINDS trial that was conducted in 1996. This demonstrated that alteplase had a benefit for patients when they presented early in an acute ischemic stroke. And we still are tied to that very early time window. Although some subsequent studies have shown that we can go out to four and a half hours in most cases and potentially even a little bit longer with some select patient populations. But, to date, alteplase remains our standard of care.
Host: Well, then now tell us about tenecteplase. How has this entered the picture?
Dr. Wilson: So tenecteplase is actually very similar to alteplase. We're really talking about a recombinant form with a modification of only a few amino acids. But those amino acids do make potentially a significant difference. So alteplase has a couple of limitations that make it a little bit difficult to use in certain situations.
One is that it has a very short half-life. And so what that means in clinical practice is that you have to provide a bolus right upfront, but then also a one hour infusion. And this can be a challenge, if there was a patient, for example, who is being transported to a higher level of care, often transportation doesn't want to move the patient if they're on an active infusion.
And so this can slow things down. Also, it takes a lot of nursing involvement, to monitor that drip for an hour. And so that can tie up resources and then can also be challenging especially in the COVID pandemic where we're trying to, sometimes limit the amount of time that, the personnel are spending in a patient's room, for infection purposes.
And so the nice thing about tenecteplase, is that as a result of the modification, it has increased resistance to degradation in the bloodstream. So this gives it a longer half-life and it can be administered as a single bolus injection. So, really bypasses a lot of those concerns about needing to be on an active infusion.
The other limitation that we're all familiar with, with alteplase is that, the potential downside and one of the risks that we need to take into consideration when the patient is being considered, you know, risks and benefits is that there is a risk of hemorrhage associated with the medication, and tenecteplase doesn't completely remove this risk, but there is, in theory, because it has a greater specificity for the plasminogen that's bound to fibrin, so attached to a clot, it should be more specific for attacking that clot and not just kind of causing hemorrhages. So, there should be a lower risk of hemorrhage overall. And then another benefit is that it is less expensive than alteplase.
So neither of these medications is particularly inexpensive. But it can be a little bit helpful that this is a less expensive medication. And then the final limitation with alteplase, that we are certainly aware of is that the larger the clot; and so when we have large vessel occlusions, for example, these are the most devastating types of stroke; we know that alteplase doesn't work particularly well in opening up those types of clots. Thankfully, we do have mechanical thrombectomy as a treatment, in certain situations. But, because tenecteplase again, attacks the plasminogen, or it's bound to fibrin and potentially is more specific for the clot; what we found in some of our clinical trials is that it's particularly helpful for that patient population with large vessel occlusions.
Host: Well, thank you for that. And I'd like you to expand on what you just said as you've been comparing and contrasting alteplase and tenecteplase for stroke. Can you characterize the population of patients that would benefit the most from tenecteplase treatment, expand on your patient selection for us? You just mentioned one. Can you give us some others?
Dr. Wilson: So there've been two pools of patient populations that have been addressed in the clinical trials. The first is kind of an all-comers, the folks who are having an acute ischemic stroke, are presenting within the time window, where they would benefit from treatment with a tissue plasminogen activator.
And so we have several clinical trials that were smaller comparing tenecteplase and alteplase. And that patient population showed that tenecteplase, likely works as well as alteplase in that population. But really there's only been one published trial that looked at a larger patient population in kind of all-comers of stroke.
And that was the NOR-TEST trial that was published in 2017. This looked at a higher dose of tenecteplase than is used in some of the other studies. So this is 0.4 milligrams per kilogram of tenecteplase, rather than the lower dose of 0.25 that was used in some of the other trials.
But so using this higher dose and looking at, enrolling a little over a thousand paitients, the NOR-TEST trial again, compared all-comers, folks who came in and met kind of the standard alteplase treatment definitions within four and a half hours. And within this patient population, again, you know, tenecteplase and alteplase where across the board fairly similar, no benefit to one over the other.
But it's important to realize, number one, that this trial skewed towards a milder stroke population. So most of the folks in this trial, had an NIH stroke scale of seven or less. And so that's an important thing to keep in mind when you're assessing whether your patient might benefit. And so, they did do some subgroup analyses after the fact and showed that in patients who had more moderate levels or severe strokes when they came in, that they likely benefited as well.
But of course, a subgroup analysis with smaller numbers, it's always a little bit challenging to really, determine whether that is truly an effect. And so, it would be helpful to have some additional studies looking at this. These are ongoing, but have not yet been replicated. So, the 2019 American Heart Association and American Stroke Association Guidelines, consider this patient population of all folks who are presenting with an acute ischemic stroke in that treatment window.
And they say that the higher dose, the 0.4 milligrams per kilogram can be considered as an alternative to alteplase. So again, in those situations, where there is a nursing issue or a transport issue, or, there's currently a national shortage of alteplase.
And so that may make tenecteplase look a little bit more attractive in certain situations. But I would say that the bigger population that we are focusing on at the moment is those patients with the large vessel occlusion, as I mentioned, earlier.
Host: So, where are we now in trials? And what do you think will happen and when?
Dr. Wilson: So I think, it's an interesting time. There's a lot of potential and judging from the feel on the ground at the International Stroke Conference when folks are talking about this, it seems like there's a lot of excitement and I envision that at some point we're going to make a full transition after we have a little bit more trial data.
Here at UF Health Shands Hospital, we have actually started to make that transition. So specifically looking at the patient population with large vessel occlusion, given that we have a bit more data there to suggest that those patients actually open up that clot, before you even take them for mechanical thrombectomy, that that's more likely to happen with tenecteplase than with alteplase.
And so we've incorporated that in, into our protocol here. And so if someone presents with what appears to be a clinical large vessel occlusion, which we subsequently confirm on our CTA, which is part of our stroke alert process, but we certainly don't wait to treat, you know, until we've determined that. So, if they present with a clinical large vessel occlusion, they are being treated with tenecteplase at this point.
Host: Really? That's amazing. And what an exciting time to be in your field. Dr. Wilson, as we wrap up, anything you're doing at UF Health Shands Hospital that other providers may not know about? Any research studies related to thrombolytics for acute ischemic stroke and really what you would like the key message to be about tenecteplase and what you're doing there.
Dr. Wilson: So I think there's lots of potential to explore this a bit further and one patient population that we don't have data yet, but I think might be of interest is in the extended time window of treatment. Many of our treatments, especially with thrombolytics have been very time locked that we have really focused on that four and a half hour time window. And unfortunately, a lot of patients present outside of that window. It's later. They don't necessarily recognize that they're having stroke symptoms. They don't realize that they should call emergency medical services. And so, may drive themselves to the hospital, and be stuck in triage or something like that, where they're not getting that treatment within the time window.
So there are some ongoing trials looking at tenecteplase within that extended window. And it's certainly, hoped that, that patient population may show a benefit as well. So I think in summary, where we are currently, it's really an exciting time, for particularly large vessel occlusions that we not only have the mechanical thrombectomy, which has been shown in multiple clinical trials to have an efficacy, especially in those patient population, with the anterior circulation, large vessel occlusion.
But now this data from the Extend IA tenecteplase trial that was published in 2018, showing that, patients would potentially benefit from tenecteplase over alteplase as well.
Host: Such an informative episode. Thank you so much, Dr. Wilson for joining us today. To refer your patient or to listen to more podcasts from our experts, please visit UFhealth.org/medmatters. And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
Additional Info
- Audio Fileuf_health_shands/ufhs061.mp3
- DoctorsDoonan, Bently
- Featured SpeakerBently Doonan, MD
- Guest BioBently Doonan, MD, MS is an assistant professor in the Division of Hematology & Oncology at the University of Florida College of Medicine. Dr. Doonan earned his undergraduate degree in biology, cum laude, from Coastal Carolina University.
Learn more about Bently Doonan, MD - Transcriptionpreroll: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And I invite you to listen as we discuss emerging therapies for metastatic melanoma. Joining me is Dr. Bently Doonan. He's an Assistant Professor in the Division of Hematology Oncology at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital in Gainesville, Florida.
Dr. Doonan, it's a pleasure to have you with us today. We have a lot of exciting emerging therapies to talk about. Before we get into some of those, tell us a little bit about metastatic melanoma, its prevalence, and what you've been seeing in the trends.
Dr Bently Doonan: Yeah. Well, thank you so much for having me first and foremost. It's great get to talk about this field, talk about something that I'm sort of very passionate in in patients that I see every week in my clinic. So I primarily treat patients with advanced cutaneous melanoma and other cutaneous malignancies at UF Health Shands Hospital. So it's really at the forefront of what I do.
And really the other part of it is that I'm also a clinician scientist. So I do research in the field and in the area and have been doing that since dating back to 2008. And so, to give sort of a big picture focus on the field, really going back to when my career first started looking at research in melanoma, we had nothing. We had some experimental therapies, we had some promise for immunotherapy and nothing had really cracked through the ceiling to give us much benefit.
And the world really changed in 2011 with the advent of ipilimumab or ipi, that really sort of changed the game and changed the landscape and followed three years later by nivolumab and pembrolizumab or nivo and pembro, to make it easier, really changed the world. So we went from completely having no beneficial therapeutics available to then having three or four different drugs and targeted therapies soon followed after that, that really changed the landscape and brought this completely uniformly fatal disease to having patients that are long-term survivors, patients that achieved durable remission and some long-term cures.
And so really when we look at the landscape for the first 50 years of modern oncology, there is nothing for melanoma. And then in the last decade, we were given these three to five new therapies, three of them being immunotherapies, and then the advent of the targeted therapies. And we won't speak today about T-VEC, but that's another sort of immune-based therapy in the space that have really, really changed the game.
Looking at the next 10 years going forward, we're really sitting on the cusp of another major leap forward. There are some therapies that are likely to come out within the next really 12 to 24 months. Some of that being delayed by just the effects of COVID on the research development on clinical trials is really going to change the field that much further. So it seems that 10 years in melanoma really is game-changing.
Melanie Cole (Host): Wow. That is fascinating. What an exciting time to be in your field. And thank you for telling us how it's evolved in recent decades and why alternative pathways and these novel strategies were so desperately needed. So identify LAG-3 inhibition and its role in melanoma for us.
Dr Bently Doonan: Yeah. So most practicing physicians realize that the real breakthrough in immunotherapy has been checkpoint inhibition. And when we speak about checkpoint inhibition, what we're really talking about is that there are natural mechanisms that exist in the immune environment that limit how activated your immune system gets against itself. And this is a protective mechanism that then gets abused by cancer cells. We're having this unchecked inflammation that really can drive T cells to actually not function appropriately. And this is sort of a hallmark of many cancers, is the up-regulation of these immune checkpoints. And the ones that people are most familiar with are CTLA-4 and then PD-1 and those are the targets of the drugs that we've spoken about so far, ipi and nivo. These have been really well-validated among many cancer types. But unfortunately, really we still see about 20% of the total cancer population, higher in melanoma than other cancers, but about 20% sort of globally and probably closer to 40% of our melanoma patients that really derive benefit from this, that really we don't know is what happens when patients don't respond to this or what happens after that.
There's lots of mechanisms at play for why these therapies fail or why they don't work or why they become sort of obsolete over time. And one of that is because the whole process of checkpoint inhibition is actually much more complicated than just having two or three different receptors or logins on the surface of these cells that silence the environment. There's multiple other checkpoint inhibitors like LAG-3, which is the one we'll talk about today, but there's multiple other ones that are downstream of this that function similarly to what we're talking about.
Now, LAG-3 is important to discuss here because this is really the next one up at bat. This is the one that's in the batter's box. This is the one that's the furthest along in clinical development. And it's the one that's got the most promise to get into the clinic the soonest. So LAG-3 or lymphocyte activation gene 3, you can think of it as just being another step on the cascade of immune checkpoint pathways.
It doesn't have the same breadth or depth of knowledge that we have about CTLA-4 or about PD-1, because it doesn't have as simple of a lock and key mechanism with its login that other agents do. But what we do know is that when we inhibit this, both in preclinical studies and what we have now from some early first-in-human phase I, phase II, and even up to phase III data now is that in humans it can be quite effective in diseases where T-cell exhaustion is a problem. And melanoma's really the hallmark disease for having a T-cell based immune effect to be effective, that's where ipi and nivo and pembro have really shown the biggest benefit.
Melanie Cole (Host): So then familiarize other physicians with TIL therapy. Speak about tumor-infiltrating lymphocytes. I found this fascinating in my research.
Dr Bently Doonan: Yeah. So TIL therapy, again, this is another aspect of immunotherapy that's sort of was pioneered and started in melanoma and then is a technique that's the hopeful ability to span across multiple tumor types. So this is really pioneered in the '80s by Steve Rosenberg's group at the surgical branch of the NIH. And he had a seminal paper in mice back in 1986, where they were showing the potential of actually taking a tumor and then you remove it from a host and ex-vivo expand it. There's T-cells that are embedded within the tumor that are effective at killing that. And by expanding those T-cells and reintroducing them into a new host or into the same host, you could actually show an immune response.
Now, they quickly followed this in first-in-human studies in the late '80s. And this is some hallmark pictures that are in pretty much every immunology textbook in the country, showing that patients with large aggressive metastatic melanomas, when this therapy worked, it was profound. We were talking about a 34% overall response rate, which was better than high dose IL-2, which is really the only game in town at that point. And within that, there was about 6% to 7% that had complete responses that are very durable responses even up to four or five years later.
But it didn't really change the landscape. And part of this was because it's difficult to do the handling of cells and expansion and really coordinating this in the early '90s was very difficult. It really wasn't until advent of CAR T-cell therapy and some of these other cellular therapies like dendritic cell vaccines and our ability to improve the way that we can handle, process, deliver and treat patients with cellular therapy, the TIL therapy really started to come back into the forefront and really into the forefront for melanoma.
There was a company that sort of partnered with Dr. Rosenberg's group and sort of took his ideas and collaborated with the NIH called Iovance, and they've created a product called lifileucel. And lifileucel is likely to be the first commercially available TIL-based therapy in the next 12 to 24 months. Their goals was actually to have this approved or sent to the FDA last year, but they ran into some roadblocks with some internal testing and some analysis they needed to do on followup and also the COVID slog that's happened to the NIH.
But what they're showing in some of their data that they presented at ASCO last summer, was that in heavily pretreated patients, so these are patients with advanced metastatic melanoma and on average had received three or more than three lines of prior therapy. So this is either having targeted therapy, receiving both ipi and nivo or other cellular-based vaccines. And what they saw was an overall response rate of about 35%, which is good. But really the big thing that they saw is there was a disease control rate of 80%.
Now, a disease control rate means you're not going to likely die from your disease. Now, it might not make your disease go away, but if it holds your disease at bay, it's really effectively doing the same thing for the patient and really turning it into more of a chronic medical condition. Almost everyone who saw a response or reduction in their primary tumor size, and these responses were very durable, so they were really durable and they actually deepened over time. And adding to this, it was really generally well-tolerated. The side effects that we're seeing with it is that the cellular therapies actually followed by a period of high dose IL-2, which is really where all of the toxicity comes from.
And so my suspicion is, is that when they get these things ironed out with the FDA and they submit their application next year, that this is going to be a therapy that's viable and approved by the FDA likely in 2022, if not by 2023. And so what we've done seeing this sort of potential for this in the future here at UF Health Shands Hospital, is that we've actually in discussions with Iovance at becoming one of the treatment centers for lifileucel when it inevitably gets that approval.
Melanie Cole (Host): Dr. Doonan, TIL therapy sounds absolutely fascinating. As you said, it's progressing to FDA approval likely in the next year. Tell us a little bit more about how it's even done.
Dr Bently Doonan: Absolutely. So cell therapy is really interesting. It's very viable and what we've learned a lot from the CAR T-cell-derived products is that we actually need to do more than just give cellular product. So how it works is a patient's identified as meeting the criteria. So this is people that have progressed on previous lines of therapy. And we actually would bring them in and do a surgical removal of one of their tumors. That gets sent off to the company for the actual expansion of the TILs and they develop the product that's then going to go back into the patient. That process takes about three to four weeks, depending on the turnaround time for it.
While that's happening, the patient is going to be admitted to the hospital and they actually have to receive something called lymphodepleting chemotherapy. Now, lymphodepleting chemotherapy is non-myeloablative, so it does not reduce your bone marrow down to the part of, say, receiving a transplant, but it does condition the immune environment to remove some of those cells that are going to inhibit the function of the TIL therapy.
After you've received the lymphodepleting chemotherapy, you then receive the TIL product. And what we know is that patients generally have no negative response to that. It's your own T-cells, there's very limited risk of having a reaction to it. And it's even probably less than that of getting an autologous transplant for a disease like multiple myeloma or lymphoma. After you receive the product, then the only issue that really we're seeing with the toxicity is that following the TIL administration is that we give a drug in the adjutant setting to expand the function of that TIL product, and that's IL-2. IL-2 is tried and true long-term therapy that's been given in melanoma, and this is sort of what we call moderate dose IL-2. It's still a high dose, but you're only going to have to receive five or six doses of it every 12 hours or so. So it's in typical fashion with high-dose IL-2, it's given multiple sessions as the patient can tolerate over many weeks, many return visits to the hospital with lots of toxicity.
This therapy has a much briefer window of giving the IL-2 as an adjuvant. And once that's complete, there's no further therapy that's needed. So after recovery from that period, the person's discharged from the hospital and then does the remainder of their care in the outpatient setting.
Melanie Cole (Host): Can you discuss briefly for us outpatient systemic cytokine therapy for relapsed metastatic melanoma, because we have a lot to get through. Wow, this is such an interesting podcast, but briefly go over this outpatient cytokine therapy for us.
Dr Bently Doonan: Yeah, absolutely. So what we were talking about with the lifileucel and the big side effects or the toxicity that it has on the tail end of that therapy is because it requires administration of high-dose IL-2. Now, high-dose IL-2 has been used since the early '80s for melanoma. It's effective. It's also been used in renal cell carcinoma before. But it has to be administered really in an intensive care setting. Some of the side effects can be severe or life-threatening, renal failure, pulmonary edema, and some other really high risks syndromes.
So though we know it's always been effective in melanoma, the ability to deliver this to patients has really been really focused at some high volume centers with expertise in it with also some high risk. And it really has been supplanted by checkpoint inhibition in terms of its value. Now, company or a group of investigators, what they did is they sort of found a novel way of addressing this ability to expand IL-2 through the advent of a drug called bempegaldesleukin, or we can call it bempeg. It's much easier to say Bempeg. But it's the first in its class, immunostimulatory IL-2 cytokines pro-drug, which means when it's engineered, it can be given in a controlled and sustained release instead of as a high dose sort of cytokine surge. Most cytokines when given actually have an incredibly short half-life on the matter of seconds to minutes. And that's by design because if these were to stay on and turned on at a very high level, the side effects are incredibly high.
So in the formulation that they've made, it's able to deliver a similar effect to what high-dose IL-2 can do, but in a much safer, slower, controlled, and most importantly, outpatient environment. And so what they've shown so far, and they've only reached sort of phase I, phase II data, there was a trial called PIVOT-02, which was giving this drug in addition to nivolumab every three weeks. And it was really remarkable, the level of response that they were seeing, is that they were seeing a 52% response rate to treatment.
Now, this is a small sample size, and this is really feeding into a much larger phase III clinical trial, called PIVOT IO 001 that's currently enrolling. But what this would potentially do is it really keeps the treatment of melanoma in the clinic. And it really gives some therapies that we know have been effective for the last 20 or 30 years a much better toxicity profile and a much better and easier delivery mechanism. So the ability to deliver this to patients in the outpatient setting is really going to be revolutionary for what we can do.
Melanie Cole (Host): As we continue this, talking about efficacy and trials for metastatic melanoma, has the combination of nivolumab and RELA shown efficacy? Tell us through which mechanism this works.
Dr Bently Doonan: Oh, absolutely. So that's really what we've seen with all checkpoints, is that each checkpoint is likely to have some degree of individual drug-specific effect. So as a monotherapy, each of the previous checkpoints have some effect and, for a select group of patients, it's probably the only thing they need, even in the early ipi studies. There's probably about 8% to 10% of patients with melanoma that a dose of ipi or multiple doses of ipi is probably the only thing they would need to actually have their disease response. And we see that similarly in both nivolumab and pembrolizumab. We also see that with relatlimab, having some single agent benefit, especially in patients that were previously treated. But when we add it to nivolumab, we see that the combined benefit from these two therapies at the same time really outpaces the individual therapy. So it's really a situation where one plus one doesn't equal two. It's that one plus one really equals three or four.
Now, we see that similarly with the ipi-nivo combination, but the big issue there is that when we're compounding the effect, we're also really compounding the toxicity. So, if you look at the individual toxicities of a drug like nivolumab or pembrolizumab are severe side effects, really only happen in 10 to 15% of patients. And in clinical practice, it's probably even a little bit less than that. When we do ipi, we're really looking at 30% of patients, if not more, are going to get a serious one. And when we combine those two, it doesn't go, "Well, 30 plus 10 should be 40. It's 30 plus 10 really turns into 75." So it really becomes almost everyone is going to get a more significant side effect from the combination.
Now, when we do relatlimab plus nivolumab and what they've shown in some of the clinical trials is that you do get that same compounded effect in terms of improving the effect of the drug. So, if you look at the efficacy of nivolumab alone, in terms of progression-free survival in this trial that they did, you saw about four and a half months of progression-free survival with nivolumab, which similar to what we see in the community. Now, with the addition of relatlimab to nivolumab, it was significantly increased. That went up to 10 months, so more than double the actual progression-free survival effect by adding the two drugs together.
And the best thing that we see with the combination is that we're really not seeing a huge increase in the treatment-related adverse effects. And so this is the potential to then give us the benefits of doing combination immunotherapy, similar to ipi and nivo without having to take on the increased risks that ipi and nivo had in terms of side effects. So instead of going up to a side effect profile of say greater than 50% of patients having a grade 3 or 4 adverse effect with ipi-nivo, it's really more like 18% of patients. And so it's less than half the degree of toxicity that ipi-nivo carries and probably a very similar efficacy to it.
The other benefit is that since this is not a competing mechanism, is that you still allow ipi to be used in the future. I really feel, and I think probably most people in the field would say that if the rest of the survival data that's sort of being worked on in these larger trials bears fruit that shows that not only progression-free survival we're seeing, but if we're also seeing overall survival, the combination of relatlimab and nivolumab is really going to supplant the use of ipilimumab or ipi in the first-line metastatic melanoma.
Melanie Cole (Host): Along those lines then, what was the overall response percentage rates seen in the potential application of bempeg in combination with nivolumab?
Dr Bently Doonan: So looking at bempeg, the overall response rate with bempeg plus nivo was 50%. And so that 50%, it's important to say is in a much smaller cohort of people. So the nivo+RELA trial was up to, I think, 750 people that were stratified against the two arms versus this being both a signal-seeking, toxicity-seeking, and then early expansion cohort, the bempeg PIVOT-02 trial, I think was only in a matter of, say, like 50 or 60 patients.
So with that though, 34% of the patients in that trial had a complete response. Now complete response is something that we achieved for in all trials and in all therapies, because those are patients that are the most likely to remain cured. But chasing a complete response really overlooks that if you can just have stable disease or prevent progression of disease, you have an overall response rate that's really clinically meaningful to your patients.
Now, the other interesting things about the bempeg is that the duration of response in this trial has not been reached. So this is in those patients who respond, they tend to respond for a very long time. And so those that reached some degree of disease control by modified iRECIST criteria maintained that control rate for more than 30 months. And the progression-free survival in this intent to treat population was almost three years long.
That's really probably stronger and more robust than what we're seeing with some of the other combinatorial data. But if you think about it, it's because this is actually putting something into the mix that's got some cytotoxic effect against the melanoma cells, but also stimulates wider T-cell expansion. So IL-2's mechanism of action is slightly different than the mechanism of action with the relatlimab. And because of that, I would probably say that the bempeg probably does carry a slightly higher side effect profile risk than does the relatlimab.
Melanie Cole (Host): What an informative podcast this is and you're an excellent educator. Dr. Doonan, as we wrap up, discuss any ongoing research studies, research that you're doing at UF Health Shands Hospital. Any game-changers that you see? What would you like other physicians to take away from this podcast today?
Dr Bently Doonan: Absolutely. So I think as a practicing clinical oncologist, I think we're all going to see the benefit of a lot of these sort of multinational and these bigger projects and this work that we talked about in the next 12 to 24 months. And it will really be practice-changing. What I do here at UF Health Shands Hospital, as part of both a practicing physician and also as a physician scientist, is I really focus on strategies to overcome this resistance to immunotherapy and to overcome the tumor microenvironment and how it inhibits the ability to deliver immunotherapy.
And with that, I focus specifically on the most advanced and the highest risk melanoma lesions, which are melanoma brain metastasis. And so my research focus really is looking at new novel mechanisms of therapy and ways of targeting brain metastasis in patients with metastatic melanoma. And it's important because all of the trials we talked about today and all these therapies, they're going to make these patients live longer if they are going to be effective and we're going to be seeing patients with melanoma live longer and live better. And the double-edged sword to that is that whenever we have therapies that make cancer patients live longer, as long as the disease is still present, what we're really doing is also increasing the likelihood that they'll develop a distant metastasis at some point or develop brain metastasis.
Now, in some studies we're already looking at about 40% to 60% of patients with advanced melanoma, having melanoma brain metastasis at some point during the course of their treatment. And when they get those lesions, it's really tough sort of decide how we treat them. The treatment paradigm has not fully been established, but it follows the similar course of how we treat systemic disease, where we look at double agent immunotherapy to treat it.
Unfortunately, because the brain is a little bit more complicated than the rest of the body in terms of the tumor microenvironment, the therapies are less effective in the brain. So single agent immunotherapy has very poor response rate. The addition of double agent immunotherapy improves that slightly, but in these patients, the risk of relapse is really high.
So one of the first and foremost programs that I'm sort of to develop here with my research and with my clinical aspect is to really come up with trials that are directly targeted for these patients with melanoma brain metastasis. We have some drugs that we're testing in collaboration with some of our industry partners that we think are going to have a very high likelihood of success in this space and we've got some promising preclinical data and some promising preclinical work. And so I do this research at UF Health Shands Hospital as part of also our University of Florida Brain Tumor Immunotherapy Program under the guidance of Dr. Duane Mitchell. And so our goal is to really create a clinic and a landing point for patients of all types with brain metastasis, sort of starting with patients with melanoma brain metastasis, where we're going to have the science, the scientists, the preclinical acumen, and then the ability to deliver our therapy to patients with advanced disease. And so that's something that we're really, really excited about here at the University of Florida Health Shands Hospital and what we're going to have in the future.
Melanie Cole (Host): Dr Doonan, that was outstanding. Thank you so much for joining us today and telling us about all the exciting emerging therapies for metastatic melanoma and the game-changers. I hope that you'll join us again and fill us in as things progress. And thank you again for being with us today.
To refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. - HostsMelanie Cole, MS
- Post Test URLhttps://cme.ufl.edu/mededcast/
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