Unlocking Treatment Strategies for Anaplastic Thyroid Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig phase one and Cleveland Clinic sarcoma programs. Today I'm happy to be joined by Dr. Joe Scharpf, director of head and neck endocrine surgery at Cleveland Clinic. And Dr. Emrullah Yilmaz, a medical oncologist at the Cleveland Clinic Taussig Cancer Institute Head and Neck Program.

They're here today to talk to us about progress in treating anaplastic thyroid cancer. Dr. Scharpf was previously a guest on the podcast to discuss advances in treatment of aggressive thyroid cancers. And Dr. Yilmaz has been a guest to discuss ASCO guidelines for recurrent and metastatic head and neck cancers. Today, they are here to talk about management of anaplastic thyroid cancer. So, welcome back to the podcast.

Joseph Scharpf, MD, FACS: Thanks for having us.

Dale Shepard, MD, PhD: Absolutely.

Emrullah Yilmaz, MD, PhD: Thank you so much.

Dale Shepard, MD, PhD: So, maybe just to remind us, Joe, what do you do here at Cleveland Clinic?

Joseph Scharpf, MD, FACS: So, I'm a head and neck surgeon, otolaryngologist, professor of otolaryngology, and most of my practice is centered on head neck endocrine surgery, so thyroid, parathyroid, with special interest in advanced disease. I do other head neck cancers, but that's my primary focus from an academic research standpoint and even clinical practice.

Dale Shepard, MD, PhD: All right. Emrullah, what do you do here?

Emrullah Yilmaz, MD, PhD: Yeah, I'm a medical oncologist, specializing in treating patients with head and neck cancers, including thyroid cancers. And we collaborate with our colleagues in different departments and make sure they get the right systemic treatment for thyroid cancers. I'm also associate director of the Precision Oncology Program, so that is relevant to thyroid cancers at the same time, since there's a lot of changes in the precision oncology recently.

Dale Shepard, MD, PhD: Excellent. So, we'll end up talking a little bit about the management and that precision oncology component, but lots of different people might be listening in, may know a little bit more or less about thyroid cancer. Anaplastic thyroid cancer, Emrullah, let's start with you. Tell us a little bit about anaplastic thyroid cancer.

Emrullah Yilmaz, MD, PhD: So, anaplastic thyroid cancer is actually a rare type of thyroid cancer. It's not among the common thyroid cancer patients that present with the surgery get iodine treatment, so this is a different one. So, this is an aggressive cancer and on diagnosis, most like its stage, like stage 4A, 4B, 4C, we don't have stage 1, 2, 3 for this cancer. So, that talks about how aggressive these cancers are. And they are managed separately from other types of thyroid cancers.

And so, the patients usually present with large neck mass, rapidly enlarging neck mass. And our clinical suspicion starts with the time that we are seeing the patients because a lot of times, these patients require rapid diagnosis and rapid workup and treatment decisions very quickly. So, these patients, a lot of times, require seeing different types of specialists right away.

Dale Shepard, MD, PhD: And so, Joe, maybe from your perspective as a surgeon, this does fall a little bit different than most thyroid cancers. So, from a surgery standpoint, when you see these patients, how does the initial management vary?

Joseph Scharpf, MD, FACS: It can vary quite a bit. Unfortunately, sometimes we meet these patients in the emergency room as they're obstructed from their breathing, swallowing difficulties. We do want to get tissue on them immediately, as Dr. Yilmaz had said, to help diagnose what we're highly suspicious of, so that if there's a rapidly growing mass, particularly in elderly patients, we have to be suspicious that it's an anaplastic cancer, potentially lymphoma, but a lot of times more worried about anaplastic thyroid cancer.

And so, their airway may be at risk, that has to be stabilized. We try to avoid doing tracheotomies on patients, but if they're in such a desperate situation, sometimes we have to do that almost on presentation even, it's that aggressive.

Dale Shepard, MD, PhD: And so really, we're thinking maybe from a surgical standpoint, it's as much about airway management and things like that than actually primary therapy for the tumor.

Joseph Scharpf, MD, FACS: Right, so most of them will come in at a more aggressive, maybe even unresectable, stage. And unresectable would mean encasement of the carotid artery into the prevertebral musculature, or very morbid where you'd have to remove a larynx. There are some patients where they could come in at stage 4A, where it could be potentially surgically resectable and you would want to surgically resect those if you could. And we've had patients with great success doing resections for stage 4A tumors. But once they start to get into stage 4B, which means regional lymph nodes which are enlarged, or 4C with distant metastasis, then we're thinking in other directions now, of trying to get the best outcome for patients.

Dale Shepard, MD, PhD: And then from that multidisciplinary standpoint, Emrullah, what's your, as we see a new diagnosis, how is medical oncology involved?

Emrullah Yilmaz, MD, PhD: So, the involvement of medical oncology, again, especially within our multidisciplinary team, begins even before the biopsy. So, a lot of times, these patients end up seeing our colleagues in ENT, head and neck surgery, and then when there's a suspicion up upfront, they alert us. And that also includes, for example, pathology with the diagnosis as well, because even the diagnosis of these cancers might be challenging because a lot of times, they might end up getting a needle biopsy and it might be looking like a sarcoma, differentiate from different types of cancers. So, I have to make a really accurate diagnosis. And then we talk to the pathologist to try to get the markers run quickly so that we can make a treatment decision right away. Because if the patients are deemed not candidate for surgical resection, then they will need systemic treatment planned right away. And we would like to have that plan moving from the time that the patient comes to the clinic.

Dale Shepard, MD, PhD: And so, I guess when you talk about precision oncology and things, certainly, markers are important, aggressive disease, these things don't, we don't get that information quickly. How do we manage in that situation?

Joseph Scharpf, MD, FACS: Well, we were able to get it very quickly for some of the patients because one of the big markers is BRAF mutation for this particular diagnosis. So, we'll rapidly try to find within a day if it was BRAF positive and if it's anaplastic. And so, if that requires an open biopsy, often we don't have to do an open biopsy, usually can get with a core biopsy without going to the orb. But if we needed to, we want to get that as fast as possible to get that information within a day.

Dale Shepard, MD, PhD: So, we're actually able to get that within a day? So, in some cases, when you're doing more full panels, it takes significantly longer.

Joseph Scharpf, MD, FACS: And we will send that out for more full panels, but for some of the newer treatment paradigms, we really want to know BRAF status for anaplastic thyroid cancer.

Dale Shepard, MD, PhD: So, related to that, back to you Emrullah, standard of care right now, what do we do for anaplastic thyroid cancer?

Emrullah Yilmaz, MD, PhD: So, standard of care with the systemic treatment chemotherapy has been the backbone of the treatment. And even with those chemotherapy, as the agents that we use are from decades ago, we don't have any novel chemotherapy that is very effective for this type of cancer. So, that's why even though it is rare, the mortality rate has been really high for these types of cancers, patients living six to nine months in different studies.

But the findings about the BRAF made a big difference that the patients with BRAF mutation can have a good response to BRAF targeted therapies, which is dabrafenib and trametinib combination, which is an approved treatment for this type of cancer. So, for the patients who have BRAF mutation, if we start dabrafenib and trametinib, so that patients might have a quick response and can live longer than we know so far.

So, that's why we really would like to know about the BRAF status right away for these patients. And that's why, starting from the diagnosis, we are in touch with the pathologist, trying to get the immunohistochemistry right away. And if the BRAF is positive, we start the process of getting the patients starting the dabrafenib and trametinib immediately. Sometimes the tissue might be challenging, so that's why we ask our ENT colleagues, Dr. Sharpf's team, to see if another biopsy would be possible just to check the BRAF.

And the other alternative, with the advances in precision oncology with genomic testing, the blood testing for the mutational status. So, that might give a little bit quicker result than tissue testing. So, that's why we tend to send the patients for blood testing for genomic analysis. And eventually, we get the tissue analyzed for detailed genomic analysis, to make sure that we know as much as it is possible about the genetic changes going on in the tumor.

Dale Shepard, MD, PhD: When we think about the BRAF, specifically the V600E, what percentage of patients have that mutation, with anaplastic thyroid cancer?

Emrullah Yilmaz, MD, PhD: It's up to 40 percent, 50 percent of the patients. And even, and this Dr. Scharpf published, so it was in that range that we see the BRAF mutation in our patients as well.

Dale Shepard, MD, PhD: All right.

Joseph Scharpf, MD, FACS: It's been widely published about that number. We came out 47 percent, so we were in line with what other literature has been showing for it.

Dale Shepard, MD, PhD: All right. So, Joe, let's switch over to you here and tell me a little bit about that. You published a look back at a long experience here at Cleveland Clinic in terms of anaplastic thyroid cancer. Tell us a little bit about that.

Joseph Scharpf, MD, FACS: Sure. So, guidelines came out from the American Thyroid Association in 2021 for anaplastic thyroid cancer. And a lot of it has centered on this rapid team approach and also diagnostic testing with the molecular testing. And so, with this paradigm shift of treatment, we wanted to look back at our experience to get a sense of where we've been and what results we were getting. And then we'll be able to compare going forward to what we're going to find.

And we looked at about a 20-year experience. We had a large study, especially for the literature, of 97 patients. And as we would expect, our results were poor outcomes for patients for this disease process, for everyone in line with it, with a median overall survival of only six and a half months. Very humbling, very humbling disease. And so, we also got a sense for how many patients would have BRAF positive mutation, that came out to about 47 percent. Patients who could have surgery, maybe 4A or more resectable tumors, obviously did a lot better than other patients. And so, now we have a baseline going forward and we're involved with clinical trials to see how patients are going to do going into the future and compare those results.

Dale Shepard, MD, PhD: And I guess, just for perspective, Joe, we've talked before on another podcast about thyroid cancers in general and there's a wide range of thyroid cancers out there. Again, more for perspective about this particular disease and its aggressiveness. Yeah, six months, six-to-nine-month survival. How does that compare to most other thyroid cancers?

Joseph Scharpf, MD, FACS: So, the vast majority of thyroid cancer is a very good prognosis with 90 percent, 95 percent or greater percent survival. And so, it's a fascinating organ where you have some thyroid cancers that are small, quite indolent, to the point where there's very good evidence for active surveillance, not even operating and watching patients, all the way up to one of the worst cancers in humankind, with anaplastic thyroid cancer. So, they're at the complete end of the spectrum, but the vast majority do very well. This is rare.

Dale Shepard, MD, PhD: I just want to make sure that people, as they hear thyroid cancer, realize this is a pretty aggressive subset. So, Emrullah, when you think about therapies, we talk about really what the dramatic changes with BRAF therapies. What are other targets that might be in play? Have we identified other good targets that might be active for these patients?

Emrullah Yilmaz, MD, PhD: For these patients, even if there is BRAF mutation, like with the BRAF non-mutant cancers, there are a lot of a wide variety of the mutations that can be seen. And those so far have not been found to be a very good target. There are a lot of studies going on among that.

And the other one is immunotherapy. We use PD-L1 targeted immunotherapy, immune checkpoint inhibitors, for a lot of different diseases. And there is a lot of data coming up with the effectiveness of immunotherapy in anaplastic thyroid cancer. The only issue is this is a rare cancer first and also, a very rapidly growing cancer. So, that's why designing a clinical trial and getting the patients on a clinical trial a little is a little bit challenging. Because you want to start a treatment right away and you have a very short window to try to get the patients to clinical trial. So, that's why having prospective established clinical trial data is a little bit challenging for this cancer.

But one of the things, again, systemic treatment is important, but what we are hearing is, and what we are knowing is, surgery even though this with the patients with the metastases, surgery is very important. And Dr. Sharpf's study, even the patients with this metastasis, if they had surgery, their outcome might be better. So, that is one of the things that is moving forward with the treatment of anaplastic thyroid cancer, is about how to integrate that systemic treatment, safe, effective systemic treatment, with the surgeries. So, that's why we recently opened up a clinical trial here at the Cleveland Clinic, that is led by MD Anderson. And that's for the BRAF mutated patients, to combine immunotherapy pembrolizumab with dabrafenib and trametinib. And this is for unresectable metastatic patients. And if with these systemic treatments, if they become resectable, even though patients had this metastasis, see how the outcome changes with the surgical resection. So, that's why integrating targeted therapy, immunotherapy and also surgery for these patients. So, that seems to be one of the things that we're looking at in the future.

Dale Shepard, MD, PhD: It's really stabilizing the disease with that upfront systemic therapy, followed by surgery. So, Joe, tell us a little bit about from a surgery standpoint, your perspective as a surgeon. A lot of head and neck cancers are localized, the head and neck, they haven't spread. In a situation like this it would be, are you mostly looking at the prospects of taking out the primary tumor or also taking out the mets, from a surgical perspective?

Joseph Scharpf, MD, FACS: So, we do have a patient that's undergone trial and I'm operating on next week who has regional mets to the neck. Not evidence of distant disease at this point, but even if they did, I would still look to get control of that because we don't want to ever lose control in the neck for breathing, oral alimentation, quality of life, all of that. We just don't want to see patients suffering from those basic human functions. So, we do want to try to find a balance here to get control of the situation. So, we would offer surgery to allow patients, even if they had metastatic disease in another part of the body, hoping that other treatments may improve and can sustain a longer quality of life for them.

Dale Shepard, MD, PhD: Yes, I mean, resection of metastases seems to be a much more effective strategy in some cancers than others. But really, maintaining control in the neck seems to be the biggest concern.

Joseph Scharpf, MD, FACS: This is a very multidisciplinary team approach. So, there might be mets in the lungs, where Dr. Koyfman may be able to use SBRT on, or a different treatment to try to get control in those areas as well. Or our pulmonary doctors, thoracic doctors, may think of removing certain types of oligometastatic disease. We'll have to think that way about it and see how they're responding to the treatment.

Dale Shepard, MD, PhD: And so, this is, it's a rare subset of thyroid cancer. It's aggressive, so by nature people don't, they need to start treatment soon. Some of the advantages of coming to a place like Cleveland Clinic with multidisciplinary care, should everyone with an anaplastic thyroid cancer try to get to a specialized center?

Joseph Scharpf, MD, FACS: Absolutely. Unique to the Cleveland Clinic is our team approach. Even at major centers, they don't always have the rapid team response that we have. If someone we find out has anaplastic cancer, someone from our team will see them that day. I know Dr. Emrullah will see him immediately that day or the next day, same radiation oncologist. So, everyone comes together very, very quickly here to do it. We also are offering these trials that other centers aren't offering. It's very rare, even at major centers. So, you would think that some of them may want to send them to see us as well to offer this kind of treatment.

Dale Shepard, MD, PhD: Is there anything from a surgical technique standpoint that's particularly different from anaplastic cancer? We talked about the timing of systemic therapies, anything from a technical standpoint that is up and coming?

Joseph Scharpf, MD, FACS: Yeah, so from a technical standpoint, the cases are certainly going to be expected to be a lot more scarred tissue within the neck and area. So, we do have a lot of experience here and there from our other head neck cancer patients, who have had chemo radiation for say, squamous cell cancer, other types of cancer. So, we have a lot of experience of safely managing airways, major blood vessels, nerves, in those situations.

So, it's not a type of thyroid that would be done in the community at this point, I would expect. It would be something where you'd want a very good multidisciplinary team, and you may need vascular surgeons or thoracic surgeons available and one backup for those type of cases.

Dale Shepard, MD, PhD: And anything particularly unique from a reconstruction standpoint?

Joseph Scharpf, MD, FACS: Yeah, and so we have had situations, and we have not done this for anaplastic yet, but I have for other aggressive variants where some of my reconstructive partners have put free-flap tissue into reconstruct esophagus, to let patients swallow and breathe more comfortably. Regular oral diet, again, we've achieved for patients, when they have invasion of the cervical esophagus. So, that's a very unique thing that we offer for the patients.

Emrullah Yilmaz, MD, PhD: Just to add to that multidisciplinary approach, I think this can give an idea about how we are approaching. Because just for example, in the last few months, one of the patients who came in, the way that we approach is the patient's CT scan showed a large thyroid mass suspicious for anaplastic thyroid cancer. And then that same week, earlier in the week, I think it was a Monday or Tuesday, that the patient saw Dr. Scharpf had a biopsy, and while the biopsy's pending, the patient was scheduled to see us in the same week. And then while the pathology was pending, we reached out to the pathologist to be ready for the BRAF staining. By Friday, we had the BRAF status, but while BRAF was pending, our radiation oncologist was aware and ready to start radiation on the weekend if needed. But Friday afternoon, we got the BRAF result, and then Friday evening, we started the first dose of the BRAF inhibitor, and the patient did not need to get the radiation and had a very quick response right away with the BRAF inhibitor.

So, that's why basically when we're talking about multidisciplinary and quick diagnosis and approach, we're talking about days for this cancer. And we are able to make a treatment plan within days when we see this type of cancer.

Joseph Scharpf, MD, FACS: And that particular kind of patient too. In the past, I may have had to come in on Saturday in the middle of the night to do a tracheotomy. It's that rapidly growing into the airway, where he may have needed a tracheotomy just to breathe somewhere on Saturday or Sunday. But yet, we were able to find that and avoid that for him, which was great.

Dale Shepard, MD, PhD: Wow, that's impressive. So, great multidisciplinary management. We have some encouragement from medical oncology, targeted therapy, and new approaches.

Emrullah Yilmaz, MD, PhD: And on top of that, with a city with our basic research department over there, we have really great scientists, very experienced, well-known scientists, with ongoing research on identifying novel targets and resistance to the BRAF inhibitors, how to alter those resistance. So, we have a lot of basic research going on at the same time, and we're trying to get our clinical knowledge and experience to connect with the basic science to see how we can improve the future treatment approaches for these patients at the same time.

Dale Shepard, MD, PhD: That's great. So, really bad disease, but looks like a promising future in terms of new approaches?

Joseph Scharpf, MD, FACS: Yeah, I'm seeing results I wouldn't have expected to see in my lifetime actually, with what we're seeing. We have this one patient on study, just the results that Dr. Emrullah has gotten for her this past couple of weeks, with the targeted therapy has made her a resectable case, and I'm hoping she's going to do well. There's hope that's being provided, that was going to be difficult to provide in the past, as we've seen from our own evidence, our own studies of how patients did over the years with this disease.

Dale Shepard, MD, PhD: Wow, that's fantastic. Well, thanks for being with us today.

Joseph Scharpf, MD, FACS: Bye.

Dale Shepard, MD, PhD: Appreciate it.

Joseph Scharpf, MD, FACS: Thank you very much, that was great.

Dale Shepard, MD, PhD: Thank you.

Emrullah Yilmaz, MD, PhD: Thank you so much.

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