Hi, welcome to the session of Advances in the Management of Thyroid Cancer. My name is Sina Jassim, and I will be serving as your moderator today. You'll be hearing a lecture from Dr. Naifa Boussaidi, Dr. Mike Tuttle, and Dr. Shelby Holt on this very fundamental subject. For introduction to our speakers today, Dr. Naifa Boussaidi, many of us know her, is a tenured professor at the Department of Endocrine Neoplasia and Hormonal Disorder at the University of Texas MD Anderson Cancer Center. Her clinical expertise and research interests are primarily focus-driven to treat and improve outcomes in patients with aggressive thyroid cancer. Dr. Boussaidi trained at Baylor College of Medicine for medical school and stayed there for her internal medicine residency and then fellowship combined with her training at MD Anderson. She joined faculty at UTMD Anderson since 2004. She serves on several institutional and national committees. She's a member of ITOG, ATA member, and she's also a member of ACE, Endocrine Society, and several other societies and committees. Dr. Mike Tuttle is a professor of medicine and clinical director of the endocrinology service at Memorial Sloan Kettering Cancer Center in New York, designed and validated the first real-time risk assessment model for thyroid cancer management in which individual risk estimates are modified over time as a function of response to initial therapy. His research continued to center on important management aspects of thyroid cancer, including efforts to better understand and define the risk of recurrence and risk of death and potential role of observation in low-risk thyroid cancer. His clinical practice is devoted to patients with thyroid cancer, with particular emphasis on cases with aggressive thyroid cancer and complicated management issues. And our last but not least, Dr. Shelby Holt is a professor at UT Southwestern Medical Center, Department of Surgery. She specializes in thyroid and parathyroid surgeries. Dr. Holt serves as the chief of the Division of Endocrine Surgery. She completed her general surgery residency at UT Southwestern, followed by advanced endocrine surgery training at Mayo Clinic and University of Michigan. Dr. Holt is highly valued clinical educator and expert in her field. She runs the multidisciplinary thyroid cancer at UT Southwestern Department of Surgery, and she also serves as a director of the Task Force on Diversity, Equity, and Inclusion, as well as a senior faculty advisor for women in surgery program. She received numerous excellence in teaching awards. She's a fellow of the American College of Surgeons, a member of American Association of Endocrine Surgeons and American Thyroid Association, American Association of Clinical Endocrinologists, and the Western Surgical Association, the Texas Surgical Society, and the Association of Women Surgeons and the Parkland Surgical Society. So welcome to our speaker, and our first speaker is Dr. Holt. Hello, my name is Shelby Holt. I am chief of the Division of Endocrine Surgery at UT Southwestern Medical Center in Dallas. I want to thank the American Association of Clinical Endocrinologists for the opportunity to speak with you. I look forward to future personal interactions with you, but for now, I'm certainly thankful we have this platform to continue important educational efforts such as the ACE annual meeting. Let's talk about the treatment of patients with papillary thyroid cancer. When I trained in the 90s, all patients with PTC got a total thyroidectomy, withdrawal, stimulated radioactive iodine, 100 or 150 millicuries, and complete TSH suppression. We have certainly evolved away from this one-size-fits-all approach, recognizing the spectrum of disease and need for individualized therapy. However, what has not changed is the need for surgery to treat papillary cancer, but perhaps there has been a shift in the recognition that surgery is the most important step in the treatment of most patients with papillary cancer, since we've learned that radioactive iodine is not the magic bullet and does not achieve everything we would like it to. In addition, surgical treatment of papillary cancer has become individualized, taking into account different biologic behavior and recognizing the importance of risk stratification. So, goals of therapy? Complete lists of resection and adequate surgery being the most important treatment variable influencing prognosis. Again, in the setting of significant disease, a good clean-out is imperative, and the extent of surgery and the experience of the surgeon play important roles in determining the risk of surgical complications and the outcome. I will not overload you with data today, but rather my goal is to give you some practical pearls and food for thought to foster interdisciplinary collaboration to optimize the management of patients with papillary cancer. At UT Southwestern, we have a multidisciplinary thyroid cancer tumor board that meets twice a month to discuss cases. If this formal-type interaction is not feasible in your practice, I hope you still talk to your surgeon and ask them, what did you see? What did it look like in there? How bad was it? Did you get a good clean-out? I would also encourage you to put on your surgeon's cap when you're evaluating PTC patients, since again, the goal is optimal surgery and complementary counseling for our patients. Lastly, if you have not been in the operating room since your third-year clerkship in surgery in medical school, get in there and see what papillary cancer, parathyroid glands, recurrent laryngeal nerves, metastatic lymph nodes look like. This will give you a much better understanding and appreciation of the surgical treatment. So, let's walk through a recent case of mine that illustrates several management points. Mr. KG is a 23-year-old man presenting with a palpable left lateral neck mass. He is obese and has subsequent fatty liver. He has never had neck surgery before. His family history is negative for thyroid cancer. He has had no exposure to head and neck radiation treatment in the past, and he is a non-smoker. He's clinically and biochemically euthyroid. Imaging demonstrated a sonographically suspicious thyroid spive left thyroid nodule and a left lateral neck lymph node. Finally, elasperation of both of these sites showed papillary thyroid cancer. The CT scan demonstrates the bulky left upper lateral neck lymphadenopathy. The transaxial ultrasound imaging shown illustrates the left thyroid nodule with microcalcifications. I want you to note that you cannot see the posterior aspect of the mass or the deeper tissue planes. This lack of posterior penetration may reflect the depth of the ultrasound penetration. Difficult in this obese man with a very short, deep neck. He underwent a total thyroidectomy with a left modified radical neck dissection. Pathology showed a greater than six centimeter classic papillary cancer with extra thyroid extension and positive margins. 19 of 25 lymph nodes were positive, the largest measuring 3.2 centimeters with extra nodal extension, so extensive disease. The surgery was complicated by permanent hypoparathyroidism. His postoperative thyroglobulin level after thyrogen stimulation for radioactive iodine was 292. He received 150 millicuries, and the post-treatment scan demonstrated metastatic nodal disease. The post-treatment scan as shown demonstrates multiple foci of neck uptake, specifically fused with the CAT scan images, left upper retromparangeal lymphadenopathy and right central neck adenopathy. He presented to UT Southwestern with a thyroglobulin of 51 and an unsuppressed TSH. He has imaging evidence of the metastatic nodal disease sites as shown in his right central neck, right lateral neck, and left retropharyngeal area. He underwent a reoperation to include central neck dissection, right modified radical neck dissection, and left retropharyngeal node dissection. So what can we learn from this case? Was the extent of imaging adequate to determine the extent of disease and plan for the appropriate operation? Was the extent of surgery appropriate? Were the tenants of compartmental node dissection adhered to? Was the true extent of the disease appreciated? And postoperatively, could we have recognized residual structural disease necessitating surgery sooner? Ideally, a complete resection the first go-around is the outcome as a reoperation is associated with higher risk. While we all know the importance of a good complete ultrasound of the thyroid and nodal compartments, is that always sufficient? When do you need cross-sectional imaging? This patient illustrates multiple reasons why cross-sectional imaging can be important to define disease extent and optimize surgical planning. For the trainees, I like to use the term or words cross to help you remember all of these specific areas necessitating cross-sectional imaging. Areas that you can't see by ultrasound, mediastinal and retropharyngeal. When you're worried about locally invasive disease, a preoperative vocal cord paralysis or fixed mass on exam and size, patient body habitus, clearly obese, deep, short neck, more difficult to visualize completely with ultrasound, a bulky tumor and bulky adenopathy. What about the extent of surgery? For him, the recommendation for initial surgery is total thyroidectomy, central compartment lymph node dissection and lateral compartment lymph node dissection. Just for vocabulary to make sure everyone's on the same page, the central compartment is also synonymous with level six. Level seven is the upper mediastinum. The lateral neck compartment primarily includes the jugular chain lymph nodes with two, three and four and lateral or posterior triangle nodes at level five. The boundaries of the central neck dissection are the hyoid bone, the innominate vessels and the carotid arteries laterally. These include the Delphian lymph node overlying the larynx above the thyroid isthmus and the paratracheal lymph nodes primarily. This cartoon illustrates the specific central neck lymph nodes, the larynx, cephalad, the sternum, inferiorly, the trachea, the carotid sheath vessels, the recurrent laryngeal nerve running in the tracheoesophageal groove and the paraesophageal lymph nodes. These correspond to the ultrasound images below sagittal and transaxial trachea carotid internal jugular vein and these paraesophageal lymph nodes appear posterior to the carotid also seen sagittally. This cartoon again head and feet demonstrates the paratracheal lymph nodes anterior to the recurrent laryngeal nerve and running with it. Again longitudinal and transaxial ultrasound images showing this chain of lymph nodes. How and why does the central neck get missed during surgery? Number one, preoperative ultrasound is not sufficient for detecting all central neck nodal positivity. The sensitivity is actually quite low with the thyroid in situ. The specificity is high but you're not going to be able to exclude all central neck adenopathy with preoperative ultrasound. In addition, in the setting of bulky lateral neck adenopathy it may get missed assuming a skip metastasis meaning lateral neck nodal disease without central neck nodal disease. This pattern of spread is actually quite unusual so most often the tumor will go to the central neck and then the lateral neck in that pattern of progression. This is a nice illustration of the central neck and you can keep this in mind when you're doing your ultrasound images. This is again a sagittal view with the larynx in this case as opposed to the thyroid in situ where you will see it with your preoperative ultrasound. It's been mobilized immediately and we're demonstrating the central neck compartment lymph nodes which again run right along the recurrent laryngeal nerve. What could we learn from his post-operative disease status that might have changed our management? During the conferences for tumor boards someone always asks what's the post-operative disease status? A post-operative thyroglobulin measured somewhere greater than three to four weeks based on a long half-life gives you a prediction of response to surgery with higher thyroglobulin levels corresponding to a higher risk of disease persistence. Higher levels independent predictor of persistent and recurrent disease. There's not a specific level above which we're confident in residual disease but it's really the extremes that should get your attention. So very high levels of thyroglobulin in this case his was 292 versus very low levels more indicative of excellent clinical outcome following surgery alone. Ultrasound is an excellent way to evaluate for persistent nodal disease and the setting of a high post-operative thyroglobulin. So remember the goal is complete surgery it's not a race to radioactive iodine. So if the post-operative thyroglobulin level does not meet the eyeball test it's quite high then do imaging to look for residual structural disease that would warrant surgery. So in summary our three opportunities to optimize this patient's management include pre-operatively with imaging. Thyroid surgeons are not trauma surgeons we don't like surprises we want to know and be able to plan for disease extent. Recognize that as good as our imaging is you're not always going to know everything that you're going to find intraoperatively. Specifically extrathyroidal extension and central neck node positivity and certainly unique anatomic considerations such as a non-recurrent laryngeal nerve. In the operating room we want to balance a good surgical clean out with minimizing risks and again recognize that typical pattern of nodal spread from the central neck to the lateral neck and then realize what you can learn post-operatively to guide further therapy and decision making about radioactive iodine. Ask your surgeon did you get a good clean out? I say no it was extensive and I had to leave a larger thyroid remnant than I normally would to protect the last remaining parathyroid or I felt like it was a very good surgical clean out. Correlate that with with your post-operative thyroglobulin and potentially imaging that will help you make the decision about radioactive iodine based on the Martinique principles of using it for ablation, adjuvant therapy, or treatment. This is usually the time in the talk when I involve the audience with specific case scenarios and discussion but in lieu of that given this platform I wanted to walk you through multiple questions and scenarios that I am frequently encountered with and asked including how many times can you reoperate on a patient? Why don't you just take it out when you're there? Why would you leave a remnant? What guides extent of surgery? How do you decide to re-operate on a patient? Who's good for surveillance as opposed to operation? So let's walk through each of these. How many times can you re-operate on a patient? Well, there's not a specific number of times above which we say no more operating. It depends on complications from prior procedures and location of planned re-operation. Specifically, if the initial operation was complicated by a permanent vocal cord paralysis and you're re-operating on the contralateral side, that's a high risk operation. If you're planning a re-operation in a compartment of the neck or tissue plane that was not previously operated on, effectively that's the same risk as your first operation versus one that has been completely dissected out. Thus, and more difficult tissue planes. And then, of course, whether or not, number one, does the disease really warrant intervention or is it small, indolent, and just worthy of monitoring? Or are there other strategies such as percutaneous alcohol ablation? Not every re-operation is the same. What do we want to know when we make the decision about re-operating? Three things of note. Review the prior procedure note. What did the surgeon say they did? Look at the neck. Is the scar extensive? Is it tiny? That gives you a flavor of the scar that will be present where you plan to re-operate. Do they describe specific anatomy that was challenging? The tumor was adherent to the nerve. They had to shave it off. The nerve was in an unusual location, etc. And certainly review the initial pathology report. Are there three parathyroid glands in the specimen and you're about to re-operate where the last fourth gland is? How many lymph nodes are in the specimen? Is it just a single parathyroidal lymph node, in which case a complete central neck dissection was not done? And then, again, wanting to know any complications from the initial procedure, specifically vocal cord dysfunction and hypoparathyroidism. I want to point out, again, the same illustration of the central neck compartment so you can get a flavor of why we do not like to re-operate specifically in the central neck. Again, the recurrent laryngeal nerve runs in the tracheoesophageal groove and the central neck lymph nodes run right along that trajectory anterior and posterior to it. Also, the inferior parathyroid gland is supplied by a branch of the inferior thyroid artery that is often taken during a central neck dissection to get a complete clean out, so more difficult to preserve inferior parathyroid glands. Now, again, re-operation in the central neck is certainly not prohibitive in all patients. It depends on the extent of the initial operation. Sometimes a plane of dissection ends at the thyroid bed and there is absolutely no dissection inferiorly, so view of the operative note and the pathology report help guide that decision making. These two ultrasound images help illustrate what would be considered a high risk for it versus a low risk operation. This is a transaxial view showing a central neck or thyroid bed abnormality and high risk in the setting of a contralateral vocal cord paralysis. Thus, the risk is injuring the ipsilateral nerve causing an airway compromise. Effectively, the recurrent laryngeal nerve sits right here adjacent to this. Compared to a low risk, if the lateral neck compartment has not been dissected, this anteriorly situated lymph node is in an undisturbed tissue plane, so very different risks of re-operation. This illustrates the lateral compartment and the nerves and structures at risk for a modified radical neck dissection or lateral compartment dissection. Similar to deciding about risks of re-operation, those of you who perform percutaneous alcohol ablation do not like to perform this in the central neck due to the proximity of the recurrent laryngeal nerve. These particular ultrasound images demonstrate a very small focus in the central neck that would be adjacent to the recurrent laryngeal nerve as opposed to these images illustrating a small lateral neck lymph node that would certainly be amenable to percutaneous alcohol ablation if that compartment had been previously dissected. Why don't you just take it out during the procedure? Specifically, what I'm illustrating here is an indeterminate left level two lymph node seen on preoperative ultrasound. Your collar incision is here. You are not in the lateral neck when you're taking out the thyroid, so preoperative fine needle biopsy of lateral compartment nodes to guide surgical extent is appropriate as opposed to just take it out when you're there. Why do we leave a remnant of thyroid tissue? It's all about the anatomy. In this case, the ideal scenario is thyroid tissue that's not right up against the anterior branch of the recurrent laryngeal nerve. The anterior branch is the motor function to the vocal cords, so when we have thyroid tissue immediately adjacent to that nerve, sometimes a rim of thyroid tissue is left in that location or to save parathyroid blood supply. What can frozen section tell you to guide surgery or not? It can tell you the tissue is parathyroid. It can tell you the tissue is metastatic lymph node, but don't expect it to tell you the definitive diagnosis. Some of the interoperative findings that absolutely change the game are extra thyroidal extension present posteriorly impacting recurrent laryngeal nerve function, identification of central neck nodal metastases, and need to leave thyroid tissue in order to preserve parathyroid function. In terms of completion thyroidectomy, it's not as simple as it's cancer. We need to go back and take out the other lobe. Considerations include do we really think there's residual disease and the tumor is best treated with total thyroidectomy and radioactive iodine, or is it an indolent lesion that will not be impacted by total thyroidectomy with radioactive iodine, or again certainly in the setting of prior complications. Lastly, this illustrates what your surgeon can tell you about patients that may or may not be candidates for surveillance for microcarcinoma. Those that are posteriorly situated right where the recurrent laryngeal nerve is, such as these, would not be ones for good surveillance because extension could involve the nerve versus ones that are anteriorly situated and completely surrounded by thyroid tissue. This ends my glimpse into the surgeon's brain and clinical practice. I look forward to your questions and comments during the Q&A session at any time. Hi everyone. Good evening, good afternoon. It is my pleasure to be here and talk to you all about the advances in the management of thyroid cancer. That topic is very big because there have been a lot of advances to talk about in 30 minutes, so I'm going to limit it to advanced thyroid cancer and the vast majority will talk about differentiated thyroid cancer because that's the most common cancer that you'll see. These are my relevant financial disclosures. So a little bit about background of thyroid carcinoma. The incidence in the United States is about 64,000 people and the vast majority of those patients with thyroid cancer have papillary or follicular, and throughout this talk I'll be calling that differentiated thyroid cancer. A small percentage are medullary thyroid cancer and an even smaller percentage, thankfully, are anaplastic thyroid cancer, so I'll be spending a small portion of this talk discussing those. Thankfully, the death rate has remained fairly stable in this disease. Let's start with differentiated thyroid cancer, as it is the most common. The standard therapies for differentiated thyroid carcinoma, as everyone in the audience knows, is surgery followed by radioactive iodine for the more advanced patients, followed by thyroid hormone suppression, okay, and sometimes when patients get recurrences you go back to surgery with or without radioactive iodine. But I do want to point out in the advanced patients that there is improved survival after radioactive iodine in stage three and four patients, right? So we're going to talk mostly about radioactive iodine refractory patients, but I don't want us to forget about the importance of radioactive iodine, and that TSH suppression in advanced disease is very important and studies have shown improved overall survival with TSH suppression in stage three and four. A little bit about medullary thyroid cancer, so we all know that surgery is the best chance at getting rid of this disease. There are some localized therapies that can be used and systemic therapy is reserved for progressive disease, and we'll talk a little bit about the newer systemic therapies in this talk. So dedicating to metastatic thyroid cancer, in differentiated thyroid cancer staging does predict death, and this is just a reminder of why we use staging. And staging, if you're under 55, can only go stage one or two because age does come into play. And if patients have lung metastases in this example that are radioactive iodine non-avid, shown here in red, their overall survival is much shorter than those who have lung metastases that take up radioactive iodine. What about recurrence of disease and differentiated thyroid cancer? So if you take all comers of patients with differentiated thyroid cancer, about a third of them will have recurrent disease, 10% of them will have metastatic disease, and about 5% of them will be radioactive iodine refractory differentiated thyroid cancer. But this is where most of the advances have happened in the last couple of years in systemic therapy for those patients with radioactive iodine refractory disease. And when we use the guidelines to talk about response to therapy, the vast majority of these patients will fall under that category called structural incomplete response, because remember, 50% to 85% of those patients continue to have persistent disease. These are patients where you see disease on imaging somewhere in the body, and the death rates are highest here at 11% to 50%. So only one slide about radiation. So radiation therapy to the neck is used less than it used to be, given that there are better targeted therapies, and patients are at high risk of having distant disease. And so the targeted, the side effects from the targeted therapies are high. So we currently reserve radiation therapy for older patients in the adjuvant setting when surgery would be more morbid in a recurrence. There's also a role for symptomatic or for radiation in patients who have symptomatic or threatening metastatic disease in their bones or their CNS, like spine or brain, and sometimes in the mediastinum. So those are reserved special cases. So thankfully, and the rest of this talk will be discussing the advancement, the treatment options in the patients with advanced thyroid cancer used to just be there's no cure, there's not even a race for cure. And now we have a slew of drugs that we're going to discuss that have come out, so it's good. So when we talk about treatment options for metastatic disease, of course, we always remember the basics TSH suppression and radioactive iodine if it takes up iodine. But beyond that, we have localized therapies like external beam radiation, surgical metastatectomies, RFA ablations, embolizations, cryo ablation. So we can't forget our colleagues that do these localized therapies, and we always consult them as well. And then there's systemic therapies that we will discuss. So when we think about whether or not these patients are going to get into trouble from their disease, we ask ourselves five key questions. Where is the metastatic disease? Is it in a critical location? Is it refractory to radioactive iodine? Do they have symptoms? And is it from the disease? And what are the size of the tumors? Are we likely to get it with our therapies? And do they have structural progression? And all of these should always be at the top of your mind when you're thinking about treating these patients. So if you've determined that the patient has radioactive iodine refractory disease, then you evaluate whether or not they have progression of disease or clinically significant disease, meaning causing symptoms or will cause symptoms if it grows. And then if the area that has progressed is amenable to localized therapy, do that first. If not, then we assess the patient's performance status and contraindications to certain therapies and talk about the systemic therapies. So what is the definition of radioactive iodine refractory? We need to always keep this in mind. So there's four, and the evidence gets softer as you go down. So if the patient has known sites of metastatic disease with no iodine uptake, or they have confirmed disease progression within six to 12 months of treating them with radioactive iodine in an area where there was confirmed iodine uptake, or their total cumulative dose is 600 millicuries or more, or if they have FDG avid disease on a PET scan, even if they took up iodine, it's less likely to respond to that. So when we talk about, we look back at the guidelines and say, okay, so what do we do with patients who have radioactive iodine refractory disease, but they're asymptomatic, and it's stable and it's non-progressive, then we tend to just monitor them with scans every three to 12 months and continue their TSH suppression, right? Because we don't have those cures that often watching the disease is less harmful than actually giving a treatment. So be careful. However, if we have patients who have progressive disease, we have FDA approved therapies, and we also talk about clinical trials. So I'm going to cover those. We have to always remember, and when we're talking to the patients, that there's so much we don't understand, right? Because it's frustrating to the patients, and the sooner we explain this to them, the more trust that they will have. You have patients, if your x-axis is the normal lifespan, your y-axis is your volume of disease, you have patients that have anaplastic thyroid cancer in one end of the spectrum that never reached their goal line, right? And then you have patients with metastatic thyroid cancer that's responsive to radioactive iodine, and they may actually reach their goal line. However, it's these patients who have radioactive iodine refractory that we're going to spend the rest of the talk discussing, that some of them reach their goal line, and some don't. And what's the difference between those? And we need more people doing research in that arena to try to figure that out. So cytotoxic chemotherapy does not work. While you can have some partial responses, they're very short lived. So it's pretty much not used very often except in anaplastic thyroid cancer when it's combined with radiation often. Doxorubicin is FDA approved, however, in that setting. So targeted therapies are the systemic therapies that we're going to spend the time discussing. They're more specific to cancer cells rather than simply killing off rapidly dividing cells. And the goal is to get the cancer cells and less harm to the surrounding cells. And if we know the target on the cancer, if we can attack that target. So remember, radioactive iodine is a molecular targeted therapy and very important uses except in the radioactive iodine refractory setting, but we'll talk about re-differentiation afterwards. So what are the targets in thyroid cancer? Well, there's a slew of targets. One of the most common in papillary thyroid cancer is BRAF mutations, most commonly V600E, but one can have RAS mutations, as well as more poorly differentiated patients can have PI3 kinase and mTOR alterations in that pathway on the left. And then there's also rarely, there are RET alterations in differentiated thyroid cancer and NTREC alterations. And so the reason these are important is there are newer drugs and that's where the advances have occurred most recently. So biomarkers to remember in thyroid cancer, differentiated thyroid cancer and anaplastic thyroid cancer, important targets are BRAF, RAS, RET, and NTREC. And in medullary thyroid cancer, RET mutations, RAS mutations, as well as there are some others that are up and coming, but the vast majority fit the top two. Of course, we have to remember that thyroid cancers are very bloody. So anti-angiogenics are very important or some property thereof, but we try to take advantage of this alphabet soup that is known in the cancer world or in cells in general, and how can we use this to treat thyroid cancer? So here is a list of targeted therapies approved in thyroid cancer, okay? So for differentiated thyroid cancer, that's progressive, serafinib and lenvatinib, and I'll show you the data briefly for that. In anaplastic thyroid cancer, BRAF, that is BRAF mutated, debrafitib and trametinib in combination are FDA approved for that. And in medullary thyroid cancer, that's progressive vendetinib and cabozantinib are FDA approved. Now the targeted therapies that are tumor agnostic, meaning it doesn't matter whether you have medullary, differentiate anaplastic or any other cancer with these alterations in your cancer, these drugs are FDA approved, right? So that means it is FDA approved for thyroid cancer. So Ntrek altered thyroid cancers, larotrectib and ntrectib can be used. RET altered thyroid cancers, whether it's differentiated, anaplastic or medullary, salpercatinib and pralsetinib are approved. And then if patients have microsatellite instability that is high, then pembrolizumab is FDA approved. So these are across the board for all cancers so we can use it in thyroid cancer. So briefly I want to show you the data that I know you all know, the oldest drugs in differentiated thyroid cancer, but I want you to keep in mind the progression-free survival and the response rate. So the first drug is seraphinib and we all know this was a randomized trial looking at seraphinib versus placebo. The median progression-free survival was 5.8 months in placebo and 10.8 months in the seraphinib and the median overall survival had not been reached but it got FDA approved. The second drug to come out was linvatinib. This was based on a randomized controlled trial of linvatinib versus placebo in two to one and the median progression-free survival in the placebo treated patients was 3.6 months and in linvatinib was 18.3 months. And this didn't, in this study they included patients who had received tyrosine kinase inhibitors before and those that had not but they had similar progression-free survivals on the order of 15 versus 18 months. So with that we got two FDA approved drugs for metastatic progressive differentiated thyroid cancer, seraphinib and linvatinib. Now in moving gears a little bit to medullary thyroid cancers, vandetinib was FDA approved based on this study, vandetinib versus placebo in medullary thyroid cancer. The progression-free survival had not been reached in the vandetinib arm and in placebo was 16.4 months. Cabozantinib similar got FDA approved in medullary thyroid cancer. This was cabozantinib versus placebo in medullary thyroid cancer where the median progression-free survival in placebo was four months versus 11 months in the cabozantinib treated patients. So there's a slew of multi-kinase inhibitors in thyroid cancers. The ones shown in yellow are the ones that are FDA approved for some type of thyroid cancer, but there are others that are not approved in thyroid cancer that people are using, especially when you've progressed on one. So you can use another kinase inhibitor once you've progressed on one and they patients do tend to respond similar to what we see in kidney cancer. So this was a nice study showing that targeted therapy can improve disease-specific survival. So while they're not cures, we do think that they are effective therapies, but we have to remember there's a slew of side effects, right? And they may be attributed to different actions of different targets of the drugs, but we do need to care about them because patients care and because they can limit the dose that we can give the patient and the duration can limit the dose that we can give the patient and the duration, how long we can give it. So we need to upfront, they're manageable side effects, but we need to treat them upfront. What if patients have progressive disease? We also want to consider clinical trials. So several clinical trials have been done, and this is where some of the most advances have occurred that I'd like to share with you. So in differentiated thyroid cancer, remember that 40 to 80% of papillary thyroid carcinomas have BRAF mutations. And so there was one of the studies done, there've been several studies done. One of them was dibrafinib versus dibrafinib intrametinib. So that's a BRAF inhibitor compared to a BRAF in combination with a MEK inhibitor. This trial had 52 patients. The objective response rate was 50% in the dibrafinib arm or 54% in the combination, meaning we did not see a statistical significant difference between single agent BRAF inhibitor versus combination with MEK inhibitor. And similarly, while the medium progression free survival trended towards a longer time, 15 months, it was not statistically significant. So it wasn't that we could prove two drugs is better than one in differentiated thyroid cancer, but the vast majority of patients had shrinkage in their disease. So imagine if they have progressive disease, that stabilization is actually a good thing, right? So I want to briefly show you a case example of where this was important. So a 55 year old gentleman who had a total thyroidectomy and radioactive iodine and was on thyroid hormone who presented with lung metastases that were now radioactive iodine refractory. He was started on serafinib and he developed adverse events. So quickly was switched to lenvatinib, which lasted a year before he developed progression. He developed shortness of breath, pleural effusions. He was on oxygen and in the hospital. So we then placed bilateral Denver catheters, but what next? Well, this is what a slice of a CT scan look like where he had progression after the lenvatinib with multiple almost lymphogenic spread of his thyroid cancer. And anytime we change systemic therapy, we do an MRI of the brain before starting and at change, right? So here he had progressed on lenvatinib. So we got an MRI of the brain. And as the arrows show, he had multiple small brain metastases shown. So given that he had progression on lenvatinib and serafinib, those were the only drugs that were FDA approved. The question was, what do we do next? Right? We had tested his tumor and he noted to have a BRAF mutation, but we couldn't get insurance to pay for a debrassinib or a BRAF inhibitor. Finally, they approved since he progressed on both drugs. And we had data that in melanoma patients who had brain metastases with that the BRAF inhibitor can shrink those brain metastases without doing radiation, especially if they were small. So in him, we started debrassinib in only a few months, he was doing well off of oxygen. The brain metastases were no longer visible on his MRI. His PET scan showed improvement in his lungs and bones. So with that, I just want to say that I think knowing the target can be important and it literally changed this patient's life. He was on this drug for almost three years. And he ended up passing away with aspiration pneumonia, unfortunately. Now, I do want a word about anaplastic thyrocancer because I mentioned that debrassinib and trometinib are FDA approved. There was a basket trial of the combination of the BRAF inhibitor and MEK inhibitor. And this was the responses of the ATC patients. And as you can see from this waterfall plot, that every patient represents a bar, almost everybody had shrinkage in their tumor. The objective response rate was 69% with an overall survival of 80% at one year. So in anaplastic thyroid cancer, these patients have even better and deeper responses than in differentiated thyroid cancer. And they had prolonged duration of responses in these patients. And these responses can generally be rapid and dramatic. As you can see in the picture on the left, before treatment, the patient's anaplastic thyroid cancer was coming out of his skin. And just five weeks later, right? These patients can notice a difference within days of swallowing. And then within weeks, we can notice it on scan. So with that, the FDA approved debrassinib and trometinib in anaplastic thyroid cancer, again, it's not FDA approved in differentiated thyroid cancer, but we do use that in the off-label manner. So then some of the newer drugs that got FDA approved in the last couple of years. So Ntrek inhibitors or neurotrophic receptor tyrosine kinase inhibitors. So many cancers can have Ntrek alterations. And so this was a basket trial where they took patients with all cancers, as long as they had some sort of Ntrek alteration. And they used a drug called larotrectinib. And what they found was that there were several deep responses in many cancers, the thyroid cancers, it's hard to see because there's many greens here, but we're shown in this lime green, excuse me, with good partial responses. And they had long duration of responses. And similar with another drug called ntrectinib. I'm just not showing you the data for interest of time. So the FDA approved both larotrectinib and ntrectinib for Ntrek altered cancers across the board, right? That surgery can't get rid of their disease. And so therefore they are FDA approved for thyroid cancer, because it's a good for all cancers. So the next kid on the block that came out recently were RET inhibitors. So there's two drugs that are FDA approved that I'd like to talk to you about that are important for thyroid cancer. One is was called blue 667. And it was evaluated in advanced RET altered thyroid cancers. So this included medullary thyroid cancer, each patient when the light blue shown on this waterfall plot and dark blue were the papillary thyroid cancers. Okay. So the medullary thyroid cancer patients had RET mutations, the papillary had RET fusions. So we call all of these RET altered patients, but 90% of the valuable RET altered thyroid cancer patients had tumor shrinkage with nice prolonged duration of responses over time. And in I'm I'm down early on the second RET inhibitor that came out was called LOXO 292. And this also was evaluated in RET altered thyroid cancers, and also included both medullary thyroid cancers here shown, sorry, shown here in the group on the left, and then the RET fusion positive thyroid cancers on the right. And what you can see is in medullary thyroid cancer, the objective response rate was 59%. And in RET fusion thyroid cancer, so meaning the DTCs, potentially ATCs was 78%. Right? So very nice shrinkages in these tumors, and they had good duration of response and good decline in their tumor markers, similar to the other RET inhibitor. So with that, there were two RET inhibitors available to thyroid cancer patients that the FDA approved. One is known as selprocatinib, and the other is pralsetinib. And they're both for patients that have a RET alteration, whether it's a fusion or mutation in thyroid cancer that have progressive disease, that's not responding to treatment or your previous treatments. So I want to just review briefly these response rates in thyroid cancers. So if you have patients with BRAF monotherapy, I tried to summarize some of the studies here. The response rate is 30 to 39%. And in papillary thyroid cancer in combination is about 33%. So similar, right? And in ATCs, that response rate is a lot higher. If you go down to RET inhibitors, you have a 50 to 60% response rate, Ntrek inhibitors about 79%. And then you have your usual anti-angiogenics, and it's on the order of about 30 to 60%. So your response rates are not far off from each other. And it's going to be important to think about various factors when you look at these patients. So there's a couple of things I briefly want to talk to you about when you think about these drugs, right? So when do you actually pull the trigger? And what factors should you consider? So there's patient factors, and there's tumor factors. When you think about patient factors, you want to know about their patients comorbidities, right? What's their performance status? Are they in bed more than 50% of the day? What symptoms do they have? Is it from the cancer? And what is their social support, right? And what's their preference, right? Because you always want to tell the patient that this is not a cure, but we can handle these side effects. And this is the options that we have. And when we look at performance status, it's much like you do whether a patient can handle surgery or not, right? You use that to decide if a patient can handle chemotherapy. This is one example called the ECOG performance status, and it's graded zero to five. Five is always dead, zero is that you can do everything. And then there's the numbers in between. Usually we'll treat patients with systemic therapy if they have a zero, one, or two performance status. If they have a performance status of three, we will sometimes treat them if we think that the symptoms are from the disease and we could improve that. So what about the tumor factors? Well, it's important to look at where the tumor is, right? What organ is involved? Is there an involvement of the trachea, blood vessels? Because if we shrink that too fast, can we actually cause more problems than the patient currently has? And what's their burden of disease and their pace of progression? So all important things to think about when you look at this patient. So, you know, some of these drugs have strong anti-angiogenic inhibition. And so it's important that we think about when would we use some of these more targeted therapies with less anti-angiogenesis versus it's okay to use the antiogenic. So if you have tumor that invades the trachea or blood vessels, then you may want to consider using a more targeted agent because you can get into trouble. Or if a patient has MIPE or cardiovascular events, you may want to consider avoiding them, but sometimes you can't, right? So you work in conjunction with your colleagues in cardiology and hematology, severe hypertension or heart failure can worsen with anti-angiogenics. And sometimes you'll have an identified target of a mutation that may have an improved response. So we came up with this algorithm at MD Anderson. It's not something in the guidelines. So I'm told that is my disclaimer. I just want to share it with you how we think about first-line therapy of progressive radioactive iodine refractory differentiated thyroid cancer, because that's where it gets most confusing. So we, if we're thinking about systemic therapy, we always get mutation testing on the tumor. If they have a BRAF mutation and there's a contraindication to anti-angiogenics, it's a simple decision to go onto a BRAF inhibitor with or without a MEK inhibitor. And sometimes we'll re-differentiate, which I'll show you that data to treat them with radioactive iodine. If they don't have a contraindication to anti-angiogenics, remember BRAF inhibitors are not FDA approved. So we would either go with the BRAF inhibitor or go with the anti-angiogenics. If they have a rare mutation like Ntrek and RET, like the data I just showed you, we would consider a RET or an Ntrek inhibitor or put them on a clinical trial for such, for their rare alteration. And then if they're BRAF wild type and they don't have a contraindication to anti-angiogenics, we go with Linvatinib often first-line. If they do have a contraindication to the anti-angiogenic, then sometimes we will use Serafinib or a clinical trial, or if they have a RAS mutation, we're starting to use MEK inhibitors and consider radioactive iodine. Again, this is not what the guidelines say and some of these are not FDA approved. So what about re-differentiation with radioactive iodine uptake? So remember these tumors are refractory to radioactive iodine. Can we use targeted therapy to re-sensitize the tumors to radioactive iodine? And one of the first studies all of you are familiar with was at Memorial Sloan-Kettering where they use Selumetinib and differentiated thyroid cancer, and they showed with four weeks of this MEK inhibitor, they can increase uptake in the tumors, especially if they had a BRAF or RAS mutation, and then they could actually treat them with radioactive iodine if they reach that dosimetry threshold. Mass General looked at BRAF mutated papillary thyroid cancers and used Dubrafinib to enhance the radioactive iodine uptake and found that after one month of Dubrafinib that if the patient's diagnostic scan then showed a iodine uptake that they could treat these patients with good shrinkage. And so we have looked at our off-label experience, which I want to share with you briefly, because there's a couple of points that I want to point out, right? So what is the re-differentiation strategy that people use, right? So a patient could be on a kinase inhibitor, either because you put them on it because they had progressive disease, or you wanted to specifically put them on for re-differentiation. Then you can do a diagnostic whole body scan or just treat them with radioactive iodine, and then do the post-treatment scan, stop the kinase inhibitor, and then have them come back at three months to restage them, right? So the idea of, or the advantage of potentially using a re-differentiation strategy if they take a iodine, is that you can then get them off the kinase inhibitor for a break, or however long that they have stable disease afterwards. So a picture speaks a thousand words, so I'd like to share it to you. On the left is a whole body scan that did not have any uptake, but we knew the patient had lung metastases, and after re-differentiation you can see on the right-hand side the patient has lung metastases that light up. And same thing with the second patient on the left is, what's on the right-hand side of the screen here, is a negative whole body scan, and then their lungs take up nicely after the re-differentiation with the targeted therapy. So remember, these patients can be on a duration of targeted therapy, they then receive their radioactive iodine, and then there's follow-up after the radioactive iodine off of the targeted therapy. And the 22 patients that we looked at, I just, this is a busy slide, but I just want to point out that 40 percent of the patients had a decrease in the size of their lesions after radioactive iodine, right? So there is some help here, it's a matter of figuring out what and for how long. And remember I showed you progression-free survivals in the trial, so I want to show you, and I realize this is not a randomized trial, this is retrospective data, but the median progression-free survive, the median follow-up time was 18 and a half months after radioactive iodine, and the median progression-free survival was 29 months, right? And the medium time to progression was 20 months. So if it means that patient for almost two years being off of some sort of systemic therapy, then maybe there is some role to this, but we just have to figure out who is the right patient for this. So with that, I just want to talk briefly about site, don't forget about site-specific treatment of metastases, we do have surgery, image-guided radiotherapy, as well as bisphosphonates and denosumab, so when you think about especially bone and CNS, think about your localized therapies that involve your collaborators, your colleagues, and then people always ask about immunotherapy. So I want to briefly share this with you, that with immunotherapy, basically the newer checkpoint inhibitors are treatments that use the immune system to eliminate the cancer, right? And so there was a trial called Keynote 28, where they looked at a PD-1 inhibitor called Pembrolizumab, single-agent and differentiated thyroid cancer. They had 22 patients who failed prior therapies, but the objective response rate was 9%, right? Two patients responded. So it's actually less than a lot of our systemic therapies, and part of the problem I have with the stable disease is they didn't necessarily require the patients to have progressive disease to get on this trial, but basically this data and other data have shown us that single-agent immunotherapy is probably not going to work in differentiated thyroid cancer. In anaplastic thyroid cancer, there was data recently published last year looking at an anti-PD-1 PD-2, which is an immunotherapy, and they looked at it at anaplastic thyroid cancer, and they had 42 patients. Their response rate was 19%, and the median progression survival was two months. Now remember, these numbers are very different because this is anaplastic thyroid cancer, but I wanted to show it to you because there was some hint here that the patients who had PD-L1 expression had better responses, right? And the median overall survival here was six months, and 40% of those patients were alive at one year. So while this data may not look very exciting to you, I think there is some hint that there is a role of immunotherapy in anaplastic thyroid cancer, and suffice it to say that I think the answer is combination immunotherapy with targeted therapy in both anaplastic thyroid cancer and differentiated thyroid cancer. So trials that recently have either accrued or opened combination of immunotherapy with targeted therapy and lenbatinib in differentiated thyroid cancer, they've completed accrual, and then in anaplastic thyroid cancer and poorly differentiated thyroid cancer, looking at targeted therapy with atezolizumab, a different immunotherapy, and there's many, many trials that are looking at more selective checkpoint inhibitors as well as combination of targeted therapy. So there's a lot more to come. I just think the jury's not out yet exactly what, how, and we use immunotherapy. So please refer to clinical trials in thyroid cancer at one of the sites presented here. And with that, I'd like to acknowledge that it takes a village. So I'm just up here giving this talk, but the patients are at the center of that village, but it takes a multidisciplinary team to take care of these patients, and I'm thankful to each and every one of them. So thank you, especially to all the patients who trust us with their care, and thank you very much for your attention. Thank you very much. This is one of my favorite topics to talk about because this has changed so much over the last sort of five to six years. So we're gonna talk about active surveillance and low-risk papillary thyroid cancer, and really, from a clinical perspective, ask that question, is immediate surgery always necessary? The only relevant disclosure I have is from a laser company named Allesta that I'll show you at the end of the talk, some experiments we're using to do some laser ablations of some of these small papillary thyroid cancers. Well, as always, we start with cases. These are real cases, and as I think through them and talk through them, think about what you would tell this patient. An 83-year-old gentleman, hadn't seen doctors in a long time, had a routine blood test at a TSH of 5.7, probably not even abnormal in an 80-year-old, but that led to an ultrasound, and they found this little, small, five-millimeter thyroid cancer, and he comes to you. Somebody had already biopsied it, and what do you do now? He's 83 years old. He's got a diagnosis of thyroid cancer. Do you operate on him or offer him a chance of observation? What about the opposite? This is one of a 65-year-old female that I saw here a few months ago, brand-new diagnosis of stage four, non-small cell lung cancer, with pleural effusions, and needing to get on a systemic therapy yesterday. As part of the staging on the PET scan, they found this same five-millimeter nodule that had been biopsied and it was papillary cancer, but within the context of widespread lung cancer, do we really need to treat a thyroid cancer now? Now, this one was a little bit more challenging, and I think if you're honest, we've all seen cases like this. This is a 25-year-old female. She was getting married in three months. This was a couple of years ago, and of course she asked me, I don't wanna have a scar on my neck before the wedding. Can we delay the surgery until after the wedding? Well, of course, it's a five-millimeter papillary cancer. Then she came back from the wedding. Her father lives here in Manhattan, apparently has too much money, and was gonna send both her and her new husband on a three-month vacation throughout all of Europe. This was obviously not last year, and she wanted to wait for another three months. Well, we thought, well, six months, that's not too long. It's still small, we could do that. And then she gets back. Now she's back in town and she has just got the dream job and she wants to wait another three months. Now, I could go on and on, but at some point we would all say, well, should we do something about this? On the other hand, she's now, I've reluctantly agreed to watch for nine months and repeat ultrasound shows exactly the same thing. So the clinical dilemma that we're faced with now really is because of all these highly sensitive detection and diagnostic tools. But I really framed this a few years ago when we wrote this with Dr. Al-Azrani from King Faisal Hospital in Saudi Arabia. He was here on sabbatical and we were talking about these issues. And we began to talk about detectable findings from actionable findings, detectable findings from actionable findings. And with all of our ultrasounds and CT scans and PET scans, and you name it, that we can now find little small things, sometimes in the primary setting like this, but also in the recurrent disease setting. And it begins to make us ask questions like, just because we can detect something, do we really need to make a diagnosis and do a treatment? And then the easy question I think is, is there a benefit to doing that? But I think we also have to ask, is it potentially harmful? If that 83 year old gentleman with a five millimeter papillary was my dad and you biopsied that and you made him a cancer patient, he will tell everybody he has cancer. And then if I tell him not to do anything, he'll tell everybody he has untreated cancer. How will that change his life? Change his perception, change how he does things. So just because we can find small stuff doesn't necessarily mean we need to do anything about it. Now, we ask questions like, you can tell him my bias here in the graph, that I think there's a large realm of detectable findings that are really not actionable, that we really should be watching. Now, if you look at what's been in the guidelines, we've had sort of a long history of making the point that early diagnosis and immediate therapy is not always the best approach. That for many years, we said, if you have a highly suspicious nodule and it's less than 10 millimeters, you don't have to do a biopsy. Previously, it had been less than five millimeters. As far back as 2009, we said, look, we know the ultrasound can detect these little small lymph nodes in the neck that are probably recurrent thyroid cancer, but maybe they're too small for the surgeons to find. And even if they could find them, what data is there that treating that person is gonna help them? We know the surgery could put them at risk. We could damage parathyroids, we could damage recurrent renal nerves, but what's the data that we're gonna help? And then I think all of us over the years have realized that we don't have to make that last molecule of thyroglobulin go away anymore, and have been pleasantly surprised in a lot of people that these thyroglobulins trail downhill over years and years. And if we're honest, the majority of patients I have with distal metastasis, with small volume lung metastasis, I am probably watching rather than treating, because it's very small volume, it's asymptomatic, it's not growing very much at all. And then we finally come more recently to the active surveillance piece. But the active surveillance of these small thyroid cancers really is just another example of when we're doing watchful waiting. Now, I know we've sort of restricted the word active surveillance to just mean this papillary myocardial sonoma, but in an oncology sense of the word, active surveillance means we're watching all kinds of small stuff. And in fact, could apply to any of these situations. Well, it only makes sense that if we're gonna say there's a difference between what's detectable and what's actionable, is we need to define what's actionable. What are the things that we're sitting in clinic and we're looking at the scans and we're talking to the patients, how do we decide when it's time to do something? I spend a lot of my career doing nothing, watching little small stuff, but what is the things that make us change our mind? I see these five things, it's sort of like a pilot's checklist. No matter how experienced the pilot is, no matter how many times he's taken off or flown, there's a certain checklist that they go through every time before they take that plane off. And I think we should do this when we're looking at papillary microcarcinomas or lung metastasis or small volume lymph node metastasis, any structural disease, if you think through these five things, it can help you make the decision. What's the size of the tumor? How rapidly is it changing? What's the location? Because sometimes small things and bad locations need to be treated. On the other hand, the bigger things and less worrisome locations we can watch. Is the patient having symptoms or we think they may be having symptoms in the future? And then clearly there's this patient preference. We'll come back to it in the papillary microcarcinomas, but there are clearly some people that have no intention of watching. They want surgery done and they want surgery done now. And then there's other people that are always negotiating, well, tell me about the risk and benefits and how much good are we gonna do treating now? How do I know when to treat a distant metastasis with a kinase inhibitor? How do I know when it's time to go to surgery? So we'll come back at the very end of the talk and see how we take these five features and apply them to active surveillance. Now, active surveillance is not a unique terminology for thyroid cancer. Active surveillance is an oncology term. Some people refer to this as deferred intervention. I call those guys the pessimists. They think these people I'm watching, I'm gonna really end up treating all of them. I'm not certain that's the case, but I'll say, okay, deferred intervention for some people. And the idea is that it's an active observation approach. We either know they have disease because we biopsied it or it's really highly suspective, very abnormal on some scan and the TG is elevated. We know in our heart our heart's at thyroid cancer. And the key is that a therapeutic delay, if it's required, doesn't have any impact. Our treatments are gonna work just as well and it's still gonna be effective. It's not palliative care. We're not giving up. It's not watchful waiting. Watchful waiting implies you're never gonna do anything. It's gonna be a persistent disease. Active surveillance, or some people prefer the term active monitoring. Active means we're doing something, even though I'm really doing nothing, that something is repeating the ultrasounds, reevaluating the patient every time. And of course, this was first well-known in prostate cancer, but then other cancers. We all have patients with CLL that are being watched. And now obviously lots of patients with papillary thyroid cancer. Well, this idea of active surveillance really grew up with Dr. Miyauchi at the Kuma Clinic in Japan. Akira was a surgeon. He was one of the first people to do fine needle aspirations in Japan. And he also recognized early on when all of these small thyroid cancers were being diagnosed had the courage to say, I know I'm a surgeon, but is it really necessary to take out these low-risk thyroid cancers? And over the years, now for more than 20 years, he's been offering people the option of following with observation. Now, I think he does a good job presenting the data because in all of his studies, about half of the patients say, yes, I'll watch with you. And the other half say, no, I wanna go to surgery, indicating that it is shared decision-making. He's having that discussion with the patients. And if you look at most of his studies in follow-ups of up to 10 years, but mostly in the four to five-year range, 92% of the patients that were low-risk that he offered observation are still on observation after those years. A few went to surgery because they had stable disease. They were either worried or something was, the cancer didn't change, but they changed their mind and wanted to go to surgery. Only about 2% increased, and less than 1% had any abnormal lymph node metastasis identified during follow-up. One of the real keys to his studies that he's shown many times now is that salvage therapy is very effective. So these papers, while not done outside Japan for a long time, were very well-known. And even in 2015, when the guidelines were written, we had to recognize that. And we put in here, an active surveillance management approach can be considered. This is pretty soft, right? And we're not saying do it, but we're also not saying it's wrong. That in patients with very low-risk tumors, these papillary microcarcinomas, or patients like we started with, high surgical risk, they've got some of the disease that needs to be treated or some of the medical issue that needs to be treated. Now, if you look at the studies that have been done, the studies now are, there's about 10 on this slide, and they're all remarkably consistent. Some of them smaller, but lots of them, 300 patients, 1,200, 300 patients. Most of the tumor size, less than a centimeter, but a good number of groups, including ours, watching things up to one and a half centimeters. And if we're honest, follow-up durations around five years. Some as short as two years, some up to seven or 14 years, but largely around five years. And we've all sort of recapitulated what Dr. Miyauchi had shown us years ago, that if you look at the increase in the size by three millimeters, because that's basically the measurement variation you can tell on the ultrasound. If it's less than three millimeters, you don't really know if it's changing. Three millimeters or more, that's not a measurement variation. And in the shorter studies, about three or 4% get bigger by three millimeters. In some of the longer studies, it's more like eight to 10%, but a small number. The majority are stable. And the identification of lymph node metastasis is around one or 2%, maybe three or 4% if you look at the long-term studies. So all of this pointing out that there's nothing unique about the Japanese experience. There's nothing unique about the Japanese patients. This is the natural history of papillary thyroid carcinoma. And when you select the same patients, no matter where they're seen anywhere in the world, we're gonna have these same outcomes. Now, when we got interested in this, I've always been sort of a math person and I like math and three-dimensional stuff. I hang out with the surgeons a little bit too much and sort of had a good understanding that a one-centimeter nodule was not just a one-dimensional structure. And I thought if we looked at the volumes of these tumors, just like we look at the volumes of nodules and the volumes of multinodular gorders, if we look at the volumes, we'd have a better understanding of what these tumors were doing and how they were changing. And these are the data on our first nearly 300 patients that we were watching with observation. Much of it does look like what the Japanese had published. So about 80% are no different. When you do volumes, it's plus or minus about 50% is the measurement variation. So no change in about 80%. Here's the three or 4% that got bigger than three millimeters in red. But some of these other patients, while they weren't three millimeters longer, they were one or two millimeters bigger in a couple of dimensions, which meant their volume was increasing. So in this paper, we said, now, if you follow people over about two years, about 12% will get bigger by volume. Yeah, it's only three or 4% that'll be bigger by three millimeters, but the more accurate numbers, if they're changing by volume, it's gonna be about 12% of those patients. This is the new data. We haven't published this yet. We're still analyzing it. This was this spring. So here we're now three and a half years of follow-up, nearly 500 patients. And we're gonna show basically the same thing, about 80% of the patients continue on active surveillance, no change, nothing going on. A few do transition to surgery, but not very many. Four out of this entire group. Three of them because either they or their family member was worried. And sadly, one person because they were changing insurance plans. And if they wanted surgery, they wanted their favorite memorial surgeon to do the surgery. But if you look at the who ended up going to surgery, we had about 5% go to surgery because they had an increase in the size of the tumor. About 1% went to surgery because they had a new lymph node metastasis. And about 4% went to surgery for some other reason. A couple of them had hyperparathyroidism on the same side that needed to be fixed. So they got a lobectomy. A couple of them had benign nodules and the other lobes start to change. So all the reasons that people would normally have surgery. The other thing that we sort of figured out from these folks, when you look at their volumes, you can actually get a feel for how these tumors are changing. So here's our 70% that have no change whatsoever. These are just the normal measurement variations. The blue box is plus or minus 50% tumor volume. So this was just measurement variations and no change over time. This was an example of one of the patients that 17% that were definitely growing and getting bigger. These are volumes going up over time. And there's that 12 to 17%. And you can tell every time we did the measurement, it was getting bigger. That one's pretty easy to figure out. Six months, one year, two year, it declared itself and it came out of there. This group, we're still analyzing and I find them fascinating because we have almost as many that are decreasing by volume that are increasing by volume. Why is it that this 14% are getting smaller? And this is an example. This is not a measurement error. These are gradually getting smaller. Some of these are really small thyroid cancers that maybe the biopsy actually destroyed the vasculature and maybe they died. But some of these are one or one and a half centimeter tumors. We know benign nodules can get smaller, but the idea that thyroid cancers could get smaller was sort of interesting. This is the one everybody always asked me about. Sure, you've got 70% stable for a long time, but can't they pick up another mutation? Can't something bad happen? And the answer obviously is yes, right? That's a random event, but this is the first time we've seen it in nearly 500 patients, a fellow that I've been following for four years, perfectly stable, and then over time developed presumably some change and began to rapidly grow in required surgery. Still, we picked him up on the once a year program, but it does show that there will be some rare background events that have been stable for a while that begin to change. Now, from a practical standpoint, then how do we implement this? How do we sort of figure out, how do we teach which patients to watch, which patients go to surgery? And with J.P. Brito, when he was a fellow here with me, he's now one of the fine attendings up at the Mayo Clinic, we realized in our first 50 patients that we were talking about sort of three interrelated domains, that what were the tumor and the ultrasound characteristics? What were the medical team characteristics here or someplace else in the world? And then the fascinating was the patient characteristics. And we took these three domains and developed some wording and said, look, well, let's classify people as either ideal, you're the perfect candidate to watch. Maybe my 83 year old dad with a five millimeter papillary cancer that hates doctors. He's probably the perfect person to watch. There are certainly some that are inappropriate and we'll talk about what those are. And then there's the bigger number that are appropriate. And so this has evolved a little bit over time, but for us, the best tumor characteristics would be Bethesda sixes, fives, if they have a highly suspicious ultrasound. We're perfectly happy to watch these BRAF mutated, the B600Es, about half or two thirds of the papillary microcarcinomas will have that. We don't require molecular testing to watch. We do want the cytology interpreted here. We'll follow tumors up to about one and a half centimeters. We're fine with background nodularity and Hashimoto's as long as the patient understands that's gonna be a little bit more difficult to follow, but not with lymph node metastasis, not growing outside the thyroid and not in a location adhesion to the nerves. Now it's important for us as the endocrinologist because we're the ones looking at these ultrasounds to really think about where these nerves run. On the left hand side we all know it's in the T. E. groove. So thyroid cancers that are in this T. E. groove near the ligament before the nerve goes into the voice box. But on the right hand side this nerve sweeps behind the thyroid posteriorly often touching the capsule behind it to reach this medial position. So on the right hand side it's a nodule in the right lower lobe that's on the posterior capsule that we should be really careful of because we don't want to lose a nerve while we're trying to meaningfully watch some of these tumors. From a management approach I think this is important as well because when you begin to ask can I do active surveillance in my setting, in my country, in my state, in my hospital, there clearly is some technical issues and some expertise that's required. And we think this is best done by a multidisciplinary management team. Oftentimes many of these patients see both me and one of the surgeons so they're presented with both options of watching or doing surgery. Quality ultrasonography is really important. Not only how good's the machine and are they using the right probe, but are they telling us the things that we need to know? What's the size? What's the location? Is there any invasion of the capsule? All of those details I need to know. If you tell me you have a one centimeter papillary that doesn't help me. We need to know a lot more about that information. And then the interesting piece to me has been the patient characteristics. There are clearly some patients that would love to watch forever and try to avoid surgery. There are other patients that say do my surgery yesterday. My best example is a nurse here at Memorial that on a Thursday morning found out she had a nodule. She talked herself into a biopsy and cytology by lunchtime on Thursday. She came back to the clinic that Dr. Shaha and I run on Friday morning together, knowing that the results would be back. And they were, they were papillary cancer. And when I walked in the room, she said, just so you know, I'm MPO. I'm ready for my surgery. Can you guys do it today? Probably not a patient to talk about for long-term monitoring. I did mention watching to her and she pointed out she'd been watching for 18 hours. She was done watching. She wanted this treated. And when I was telling these sort of anecdotal stories when I was at Harvard doing some talks up there, Pam Hartzband, one of the wonderful endocrinologists was there, showed me this book that her and her husband had written that talked about patients being maximalist and minimalist. Maximalists want to be ahead of the curve. Why wait? More is better. Minimalists, less is more. The complication is always me. Every time something happens, it's always me. And you've probably already identified yourself as one of these two characteristics because these characteristics of minimal and maximalist not only apply to the patient, they apply to the doctor. Now, you guys that have heard me lecture for a while, if I gave you a quiz and said, am I personally a minimalist or a maximalist, I don't think anybody would mistake me for a maximalist, right? The risk stratification and lobectomy and don't use so much radioactive iodine, don't use so many ultrasounds, watch, don't do it. That's a minimalist mentality. So I'm going to be very sort of resonant with that when those opportunities come. It's not just cancer. It's in blood pressure and cholesterol and glucose, how we make those medical decision makings. And we need to be sensitive to that so that we walk into the room. Sure, there may be a person who's the perfect candidate on ultrasound. It's a six millimeter nodule right in the middle of the right lobe, lots of normal tissue around it. You're in an ivory tower institution that does this for the living. And yet, if that patient is not comfortable with observation, then I don't think it's the right thing to force them down that pathway. So I think we need to be sensitive. I often, in these sort of situations, describe the choices here as choosing between two right answers. I'll walk in the room and say, I've seen all the stuff. I've seen all the information. And as we sort of finish our visit, I'll say, I think we're choosing between two right answers here. One right answer is surgery. The other right answer is following with observation. And so let's explore the good parts and the bad parts of both of those. Let's get rid of a right and a wrong. There's probably not a right and a wrong. And we'll spend the next 30 minutes or so saying, OK, for you, there's only going to be one answer. So let's try to figure out, out of these two right answers, what are the ways that we would be able to follow you and you would be most comfortable with understanding what I think about the tumor and the ultrasound, understanding what both of us think about the medical team and where you're going to do your follow up, and me understanding sort of where you are in terms of patient characteristics. Now, from just a practical standpoint, how do we do this? So we very carefully review the cytology. We review the ultrasounds. And if we think you're an ideal or an appropriate candidate, as a general rule, I'm going to do ultrasounds every six months for two years. And then after that, once a year. That every six months is not because I think something's going to rapidly change because that hardly ever happens. But if you get four ultrasounds over those first two years, I can tell where you are on the curve. If they're all four flat, we're going to be flat for a long time. If every time I do it, the volume's getting a little bit more and you're 55 years old, then I'll say, OK, do you want to have surgery when you're 55 or when you're 65? I can do deferred intervention with you, but we have to work on that timing a little bit. And in fact, what I'm doing at each visit, I'm back to my same five factors that we looked at. What's the size now? What's the location? How much has it changed, if at all? Do we think you're likely to develop symptoms if it's near a nerve or near a trachea? And then what's your preference? I tell patients I reserve the right to change my mind every six months. They can change their mind about watching any time they want to. They're not signing a contract with me. They just have to be comfortable doing that follow-up. I don't use TSH suppression. There is some data from Korea that shows if the TSH is consistently a lot more than three, it may make it more likely for these to grow. So I do yearly thyroid function tests. Serum thyroglobin really don't help me at all. So when do we change our mind? When do we go from detectable to actionable? In most of the time, it has to do with the size of the primary tumor. Did the tumor get three millimeters bigger or not? That's the plus or minus three millimeters. That three millimeter increase corresponds with about a hundred percent increase in volume. So if they have that, we're going to be talking about surgery. If we find the lymph node metastasis, if it starts to invade into the capsule around the thyroid, or if the patient changes their mind. Now, you'll notice that this decision for surgery, I don't always wait until it's a hundred percent bigger. For example, once it gets 50 percent bigger, I know that it's growing. And if it's relatively close to the capsule, or sometimes the patients go, all right, as soon as I know it's growing, I want it to come out of there. Or if it's a bigger tumor, then we would go to surgery. On the other hand, I've got some of these patients that it's taken me eight or nine years to be able to tell that the tumor is growing. And in those cases, based on location and where it is in patient preference, we know it's slowly growing, but we opted to keep watching anyway. So if you think plus or minus three millimeters, plus or minus a hundred percent, you're always safe if you do surgery at that point. And then tweak it a little bit, depending on what's happening with the volume before and after. I'll finish with this. Obviously, many of the patients ask us, Doc, I don't want you to take my thyroid out. Can you just take out that little lump that we have? And we all know that there's a huge literature, largely from Europe and outside the United States, of destroying benign nodules with various ablation technologies, including radiofrequency ablation and laser ablation, microwave ablation. And now many of these in a research setting are being applied to small thyroid cancers. And in our particular trial, we're using laser to do it, but radiofrequency or microwave or alcohol ablation, all of these are sort of individual ways to try to destroy these tumors. So I hope what I've given you is a picture of the future here. We don't want everybody with a small thyroid cancer rushing to do surgery or an ablation, but there are patients that want a treatment they don't want to watch, but they also don't want their thyroid taken out. So I hope what I've given you over the last few minutes is an idea about where we are in active surveillance, how we think this is a valuable tool with lots of literature behind it, at least over three to five years, and give you some feel as we move forward to figure out what's the right patients we should offer active surveillance, what are the patients that need to go to surgery, and what are the factors that we need to consider when we're making that decision. Thank you to all our presenters on this very informative topic. We will now go ahead and open the floor for Q&A. Please type your question into the chat, and we will do our best to try to address each and every question. So we have a question here. In patient with two and a half centimeter right-sided thyroid nodule, FNA result was AUS. Affirma suspicious for BRAF mutation. Left thyroid lobe had benign nodule, no lymphadenopathy on ultrasound. Patient deferred surgery despite recommendation and referral to surgeon. Can such nodule be washed? If surgery is decided, should it be total or lobectomy? Yeah, that's a great question. I mean, all of the data on active surveillance, the vast majority of it's less than a centimeter. We've extended up to about one and a half centimeters. I can find very few nodules that are two centimeters that I'd be comfortable watching. They're just mashed up. That's wider than the thyroid. They're on the capsule anterior and posterior. And when they start getting around two centimeters, you start getting lymph node metastasis. So even though this was atypia, that BRAF V600E means it's a papillary thyroid cancer. So we would certainly recommend surgery in this setting. If the contralateral lobe is normal or if it's benign, we're okay with lobectomies depending on the age of the person. If there's nodules on both sides, we're probably just going to go with a total thyroidectomy unless they feel otherwise. So Shaha, my surgeon, refers to this as these are patients that are outside the box that we'd be watching. So if we watch these kind of folks, they truly are refusing surgery for some reason. But no, this is one that we would consider really inappropriate for an active surveillance management approach from our standpoint. There is another question about the, in case of differentiated thyroid cancer recurrence, when do you consider external beam radiation? Also in cases of Hertzell cell, poorly differentiated and tall cell variant. There's a growing evidence from the Head and Neck Society supporting the use of external beams. So I was interested in looking into your practice in MD Anderson and Memorial Sloan and making these decisions. Yeah, so it's a great question. So I think we used to use external beam radiotherapy postoperatively in the neck a lot more than we do now. I think, you know, with better and better treatments, we're finding that patients are living longer. And, you know, to then survive and get another cancer like sarcoma is not good or live with swallowing problems and dry mouth. So we're a lot more conservative in our utility of it in the setting, in the adjuvant setting, right? So when patients have had full surgery and the surgeon says they're older and the surgeon says I've removed all the macroscopic disease, there's microscopic disease for sure left behind their high risk of recurrence, 30 percent or more. But they I don't want to go back in their neck. Right. So those are people that we would still consider to get external beam radiotherapy in the adjuvant setting. But we do use a lot of stereotactic radiotherapy or proton beam or radiation for localized therapies and oligometastatic disease. So bone, hyaluronic lung disease. Dr. Tuttle. Oh, so go ahead. No, I was just going to say you also wanted Memorial's opinion. Yeah. Dr. Tuttle. Yeah. Yeah, I agree. We've we've all come from using it like really excessively for adjuvant therapy in very wide fields to now smaller fields, more focused. Our our plan is the same as what NYFA outlined. We're much more restrictive with it these days. Thank you. There is another question for Dr. Tuttle on active surveillance patients. If TSH between three and four point five, would you start levothyroxine? You said go TSH less than three. I wanted to double check. OK, so that's probably somebody that I'm following a patient with them and it's three and a half and I'm not doing anything. So so as a general rule, I want it less than three. There's a little data from Korea that if it's more than three, that maybe there's a slightly higher risk that they progress a little bit. Honestly, we haven't seen that. And if it's your 70 or 80 year old person with the TSH of three, I'm probably going to be fine with that. So I use those as general guidelines, recognizing we don't have a lot of data. We certainly don't want to keep persistently high TSH because these are well differentiated papillaries and would probably grow. So for most people, I would probably start levothyroxine. The trouble is part of the reason these guys don't want surgeries, they don't want to be on levothyroxine. So they will push back unless there's some really good reason, just because that's the nature of who they are. So I would above three, I would at least talk to the patient about it and kind of lean in that direction. The more above that it got, then I would push a little bit harder. But I've got a good number that are between three and three and a half that we're watching with no thyroid hormone pills. So since it's just the four of us, I can admit that. So we're fine with that. There is a question asking about the new JCM article data on free cell DNA analysis. What is your intake on that? NYFA gets that one. Can they clarify which article? There's a couple of them on cell free DNA. Are they just asking for clarification when to use it, maybe? I'd just pick one that I read and answer the question. So the idea with cell free DNA, right. So when we're looking for mutations or alterations in the tumor, like what are some proteins that can make the cancer grow that we can then target with therapies to treat it? So normally we'll take a biopsy or the thyroid, the tumor from the thyroid itself and test it for abnormal genes with whatever next generation sequencing that you have. And this is one way if you don't have access to tissue, somebody's had their thyroid out 10 years ago and they don't want a biopsy or their tissue is difficult to access. You can draw their blood and see if they're spilling that mutation like BRAF or NRAS or what have you in their blood. It only works in about 30 percent of differentiated thyroid cancers. It works in about 90 to 95 percent of anaplastic thyroid cancers. And we don't know the exact number from medullary yet because there's a few spattering of studies. So so I think that, you know, and you can use them in other cancers. You can use them in following the treatment. Right. So if your therapy is working against that target, it should go down in the cell free DNA. There's data in medullary thyroid cancer that if you can actually measure the cell free DNA in the blood like RET918, that that has a poor prognosis and that you obviously have more tumor to shed, which is probably why anaplastic has, you know, a higher rate of having tumor in the blood. So it's basically a way of measuring tumor burden and progression. Is that fast enough? Fair enough. I think there is a question regarding how do we refer to one of your cancer center if we practice in rural area with limited resources? Yeah, this is really a challenge. Right. If we're just honest, it's expensive to come see us. I work in Manhattan. Even getting here is expensive. So I think you'll find most of us do our best to answer as many emails as we can and have people reach out to us because we recognize that many times the patients don't physically have to see me. We can help out the doctors with questions. So don't everybody email me tonight because I'm going to dinner in a few minutes. But most of us that I know, NYFA and Steve Sherman and their group and our group are trying, you know, as best we can help from doctor to doctor communications is probably the best way from folks from limited resources. Hopefully in the future with telemedicine and Zoom, that might be something to consider. It has been. I mean, every state is kind of being a little bit different about that now, but that's helped out. And a lot of centers offer kind of mail consults. We've traditionally done this internationally, right? People get to send all the records and they send the CDs of the scans and they send the slides and they get read here at Memorial. And then we dictate a consult without seeing the patient. So I know some centers are doing that as well, certainly internationally and now maybe even starting to do it nationally. So, you know, those are opportunities in this day and age that we ought to be able to help and do. And not I think we've learned that not everybody has to come to Manhattan for us to be able to help. What do you think of performing FDG PET before radioactive iodine if the pathology reported to a cell in about 60 percent or more? Yeah, I mean, I can just take that. I mean, you can do a PET, but I think that we want to think about what why are we doing the PET for what utility? So, you know, Memorial Stone Kettering's data, which Dr. Tuttle can share with you, has nicely shown, right, that, you know, when tumors are FDG avid, they're less likely to take up radioactive iodine. But it doesn't mean that they're not going to. Right. So I wouldn't use it in at least we don't use it in lieu of radioactive iodine, especially poorly differentiated. Sometimes we'll take up FDG and iodine. It's probably more likely that iodine will not work very well, but it doesn't mean we skip it. What payers will pay for, which also goes with the data for the utility, is those patients who, if you're using it for prognostic purposes or the thyroglobulin is greater than 10 and you can't find it with other imaging, is probably the best utility. Great. Thank you. I think this is all the time we have for today's session. Unfortunately, we can't accommodate all questions, but we'll try to answer them in the chat. Thank you very much for participating and we appreciate all our speaker time on today. Enjoy the rest of your day and the rest of the meeting.

Thyroid cancer management

Individualized therapy

Surgery as primary treatment

Systemic therapies

BRAF and RET inhibitors

Thyroid cancer surgeries

Active surveillance

Ultrasounds and follow-up

External beam radiation

Poorly differentiated variants

Cell-free DNA analysis

Tumor burden and progression

Specific mutations