While medullary thyroid cancer remains a surgically treated malignancy, the opportunity for cure is dependent on early diagnosis and treatment. After a brief review of current treatment guidelines, panelists and moderator, Susan Mandel, MD, participate in a semi-structured case-based discussion of disease management focusing on areas of critical importance to management and those that remain controversial.
This panel discussion of specialists from across the Penn Medicine health system include endocrinology, pathology and laboratory, medical oncology and surgical oncology discusses Medullary Thyroid Cancer in the context of diagnosis, surgical management, surveillance and systemic therapy indications, and research—including the new MTC CAR-T Clinical Trial.
Enrolling Now: A CAR-T Trial for Medullary Thyroid Cancer Annual Updates in Management of Thyroid Nodules Management of High Risk Thyroid Cancer See Dr. Kelz's physician profile See Dr. LiVolsi's physician profile See Dr. Mandel's physician profile See Dr. Nathanson's physician profile See Dr. Sun's physician profile
Okay I think we'll start to get a timely start because we have some fascinating content to cover. And um this way at least we'll get the get through the introduction. So good morning everybody and welcome to the CMI approved webinar. That's sponsored by the thyroid disease team here um at Penn at the Abramson Cancer Center. So today our focus is the evaluation and management of patients with medullary thyroid cancer, the less the least common or one of the least common thyroid cancers. And this cancer originates from the sea cells of the thyroid as opposed to the more common follicular cell derived thyroid cancers which are popularly thyroid cancer and its variants and follicular direct cancer. Medullary accounts for only about 1 to 2% of all thyroid cancer diagnoses and mostly sporadic but about 25% are familial as part of the M. E. N. Or multiple endocrine er Play asia type two syndrome. My name is Susan Mandel and I will serve double roles both as moderator and then in my professional role here at pan is the endocrinologist on the team and I'm joined by for outstanding colleagues who disciplines disciplines, represent the multidisciplinary collaboration essential for care of this patient population. So we have from pathology, dr Virginia lee Woolsey from medical genetics, Dr cat kate Nathan johnson from medical oncology. Dr love his son and from endocrine surgery dr Rachel kills so together today our goal is to define and review the approach to a patient who is found to have medullary thyroid cancer and this approach should be evidence based and patient centered. So we'll first focus on initial therapy surveillance and then additional treatment options is indicated by the course of the disease including including highlighting the new clinical trial here at Penn on car T cell therapy. The webinar will discuss points of care relevant to the management of these patients across the spectrum of their disease and that involves the entire care team. So because it's focused on management will be sharing the clinical vignette verbally and providing pathology and radiology results. So our objectives are to describe the diagnostic evaluation for this. This category of patients diagnosed with medullary thyroid cancer, explain principles of appropriate surgical management, discuss evidence based surveillance strategies and review indications for systemic therapy. Our our patients, our speakers have no relevant financial disclosures. Um This webinar is live and will be conducted as a panel discussion at any time in the webinar. Please use the Q. And a function, not the chat function to enter questions. And some of our panelists will even try to answer those during the webinar and we have reserved 10 minutes for questions at the end of the session. The session is also being recorded and will be available for future listening. So within a week after the meeting you'll receive an email from Penn CMi with instructions on how to complete on the evaluation and claim your credit and you will not be able to claim credit until after you receive this. So first I'm going to start with the case. Um and um I will oops um I somehow think this is on automatic, I'm not quite sure. But let's see what happens here. Um so I'm going to start with the case. It's a 47 year old male who sees his internist because he feels a lump in his neck while shaving. So not an uncommon story for some of our patients with thyroid nodules. He has no family history of thyroid cancer, no personal risk factors for thyroid cancer and he's you thyroid. His internist obtains the neck ultrasound that demonstrates a left three centimeters solid nodule and several Sana Sana, graphically abnormal left lateral lymph nodes and F. N. A. Of both. The cyber nodule and a 1.5 centimeter left lateral neck lymph node reveals medullary cancer. So for me as an endocrinologist when I see a patient and I may have actually done the F. N. A. Or the FDA may have been done by one of our surgeons or in our bio radiology colleagues. The first question is the initial evaluation of this patient. So we've done the ultrasound we've looked at lymph nodes. We've got we've obtained a family history. So the thyroid c cells which are the origin of medullary cancers secrete several proteins that can be used as tumor markers. The more specific calcitonin and the less specific ce a and both should be measured at the time of diagnosis. In addition. Very importantly, genetic testing for a red germline mutation is required which is available commercially and for today's webinar. However, I will turn to our geneticist Dr kate Nathan johnson to take us through the evaluation when she sees a patient newly diagnosed with medullary cancer. So kate, I turned it over to you. Thank you. So I think it's important, although this has been true for for many years to remember that genetic testing of the red proton to jeanne are looking for mutations in that gene is really considered standard of care. Um If mentally thyroid cancer is diagnosed by FN A. As Susan mentioned, genetic testing is recommended prior to surgery to help with surgical management. Um, it's important to recognize that about 25% of patients with medullary thyroid cancer have uh multiple intracranial pressure type two or MD. N. To a um, familial medullary thyroid cancer is not really a term that we use anymore. Um all patients are considered to have M. E. N two A with variable penetrates of futurama site Omagh's and hyper parathyroid is um um and uh M. E. N two B is a rare uh mainly childhood entity that rBc with patients with multiple other features, dis mythology, um, mucosa and aromas and Marfa annoyed habitats. Um about 20 in patients who have uh multiple endocrine type B and type to a um uh many of them do not have a family history. Um so it's important to do the genetic testing even if you don't have a positive family history. I'm sorry go on. Yeah. So um next as I just mentioned, the other manifestations your disease associated with red mutations are harmless Natomas and hyperthyroidism. Um It's important to screen for those prior to surgery. You want to medically optimize your patients um particularly you don't want to go into surgery with have a patient with a psa creating uh como se toma. Um And so that's important to do. Just to note there's really a low risk of expert adrenal disease with this with reputations. But bilateral fuel for most items are common with particularly with certain mutations. The biochemistry is one should check plasma metadata. Friends column means P th and calcium, as I mentioned prior to surgery to medically optimize them. And obviously when we identify a mutation, we also think about familial testing for other family members um and that can proceed um uh with your genetics colleagues. Mhm. Thank you. Um So now this test is certainly available so that many times this test may be ordered by the clinician who first sees this, this patient. Um And um in this particular patient the calcitonin was 2200, so quite elevated. The C. Ea was 15 and the red testing did not show any mutations. So ideally if you had the right result, there would be no indication for testing for either hyperpower authorities um or fio chromosome toma for the familial syndromes But pragmatically since red testing can take up to three weeks to return and often the surgery, the surgery may occur before that as endocrinologists. And it's under concert agents. We often screened for the fia chromosome Tacoma with the plasma metal reference. And hyper parathyroid is um with the serum calcium because we don't have the red tests back at the time of surgery. But clearly if it's back and if it's negative, we don't need to do that furthermore. Um if the serum calcitonin is over 500, pre operatively distant metastases are more likely. And the American Thyroid Association 2015 guidelines do recommend additional imaging cts of the neck, abdomen and chest with contrast. All done for this patient. And only local regional disease was demonstrated in the left lateral neck, but no pulmonary or no hepatic metastases. So, Rachel as a surgeon, then you're seeing this patient who is negative for red oncogene and who has a left medullary thyroid cancer and an abnormal left lateral neck lymph node. Can you review your approach to surgery for this patient? Um for sure. So the management for this patient is relatively straightforward because they already have documented lateral neck disease. So in all patients with medullary thyroid cancer. Unlike the well differentiated thyroid cancers, they should have a total thyroidectomy with a central neck dissection, which means that you want to send them to somebody who's a high volume thyroid surgeon so that they are able to minimize the risks to the recurrent torrential nerves and the parathyroid plans during the central neck dissection for our patient. Because they have clinical evidence of lateral neck disease, they're also going to get a left lateral modified modified radical neck dissection on the left side. And you can also have a conversation with such significant disease about whether or not a contra lateral prophylactic neck dissection should be performed, although with our radiologists and the their expertise with neck ultrasound, if there is not any evidence of radia graphically evident right lateral neck dissection, then they would not need to have that operation at this time. So, a follow up for this question. So here there were it's a lateral um it's a lateral neck lymph nodes. So in the left lateral neck. But what if the preoperative ultrasound had just shown the left medullary thyroid cancer nodule. And our radiologists also told us that the left lateral neck look fine. What is your surgical approach then when we think that the medullary cancer may just be in the thyroid without Sana, graphic evidence of abnormal lateral lymph nodes. So in that setting, um the calcitonin may be elevated or not elevated. And that's something that we're going to think about. But in in the 80 a guidelines, they did not come to a consensus on the role of lateral neck dissection in that setting. I think our practices moving more and more to a conservative approach. So without any evidence of lateral neck dissection for that patient. I would usually perform a total thyroidectomy with the central neck dissection and they would understand the importance of their surveillance studies um in the future to detect any lateral neck node recurrences in a timely fashion. And then can you comment a little bit about what you said about the calcitonin again, just to um even if the ultrasound is negative, how do you um operate then based upon the serum calcitonin level? So with a three centimeter tumor, it's not unusual that we'll see a calcitonin level that's elevated certainly beyond 20 which is the lower threshold that we think about. Um but it can be elevated into a couple 100. and so the guidelines, as you mentioned, you have a cut off of about 500. Now they used to be a 200. The European guidelines are still a little bit lower than ours but almost regardless of the calcitonin level, if there's no evidence of radiographic lee obvious lymph node disease, then a total thyroidectomy of the central neck dissection is a reasonable choice in this patient. Thank you. And um so um I will now turn to our pathologist before I tell you what the actual pathology was after surgery. So I turn to our pathologist dr Virginia lee Woolsey who will share her slides and will educate us about the origin of medullary cancer of the thyroid c cells and then described her approach to evaluating the surgical specimen for identifying more aggressive features and how she evaluates your c cell hyperplasia. Wow, okay, so I wanted discuss some pathologic aspects of both medullary thyroid carcinoma as well as c cell hyperplasia. And because we are at penn today, I just wanted to say that the originally um original paper which described medullary thyroid carcinoma in the english literature, was from Penn Dr robert Horne, who was then the director of anatomical pathology here at hub in 1951. In a paper in cancer, he did not call it medullary. He called it carcinoma with solid features describe seven patients and said that it was prognostic lee. Somewhere between papillary or follicular thyroid cancer and anaplastic carcinoma. six of the seven patients died of disease. Um It was named medullary carcinoma in 1959 by Dr. Hazzard and his colleagues at the Cleveland Clinic and they attributed the original description to Dr Horn in their paper, as has been said already. Most medullary carcinomas are sporadic and present as a painless neck lump, either in the thyroid or a neck node or both rarely excess calcitonin markedly excess calcitonin may cause symptoms. Familial cases. Often have a positive family history of thyroid nodule or thyroid cancer. They have bilateral multifocal nodules and other endocrine lesions in the parathyroid and adrenal. I want to make a comment here about F. N. A. Of medullary thyroid carcinoma. It is not an easy diagnosis to make, please be aware that approximately 3 to 4% of F. N. A. S diagnosed in this country as a tipi of uncertain significance or follicular lesion of uncertain significance, turnout on surgical pathology to be medullary carcinoma. Um Also on F. N. A. S, especially if there are cell blocks. You must be aware that there are problems with calcitonin immuno staining on both smears and cell blocks of medullary carcinoma because lesions of follicular derivation, especially those which are on pacific or hurdle cell, can pick up calcitonin antibody and give you a false positive result that it is a calcitonin positive tumor that is a medullary carcinoma. The clue on F. N. A. Of the nuclear features which should be neuro endocrine and amyloid can help but amyloid is present in only three quarters of the cases and often on F. N. A. Is not recognized. Um What about evaluation of the surgical specimen? Obviously if you have a total thyroidectomy, you should weigh and measure the specimen, measure and describe the largest nodule and note any other lesions in the gland, assess for gross extra thyroid als spread, which probably had been noted by the surgeon, check for lymph nodes and parathyroid that may be attached to the thyroid take sections including two more to the surrounding land and also take sections of the non temporal, non non modular thyroid to assess for the c cells. Microscopic assessment includes tumor size and pattern, especially if unusual and the presence of invasion in the thyroid one should note lymphatic vascular and or Perrin neural invasion access, assess for extra thyroid all extension. Note other lesions, especially c cell hyperplasia. Give the number of positive lymph nodes the size of the largest node and if there is extra nodal extension, all of these tumors should be immunosuppressant for calcitonin and monoclonal cE A to solidify the diagnosis and to assess the percentage of positive cells in the tumor. Also it is important to look for necrotic fosse and to assess my tactic activity. If there is a suggestion that this is a familial case or there is multi focal disease, one needs to look at the non tumor blocks for for C cell hyperplasia. And sometimes that requires immuno staining to look for the C cells. Sometimes, as I will show you in a minute, you can see the sea cells on H. And E. Histological medullary carcinoma is the great imitator and there are numerous patterns including epithelial spindle, follicular papillary giant cell etcetera and the products that these tumors can make including calcitonin. Probably the most important T. T.F. one which is present by immuno stating in about 30% of cases they can produce a C. Th hcg and from a non immuno point of view they can produce amyloid which is a pro calcitonin precipitate within the tumor and they can also produce melanin mimicking metastatic melanoma to the thyroid. Here's a classic medullary carcinoma arranged in nests and you can see the around the nests of prominent pink vascular pattern. On the middle photograph, you will see the red color amyloid. You will note the stay on the lower left, the presence of the so called neuro endocrine nuclei, which have been described by pathologists as salt and pepper and on the lower right presence of calcitonin. In virtually every tumor cell, one can have spindle cell patterns as can be seen on the left with the arrow pointing to the amyloid and one can have giant cell vocabulary carcinomas as well. The sporadic medullary carcinoma, which is the most common, is usually a solitary tumor without c cell hyperplasia and no other endocrine open these. I want to just make a point about lymphatic invasion in the thyroid and where one can see um what looks like perhaps a second primary, Be sure that you're not dealing with vascular or lymphatic invasion rather than a second primary. Now, familial medullary carcinoma can have as dr Nathan seuin indicated only MTC at least clinically or maybe associated with parathyroid and adrenal medullary disease in M. E. N. Two A. Or two B. It's multifocal and bilateral and associated with c cell hyperplasia. In prophylactic thyroidectomy is especially in individuals who have been diagnosed by genetic testing or by screening for calcitonin. You may find only c cell hyperplasia or micro medullary carcinoma And if that tumor is less than five, according to a study from Memorial Sloan Kettering in New York, There were no metastases metastases. If the tumor is a microcosm noma but is greater than 5, 1 can have central compartment lymph node micro metastases. Now this is a micro medullary carcinoma. You can see there are still residual follicles around which the tumor is growing and in the lower right you can see the immuno stained for calcitonin. Here is lymphatic invasion and the medullary carcinoma. This is not multifocal medullary carcinoma. This was a sporadic case in a 75 year old patient. Uh and the pathologist needs to be careful not to misinterpret this as multifocal disease. Recently we have come upon the concept of grading of medullary thyroid carcinoma equivalent to grading of follicular derived tumors. And grading includes a high metabolic rate with abnormal mitosis and the presence of necrosis. And there have been three papers now, two studies, one from the United States, one from Australia and an international panel that agreed that medullary carcinoma should be graded as well or poorly differentiated and poorly differentiated if these features are present, these have an aggressive clinical behavior and it is important to remember That an old study from about 50 years ago from MD. Anderson showed that if a tumor is confined to the thyroid has a small size and lots of amyloid, With over 75% of the tumor cells being calcitonin positive. Those tumors tended to do better than those that were had either large size or extra thyroid extension. Here is a fully differentiated medullary carcinoma. And in the center you can see what we as pathologists called coagulated tumor necrosis. This patient at presentation already had bone and liver and lung metastases. Now let's get to the C cells. For many years. These were thought to be of neural crest origin. But over the past five years, elegant molecular biology and embry a logic studies in mammals show that they really are derived from ended ERM They migrate into the thyroid with the Ultima Bronchial body which is derived from the 4th 5th bronchial pouch as such. They are found in the normal human thyroid, in the lateral aspects of each lobe, The Upper 2/3. Hence this is where most medullary carcinomas are found. If one finds a medullary carcinoma in the isthmus, this should be considered a met and not a primary and it may actually represent a nodal met in the area of the isthmus. Now if c cells are increased we call it c cell hyperplasia. Um And this is a disputed entity in cases in which there is not familial medullary thyroid carcinoma. There's a great debate upon how many normals what the number of normalcy cells in normal thyroids should be many. Believe that you should not see normalcy cells on H. And E. And require calcitonin immuno hist. O. Chemistry, neo plastic c cell hyperplasia can be seen on H and E. And I'll show you that In a study from the University of Sydney Australia a couple of years ago they examined 118 completion thyroid lobes. In patients without medullary carcinoma without a family history or elevated calcitonin. In these lobes the number of C cells was increased in 5-36% of these cases endocrine illogically normal adult men seem to have more C cells than adults women And by some definitions 30% of normal males will have C cell hyperplasia. There is something very wrong here. These are the sea sells these sort of gray cytoplasmic cells around the follicles. And here is in a familial case c cell hyperplasia. Where you see a lot of these gray staining cells. This gray staining is granularity and these are the neuro endocrine um bodies which are seen in by electron microscopy in these cells and are the source of the calcitonin. This is from that paper from Sydney Australia and they looked at the literature and found that in normal individuals the number which would have C cell hyperplasia if every thyroid block was stained with calcitonin Is all the way up to 36% of normal individuals does not sound right. So the concept of secondary or reactive c cell hyperplasia has been discussed a lot in the literature. It is known that one can have it near follicular cell derived tumors, both benign and malignant and in hashimoto, thyroid itis, especially severe thyroid itis. This was originally described in rodents and thought to reflect the result of increased TSH which can stimulate the c cells. Subsequently, it was described in humans with severe hashimoto disease. Some people felt feel that there can be a secondary c cell hyperplasia with parathyroid hyper function and in patients with severe osteoporosis. This is all I think extremely controversial and needs to be studied further. And another important concept that I want to end with is that there our studies predominantly in rodents showing increase in the number of c cells, an increase in calcitonin. In rodents given glue coogan like peptide one receptor agonists for diabetes. However, in human trials there has not been found that calcitonin is elevated and of course we're not going to get the thyroids out to see if there is increased C cells but there does not appear to be an increase in medullary carcinoma. However, if one watches television, one will see that there is an FDA warning on this whole class of drugs about not giving them to patients who have a history of medullary carcinoma or of M. E N two. A Thank you. I'm giving it back to Susan I will and I will share my screen again. Um We go down here. Thank you Virginia from here Susan I think right before you get into this. Um it's just important to highlight the fact that you know this is a surgically treated disease. And so as Virginia pointed out you have to make sure to be very complete about your reception because that is going to be the patients only chance of cure and the balance for the prophylactic dissections has to do with the risks of the prophylactic operation and the likelihood of achieving a long term cure. Thank you for those comments. Um I'd like to bring up something that we sometimes see here occasionally because we have kate here which is sometimes although from a commercial lab the original red test is negative. A pathologist like dr Livesey reports that there is true pathologic c cell hyperplasia. So in that case kate should there be additional genetic testing are their occasional cases of um F. M. M. E. N. Two um that are not picked up by the more commonly tested point mutations. Yes. So um many of the lab's still continue to only test certain Exxon's in the red um proto oncogene. And while those account for 95% of mutations there's an additional 5% of mutations that are outside of those canonical Exxon's. Um And so there are patients and who have c cell hyperplasia um and have no um testing on initial no mutations identified with initial testing. Um And those patients who go on to have full gene testing. Um rather than just of selected Exxon's. Um And so we have identified additional um mutations in those patients. So important to do so thank you. And hence very important for our pathologist to differentiate reactive c cell hyperplasia from pathologic c cell hyperplasia as Virginia. So nicely went through hoops. I think I'm sorry I think I'm still on yours. I thought I'd apologize. I will get down to the pathology report here. So here's the pathology on our patient. So 2.7 centimeter. Left meddler thyroid cancer with vascular invasion. No necrosis. I left out the points that are Virginia said should be in there. Um But no necrosis. Um there and no c cell hyperplasia. Um lymph nodes. You can see there are a number of metastatic lymph nodes respected by doctor kills or one of her colleagues both on the left side and in the central neck and the largest lymph node was 2.3 centimeters without any extra nodal extension. So this is a J. C. C. Eight stage for a. T. Two N. One B mm. Zero. Remember we did that chest ct in advance because the calcitonin was over 500. Um So how do we follow patients after their initial surgery? So remember this is surgery is the initial um therapy that we do. And so what we do is we measure levels of growth, serum calcitonin which you'll see abbreviated as C. T. N. And C. E. A. And these generally um nature around um three months. So they should be measured three months post operatively. Remember remember where we measured them pre operatively. And if the calcitonin was over 500 that's when we did cts of the neck, chest and abdomen. And if they're undetectable or in a very very low C. A. Can be in a normal range The calcitonin should be undetectable. But this is what the 88 guidelines say. They can then be measured every six months for a year and then yearly afterwards. So um there are patients who do have undetectable calcitonin levels who after 5-7 years will begin to go up. So this is a lifetime monitoring. However if they're detectable then they need to be measured at least every six months. Because what we're doing is calculating the doubling time. So the doubling time meaning how quickly. Especially for the calcitonin. But sometimes for the CIA especially for those tumors they tend to be less differentiated. That secrete more CIA than calcitonin is very important. Um For prognosis and ideally you would want four data points over two years to be able to calculate the doubling time But doubling times less than two years. In multiple studies are associated with more rapid progression in up to 90% of patients and at least prior to the The really revolutionary systemic therapy is that love is going to discuss with you decreased survival so that if the doubling time was less than two years survival was you know 40% or less. And luckily we've been able to to impact that. So how do we then determine imaging based upon the calcitonin. And I've taken this directly from the A. T. A. Medullary thyroid cancer guidelines. So here on the left, the status is the total thyroidectomy. And so you measure the calcitonin ce a Thyroid levels and TSS every 6-12 months. And just to remind you this is modular cancer. So the target TSH is a normal range. We are not suppressing the TSH in medullary cancer which is a non follicular cell derived malignancy. And then our follow up strategy depends upon the values of the calcitonin. So here is the calcitonin. And so if it's low or undetectable And the ultrasound remains normal, you can do it every six months for the first year and then annually. But remember there are patients who have undetectable calcitonin who sometime at 5-6 to 10 years will then have a rise in calcitonin so that this does require lifetime surveillance. On the other hand, if the calcitonin is elevated but less than 1 50. So we're now using 1 50 as our cut off. Um We obviously do an ultrasound. Um and we continue to measure the calcitonin a little bit more frequently every 3-6 months, we're looking for that doubling time. And as long as it remains less than 1 50 it's just the ultrasound imaging. But if the calcium rises to over 1 50 which is over here or if it's over 1 50 in the beginning, that's when we do imaging to look for distance spread. Because remember we've already looked at the neck with ultrasound. But this is when we begin to add cross sectional imaging. And the cross sectional imaging here includes besides the neck ultrasound, the neck, chest and abdomen cts with contrast and then also lumber spine and pelvis memory. Because of the fact that meddler cancer can also spread to the bones. So this is sort of our strategy for following patients that it's based upon calcitonin and see a measurement. And as opposed to our patients with papillary cancer where you kind of anti thyroid globulin antibodies, we do not have that dilemma of having anti calcitonin antibodies. You can measure calcitonin and cE A levels. So in our patient, um the postoperative calcitonin was 4 80. But six months later it rose to 6 65 and 12 months later it rose to 10 50. So basically it went from 4 82 10 50 within a period of 12 months. We really did not need four data points to see that the doubling time here Is less than two years and much closer to 12 months. And the patient then underwent imaging as recommended with cross sectional imaging of the neck, chest and abdomen and there were multiple 2 to 3 millimeters small pulmonary nodules in the chest. Unfortunately there was no abdominal disease. And the M. R. I. Showed no bone metastases. So what I'd like to do now is we have a patient whose neck looks clean had vascular invasion, has small lung nodules. And I'd like to turn to our oncologist Dr Leveson to discuss the approach to medullary cancer with distant mets including when you do active surveillance when you intervene. Do you ever do somatic rat testing and then to talk about our clinical trials including our new pen car T cell trial for medullary thyroid cancer. So thank you Loba. Great thank you Susan. Um So for patients like this with sporadic medullary thyroid cancer who are not found to have a germline mutation in red. It is important to do solid tumor sequencing to search for somatic red mutations these days. Most commonly done by next generation sequencing but also can be evaluated via pcR or fish. Um As you've heard before today three quarters of legendary thyroid cancers are sporadic rather than hereditary or familial. And within these sporadic new uh medullary thyroid cancer cases. Somatic mutations are found in about 40 to 60%. The most common of which is the M 9 18 T mutation on exon 16 similar to with differentiated thyroid cancer. Active surveillance is um an important part of our management approach even after a patient develops metastatic disease. Um conceptually this is because systemic therapy does not cure thyroid cancer. And the goal is really to reduce tumor burden and slow disease progression. And also because once we start systemic therapy, patients are generally on these agents indefinitely until progression or unmanageable toxicity and side effects can have a significant impact on quality of life. So in cases of small burden and slowly progressive cancer will often start with active surveillance with um CT scans and tumor markers um every 3-6 months to get a sense of a patient's disease kinetics. Um So when is the right time to start systemic therapy? When is this inflection point where the benefit of treatment is likely to outweigh the risks of toxicity? Um This is still somewhat of an area of debate with significant practice variation and individualized patient decision making. Um but in general we will consider initiating treatment when either there's a larger burden of disease. For instance, lesions greater than 1-2 cm or when doubling time of radiographic lesions or tumor markers, speeds up to less than the 1 to 2 year range similar to what you're seeing with this patient. Or certainly when there are when there is symptomatic disease progression. Um That said there is some data from the differentiated thyroid cancer space that initiating treatment earlier in the disease course may lead to better outcomes. So the timing can be tricky. Um Sometimes it's a clear cut case of small burden and slowly progressive disease where you can watch um on the other end of the spectrum, You know, larger burden disease with rapid doubling time. We certainly will start therapy but what to do with larger burden indolent disease or vice versa. You know, smaller burden, rapidly progressing disease um is still a matter of debate and um you know, timing can be tricky in those cases. So moving on to treatment options um if a patient does have a reputation, either germline or somatic, they can be treated with sulfur catnip or Proust said in it. Both of these are potent selective oral red inhibitors which have shown impressive overall response rates of 60 to 70% as you can see on these waterfall plots. Um They've also been shown to have durable durable responses and efficacy across different alterations as well as both pre treated and naive treatment naive patient upwards. Um both of these drugs are very well tolerated. Most adverse events on these trials were grade 1-2. Um but most common side effects seen were things like hypertension, lft elevations and diarrhea or constipation as well as sight opinions specifically for prosthetics. So these agents were both FADA approved in 2020 forever altered thyroid cancer with line agnostic indications. If no actionable alterations are found, we will start treatment with the multi kinase inhibitor, either cabbies antonym or van detonated. These agents have lower response rates than the selective red inhibitors and generally don't induce complete responses but have been shown to improve progression free survival compared to placebo. Um and these agents were actually approved back in 2011-2012 for metastatic medullary thyroid cancer. Um I'm showing here the exam trial um in this trial, patients treated with representative had a progression free survival of 11 months compared to four months with placebo with the response rate of 28%. Bendectin. IB is another T. K. I. Approved in this setting. This drug showed an overall response rate of 45% in the Zeta study and an improved progression free survival over placebo. Again as you can see um notably this trial enrolled in a more indolent population than the previous trial. I showed. It did not require radiographic progression, which is what accounts for the longer progression free survival in both arms compared to the exam study. Um Overall survival was not different in either of these trials. Uh partially due to the ability for patients to cross over at time of progression. Um Although um not both the cabo trials actually did not allow patients to cross over and still did not see an overall benefit. Overall survival benefit in the overall population. Um But one notable thing was that patients with reputations seemed to derive a greater degree of benefit with both of these agents. Um With a borderline overall survival Bennett competitive and Van detectives have potential partially overlapping but also somewhat distinct toxicity profiles which are sometimes used to choose between the two common side effects with these T. K. I. S include diarrhea fatigue and rash with hand foot syndrome being more common with cabins and tentative um notably van detonated can cause Q. TC. Prolongation and with cabins antonym it's important to counsel patients about rarer but serious toxicities including perforation, fistula and hemorrhage Toxicity management is a big part of our practice. Um so in the exam trial patients were treated with a high dose of 140 mg of Cabazon daily which was quite hard to tolerate. Almost 80% of patients in the trial needed a dose reduction. So in clinical practice sometimes we will start lower on the dose um And to manage these side effects in addition to anti diarrheal and topical therapies. We frequently used dose holds and dose reductions to make these drugs more tolerable for our patients because remember this is long term and non curative therapy. I will mention that although now we often use red inhibitors. Frontline for patients who are eligible by virtue of a reputation given the excellent tolerable itty and response rates I showed um The optimal sequence of therapy is still not established for these patients. Should we be starting with red inhibitors or should we be starting with multi kinase inhibitors followed by red targeted therapy which there's actually more data for. Um And this optimal sequencing is still being actively investigated in these randomized trials. I'm showing here a couple of other treatment concepts for patients with bone metastases. We will use ivy bisphosphonates um ordinance mab and we will consider locally a blade of therapy including radiation for symptom control. Although this cancer is um typically radiation resistant. So what happens when patients either progress on frontline therapy or cannot tolerate them? Um In some cases, for instance when we suspect acquired resistance to a red inhibitor, we may still pursue repeat genetic testing to search for resistance mutations like met amplification or solvent front mutations which these days can make patients a candidate for other targeted therapies or trials. Um It's also reasonable to try other T. K. I. S, including sarah punitive punitive combative or default to decarbonization based chemotherapy. But efficacy of any of these agents is very limited. So that leads us to um the clinical trial, we are very fortunate to have a trial opened up pen of the first car T therapy for medullary thyroid cancer for patients who have progressed on standard therapies. Many in the audience are probably familiar with CD 19 directed car T therapy for him a geologic malignancies. One of the major challenges in solid tumors has been finding a target for the CAR T. That's expressed on the tumor cells but will not result in systemic oft uber reactivity of toxicity. Medullary thyroid cancer is amenable to such a car T approach because there's there's a target G fr alpha four shown here which is specific to para follicular see cells which you can live without and medullary thyroid cancer cells. Um And this is the basis for the car T therapy developed in Dr Segal's lab. Um This trial is open at Penn um currently and we're actively recruiting patients and in the chat we will put some contact information as well as a link to a recent podcast that Dr Siegel and Dr Cohen did. And we encourage you to have a listen and reach out for further details. And with that I will hand it back to Susan. Great thank you. I'm about to turn it over to kate. So thank you so much and it is really exciting that we have another option. Besides our multi kindness inhibitors are rat inhibitors and now we have parked t cell therapy as well. Um So kate I'd like to take us back now leaving this patient um to the hereditary medullary thyroid cancer symptoms that are associated with red mutations. And um we know there are many different reputations as you know shown in the slides and you'll take us through this. Can you take us through genotype phenotype associations, your screening recommendations, How it may vary depending on the mutation and how you counsel family members. Sure. So um I think it's important to note um that not all reputations as I say are the same. So there is quite variable risk. I'm gonna talk on both this and the next slide. But um Susan can you uh so it's this sorry, it showed up quickly. So the most common mutation we see is the mutation at 6 30 for uh 6 30 for mutations are associated not only with a very high risk of mental every thyroid cancer but also high risk of fetal chromosome Natomas and um risk of hyper parathyroid is um um uh Many of the mutations have variable risk of fetal chromosomal toma and this really is the highest risk. Um The issue with toma with many patients having bilateral disease. Um Good. Um I also point out the 9 18 mutation. This mutation is actually the most common mutation and sporadic legendary thyroid cancer. So the most common somatic mutation that we see. Um But it's also associated with very when hereditary associated with very early onset um Mettler thyroid cancer and infancy. So in the end type to be. Um And as I noted earlier has multiple dis morphology, features with mucosal neuroma which can be in mouth around the eyes. Um And in the G. I. Tract as well as the Marfa annoyed habitats. Next slide. So um I think it's important to look also at the risk of medullary thyroid cancer and because of the differing risk of medullary thyroid cancer, there are different screening recommendations which I'll talk about on the next slide. Um but important to note that the highest risk as I mentioned is 9:18 with Prophylactic thyroidectomy basically recommended in infancy, interestingly. That's more difficult because most of these patients tend to be new mutations. Um due to mutations because of the high lethality of the thyroid cancer patients don't often go on to have Children. Um and then um in childhood prophylactic thyroidectomy is recommended in the sort of C60 uh for the 64 mutations and the 883 mutations. And then we'll talk about sort of the screening for the moderate level risk as noted. These are and mentioned across the different exxons and um sort of in different locations. Next there we go. Oh okay. Actually go back to that slide, sorry. Um and I just want to note the differing risk of fetal coma se toma and hyper parathyroid is um as well. Um And so you can see as I noted that 34 has very high risk of hyperthyroidism um as well as a 6 31 and then there's less hyper parathyroid is. Um and some associated with some of the other mutations. And again the risk of um um uh como se toma is variable as well. Um And then you can see some patients get something called a cutaneous, like an amyloidosis which is on the back of the neck and sort of a discoloration and that varies by mutation as well. So really important to understand and identify what the mutation is of the patient and taylor risk on that basis. So this is something so as I mentioned um when you have uh you know I've done this long enough. It used to be that everybody with a red mutation was recommended to have a prophylactic thyroidectomy and that's really still true for patients. As I mentioned with the high mutations, it's 9 18 mutations and 6 34 mutations. But now particularly if patients are diagnosed in adulthood um really the current recommendations suggest that you can have um routine calcitonin screening and then if the calcitonin screening for the moderate penetration mutations and then if you have the calcitonin screening um every year um and it remains low then you really have no you can continue to do annual testing and then once it becomes elevated then you can go on and you consider prophylactic thyroidectomy and you can do that um sort of in the age starting at adulthood for some mutations you should start sort of indentations and some in adulthood. But I think it what I find difficult about this recommendation is human nature. Um and I have this conversation frequently with parents of teenaged boys. So it turns out that you know you have someone who has known reputation and you know they get to their mitch pennies and honestly they don't show up for five years. So yeah this is a great recommendation if you have patients who have screening and really managed to have screening every year and really we're following their calcitonin and we've had a number of patients who have been lost to follow up and have represented with medullary, thyroid cancer. And so I have a really a discussion with people about this is a good recommendation if you follow the recommendation, but it's not a good recommendation if you decide that you're going to get screening every five years because you can show up with medullary thyroid cancer because you haven't had routine screening. So I um have a more nuanced conversation than the sort of documented um discussion about like let's do calcitonin screening every year for the moderate um very interesting here what other people think about this but for the moderate penetrate expectations because I find that that you have to point out that it's you have to follow up every year. Otherwise it's not a worthwhile recommendation. But nonetheless the current sort of standard recommendations are that you can um have calcitonin on an annual basis. But I think as I said, it's really important to account for human nature and whether or not people will follow up um and we do have patients who say I'm never going to fall off every year, just do the prophylactic thyroidectomy. So I just think it's really important and I I've had parents of particularly teenage males decide that they would like to have their kids have the prophylactic thyroidectomy because they are concerned that they will not follow up in later life. So I'm not, as I said, perhaps I shouldn't say but we don't I tend to have a more nuanced conversation about how this might be matched. So next no, thank you. Um this is I will actually lead the slide up because one of the questions I was going to ask you because I just want to emphasize this is that if you notice on this slide, the way you manage patients is different as to whether they're a child or an adult. And since we do obviously genetic testing, red testing and all of our patients with newly diagnosed Hegeler carcinoma, we often find from the pro band a new pro band asymptomatic family members and adults. And I just wanted to add that the one thing that we do do because sometimes feel chromosome coma can actually um potentially proceed. Um the diagnosis of medullary cancer. The one thing that I think is important to note here is that when we're following an adult it's not just the serum calcitonin that we test annually. We also test if the mutation is associated with the fio sierra meta references as well as calcium. So the annual testing for an asymptomatic adult with a mutation includes obviously the ultrasound initially and then the calcitonin, the meta ness vitamins and the calcium. Um kate. Would you agree with that adding the medication? I'm sorry. Yes and I'm sorry, I should have emphasized that point as well. Um We've actually had a number of patients now who have been identified through um actually at Geisinger through their point with reputations through their bio bank and through screening and many of them actually interestingly enough have had medullary thyroid cancer when getting evaluated as adults. So now with the genome first we're definitely seeing those seeing patients like that. But I completely agree with you Susan. And I think that if you from saitama surveillance should be done as well for these patients, luckily it's all just blood tests and it's it's pretty easy. Um Rachel there is one question in the chat which I think I'll ask you to address as a surgeon. But um I'd like to ask you another question that sometimes happens because Virginia had mentioned this. She said that some of the medical areas were diagnosed as a process to three na jewel. And so especially if um um mutation testing has not been done because both the very site and the thoracic test will pick up medullary cancer. So if you have protested three psychology and you do either the afirma gsc or the thoracic version three. It will pick up meds Hillary. But let's say you either protest or three or four psychology. You do not do molecular testing and you do a low back to me and you find that there is a meddler cancer confined to the thyroid and it's red negative and the ultrasound is negative in that situation. Do you think additional surgery is needed. So if the calcitonin is five after a lumpectomy there's no abnormal inference and the red is negative. Um And now you found out it's a medullary, is that something where you would counsel a patient about additional surgery, the completion and the central neck or would you just follow that patient? So this happens, you know, not infrequently and in patients who as you mentioned our germline mutation negative, there's you don't have to routinely perform a completion thyroidectomy so they can be followed um in patients who do have elevated calcitonin levels are abnormal lymph nodes in the neck then of course they should undergo not just the completion thyroidectomy but also the lymph node dissections to go along with that presentation. Great thank you. Um um there is a question and we want to, we want to answer that, but I did want just before we go because sometimes the thanks get cut off at the end um and so that it's not over, we're going to do some more questions but I did want to again, just while everyone is on the call, thanks are amazing colleagues, you know Kate Nathan and Rachel kills Virginia level C and Levinson for joining us today and especially Amy Kliger and Tara click from the Abramson Cancer center for organizing this and for all of you for joining us today and please look in your chats, it's a great podcast to listen to about the car T cell therapy as well as the link to the clinical trial? Um there is a question in the question, did you already answer it? Um I did. So it was actually a good question to discuss this? And I think for the multidisciplinary team. Um so there's a patient who had what I understand to be a a surgical resection for Medullary thyroid cancer in Jamaica in 1996. Um who underwent external beam radiation therapy following surgery And now presents with a 1.4 centim lymph node. I'm not clear on whether or not it's in the central neck or the lateral neck, but uh doesn't threaten any of the vital structure structures. And so the question is, what are you looking for? Um if you continue to do active surveillance and what would be the triggers to do surgery? Um So I thought this was a great question. Um Susan maybe you can answer what you're looking for if you're going to continue active surveillance. So, active surveillance for metastatic lymph nodes is very well described for papillary thyroid cancer. Um active surveillance and for example, there there's, you know, size cutoffs that a lymph node that, you know, is less than eight in the smallest dimension in the central compartment and less than 10 in the lateral compartment might be a candidate for active surveillance. Active surveillance is not described for medullary cancer, that is a surgical disease. So there have not been very many studies that have looked at that. And so generally the recommendation is for surgery. I think the potential complication here is how does the prior radiation therapy make the surgical resection more difficult. And then would you do simply a berry picking and pick out that one lymph node or would you do a more comprehensive neck dissection? And I think that's something um that would be a discussion with the surgeon. But active surveillance is not generally an option for now. Obviously Dr Lova talked about it for pulmonary nuts, but it doesn't have the same body of literature to support it as popularity cancer does. Um And with respect to the surgery, you know, I think one of the things that we're looking for is how woody does the neck feel. Um it's a terrible term, but it is a real uh you know, something real that happens after external beam radiation. And so um you know, I think myself or any of my colleagues at penn if the patient's local, would be happy to see the patient um and have a conversation with them and and get more information about where the note is located, etcetera. I just want to make a comment for all the clinicians on here, which has to do with calcitonin measurement. You know, we rely a lot on calcitonin measurement. You heard both love and I talked about doubling times. Um, and the american thyroid association on their website. They do have a calculator for doubling times, which unfortunately has been down for the last four months. But I'm told that it should be reinstated on the website because it's what all of us use when we're seeing our medullary cancer patients to calculate the doubling times. But really important clinical pearl, you've all seen how much the calcitonin varies and especially um the coefficient of variation is um certainly um a little bit higher the higher the calcitonin is. And since we um use that so much as a trigger for imaging, It's really important to know when to measure it. And it really turns out that measuring your calcitonin fasting in the morning is probably the most reliable. So I've seen a number of cases on referral where the calcitonin has gone from 2000 to 2900 And the person measured it in the afternoon and I just asked them to re measure it in the morning and it's 2100. So again, trying to do your calcitonin fasting in the morning, especially when you're looking for those changes. Is important because once you've done that imaging, let's say you've done the comprehensive imaging when the calcitonin is a 2000. Your next trigger to do that imaging again is when it goes up by let's say an additional 50%. So getting to that 3000 maybe the next time that you're going to be doing the comprehensive imaging. So it's very important that you can rely on calcitonin measurement. So I just want you to put that out there as a clinical perot along those lines. Um Susan there is a question in the chat about if you could just comment on calcitonin levels in different labs, we've had this conversation. Yeah, so um that's a real challenge to um and um it's there's less data about calcitonin for example, than thyroid librarians. They do generally use the same kit but it's best to keep it at the same lab and best in the time of day and I saw one on dialysis, calcitonin is can go up in renal failure. It can be a little challenging. So in that case I think it's best to do it fasting in the morning and maybe like you know the day after dialysis so try to get it at the same time in their dialysis cycle when you're measuring it. So try to standardize it as much as possible and sometimes it requires several calcitonin measurements. Um you know if I see calcitonin measurement that's off before I start initiating that whole series of cross sectional imaging. The first thing I'll do is repeat the calcitonin. So if it looks like there's a change, the first thing I'll do is repeat it, you know, a week later fasting in the morning. So if someone's on dialysis, try to get it in the same part of that cycle um I actually think we are at the hour um and um we have actually answered the questions in the chat and again I just want to thank our panelists. I hope this was invaluable to all of you were all available here at Penn to answer questions again. The links to the newest clinical trial are there for you and certainly to reach out to love and her colleagues um and she can give you more information. Thank you again very much for joining us. Thank you to the staff and thank you to the panelists. And I hope you have a great rest of your day today on Tuesday and thank you Susan for your expertise and your amazing moderation as always, have a great day, everyone.