Hello, I’m Lori Worth. I am the Elizabeth and Michael Ruane chair of oncology at Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School in Boston. With me here today is Dr Jennifer Sipos, a professor of medicine and a member of the Division of Endocrinology at Ohio State University in Columbus, where she is also the associate vice chair for diversity and inclusion. Hi, Jen.

We’re going to talk today about thyroid cancer. We’re going to talk broadly about thyroid cancer, and then focus on how we treat our patients with iodine-refractory differentiated thyroid cancer. One of the interests that we have today is in how we work together across disciplines. How do we share patients with medical oncology and endocrinology? I’ll really enjoy having this conversation with you, Jen, as you are an endocrinologist, and I am a medical oncologist.

Thank you, Lori. I’m excited to be here.

One of the things that is interesting is this skyrocketing incidence of thyroid cancer in our population, and in many developed populations around the world these days. How do you see that increasing incidence? Is it something that we need to be thinking about in terms of bad thyroid cancers, or is it just a phenomenon of overdiagnosis?

Thank you, Lori. There’s definitely been a lot of interest in this area over the past 10 years or so, since we’ve started to see that increasing incidence trend. We know that the incidence of small thyroid cancers is on the rise. We know that there’s a reservoir of undiagnosed small cancers when we look at surgical series with patients who go to the OR [operating room] for nonmalignant causes needing a thyroidectomy. We see that the incidence rate is around 10% to 15%. Then when we look at autopsy series, the incidence rate of thyroid cancer for people who died for some other reason is consistently in the 10% to 15% range, on average, in the United States. There’s definitely a large reservoir of undiagnosed disease. The incidence of those undiagnosed, indolent cancers is about 1000-fold higher than what we clinically diagnose. We’re able to tap into that reservoir. When we start doing imaging for some other reason and incidentally notice thyroid nodules, which we know are very common, then that work-up leads to the diagnosis of a small cancer.

But we also know from these studies in which we’ve looked at this trend in thyroid cancer that it’s not just the small cancers that are on the rise. We’re also seeing an increased incidence of larger tumors, and more aggressive tumors. There’s probably some other factor, besides increased diagnostic scrutiny, that is leading to this increased incidence of thyroid cancers in general. It’s important to understand what’s causing this trend. But it’s also important to understand, as clinicians, that we need to be able to distinguish those indolent cancers and small tumors that the patient would have died with, not from, from those tumors that we’ve identified and which would have gone on to become more aggressive cancer. We need to be able to understand where this patient’s tumor falls on that spectrum so we can better address how to treat that tumor. If it’s an indolent tumor, we don’t need to be very aggressive with it. But if it’s one that would go on to become more aggressive, we want to be proactive in its management.

Differentiated Thyroid Cancer: Increasing Incidence

I agree that one of the interesting things about thyroid cancer is that it’s not a one-size-fits-all operation. There are varying histologies. When we’re thinking about differentiated thyroid cancer, papillary thyroid cancer is the most common type. But we also see follicular thyroid cancers; and Hurthle cell thyroid cancers, we now know they are their own entity, they’re not a subtype of follicular thyroid cancers, as we once thought. Even poorly differentiated thyroid cancers are included in the group of patients with differentiated thyroid cancer. Those 4 different entities have different natural histories and different underlying biology. Yet to some extent, at initial diagnosis, they’re all treated the same, right?

Right. I do think it’s important for us to understand the differences, not only in the histology, but also in the phenotype of these tumors. We think about histologic differences between the 4 types that you just discussed, but we also have to think about the extent of tumor differentiation in that conversation. Within the subtype of papillary thyroid cancers, the most common cancer, most of them are very well-differentiated tumors that behave very well. They’re indolent tumors. But then we can have, along that spectrum of differentiation, tumors that are less thyroid-like and less well-differentiated. Therefore, they behave much more aggressively. They can be all the way to the end of the spectrum, where they’re undifferentiated tumors, or anaplastic tumors. Within each of those histologic subtypes, we have to consider the different degree of differentiation that helps us to predict the biologic behavior of these tumors.

Also, that conversation includes some discussion of the genomics of these individual tumors and understanding how that impacts their behavior. As you mentioned with Hurthle cell tumors, we now understand these are distinct from follicular tumors. Part of that stems from understanding the genomics of these tumors. They look very different genetically from follicular tumors and papillary tumors. Understanding that genomic background helps us to also go forward with the treatment component of these tumors.

Is it fair to say that, regardless of the histologic subtype of an initially diagnosed thyroid cancer, most patients are going to have surgery?

It’s not always the case, and we’re certainly moving into a really exciting area in thyroid cancer research and management. This is a rapidly evolving field in which we are starting to understand that many of these tumors behave very well. Maybe they don’t necessarily need surgical intervention. As I alluded to earlier, 10% to 15% of people walking around have a small thyroid cancer, and if we go looking hard enough for it, we’re going to find it. Perhaps those tumors, if we left them alone, weren’t going to become aggressive tumors and manifest themselves in any way, had we not gone looking for them. Maybe we can simply observe them.

We’ve been following these data now for about 10 years. Centers in Japan have been observing small thyroid cancers, rather than operating on them. The consensus in the Japanese studies, and now in some of the evolving United States studies, the numbers are remarkably consistent in showing that it’s the minority of those small cancers that progress when they’re observed. We can take away that perhaps there’s a decent percentage of patients in whom observation alone would be adequate therapy, rather than proceeding with the traditional mode of surgery, followed by possible radioiodine.

Jen, who are the patients in your clinic who you feel meet the criteria for observation?

There are a number of things that we should consider in this. One is the appearance of the tumor on ultrasound. How big is the tumor, and what is the size threshold for observation, whether the tumor is 1 cm or less, or some studies are now using 2 cm or less as a threshold for observation. Then, there’s the sonographic appearance of the nodule. Does it look like there’s extrathyroidal extension? If so, maybe that suggests a more aggressive tumor that we wouldn’t want to observe. Does it look like a blander-appearing nodule that is well-contained within the thyroid and isn’t posing a threat of extending outside the thyroid into surrounding tissue? That’s one component. We look at the tumor itself.

The other piece of it is looking at the patient. We know from the Japanese studies and looking retrospectively at who progressed in multivariate analysis that tumors that are larger were more likely to progress. But also, those tumors that were present in younger patients were more likely to progress. If we take that back to our clinic, we may say, “You’re younger. There’s a longer lifespan ahead of you whereby this tumor may continue to grow and progress.” We’re more likely to remove it earlier, versus an older patient, or someone who has multiple comorbid conditions. In that situation, thyroid cancer falls pretty low on the spectrum of concerning clinical factors. Maybe there are other primary malignancies, uncontrolled hypertension, or cardiovascular disease that may take a higher precedence over treating their thyroid cancer.

DTC: Histological Subtypes and Tumor Differentiation

What about those patients who do have surgery? What’s happening these days with the use of radioiodine treatment in patients following a standard thyroidectomy, plus or minus central neck dissection, for a fairly typical, garden-variety differentiated thyroid cancer?

We’re using a lot less radioactive iodine [RAI] than even in the recent past. When I first started treating patients with thyroid cancer about 15 years ago, we used radioactive iodine in just about every patient, except for a small portion of low-risk tumors that were less than 1 cm. Some of that was my own training, where I trained, and with whom I trained. There are certainly regional differences in the use of radioiodine, but we’re all moving along that spectrum toward using a lot less radioiodine. That largely stems from the observation of a number of studies that radioiodine is not necessarily associated with improved survival in low-risk patients. We can probably be more selective in the population of patients for whom we use it.

We are utilizing radioiodine therapy with 3 intentions. The first intention is to ablate residual normal thyroid tissue. We call that remnant ablation. The second indication for radioiodine therapy is adjuvant therapy, or when trying to treat subclinical micrometastatic disease we think may be there. It may or may not be there, so we call that adjuvant therapy. The third indication is to provide treatment of clinically apparent residual or metastatic cancer. 

We are coming into this equation with the intent that we want to reduce the likelihood of this disease coming back. Those 3 indications I just mentioned are the idea of going forward and how we’re going to treat these patients. With that in mind, we think about our patients in 3 general categories: low, high, and intermediate risk of recurrence. In patients with low likelihood of recurrent disease, radioiodine is not routinely recommended. That would include patients who have tumors that measure less than 1 cm, but have no other high-risk features. It may even include patients who have a small volume of regional lymph node involvement. That means a tumor and less than 5 lymph nodes with metastatic deposits that measure less than 2 mm. So even those patients now, we don’t routinely need to treat with radioiodine therapy.

On the other end of the spectrum, for those patients with high-risk disease, radioiodine is recommended. This includes patients with distant metastatic disease, patients who have macroscopic tumor invasion grossly involving the surrounding thyroid tissue or incomplete tumor resection, and patients who have grossly residual disease. In those folks, it’s clear-cut that radioactive iodine is beneficial. It’s recommended for most patients with that disease, absent some other significant medical illness that would prohibit them from getting RAI.

Then, there are all the patients in between, we would call those intermediate-risk patients. In that group of patients, it’s more selective for whom we use RAI. That’s probably the most controversial group in which it’s debated who should get RAI and who shouldn’t. The data don’t bear out very well, from an evidence-based practice perspective, who should get RAI in that group. In those situations, I have a long conversation with my patient and say, “You’re in the gray zone. We can use it or we can choose not to, or we can reserve the right to change our minds later, if we decided at first we’re not going to give it.” I’ll utilize all the tools in my arsenal to make that decision with the patient. That will include the post-operative ultrasound, serum thyroglobulin, and evaluating all their other comorbid conditions, as well as their social situation, to help decide whether to proceed with RAI.

 In general, poorly differentiated thyroid cancers and Hurthle cell thyroid cancers are not thought to concentrate iodine. Do you consider giving radioactive iodine in patients who have resected disease? Let’s say it’s a high-risk patient. They don’t have any known metastatic disease, but they have Hurthle cell thyroid cancer that is poorly differentiated. Do you give radioactive iodine because you have to, with the feeling in your heart of hearts that it’s not really going to help the patient?

Yes, those are really tough cases. I always labor over those decisions about whether I put the patient through this procedure. That’s particularly the case in patients with Hurthle cell tumors in whom I have a good idea that they’re going to ultimately need the services of one of our oncologists. But I feel like I need to do that. The reason I do end up usually treating these patients is because, at present, the majority of our clinical trials and a lot of our decision-making regarding the use of systemic therapy is concentrated around the idea of establishing that the patient is iodine refractory. I always tell patients when we’re talking about statistics that statistics only mean something on a population basis. They don’t mean anything to the individual. If you tell me that there’s a 5% likelihood of dying from thyroid cancer, if you’re one of those 5%, then it’s a 100%. I try not to apply statistics too much here. I give the patient the benefit of the doubt, but I try to do it in a responsible way. 

If I have a patient with Hurthle cell thyroid cancer, and I have a good idea that their tumor is probably not going to be RAI-avid, but I want to give them a chance, I may try to hedge my bet a bit by going with a slightly lower administered activity. I do that rather than trying to fully blast them and ensuring that I’m going to kill their salivary glands and potentially cause some bone marrow suppression. I try to be responsible about that, but I do like to give them the opportunity to prove to me that the iodine is not going to work.

Yes, that makes sense to me. You can always circle back and give them another dose if they do….

Right. If we went low and it worked, and it gave me 12 months of progression-free management, then if it starts to progress again, I may try to give another dose.

Role of Radioiodine Treatment in DTC

What you do with TSH [thyrotropin] suppression as treatment for thyroid cancer? Do you maximally suppress all of your patients who have thyroid cancer? Do you tailor the TSH suppression to each patient, and why do we even care about TSH suppression?

TSH, or thyroid-stimulating hormone, is a growth factor for follicular thyroid cells. It modulates growth and proliferation. It can impact the progression of follicular cell-derived thyroid cancer, so we do want to use it in certain patients. We used to use it in everyone, and in those patients I follow who have been managed for long periods with thyroid cancer, it can become challenging to convince them that we don’t need to suppress them forever. But in those patients who are recently diagnosed, I’m much more selective in seeking to suppress their TSH.

My approach is to make an assessment of their risk of recurrence based on the surgical pathology. Immediately at the post-operative visit, I will try to keep their TSH range within a threshold in which it would be for that disease long term. If I have a low-risk patient and I haven’t established yet that they’re free of disease, I will generally try to keep that TSH in the low end of the normal range, rather than just suppressing everyone right after surgery. 

I try to factor in a couple of different things when I’m assessing these patients for the degree of TSH suppression. I alluded to their risk of disease recurrence. They’re grouped into high, intermediate, and low risk of recurrence. I also will assess their response to therapy. My TSH range that I’m aiming for will change over time in some patients, depending on how they’ve responded to therapy. I’m also looking at their individual risk factors for TSH suppression.

I usually have 1 of 3 reference ranges for my patients for which I’ll try to aim. In patients who are free of disease and have low-risk disease, I’ll aim for a TSH of 0.5 to 2 mIU/L. In intermediate-risk patients, or those who have had an indeterminant response to therapy, or folks who have persistent disease but have a high risk of complications due to TSH suppression, I’ll aim for 0.1 to 0.5 mIU/L. Then, in those patients who have high-risk disease or a structural incomplete response to therapy and no risk factors for complications with TSH suppression, I’ll aim for a TSH of below 0.1 mIU/L.

The individual factors that I’m looking, or comorbid conditions that I’m considering, are age over 65, postmenopausal status, cardiovascular risk factors such atrial fibrillation and tachycardia, and osteoporosis. If they have any of those factors, I’ll shift up to the next TSH range to try to mitigate some of that risk associated with the TSH suppression. Sometimes, it’s tricky. We have to walk a tightrope with some of these patients trying to fight the enemy we know vs the one that’s hiding around the corner. Whichever is more of a threat at any given time determines whether we’re moving in one direction or the other.

 I’m curious if you have the experience that I do. You see a patient and you adjust their levothyroxine dose to get the TSH within the range that you want. Then the next time you see the patient, they’ve seen their PCP [primary care physician]. Their PCP has seen that their TSH is low, and they’ve adjusted the levothyroxine. It’s like a tug-of-war sometimes.

Yes, that can be a little challenging. What I try to do at my initial post-operative visit is to have that conversation up front.

I say, “This is how you take your medicine, make up missed doses, and do not let anyone other than me adjust your medication.” That even includes our oncology team.

 I like that very much. I love to share patients with endocrinologists who I know and love. I love for them to just do it.

 I think ours do, too. They’re perfectly content to let me handle it.

We try to cut that off at the pass. I still get a few calls here and there saying, “My doctor wants to change it.” I politely give a hard “no.”

Thyrotropin Suppression as DTC Treatment Option

You mentioned iodine-refractory thyroid cancer, and those are the patients we see in medical oncology. I would venture to say that most of my medical oncology colleagues can’t recite the ATA [American Thyroid Association] Guidelines definition of iodine-refractory disease. We might mention in our notes that the patient had radioactive iodine, and that’s usually about all we think about. But what is a simple explanation of iodine-refractory differentiated thyroid cancer? How do you boil it down so you can remember it without having to turn to page 115 in the ATA Guidelines?

Page 115 of 300, yes. That’s a tougher question than advertised. This is something we labor over constantly. In our tumor boards, we go back and forth between endocrine and oncology about whether something is iodine refractory or not. Should we try 1 more dose of that radioactive iodine? That’s reflective of the literature as well. It’s about as clear as mud as to what truly constitutes iodine-refractory disease.

A group got together in Martinique recently for a multidisciplinary conversation about what constitutes iodine-refractory disease and the best way to manage it using radioactive iodine. They summarized it nicely. They came up with clinical scenarios that would indicate which patients may be iodine refractory. They had 5 clinical scenarios, but they also made the caveat that this is an individual decision based on the patient’s clinical factors, the options for treatment, and contraindications for treatment.

In general, there were 5 clinical scenarios included. The first scenario was a patient in whom there is no I 131 [sodium iodine] uptake present on the diagnostic scan. That’s probably the most widely used criterion, but also 1 of the most controversial concepts. You could make a hole in that argument because we know that diagnostic whole-body scans are not very sensitive for identifying iodine-avid disease. That’s probably 1 of the loser criteria, but it is helpful when we’re trying to assess whether someone is qualified to get into a clinical trial. We can easily order a diagnostic scan and then say, “OK, it’s negative. We’re going to proceed with getting them into a clinical trial because we know they need a clinical trial.”

A diagnostic scan is insensitive. Depending on the studies you read, when you give patients a higher-dose treatment with radioactive iodine, the post-treatment scan will show a higher percentage of iodine-avid tumor.

Having said that, the second criterion is no I-131 uptake on a post-treatment scan. That is or 1 of the clinical scenarios they outlined. But there are also some holes in that argument. You could have concerns that the patient didn’t have the post-treatment scan at the appropriate time interval. If we did a post-treatment scan 8 days after they received radioactive iodine, but we had previously done it 4 days post–radioactive iodine, perhaps we would have seen that there was some avidity of the tumor or iodine. There are definitely holes in that argument as well.

A third scenario is that there is iodine uptake in some, but not all, tumor foci. If the patient has multiple metastatic foci in the lungs and uptake in perhaps 1 or 2, but then there’s a metastasis in the neck that didn’t take up the radioactive iodine, you could use that to say this is iodine refractory. But are the areas that took in the iodine refractory or not, because they took it in? What distinguishes that is perhaps that the tumor shrunk in that area but not the other areas. We can use that to say they’re iodine refractory and potentially remove the tumor in the neck that didn’t take up the iodine. Then that patient has had a treatment for their disease in all areas.

The fourth scenario is progression of metastases despite recent I-131 uptake. We may do a post-treatment scan, and the lung nodules show that there was avidity of the iodine in those lung nodules, but they continue to grow 6 months after the treatment. That suggests that tumor does not respond to uptake with the shrinkage or stability of those lung nodules.

The fifth criterion, which is also fairly weak but important, is progression of metastatic disease despite accumulative administered activity of greater than 600 mCi. We can certainly treat patients if they’ve already received 600 mCi, but the question is whether it benefits them. Should we think about a different approach? All of us would say that there have been times when, although a patient is getting close to or has even exceeded that threshold, we’ve considered giving another dose. If they had gotten 10 years of disease stability out of those curative activities, perhaps we can get another couple of years of stability of their disease if we give them another treatment.

This is an individual decision that we as providers, both endocrinologists and oncologists, need to have careful conversation with the patient about: “I don’t think another treatment is going to work.”

The other thing we should consider that I didn’t talk about is optimal preparation. A lot of my patients come to me from the community, and it may be that the patient is the only thyroid cancer patient whom the provider sees. They’re not familiar with some of the caveats of preparation for radioactive iodine, including the low-iodine diet. We don’t have a lot of good data to support that it improves the treatment, but all of us would agree that we should try to make sure our patients are as iodine-free in their circulation as they can be. We recommend a low-iodine diet prior to treatment. If the patient had been amiodarone prior to getting their radioactive iodine, then we know they were saturated. Perhaps that treatment wasn’t going to work because of that iodine saturation.

I always look back and have a careful conversation with the patient if they got their radioactive iodine at an outside institution. I ask, “Were you on a low-iodine diet?” and those sorts of questions. “Did you have a CT scan beforehand that had contrast?” [I ask about] things that would suggest that the patient may not have been completely depleted prior to the treatment. Maybe I could get away with giving another treatment.

Clinical Scenarios to Consider for RAI-Refractory DTC 

When you’ve established that a patient has iodine-refractory disease, what do you perceive as that patient’s prognosis overall, in terms of the bucket of 1000 patients? When a patient asks you, “What is my prognosis,” what do you say?

 I try hard to be as general as I can. Everyone’s tumor is a little different, but we do know that there is an incremental decline in survival in those patients who get 1 treatment, are done, and are free of disease. Their survival, as a percentage, is in the high 90s. But once they become what we consider to be iodine refractory, their survival as a whole will drop to 60% or so. Within that population of patients, there’s a big disparity in how they do. Some of that is genomically driven, or we’re able to predict it from their genome. In others, it’s less clear. Perhaps their tumor histology plays a role, their time to diagnosis, if they presented late with lots of tumor. 

I always tell my patients, “We’re collecting data on you as we go, and your tumor is going to be the best predictor of the future, rather than looking at the whole population as a whole. The more data points I collect on you, the better I can map out that trajectory for you.” It can be challenging in patients in whom we administer radioactive iodine, but their disease seems to be progressing. That can be a short window, and it’s hard to predict that trajectory. But generally speaking, it’s not going to be a favorable 1 for them. Conversely, in that patient that I’ve been following for 15 years whose disease is plodding along, it’s a little different. Eventually, they become radioactive iodine resistant. But it’s important to see that past and incorporate it into their future. Generally, they can continue on that path of slow growth and progression.

In my shop, it’s usually at that point when patients have structural iodine-refractory disease that thyroid endocrinologists will loop me into the patient’s care. I’ve always thought that many of these patients have been under their care for 5 or 10 years. Their understanding of the patient’s underlying biology is much deeper than my onetime shot at the patient’s chart. I really appreciate sharing the patients as they’re being referred and having that conversation with the referring endocrinologist, so I can understand a bit of what they know from all the years they followed patients. I find that that joint conversation and understanding of the disease process is tremendously helpful. 

In treating iodine-refractory disease, we now have 2 VEGFR multikinase inhibitors that the FDA has approved. We have 2 gene-specific therapies as well, which are FDA approved in advanced thyroid cancer. When we started doing clinical trials, anyone who walked through the door with iodine-refractory differentiated thyroid cancer was enrolled on 1 of these studies before we realized that there are some downsides to the therapies. They don’t last forever. They’re not curative, so there’s been a lot of discussion about when we start TKI [tyrosine kinase inhibitor] therapy for the patient.

Discussing Iodine-Refractory DTC With Patients 

One of things I’ve wondered is, as an endocrinologist, what do you think about the optimal timing of therapy? I’ve always wondered, because as a medical oncologist, we give people chemotherapy. We do phase 1 trials in which we give higher and higher doses of drugs until you get to the maximum tolerated dose. You might have to back down a bit. There’s a comfort level that medical oncologists have with therapies that have toxicities. I’ve always wondered if the lens of a medical oncologist is skewed a little 1 way vs the lens that an endocrinologist brings to the thought process.

It’s a very important point. I would imagine we also fall along a spectrum. I am a pure endocrinologist. I see cancer patients, but I don’t administer these drugs. There are endocrinologists who just treat thyroid cancer patients and administer these drugs. Then there are folks like you who are oncologists and administer these drugs. I suspect we map out nicely along that spectrum in terms of our viewpoints of these agents.

My view of these drugs is that they’re associated with toxicities. My lens is tinted toward, “OK, I can watch this person a little while longer.” I have to be really mindful to loop my oncologist in. We like to try to bring in the oncologists ideally 6 to 12 months prior to when we think they’re going to need a drug so that they can establish that relationship. As you were saying earlier, it’s important to get to know the person, understand their disease course, and see how they individually have manifested with their disease. That happens organically over time if allowed. We don’t always have that opportunity to have that relationship. We don’t really want our patients to have to go straight to the oncologist, and the first thing they do is start a drug. But if they have to, they have to. 

I generally will try to follow the patients as long as I can. Once I’m starting to think, “OK, this is not going to respond to another treatment. Their disease is starting to progress a little faster,” or “They’re getting a little more tumor burden, and they’re going to need a drug within 6 to 12 months,” I’ll start talking to the oncologist. I’ll say, “Hey, I want to send this person to you.” 

Even before that point, I’ll have conversations with the patient. They’re very generic conversations. I may say, “We’re going to need a drug at some point. We have a number of drugs available, and just in the past 5 years, we’ve gotten several FDA approvals. The landscape is changing very rapidly, which is a good thing.” I just talk in general terms about how these things work and their mechanism of action. I provide a very general framework by saying, “This is what cancer is. It’s a mutation in a pathway, and these drugs target that specific mutation.” Once I’m starting to have those conversations, I’ll order genomic testing to see if there’s going to be an agent that could potentially be useful for that patient or a more specific drug. If there’s not an actionable mutation, then we’ll use the angiogenic medications at our institution. That also helps us if we’re starting to think about whether this patient will be a candidate for a clinical trial as well.

Genomic testing happens early in someone who I think will eventually need a drug. Before or while I’m having those conversations, I’m also evaluating the patient for their candidacy for a drug. Do they have a good performance status? If this is someone who has some other comorbid disease that I’m worried could pose a threat to their vitality in the next 6 to 12 months, then I’m not going to be necessarily pushing that conversation as much.

I have younger patients who have familial disease, and they had to watch a loved one on one of these drugs who didn’t have necessarily a great experience with it. They may say, “No, I don’t really want to use 1 of those agents.” It’s important from my perspective that we have conversations about these drugs. I discuss what they can expect in terms of adverse effects, what the disease response is going to be, and their wishes for end-of-life concerns. If they’re in their 80s and they say, “I don’t want to be on those drugs. I want to enjoy a good quality of life,” then I can respect that. I see that as my job to explore those conversations with the patients. If they’re not sure, then my approach is to just refer them on to oncology for more careful discussion. Hearing it from another person can give them much more information sometimes.

Yes, it sounds like a setting of the stage.

When we consider the idea of passing a baton in a relay race, you just don’t toss a baton and they’re on their way. You hand it, and you run along with them.

Management of DTC in Clinical Practice

Say the genomic testing doesn’t show an actionable alteration, and a patient needs therapy because they have progressive disease. Do you get involved at all in the discussions of which TKI [tyrosine kinase inhibitor] to use? We do have 2 approved TKIs. Sorafenib was the first TKI approved based on a PFS [progression-free survival] benefit and the DECISION trial, compared with placebo. That was followed by the SELECT trial with lenvatinib, where a PFS benefit was compared with placebo. 

The response rates were different. It was 12% with sorafenib and 65% with lenvatinib. The list of adverse events and toxicities are pretty similar with the drugs. They’re fairly similar in dose reduction and dose discontinuation rates due to toxicity. Do you talk about that with the patients and your medical oncology colleagues? Is there 1 standard approach that you have at Ohio State University in your group?

Yes. In general terms, the oncologist makes the decision of what’s going to happen with the patient once there is the need for a systemic therapy. They consider whether we have an active trial that the patient would qualify for and wants to participate in. Then we assess whether they have comorbid diseases or what their thyroid cancer is doing that would put them at risk with 1 treatment vs another. We always have to consider where the metastatic deposits are and if the patient is at risk for a bleeding complication or something, based on their individual disease or their comorbid conditions.

We have that conversation in a group in our multidisciplinary clinic or multidisciplinary tumor board. The person who is ultimately making that decision is going to be 1 of our oncologists. But we talk about it as a group among one another, and the oncology team makes that decision. 

I try 1 other thing. I try really to have a conversation with the patients when setting the stage to try to make sure patients understand what a clinical trial really looks like. I’m sure you probably hear a lot too, “I don’t want to be guinea pig.”

I try to make sure patients understand that this is the cutting-edge science, and there’s a reason to believe that these drugs that we’re trying now work. We have the FDA-approved agents as our backup if we need them, but if we have a clinical trial and someone is a good candidate for it, that’s ideal. They get their medication for free, which is pretty good.

That matters. The co-pays can be difficult with the different therapies. That’s how we do it at Massachusetts General Hospital. Ultimately, the medical oncology people are making the recommendations regarding which agent is the best first agent. My perception of the data is that the patients who were enrolled in the SELECT trial with lenvatinib and got placebo had a very short progression-free survival. They were fairly sick patients with fairly aggressive disease and a median progression-free survival of only 4-plus months. The PFS benefit was significant, so the progression-free survival in that study was more than 18 months. Those data are a bit stronger than the PFS benefit seen with the DECISION trial and sorafenib. In patients who had a placebo, there was a slightly longer progression-free survival. There’s a better drug between those 2, and it’s lenvatinib. 

One thing we do see is that there is a drop-off in patients who go on to receive second-line therapy. Only about 50% of patients with iodine-refractory DTC [differentiated thyroid cancer] will have second-line therapy. If that’s the case, I don’t want to save lenvatinib as a better drug for the second line, because a lot of patients might never get it.

We don’t want to miss out on using a better drug in that regard.

We definitely use more lenvatinib than sorafenib as well. That’s out there as an option, and it has much more use here for that reason.

Roles and Communication in Treatment in DTC

You mentioned that you do sequencing. What are you looking for?

We use a panel approach. We use a commercial panel sometimes, and sometimes we’ll use our in-house panel, to look specifically for BRAF or RAS mutation. But if we’re looking for a broader panel, we’ll send that out commercially. We’re looking to see if there are actionable driver mutations that have associated drugs that may work. If there’s a RET PTC [papillary thyroid cancer] rearrangement, we may use selpercatinib. For BRAF, we may use the dabrafenib and trametinib. We’re looking for actionable mutations.

 Yes, detecting the actionable mutations is definitely something we want to be thinking of in all our patients as we’re coming up with the optimal systemic therapy for them.

Across the different types of advanced thyroid cancers we have, all are really rich in potentially druggable targets. The first FDA approval was for NTRK-targeted therapies with larotrectinib and then entrectinib. We do see NTRK fusion rarely in about 2% of our thyroid cancers. However, that’s the case with NTRK fusions across solid tumors. There isn’t a particular solid tumor in adults that has a very high frequency of NTRK fusions. As a matter of fact, in the larotrectinib trial, the second most common tumor in adults who were enrolled was thyroid cancer. If looking for NTRK fusions is pertinent in someone with non–small cell lung cancer, it’s definitely pertinent in somebody with advanced, iodine-refractory DTC [differentiated thyroid cancer].

The second gene-specific therapy for iodine-refractory DTC approved recently was selpercatinib, the RET-specific inhibitor. Overall, in PTCs, we see slightly less than 10% of all papillary thyroid cancers harbor RET fusions, but RET fusions are more common in pediatric and young adults with thyroid cancer. They’re also more common in the radiation-induced thyroid cancers as well.

Outside clinical trials, in patients in whom an NTRK fusion or a RET fusion is detected, what is your sense of the best first-line therapy for someone with progressive iodine-refractory DTC? Should we be using a gene-specific therapy first, or should we be using a multikinase therapy like lenvatinib first? What’s your sense of the best sequence of these drugs?

I don’t know of any head-to-head studies looking at that specifically, and there are very few studies in general. This is largely 1 of those issues that falls under the category of how you like to do it. At our center [The Ohio State University Comprehensive Cancer Center], we generally will utilize a gene-specific target therapy when available. We then reach for the multikinase inhibitors as a second option if the patient either doesn’t have 1 of those actionable mutations or cannot take 1 of those actionable drugs because of some contraindication. Then we can use the lenvatinib. When we don’t know the genomics of the tumor, in those patients who are more acute, we might just use lenvatinib. We’re generally trying to get the genomics. But it is challenging to get that covered with insurance at times. That can be a bit of a challenge in getting the genomic profile for the individual tumor.

Hopefully that will be changing now that we have a second gene-specific approved therapy in these patients. Hopefully the insurers will understand that there is even greater rationale now for that testing.

Understanding Sequencing and What to Look for in DTC

I want to touch on BRAF mutations briefly, because BRAF is the gene that’s most commonly mutated in thyroid cancer, primarily in papillary thyroid cancer [PTC]. We can see it in the more undifferentiated and dedifferentiated thyroid cancers as well. We know that there was the basket trial with dabrafenib and trametinib in BRAF-mutant anaplastic thyroid cancers. That showed a really good response rate, and many of those responses were durable. Dabrafenib and trametinib were FDA approved in anaplastic thyroid cancer that has BRAF mutations.

There are many patients with iodine-refractory PTC that harbors a BRAF mutation. A lot of patients who have relatively low-volume disease that is growing slowly over time are in this group. Those are patients in whom I’m sometimes reluctant to start lenvatinib. There was a phase 2 trial that OSU [The Ohio State University Comprehensive Cancer Center] participated in, and MGH [Massachusetts General Hospital] as well. It was looking at dabrafenib plus or minus trametinib in BRAF-mutant DTC [differentiated thyroid cancer]. It was a small phase 2 trial. There’s activity there for sure but not an FDA approval.

In the patients who have low-volume disease, what do you think about if you’re thinking that they’re not ready for prime-time lenvatinib?

 We’ve started looking at potentially using some of these agents, particularly dabrafenib and trametinib, for redifferentiation therapy. We’re considering using the drug for a finite period of time. In our institution [OSU], we’re using it for a month, and then giving a dose of radioactive iodine if there’s activity on the diagnostic whole-body scan. That’s a nice bridge for some of our patients with lower-volume, slowly progressive disease. We’re in the early phases of collecting the information that is working. 

But it can be challenging in some of those folks to get them to tolerate the combination of therapies. I have less experience in using that combination outside the clinical trial. But it is something we’re excited to potentially explore down the road in redifferentiation therapy. We know that some of these gene-specific targeted treatments can impact the gene expression of some of the sodium iodine metabolism and potentially increase the iodine avidity in those tumors. It’s an exciting potential bridge between the iodine and long-term systemic therapy.

I agree. I wish we had a clinical trial that proves that there is clinical benefit, but we’re taking that approach on an off-label, case-by-case basis in patients. There is a patient population that is not going to benefit from further radioactive iodine. We know that they have cancer, but they just do not have cancer that’s bad enough to justify lenvatinib or sorafenib at the present time. We’d like to be able to help them out. Doing a short course of drug therapy, like dabrafenib plus or minus trametinib, does cause some adverse effects and toxicity. But generally, you can get people through the treatment for a month prior to radioactive iodine. Then you bring in radioactive iodine, and you’re done with treatment. You’re not committing patients to taking a cancer drug every day, week after week, for the foreseeable future. You have a month or month and a half of intensive treatment, and then they’re done. It certainly is an appealing proposition.

That’s 1 of the things I really enjoy working with our endocrinology colleagues on, because we work together as a tag team with the dabrafenib and trametinib therapy and the radioactive iodine. I always enjoy the social aspects of the multidisciplinary approach to cancers.

Yes, it definitely makes me feel like I’m much more involved in the process. I am involved in all of the patient’s care once they get on a systemic therapy, but I feel like I’m much more involved in that process and the decision to even take that approach. It’s fun for me. I feel like I’m dipping my toe in the oncology waters, and that’s nice.

Approaching Treatment of Low-Volume DTC

What is your takeaway message, in terms of the multidisciplinary care of patients with the more challenging thyroid cancer that we see?

 It’s critical that we take a multidisciplinary approach to these patients’ management because they are complex and there are a lot of factors to consider even before they get on a drug. There is also the determination of when is it appropriate to start a drug. Having regular conversations about those patients in some format—whether it’s informal talks, a formal tumor board with case presentations, or the ability to shoot messages back and forth in the electronic medical record—is critical. 

It’s really important that these patients be followed over time with a multidisciplinary approach. A surgeon, oncologist, and endocrinologist should be involved, because we always want to make sure something is not resectable before we start talking about this as progressive disease. If it’s resectable and progressing, then that’s certainly the easiest component to get rid of and perhaps the least morbid in some cases. Being able to distinguish whether something can be resected is important. Have a conversation with the surgeon to say, “Yes, there is disease that we could theoretically access, but it’s too morbid to remove,” or, “No, I can easily remove that. Don’t put them on a drug.”

Having those conversations is critical. Then have the conversation with the oncologist. They may say, “Yes, I know they could have another surgery, but this is their seventh surgery in 2 years. Maybe we need to think about using a drug, because now they’re getting pulmonary metastases.” We each bring something different to the table. Our viewpoints and the lenses that we use to see the world are different. It’s a critical component of managing these very complex patients and weighing the risks of a morbid treatment with the benefits. How much benefit are we going to get from that therapy? That’s a very important part of management of these complicated patients.

 I agree with you 100%, and you stated it well. We do bring our different viewpoints and our different expertise to bear on what is often a very complex patient problem that we’re dealing with. It offers the best that we can provide our patients while we’re working together. That’s 1 of the things that is really important about the multidisciplinary programs that we have for patients with advanced thyroid cancer.

Multidisciplinary Management for the Treatment of DTC

Thank you for joining us today on this program on radioactive iodine-refractory differentiated thyroid cancer [RAI-refractory DTC]. I’m Lori Wirth from Massachusetts General Hospital in Boston, and with me is Dr Frank Worden, a professor of medicine at the Rogel Cancer Center at the University of Michigan. Hi, Frank. 

Today, we’re going to be talking about advancements in treating patients with RAI-refractory DTC, as well as unmet needs in this setting. To start the discussion, I have to say that it’s been an incredible time in this field. In the last 10 years, we’ve made incredible progress. We’ve gone from having no drugs that are appropriate for treating patients with RAI-refractory DTC, to now all of a sudden, 6 FDA-approved drugs in our arsenal to treat patients—sorafenib, lenvatinib, the 2 multikinase inhibitors that are approved. Then we have larotrectinib and entrectinib approved for treating patients with NTRK fusion-driven cancers. Additionally, we have 2 recent approvals of selpercatinib and pralsetinib, the RET-specific therapies that are pertinent for RET fusion-positive thyroid cancer. It’s been a remarkable time, and I don’t think that that’s going to be stopping or slowing in the near future.

Frank, let’s start talking about the most common patients in our practices, patients with RAI-refractory DTC, who don’t necessarily have a gene-specific or a genotype-driven disease. Drugs sorafenib and lenvatinib are approved in this setting. Of course, the DECISION trial was the first trial completed. Please start by telling us about the DECISION and SELECT trials, and where you see the similarities and differences. 

Sure, thank you. The DECISION trial was a great breakthrough for thyroid cancer because it was the first study, it was presented at ASCO [the American Society of Clinical Oncology annual meeting] in a plenary session and later published, that shows that progression-free survival is improved with sorafenib compared to placebo. Overall, we don’t have survival data, but we have progression-free survival data, which show 10.8 months for those patients who received sorafenib. The median survival for the placebo group was about 5.8 months, and the overall response rate was 12%. 

The complicating factors or adverse features that came out of this study were hand-foot syndrome, hypertension, and fatigue. This study also had a quality-of-life analysis that showed that patients didn’t feel bad until they started medication. But once they started and they dropped to a certain level, they were able to maintain their quality of lives throughout the remainder of the study. We have very good data in about 100% of patients there. We know that these drugs are tolerable. We can adjust the doses based on adverse effects, and people can stay on the medication. 

Then came the SELECT study, which was presented at ASCO the following year at the head and neck cancers session and later published in The New England Journal of Medicine. This was also a landmark study and probably the biggest to come out of the treatment of thyroid cancer in the last several years, as you had mentioned, Lori. Similarly, it was a crossover study with a design looking at a placebo vs the multikinase inhibitor lenvatinib. Patients started at 24 mg, and then were treated until progression, and patients in the placebo group again had the opportunity to cross over.

Here we see progression-free survival that was around 18.3 months compared to 3.6 months in the placebo group. This was phenomenal, and the best part about this study compared to the DECISION study was that we saw about a 65% response rate. There were 2 or 3 patients who had complete responses, and that is something that’s meaningful for these patients. A lot of them have bulky disease. They can’t breathe, they’re symptomatic, so when you can attain a response as high as that, that’s excellent. 

We also encountered several adverse effects, just like in DECISION. Hypertension, fatigue, and proteinuria were some of the reported issues. Those were also adjusted. With this drug, perhaps compared to sorafenib, we don’t have the quality-of-life data, but it is similar. We know we can get good responses with bigger doses, and once we stop and adjust, patients can go back on. This led to, as you mentioned earlier, the FDA approval for this drug, and sorafenib prior to that. This started our breakthrough for the treatment of RAI-refractory thyroid cancer. 

RAI-Refractory DTC Trials: Phase 3 DECISION and SELECT

 Frank, I have a question. In your experience, do you see much difference in the adverse effect profile between sorafenib and lenvatinib?

I see similar things, such as the fatigue and the hypertension. We do not see as much hand-foot syndrome with lenvatinib as we would see with sorafenib in the SELECT and DECISION trials, which is the same in clinical practice. Occasionally we do see mouth sores with lenvatinib, but patients tolerate it better in that regard. The hand-foot syndrome was dose-limiting for sorafenib, prompting most of us to stop the medication, treat with nonsteroidals, and then reduce the dose. Similar to the sorafenib study, fatigue was an adverse effect in the lenvatinib study. Fatigue may be worse with lenvatinib than with sorafenib and is primarily what prompts patients to stop and causes dose reductions. 

There has also been a lot of discussion in the field about what the right starting dose is of lenvatinib. We now have data. After the FDA approval, there was a mandated study to look at the best starting dose of lenvatinib in patients with RAI-refractory DTC [radioactive iodine-refractory differentiated thyroid cancer]. Patients were randomized to 24 vs 18 mg. Before we talk about those data recently presented at ESMO [the European Society for Medical Oncology annual meeting], before those data were available, Frank, what did you do? What did you do for your starting dose of lenvatinib?

In order to attain the best response, start with the 24-mg dose. Sometimes I will prescribe a 20-mg dose, and then once patients can’t tolerate it, I’ll drop the dose. To get the best benefit we had to start early and then drop the medication. I know some will start at lower doses like 10 and 14 mg, and if the patient can tolerate that, the dose can be increased. Personally, I don’t think that’s the right way to approach it. I think we need to get a response, and then if we need to hold because of toxicity, hold, and then lower the dose based on that. 

 Usually I see the patients back more frequently. Now we have televisits because of the COVID-19 [coronavirus disease 2019] pandemic, which has made this a little easier. I will start with a 24-mg dose and check back with the patients within a week and see how they’re doing. Oftentimes, we have them purchase blood pressure cuffs, if they don’t already have them at home, to take blood pressure. If they’re not tolerating lenvatinib, the fatigue is so bad, we would hold the medication until the toxicity level came down to a grade 1 or grade 2. If the patient is doing relatively OK, I may continue treatment and check back with them the next week. I treat patients to a point where they feel that the toxicity is too much or their blood pressures can’t be controlled, despite us trying to adjust them, and then I’ll hold. But I will hold until a point where I feel the toxicity level has dropped enough, so that when we restart, the patients aren’t so fearful, and we can move forward with the treatment.

I do a similar thing. Data recently presented by Makoto Tahara, MD, PhD, look at the SELECT trial and outcomes in terms of dose intensity. The analyses showed that patients who have a longer period off of lenvatinib do worse. The analysis might be confounded a bit, but if dose holds are kept to less than 10% of the overall period, patients seem to derive more benefit, which certainly makes sense. The half-life of lenvatinib is short, so patients usually begin to feel better quickly.

 Let’s talk about the study that was presented at ESMO. 

 Marcia S. Brose, MD, PhD, presented results of the SELECT study at ESMO, focusing on the starting dose of lenvatinib. We participated at the University of Michigan in that study. We enrolled a few patients. Initially the starting dose, or the lower dose, was 14 mg compared to 24 mg. But when there was a small, short interim analysis, they found that there wasn’t a response with the 14-mg dose. To garner that response, you had to start with a dose of 18 mg. Patients were treated. They were blinded to the dose, and then the data show that it’s not noninferior. It tells us that the starting dose for lenvatinib is 24 mg. With that, just like we’ve been talking about with toxicities, we need to adjust accordingly. And I do agree with you, the shorter the hold, the better. Reducing by about 10% or so makes the most sense rather than doing a complete drop and leaving the patients at a lower level, which may cost them overall efficacy in the long run. 

 Frank, you were right from the get-go, huh? 

Right, exactly. It made sense. If you’re going to get a response—especially since these patients are oftentimes symptomatic—you want to get a response, and then you can play around with the dosing more. 

 I completely agree with you. I also find that just from a clinical point of view, it’s easier if a patient is feeling poorly on a drug to say, “You know what, let’s do a break, and then we’ll get you feeling better really quickly and resume at a slightly lower dose” than it is to say, “I don’t think you’re feeling quite sick enough on this drug. I think we can increase it. I think you can tolerate a more in the way of adverse effects.” 

 I find the latter conversation more challenging. 

 Lori, I totally agree. I think that’s why we’re friends. 

Treating Advanced RAI-Refractory DTC: A Two-Way Street: Medical Oncology and Endocrinology | Insights