Frank, what about the other drugs that we now have available for gene-specific therapy? We should talk about targeting cancers with 

fusions. I also want to hear what you do when you have a patient with radioactive iodine-refractory differentiated thyroid cancer [RAI-refractory DTC] who has a 

It’s an interesting question. Now, as compared to the targeted drugs that are FDA approved, those are obviously easy to get through insurance. That’s not necessarily the same for these other agents, though we’re seeing a little bit more variance because of the NCCN [National Comprehensive Cancer Network] guidelines, for example, leading to approvals. For a lot of these patients, I still start with a standard lenvatinib-based regimen. It’s interesting we have this discussion today. I was just mentioning to you earlier about the patient with the columnar variant thyroid cancer. 

This gentleman has a pretty aggressive cancer, and I wanted to get a nice response through his treatments. He has lymphangitic spread and extensive lung disease. I treated him with 24 mg of lenvatinib and ended up tailoring the dosage down because of the adverse effects. He attained a nice response. In fact, at the tumor board today, he’s still responding to the treatment in the liver and in his bones. But in his lungs, the lymphangitic spread is there. At this juncture, being that I’m seeing him back this week, I’m curious to see how his clinical symptoms are. They had been good in terms of his lung disease. The oxygen requirement came down to almost room air or 1 L. At this juncture, because the progression that is noted and documented on the CT imaging, I will go after a BRAF-directed therapy, either dabrafenib or vemurafenib, to see if I can gain response in there. 

So, you use BRAF-directed therapy as a second-line approach in these patients. 

Generally, I do. Do I think it’s wrong to consider it up front? Not necessarily. I think some of that, Lori, has been because in the past I’ve had to fight with insurance, and I wanted to start treatment rather than waiting for weeks to get approval. Maybe things will change, but that’s how I prefer to do it. 

Although we do have the data from the vemurafenib study that Marcia Brose, MD, PhD, was the lead author on, and then there was a small NCCN-sponsored trial that Manisha Shah, MD, was the PI [principal investigator] of that didn’t show quite as much robust activity with a BRAF-directed approach as we see with lenvatinib. 

There are patients who are not good candidates for lenvatinib in whom I would consider a BRAF-directed approach first for sure.

 But I think we have a similar approach in that regard. But we should talk about 

fusions in thyroid cancer as much as or more than in most other solid tumors. In the larotrectinib trial, thyroid cancer was the second most common adult tumor enrolled across the larotrectinib trials. So, if we’re looking for 

fusions in non–small cell lung cancer, it certainly makes sense to look for the fusions in patients with RAI-refractory DTC. What do you think of the larotrectinib and entrectinib story for these patients?

 They’re similar to the selpercatinib data that we were discussing earlier. These have been game changers as far as I’m concerned. We didn’t participate in the larotrectinib study but were in the entrectinib study at the University of Michigan. I had 2 or 3 patients who were in that study and demonstrated nice responses. One gentleman demonstrated a complete response, but the issue with this drug is the adverse effects. The patient had some ophthalmologic issues and then had some problems with extensive peripheral edema, as well as fatigue. So, after adjusting the dose, the patient finally decided he wanted to come off the study, but it has been well over a year-and-a-half without evidence of disease. It’s pretty remarkable. 

I find that these patients do garner responses quickly. The adverse effect profiles are manageable, maybe a little stronger perhaps than the selpercatinib profile, but still manageable. Once you adjust the dosage for these patients, I find a lot of them can find a dose that they can maintain treatment on and do quite well. It’s another game changer now that we have these data available. Anybody who has an 

fusion, which we typically find, are patients I start on these drugs right away. 

Videos

Treating BRAF V600 and NTRK Gene Fusion Positivity

Now that we have drugs that have great efficacy and a better adverse effect profile, are you starting to think about treating people earlier in the course of the illness? Especially after the DECISION trial, where we saw the sorafenib data that showed modest activity and moderate toxicity, the pendulum swung away from treating people when they walked through the door with radioactive iodine-refractory differentiated thyroid cancer [RAI-refractory DTC], to the end of the spectrum to hold off as long as possible before starting a multikinase inhibitor. I have had my pendulum swing back since the SELECT data became available because it showed a similar toxicity profile, but lenvatinib works better. There have been some emerging data that suggest that you get more benefit if you start earlier rather than waiting until there’s a significant disease burden. 

There are very few other settings in oncology where we follow people with known metastatic disease and keep their TSH [thyroid stimulating hormone] suppressed, but otherwise don’t do anything about it. With a patient who is 

 fusion-positive, where do you think things are going to be heading? 

 It’s a good question. I think some of the issues that come into play are that the numbers are smaller here, as we said earlier, less than 10% in many of these cases, so we don’t see a lot of these patients. We do not have a lot of anecdotal experience treating patients, even though when we do treat them, we see good responses. I believe if I have a patient who has, in fact, I do have a lady with an 

fusion. She has miliary disease, and her largest tumor in the lungs is around 0.4, 0.5 cm, so she doesn’t meet eligibility for a clinical trial if one were available. The disease has been growing slowly, so she is someone who is a late comer in terms of genetic testing. I had more of an idea about her progression of disease or her doubling of disease without evidence of what was available.  

I stop and think about this, and since progression was relatively slow, I probably would have continued to observe this patient. I don’t want to say that just because someone has a particular fusion or mutation that they automatically need to be treated because there are adverse effects associated with the drugs. However, when we didn’t have such data, when we were watching patients and they would inch along, I’d say, “Well, OK, it’s a little bit bigger this time, it’s a little bit bigger this time.” But now since these drugs are available, I’m quicker to start therapy when I know these drugs are available and we can start treatment.  

I agree with what you said about data supporting starting earlier instead of waiting until they get overwhelming disease burden or are so symptomatic. The answer is to your question is really yes. I would still observe a number of these patients, especially if they are asymptomatic, but I would observe them closely and my activation would come more quickly. 

 I have the same thoughts there. What else do you think of in terms of promising developments that we’re looking forward to in the not-too-distant future?

 A couple of things. You and I are both ITOG [International Thyroid Oncology Group] members, and we have presented our data on the use of immunotherapy with lenvatinib. Up front there are some patients who have gained responses. I have had patients who are on the immunotherapy for 2 years and stopped, which is great. At the beginning of the study we were hoping for complete responses in some of these patients and didn’t see that, so the primary end point wasn’t met. But in the second group of patients we studied, where we added pembrolizumab when patients progressed on lenvatinib instead of treating up front with lenvatinib and pembrolizumab, that showed some interesting data. The patients in the second group were progressing, and now the median progression-free survival is maybe 12 months or so. It’s still a little early, but that’s great because here we have patients who are on a dose and are tolerating that dose, progressing, and now perhaps are garnering a benefit with immunotherapy. That definitely needs to be explored.

There are other tumor types—hepatocellular carcinoma, renal cell carcinoma—where those data seem to be playing out, and they’re similar glandular-type tumors. That’s one thing I think we need to continue to look at and explore. I’m excited that we completed that study relatively quickly, and I was happy to be part of it. Eric Sherman, MD, brought up on an NCI [National Cancer Institute] conference call that BRAF inhibition will upregulate ERBB3, so using drugs like lenvatinib in combination with 

inhibitors, which is a great idea to look at, especially in a population such as the tall cells and these papillary cancers in general that have BRAF expression more so than some of these other targeted mutations that we’ve discussed today. I think those are areas that need to be looked at as we move forward. 

Something that hasn’t been discussed so much compared to renal cancer and some of the others is sequencing. We have second-line data with lenvatinib from SELECT, but that’s the only study where we do have data. We do say that we would give somebody else a multikinase inhibitor when they fail, outside of having a targeted mutation, but we don’t know what the exact sequencing is. Maybe it is the use of things like immunotherapy, but sequencing is an area that should be explored, so that we can set up options for patients instead of using what we think is the right regimen.

We didn’t really talk about cabozantinib today, but that shows some promising data in the second-line setting, too. There’s an ongoing study of cabozantinib in the second-line setting, so there's a lot of exciting things that still need to be done. Again, looking at starting and stopping these TKIs [tyrosine kinase inhibitors] and then seeing what breaks we can take to make patients feel better without losing efficacy would be something else I think we need to explore. Those are some of the things that come to mind when I think about that question.

 I’m glad that you commented on Eric Sherman’s interest in studying 

is the most common driver alteration that we see in thyroid cancer. We can do better than dabrafenib plus or minus trametinib, or vemurafenib plus or minus cobimetinib in patients with thyroid cancer. For whatever reason, they just don’t do as well as the patients with melanoma, yet that alteration is there. The other major unmet need is approaching the patients who have RAS-driven tumors. Again, it should be druggable.

I know. Well, at our center there’s a medical therapeutic study that’s opening for RAS, HRAS, and some of the other drivers. I’m excited to see if we can see something in a patient who has a KRAS or NRAS mutation. 

Great. Well, if you do let me know. I want to open a trial, too.

The Future of RAI-Refractory DTC Management

The FDA did give a line-agnostic approval for selpercatinib in RET-mutated MTC [medullary thyroid cancer], as well as RET fusion-positive thyroid cancer. You divulged your answer to the question already that you would use it as first-line therapy. 

I agree with you. I wonder if there is a rationale, in terms of the line of therapy, in thinking about second-line therapy. If we see acquired resistance emerging on a RET-specific inhibitor, do we need to think about that when we’re thinking about what the right sequence of these agents is? 

That does come to mind. Interestingly enough, pralsetinib is also approved. I have had some patients, 1 or 2, who came off of selpercatinib either for adverse effect profile or progression. They did respond to the BLU-667 agent pralsetinib. Perhaps there is something there; the drugs are similar, but there is enough variance and difference that we can see responses with one if the other doesn’t work. The next-generation RET kinase inhibitors to follow are being worked on now and being studied. That would be really important for us. The good news, as you mentioned, is that the progression-free survival hasn’t been reached yet. I’ve had patients on these drugs for over 2 years now or more, and I’m crossing my fingers and hoping for the best that we’re going to continue to see progression-free survival.

I suppose the question comes up, what happens if and when patients progress? At this point, that’s part of the reason we do the entire genomic sequencing through our studies to see if there are 

or other mutations that we should be looking at. I know with ITOG [International Thyroid Oncology Group] we had added immunotherapy to the multikinase inhibitor lenvatinib. Maybe there’s some benefit there, but it remains to be determined.

 That’s a good time to biopsy a patient who is on one of the gene-specific therapies. If you have an opportunity to biopsy a progressing lesion, then you may be able to identify the mechanism of acquired resistance. We still need to figure out more about what those mechanisms are, but that can definitely guide the next line of therapy.  

If for some reason biopsy is not possible, we’re learning more about liquid biopsies in patients with thyroid cancer, too. 

Rationale for Sequencing in Second Line

LIBRETTO-001 was a phase 1/2 first-in-human trial investigating selpercatinib in patients with RET-altered cancers. We recently published the thyroid experience and the non–small cell lung cancer experience in 

. Why don’t we talk about LIBRETTO-001 in thyroid cancer briefly?

 described the experience with selpercatinib, a RET-specific inhibitor designed to inhibit the wild-type RET kinase that’s present in the RET fusion-driven cancers like papillary thyroid cancer or non–small cell lung cancer, as well as inhibit all of the oncogenic RET mutations that we see in medullary thyroid cancer [MTC], a subject for another day. 

Additionally, selpercatinib was designed to be a specific inhibitor that targets the RET kinase as much as possible to limit the off-target kinase inhibition—particularly for VEGFR2 and the other kinases that the multikinase inhibitors inhibit—with the idea that the activity against VEGFR2 and some of the other kinases results in a lot of the adverse effect profile and toxicity of the therapy, which limits the potency of the RET inhibition that you can get. Therefore, you can’t drive up enough RET inhibition with a multikinase inhibitor the way we could hopefully with a specific drug like selpercatinib. 

There were 2 MTC cohorts that had been reported—a patient cohort with RET-mutated MTC who had been treated previously with vandetanib and/or cabozantinib, the 2 drugs approved for MTC. Then there was a vandetanib/cabozantinib naїve patient cohort. But then we also enrolled patients with RET fusion-positive follicular-derived thyroid cancer. In 

, we reported on a cohort of 19 patients. They had all received prior therapies for their advanced thyroid cancer. In terms of the histologies, most of the patients had papillary thyroid cancer, but we also saw poorly differentiated and even anaplastic thyroid cancer. One patient had a Hurthle cell thyroid cancer. 

Overall, the safety or adverse event profile of selpercatinib was consistent with what we expected for a RET-specific inhibitor. There weren’t a long list of grade 3 and 4 adverse effects. The most common grade 3 adverse effect was hypertension. We also saw some transaminitis that was generally dealt with through dose holds and dose reductions. We also saw a little grade 3 diarrhea. But overall, most of the adverse effects that were seen were grade 1 and grade 2, which were treatable or reversible. We also saw the tolerability borne out in terms of the dose reductions and dose discontinuation. Overall, 30% of patients experienced dose reduction due to adverse events. That’s less than half of what we see generally with the other multikinase inhibitors. Two percent of patients did have discontinuation due to adverse events, which is a good discontinuation rate overall in oncology. 

 In terms of efficacy, in the follicular-derived RET fusion-positive thyroid cohort, we saw an overall response rate of 79%, which is promising. In 1 or 2 of the patients with anaplastic thyroid cancer, we saw a durable response in which the patient remained in response at the time of the publication. Overall, the 1-year progression-free survival [PFS] in this small cohort is 64%, but the median duration of response and PFS had not yet been reached. I certainly was thrilled when we saw the results. 

I was too. This is a fantastic drug. We’re not really talking about MTC today, but that has been a challenging disease to treat. Even from the differentiated thyroid cancers that are refractory, selpercatinib has shown promising results. What’s so cool are the responses that you can see, the dramatic responses, the quality of life improvements in patients. 

Also, the tolerability, as you mentioned, Lori, you don’t see the profound fatigue that these other drugs cause because selpercatinib attacks the direct RET kinase vs panning out to the other VEGF1 and VEGF2 kinases. Patients are more responsive in terms of their antihypertensive regimens. They respond quickly when we hold the drug and then restart at lower doses. I’ve had some issues with patients experiencing edema here and there, too. I would say that liver issues are probably the highest. We had 1 patient who developed hepatitis but recovered fully and went back on the drug. Selpercatinib is a landmark drug. This is practice changing for sure for these patients. 

 I have to tell you an anecdote. My first patient with a RET fusion-positive thyroid cancer was started on therapy on a Friday, and his wife texted me on Sunday to say, “He’s feeling so good, he’s even doing the dishes!” I loved that text. 

I had a patient who came in a wheelchair, and I was almost worried that she didn’t make the cutoff for performance status, but we said, “OK, you can do this, you’re at least a 2.” Within a week she said she put her wheelchair in the closet, and she was back to walking about 2 or 3 miles, her little route around the neighborhood. It was incredible. 

We are seeing rapid responses to selpercatinib when we look at the RECIST measurements over time, particularly in the follicular-derived thyroid cancers. 

LIBRETTO-001 Phase 1/2 Trial Overview

 Molecular diagnostics in oncology is complicated, and thyroid cancer is certainly complicated. In addition to what we’ve talked about today, in medullary thyroid cancer we’re talking about somatic and germline mutation, which is important. It’s hard for a busy person to drop what they’re doing, run to the computer, and try to sift through all the literature to figure out what is the best test for this patient with radioactive iodine-refractory differentiated thyroid cancer. What would be your one-liner piece of advice for somebody who doesn’t see these patients often in their clinical practice but might see one coming into the clinic tomorrow? 

In this day and age, because we have the drugs that we’ve been talking about here today, we should sequence all of these patients up front. Now that we have agents that actually respond to these genetic drivers and the tolerability—the adverse effect profiles—can be much better, we should be sequencing all patients. Then if there are 

fusions of the differentiated thyroid cancers, my approach would be to treat with these agents up front and save the multikinase inhibitors as second-line agents. The field of thyroid oncology should move in that direction.

Advice for Managing RAI-Refractory DTC

 Let’s move on to gene-directed therapy, which has been another avenue of progress in the world of thyroid cancer in the last few years. I’m curious to know what you do at the University of Michigan in terms of genotyping your patients with radioactive iodine-refractory differentiated thyroid cancer [RAI-refractory DTC]. Let’s not talk about biopsying nodules and the role of genotyping in that setting, which is interesting but a separate conversation altogether. What do you do when patients are referred to you as a medical oncologist?

When patients come to us being RAI-refractory, the first thing we do if it hasn’t been done is perform panel sequencing with the internal platform we have that tests for a select number of genes. I have worked with our pathologists to make sure that all of the targeted therapies available for thyroid cancers are on that panel. It’s an RNA-sequencing panel. It takes about a week-and-a-half to 2 weeks to get back the results. We’re looking for those common mutations that we’ll talk about shortly, that we could potentially target up front. We also have our own in-house genetic sequencing panel that looks for germline mutations, as well as somatic mutations, that covers a broader array. Sometimes we’ll pick up other mutations that may provide some insight, or benefit perhaps to prognosis or some other therapies, in addition to those targeted mutations that we just spoke about. Generally, that takes about 2 or 3 months to get back, so if we want something quickly because we’re trying to decide what we need to do, we use the in-house sequencing panel. I personally rarely use FoundationOne, Tempus, or the other national panels, just because I have an in-house panel that is reliable and quick to get back results.

 Do you have difficulty with insurance coverage? 

 That’s a good question, Lori. The pathologists sometimes look for the most common mutations. If they see, for example, a tall cell variant that more likely than not is BRAF, they’ll test for BRAF. If the test is positive, they don’t have to worry about the other genes, so the insurance is more accepting to that vs the whole panel. But occasionally, I do have trouble with insurance coverage. In fact, at a tumor board today, I had a columnar variant of a papillary thyroid cancer that we were discussing, and the NGS [next-generation sequencing] panel was refused by the insurance company. Our internal MI-ONCOSEQ [Michigan Oncology Sequencing Center] panel was covered under the confines of a clinical trial, so I was able to receive data that way. 

Do you ever turn to the NCCN [National Comprehensive Cancer Network] guidelines when you’re arguing with insurers to get coverage because the NCCN guidelines do point out that there is a role for genotyping in RAI-refractory DTC? 

Yes, we do write letters. A lot of times the panel sequencing is done through the pathology group in terms of the insurance provider and not necessarily medical oncology. The drug therapies come through us. Our internal pathology group is aware of the panel guideline recommendation and uses that to argue. Since it’s not directed therapy in terms of medical therapeutics, sometimes the companies are more reticent. 

Do you go to the primary tumor and have that tested? Do you feel strongly that you need to test a progressing metastatic lesion? What sort of approach do you take? 

The University of Michigan’s sequencing program prefers the freshest tissue if it’s available, easy to attain, and the patients are amenable to biopsy. A lot of times in thyroid cancer, we have peripheral lung nodules, as you know, or hepatic lesions that are easy to get. So, if patients are amenable to getting a biopsy, we will do that. However, the presence of the driver mutation is usually there from the beginning of the metastatic disease. Oftentimes, we’ll use archival tissue. Now with the COVID-19 [coronavirus disease 2019] pandemic, because of the risk of biopsies, our group will not biopsy patients, so we have to use fresh frozen tissue for both the internal panel as well as the sequencing throughout the clinical trial. But if for some reason, patients don’t have tissue readily available—if the patient comes from a different part of the state or a different part of the country and we can’t attain the tissue—then we will probably put them through a biopsy, but that rarely happens. 

 To your point about the driver alterations for all of the alterations that we’re talking about, for which drugs and potential clinical trial options are available, they’re all there from the start. For the initial genomic testing, in general, the primary specimen is perfectly fine. Also, it’s important to note that these driver alterations are mutually exclusive. If you’re taking a sequenced approach where you rule out BRAF mutation first because that’s the most common, you’re going to see it in 60% of the PTCs [papillary thyroid carcinomas], if you see it, you don’t have to go looking for an NTRK fusion because you’re not going to find it. 

 That is a feasible and rational approach to take. I’m sorry, you were going to say something. 

 It’s interesting you bring that up, too, Lori. One of our pathologists, Tom Giordano, MD, PhD, will oftentimes say, “Well, I can stain for 

,” because if 60% of these are going to be positive, they would save the insurance issue and sometimes cost. For a lot of our tall cells if they can be easily stained, we’ll go ahead and stain for that first, and if it’s negative, then we’ll proceed with the paneling.

immunohistochemistry does work very well, so we rely on that a lot. 

Then on the other end of the spectrum, it is trickier to test for the fusions. As we know, 

fusions are seen in slightly less than 10% of all PTCs. They’re seen much more frequently in pediatric and young adults, and then even more frequently in radiation-induced cancers. We see 

fusions as well in a small subset of thyroid cancers. 

fusions are uncommon, and we’ve even seen a ROS1 fusion. We know that they’re out there. 

has now more than 20 five-terminal prime fusion partners that have been identified. In 

fusions, and both of those have multiple 5-terminal prime fusion partners as well. It’s a pretty complicated set of molecular diagnostics that we’re talking about, if we’re going to be identifying all of the patients who harbor actionable fusions, which is a challenge. What do you guys do?

We’re fortunate at the University of Michigan. Arul M. Chinnaiyan, MD, PhD, has a multimillion-dollar laboratory set up there devoted to sequencing and NGS. That was his project that he started as a junior faculty in pathology and has continued to this day. In terms of that, he has been in tune to the presence of these various fusions in these cancers. Then working with the various oncology groups at the University of Michigan, we are able to make sure that all of those fusions are present. 

The pathology sequencing, which is a shorter panel, will highlight the major fusions, and that’s part of the reason why I offer patients both. Once in a while I pick up on some germline mutation, but if there is a fusion perhaps that isn’t seen in one panel, it can be picked up on another. Occasionally I see that, but for the most part, the most frequent fusions at the University of Michigan are also found in these panels. This is probably true for the more national or standard panels as well. That’s how we have dealt with it. Other centers handle it differently. Perhaps you do things differently there at Harvard Cancer Center, but that’s how we approach it here.

I’m similarly privileged to have good molecular diagnostics in our pathology group. John Iafrate, MD, PhD, created the Archer assay, which is agnostic to the 5-terminal prime fusion partner, so we can detect rare fusions that aren’t necessarily on panels. We have identified patients with previously nonreported fusions, and when we say less than 10% of patients with PTC harbor 

fusions, we’re probably undercounting them. We probably have been historically missing some, and it may not have mattered so much in the past, but it matters now that we’ve got drugs that target these alterations and work pretty well.

Molecular Testing in Treatment Selection

 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. 

Sorafenib and Lenvatinib Side Effect Profile and Dosing

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

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

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

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

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

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

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 

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 

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

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

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.

Frank Worden, MD

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