Roundtable Discussion: Treating Radioiodine-Refractory Differentiated Thyroid Cancer

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During a virtual Targeted Oncology Case-Based Roundtable event, Lori Wirth, MD, discussed the treatment patients with radioiodine-refractory differentiated thyroid cancer with a group of peers.

Lori Wirth, Harvard Medical School

Lori Wirth, MD

During a virtual Targeted Oncology Case-Based Roundtable event, Lori Wirth, MD, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital and associate professor of Medicine, Harvard Medical School, discussed the treatment patients with radioiodine-refractory differentiated thyroid cancer (DTC) with a group of peers.

LORI WIRTH, MD: Would anybody like to weigh in on the first point? [Medical oncologists sometimes] rely on endocrinologists to tell us that [our patients] have iodine-refractory disease. Do you ever struggle with defining RR-DTC?

PAUL S. UNGER, MD: I would say we usually take our cue from the endocrinologists.

WIRTH: Yes, I think that’s a reasonable thing to do. These kinds of definitions can be finely nuanced. Although it’s usually pretty obvious—usually the case is that patients have known structural disease that you can see on an imaging study, they’ve had radioactive iodine, and they have a negative whole-body scan.

The American Thyroid Association guidelines are a good resource.1 The National Comprehensive Cancer Network [NCCN] guidelines…also provide definitions for [RR-DTC] and the occasional case [that is] may not be quite so clear.2 For example, when somebody has metastatic disease, they can still take radioactive iodine, but if the tumor progresses anyway, then clearly the radioactive iodine is not doing any good and that’s considered iodine-refractory disease, as well.

UNGER : In our area, usually the referral comes when the endocrinologist feels the radioactive iodine is no longer a viable tool and they are starting to think about targeted agents, and that’s where they feel [as though] it goes out of their comfort zone.

WIRTH: I think that’s also changing a little bit in the field of endocrinology, which in the United States is where most of these patients are being cared for initially. The idea that patients might still derive some benefit from just 1 more dose of radioactive iodine used to be the prevailing wisdom. I think that was, in part, because we didn’t have any agents that we could use that were appropriate and did not want to give these patients cytotoxic chemotherapy, for example. But I think that in the endocrinology community there is a much greater appreciation now that when the patients have iodine-refractory disease, you can give them more radioactive iodine, but it’s not necessarily going to do them any good.

How about the clinical features or molecular features that you feel are more likely to be associated with refractoriness to radioactive iodine? [For instance], T-cell features in papillary thyroid cancer mean that a tumor is more likely to harbor a BRAF mutation and [that] papillary thyroid cancers that harbor BRAF mutations are less likely to be responsive to reactive iodine. The more aggressive features that are seen in the cancer, the more likely they are to not respond to radioactive iodine. So [factors such as] thyroidal extension and extranodal extension that go along with disease [are] much less likely to respond to radioactive iodine. And then age, too—younger patients do much better with thyroid cancer in pretty much every respect.

WIRTH: The last question—when are you ordering molecular genomic testing? And what tests are you using? What are the mechanics of that in your practices?

AQEEL A. GILLANI, MD: I haven’t had a chance to do it yet, but I think genomics is the order of the day for everything. So, once patients become iodine refractory and you are thinking about [using targeted therapy], we could probably start with the tissue-based testing through one of the vendors that we use, [Foundation Medicine], and that’s where I would start. I don’t know if there is validity to doing cell-free DNA in this space yet.

WIRTH: I agree. I don’t think that we have a ton of data on the liquid biopsies. I’m trying to send my patients’ specimens out for liquid biopsy as much as possible to get more experience, but we don’t have a lot of published data.

The commercial next-generation sequencing [NGS] tests [such as FoundationOne CDx] are good. One comment that I would make is that for advanced thyroid cancer—whether it’s DTC, anaplastic thyroid cancer, or even medullary thyroid cancer—thyroid cancers harbor a high rate of actionable alterations. And so, if it makes sense to be sending off molecular genomic testing for [treatment] decisions for [individuals] with non–small cell lung cancer, it definitely makes sense for those who need treatment with any type of advanced thyroid cancer. The hit rate is going to be higher in any of the thyroid cancer diagnoses than it is even with non–small cell lung cancer.

TONG DAI, MD, PHD: Yes, I agree. We also use a tissue-based NGS panel, which includes most of the targetable mutations.

WIRTH: Do you find that you go back to the original primary tumor? Or do you go for a new biopsy? What issues come up there?

DAI: It’s variable. If the patient comes in with tissue, usually we use that for the testing, but for someone with recurrence or new metastases for the proposal confirming diagnosis, we get the new biopsy.

WIRTH: I completely agree. I always like to confirm the diagnosis…and then you have an opportunity to get DNA.

case-based roundtable poll questions

We don’t have an “all of the above,” which would be the one that I might want to select. I think there is no right answer here; this is a judgment call and I think it depends also on the individuals involved, including the endocrinologist and the patient. One of the things I like to do with my endocrinologist, [with whom] I share patients, [is] overlap rather than them giving the baton to me and me running with it. [We treat] the patients [together], and I get involved earlier rather than later so that the idea of starting another therapy for their thyroid cancer doesn’t quite seem as scary. Then there are sometimes prehabilitation things that we can do to get patients in good shape.

thyroid patient case

WIRTH: In terms of the up-front treatment options for RR-DTC, what triggers warrant a change of approach, for example, from active surveillance to active treatment? How do you decide when to start treatment and what treatment to use?

JENNIFER WU, MD: If a patient becomes symptomatic or if a patient’s disease is involving critical structures—for instance, if it is closer to the trachea or growing next to a blood vessel, which cannot have any local intervention— that’s when I usually [change my approach].

WIRTH: If at presentation or in follow-up, the patient is about to [become symptomatic], then my preference is to start treatment before they are in trouble from a symptomatic point of view. There was an analysis of the SELECT trial [NCT01321554] that looked at how patients did when they were randomized to the lenvatinib [Lenvima] arm based on whether they had a performance status of 0 [n = 144] versus 1 [n = 104].3 That analysis showed a better progression-free survival [PFS] benefit in the [participants] who had an ECOG performance status of 0 versus 1 [HR, 0.523; 95% CI, 0.353-0.775]….You can get more benefit from the therapy when patients are earlier in their disease process.

DAI: Most commonly, we use lenvatinib. The other commonly used medication is sorafenib [Nexavar]; [these drugs] basically target a similar pathway. The comorbidity and adverse effect [AE] in consideration are cardiovascular [issues]. Given the [AEs] of sorafenib in other diseases—for example, hepatocellular carcinoma—we usually recommend lenvatinib.

WIRTH: Yes, there’s a lot of overlap in the profile between the 2 drugs and then some differences. For example, you definitely see more hypertension with lenvatinib. Then, on the other hand, with sorafenib you see more toxicity with hand-foot syndrome.

GILLANI: How much do patient preferences play into your decision-making process? Patients generally tell you whether they want treatment once they find out [if] this is curative-intent therapy and they are going to have substantial toxicities.

WIRTH: Often in presentations [such as] this we forget to mention patient preference. This is an individualized team decision, and part of the team is definitely the patient. I think that really matters a lot. Different patients have different goals. For some [individuals], the idea of having any AEs that are going to affect how good they feel now is very unappealing. And, of course, other patients really want to fight their cancer, want to live long as possible, and are willing to do anything to treat their cancer.

I think one of the beauties in terms of taking care of [patients] with thyroid cancer—when it’s not anaplastic thyroid cancer—is that there is enough time to have these discussions with the patient. You don’t have to decide whether you’re going to start therapy at your first visit with them. I think that we have an opportunity to really get to know our patients and develop a rapport and trust; I think that that helps a lot, especially when we’re making these decisions with them that have a lot of judgments involved in the process. There are a lot of judgment calls that we make in thyroid cancer treatment.

Lori Wirth leads thyroid case discussion

DAI: I have 2 questions: First, is there a subgroup analysis [from the SELECT trial (NCT01321554)] looking at patients who progressed on previous VEGF inhibition? The second question is: Does the subsequent treatment play a role in the overall survival in the younger patients, because [for] the elderly patient, this might be their last treatment?

WIRTH: There was a subset analysis that was done that was prespecified taking a look at prior therapy. The patients who had received a prior VEGF or VEGFR-directed therapy had a PFS benefit [0.22; 95% CI, 0.12-0.41].4 The overall response rate [with lenvatinib in previously treated patients (62.1%)] was very close to the treatment-naive patients [65.6%]. In fact, those data have led some to say, “Well, we know that lenvatinib works really well in the second line, so I am going to use sorafenib [Nexavar] in the first line and then save lenvatinib for the second line.”

I think your second point is a good one, as well. That was what you might take home, the [efficacy in] elderly versus younger patients in terms of overall survival [in the SELECT trial]. With the elderly patients, it’s much more difficult to get on a second-line therapy, especially after they’ve been on a tyrosine kinase inhibitor for a long time. I think that’s the most likely explanation for the overall survival benefit in the older patients but not the younger patients. Then the corollary is: Does that mean that, in general, you want to use your best drug first because life doesn’t always give you second chances?

In oncology, we [generally] do use the drug that has the best activity first. That’s been my rule of thumb if it’s a toss-up between sorafenib or lenvatinib based on the patient profile and toxicity profile. I’ll use lenvatinib because you never know if you are going to have a chance to use a second-line therapy….We now have available to us data on cabozantinib [Cabometyx] in the second line. There was a randomized trial [NCT01811212] [comparing] cabozantinib with placebo in the second line or third line, and that was a positive trial.5 So we know that we have a good second-line agent, as well, that’s not lenvatinib. I think my approach would be lenvatinib as first-line treatment, cabozantinib as the second line, based on the data.

LESLIE WORONA, FNP-BC: For our patients, we usually like to meet them as soon as possible, and we usually have an ongoing discussion with the patient of when to start because there is nothing that says [definitively when to start]. Our ongoing conversation a lot of times has to do with quantity or quality of life. We incorporate this, how the patient is feeling, and their symptoms….[Perhaps] there is a goal that they have—they want to see their first grandchild or they are working on a project at work—and they say, “I don’t care. I need to finish what I’m doing. I have no symptoms right now. I don’t want to start my drug just yet; I’ll start it when this comes.” Others say, “I want to start this drug because I don’t want this disease to progress.” So, we give them the chance to choose.

GILLANI: Do you treat until progression or toxicity, or do you think about giving patients a treatment break at some point? What’s your general strategy?

WIRTH: I’m glad you asked that. I think we have good data on that. I treat to progression. If a drug is not tolerable and dose reductions and other management strategies don’t work, then occasionally we do have to stop because of toxicity.

But we try to minimize the breaks from therapy, and that’s based on an analysis that was done off the SELECT data that showed that when patients had [dose reduction] 10% or longer of the total treatment duration, they didn’t do as well in terms of PFS.6 Also, the data showed that [for] patients who did have breaks, the shorter the number of days of the break, the better they did overall.

So those data certainly have some potential for bias, but I think that’s a hint that we probably don’t want to do long breaks. But, of course, patients need to have breaks sometimes, and when they need them, we give them. One of the things with lenvatinib is it does have a short half-life and many of AEs improve relatively quickly. I think that rather than holding the drug and saying, “Come back in 2 weeks and we will see how you’re doing,” we will usually touch base with them maybe by telephone after a few days, see how they’re doing, and then come up with a plan to resume.

ABHIRAMI VIVEKANANDARAJAH, MD: For the optimal time to use the drug, my approach is that it’s better to use it sooner than later. With lung metastases—depending on [the size], how many there are, and how quickly they’re progressing—I typically start the treatment early if the patient is willing, after a discussion of AEs.

In terms of the experiment with the agents, I have used lenvatinib. It can be tough in terms of hypertension. I have a patient with terrible hand-foot syndrome. I typically start with the recommended dose and then try to give them a break for a little bit and then dose reduce, but just from my experience I have found that hand-foot syndrome can be tough for these patients. Sometimes it’s [difficult] to convince them by saying, “OK, let me reduce the dose and, hopefully, the AEs will be better.” It can be a [difficult] discussion.

WIRTH: Those are definitely 2 difficult AEs to manage. With the hypertension, [a patient’s] blood pressure can just skyrocket. That’s also good to know when you’re doing dose holds; if you have them on 3 blood pressure medicines to manage their hypertension, you have to hold a couple of the blood pressure medicines when they hold the drug, otherwise they’ll become hypotensive pretty quickly.

Proteinuria is something that tends to be a laboratory problem more than a clinical problem. I’ve had patients on lenvatinib who have developed nephrotic-range proteinuria. I send them to a nephrologist and, generally, the nephrologist will say that if you start measuring the urine protein, it would not be so much of a problem. We have started [that] approach with the proteinuria. We follow and monitor, but we approach it as clinically indicated more than laboratory indicated.


1. ATA guidelines. American Thyroid Association. Accessed March 16, 2021.

2. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 3.2020. Accessed March 16, 2021.

3. Wirth LJ, Leboulleux S, Kiyota N, et al. Influence of tumor size and Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline on patient (pt) outcomes in lenvatinib-treated radioiodine-refractory differentiated thyroid cancer (RR-DTC). J Clin Oncol. 2019;37(suppl 15):6081. doi:10.1200/JCO.2019.37.15_suppl.6081

4. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470

5. Cabanillas ME, de Souza JA, Geyer S, et al. Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II International Thyroid Oncology Group trial. J Clin Oncol. 2017;35(29):3315-3321. doi:10.1200/JCO.2017.73.0226

6. Tahara M, Brose MS, Wirth LJ, et al. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2019;106:61-68. doi:10.1016/j.ejca.2018.10.002

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