Defining RAI-Refractory Differentiated Thyroid Cancer


Dr Brose delves into radioiodine-refractory differentiated thyroid (RR-DTC), from its definition and the clinical molecular markers that impact that refractoriness.

Marcia S. Brose, MD, PhD: The definition of radioactive iodine [RAI] refractory differentiated thyroid cancer is not universally accepted, but I think because of the clinical trials, we’ve all started to settle on a couple of key points. The first is if they have known disease, they have a whole-body scan and not all of that disease takes up radioactive iodine. Well, then we know it’s refractory because it’s not avid. It’s not taking up the iodine. There’s no way the iodine can work. There’s another class of patients who have radioactive iodine, but when they have a scan 3 or 6 months later, it’s clear that they’re progressing. It doesn’t matter that they took up iodine initially for refractory because it doesn’t seem to matter. There’s probably enough RAI [radioactive iodine] non-avid disease, even in those nodules that they progress anyway.

The third category for RAI-refractory differentiated thyroid cancer is usually a cutoff of 600 millicuries. Now, that’s not a hard cutoff, but we know for a fact that patients who have more than 600 millicuries are more likely to have problems such as leukemias and other negative effects from the radioactive iodine. Primarily, the risk of cancer goes up. We also know that the vast majority of patients will have had any responses that they’re going to have by the time they reach that 600 millicurie mark. We use that as a cutoff because after 600 millicuries, it’s probably not going to work. We would consider them RAI refractory based on that. It’s interesting to note that most of the patients on either the DECISION or the lenvatinib [Lenvima] trial, SELECT, showed progression and clear RAI-refractory disease on average by the time they had had 400 millicuries. And that was the average amount of radioactive iodine people had. Usually, by 400 millicuries, you have a sense of whether or not these patients are going to respond to any more radioactive iodine, or if it’s more likely that they’re just going to have a resistant disease. It’s important to stop at that time so that they then don’t have all the negative sequelae of additional radioactive iodine when the hope of benefit is much more decreased.

The other point to be made about radioactive iodine is: are there certain clinical markers that would predict who would be less likely to respond to radioactive iodine? And there are several genetic factors. We know for a fact that people who have TERT p53, have more aggressive lesions to start with, but the most common mutation BRAF V600E is definitely associated with less likelihood of taking up radioactive iodine. I think that’s also true probably of the track fusions and of the RET fusions. There are a lot and RAS [mutations] it’s absolutely true. Many of the genetic abnormalities that we follow are often negative prognostic factors, meaning they will help predict patients who will not respond to radioactive iodine.

The factors I take into consideration when deciding when to start treatment for my patients with radioactive iodine refractory differentiated thyroid cancer is probably the most asked question I get. The answer is twofold. First of all, I need to know what is the pace of the disease. Thyroid cancer is unusual compared to other cancers. If somebody has a lung cancer, I usually don’t care how big it is. If it can’t be taken out by surgery, I’m going to try to do everything I can to either irradiate it or treat it with chemotherapy. But in thyroid cancer, some of these nodules have been present for years. In a patient that I don’t know, I always get a second CAT scan at least 3 months after a first CAT scan that they might present with in order to understand the pace of the disease. If it’s not changing very much and they don’t have other indicators for immediate treatment, those patients can be watched. And depending on how much they are changing, I will watch my patients on surveillance usually every 3 months, or if they’ve shown that they’re really even more stable, I’ll usually watch them every 4 or every 6 months with monitoring by CAT scan.

The patients that I’ve been monitoring that I would treat or, most importantly, the patients who would present to me that I would treat right away are the patients who have either symptoms or the patients who have what I would consider a quality-of-life-threatening disease. That includes anybody who has tracheal invasion or those bad prognostic features. Those people need to be treated right away. People who are symptomatic because their lungs are filled with cancer would need to be treated right away. Now, interestingly, remember in the last case I described, the patient had shortness of breath, but it probably wasn’t due to their disease. If they have shortness of breath and they’re having a lot of trouble and their disease is clear, I can look at the CAT scan and the lungs look 99% clear, those people need a cardiac workup and maybe some pulmonary function tests. And those are probably not suffering from their cancer. Again, those would be people that I would do surveillance. But let’s take a patient that started maybe like this patient who had a few nodules ranging up to about 6 millimeters. And now I’ve done a couple of 3-month CAT scans, and they really are only growing by like 1 millimeter a time. When am I going to start therapy? Well, first of all, if they’re really growing that slowly, those are the people that I would probably trust enough to change their CAT scan intervals to 4 months or 6 months. For the patients who are then being followed, if they’re starting to grow, I may not start them on treatment right away, but if they’re starting to grow a little bit more quickly, I might decrease that interval back down from 6 months down to 3 months, just to have a little bit better handle on what’s going on. What is it that triggers me to start treatment? The overall tumor burden, if it starts to get to be such that I’m afraid that when they try to break down that tumor on the lenvatinib, they’re going to end up with problems like coughing or symptoms because there’s enough tumor burden to cause that, I usually don’t want to let it go that far. Unfortunately, a little bit of that is experience. You can’t necessarily know that. But if you have any questions, the best thing you can do is show a CAT scan to an expert that treats like 200 or 300 of these a year because those are the people who can look at a CAT scan and we can look at a CAT scan and say, “Oh yeah, definitely that person needs to start right away,” until you get a little bit of a handle on what that is. But high tumor burden patients would be a reason to start therapy. For people with moderate or low tumor burden, if a lot of their disease is on the pleura or in other areas that is concerning, I would start those patients sooner. Those are patients who might have lesions that are on or near the spinal cord or the lining of the pleura is a problem because many of those patients can end up with pleural effusions at the time that you start treatment. The pace that it's growing will affect whether or not I’ll start treatment, because if it’s rapidly doubling, I’m not going to usually have time to go too many CAT scans before they’re going to have a large burden. So, the pace of the disease. As I said, the fourth is if they were having symptoms, I would definitely do it for that reason. Those are the basic criteria. Location is also important if they have a lot of bulky nodes in the pleura hilar region. They can lead to obstruction. Those are other things. I won’t just go off the report. I’ll actually look at the scans myself and say to myself, are any of these spots posing a risk in the next 3 months that if they grew my patient’s going to have problems? And I will start them on therapy based on that criteria.

This transcript has been edited for clarity.

Case: A 70-Year-Old Woman With Differentiated Thyroid Cancer

Initial presentation

  • A 70-year-old woman presents with a painless “lump on her neck.”
  • PMH: unremarkable
  • PE: palpable, non-tender solitary right-of-the midline neck mass; otherwise unremarkable

Clinical workup and initial treatment

  • Labs: TSH WNL
  • Ultrasound of the neck revealed a 3.4 cm suspicious right mass arising from the right thyroid; 4 suspicious supraclavicular lymph nodes (LNs), largest 2.2 cm in size.
  • Ultrasound-guided FNAB of the thyroid mass and the largest LN confirmed papillary thyroid carcinoma.
  • Patient underwent total thyroidectomy with central compartment and right selective neck dissection.
    • Pathology: 3.4 cm papillary thyroid cancer arising in the right lobe of thyroid, tall-cell features; extrathyroidal extension present;
    • 2 of 6 positive central compartment lymph nodes, largest 1.8 cm
    • 4 of 13 right lateral compartment involved nodes largest 2.2 cm in size, positive extra nodal extension.
  • StageT2N1aMX; ECOG PS 0

    Subsequent treatment and follow-up
  • She was treated with radioactive iodine 150 millicuries
    • Whole body scan showed uptake in the neck, consistent with thyroid remnant but no uptake in the lungs
  • Follow-up at 3 months
    • TSH 0.2 µU/mL, thyroglobulin 28 ng/mL (negative anti-thyroglobulin antibodies)
    • Chest CT scan showed 8 small bilateral lung nodules largest 1.3 cm
    • Follow-up CT neck and chest scan 3 months later was notable for 1-2mm growth in several lung nodules and 3 new distinct 9.5 mm lung nodules
  • Next-generation sequencing was negative for mutations, rearrangements
  • Lenvatinib 24mg po qd was initiated

Case 2: A 57 Year-Old Man With Differentiated Thyroid Cancer

Initial presentation

  • A 57-year-old man presents with a solitary nodule on the neck and occasional shortness of breath and intermittent excessive fatigue
  • PMH: unremarkable
  • PE: palpable, hard and fixed solitary nodule in the anterior neck

Clinical workup and initial treatment

  • Labs: TSH 10.3 µU/mL; all others WNL
  • Ultrasound of the neck revealed a 2 cm mass near the isthmus of the thyroid; several suspicious lymph nodes ranging from 0.3-2.4 cm in size
  • Ultrasound-guided FNAB: confirmed papillary thyroid carcinoma; with nuclear enlargement and nuclear grooves, no colloid seen
  • Patient underwent total thyroidectomy with bilateral central neck dissection
    • Pathology: 2.1 cm papillary thyroid cancer arising in isthmus of the thyroid, 3 of 7 positive central compartment lymph nodes, largest 1.8 cm, positive extra nodal extension
  • StageT2N1MX; ECOG PS 1

Subsequent treatment and follow-up

  • He was treated with radioactive iodine 150 millicuries
    • Whole body scan showed uptake in the neck; indicative of thyroid remnant
  • Follow-up at 3 months TSH 0.2 µU/mL, thyroglobulin 68 ng/mL
  • Neck US showed no evidence of residual disease in thyroid bed, no suspicious neck nodes. Chest CT was done: 4 lung lesions that were 0.3 and 0.6 cm in size
  • The physician recommended not initiating systemic therapy and putting the patient on active surveillance
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