Treating Metastatic DTC After Radioactive Iodine Progression

Metastatic differentiated thyroid cancer (DTC) is typically managed with surgery and/or radioactive iodine (RAI), but a subset of patients will develop RAI-refractory disease, which requires a different treatment approach. Lori Wirth, MD, a professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, led a Case-Based Roundtable event in Scottsdale, Arizona, where she discussed options for a patient with DTC who experienced progressive disease. Wirth also covered some of the current guidelines in this setting.

CASE SUMMARY

• A 43-year-old woman presented with nonproductive cough, dyspnea on mild exertion, and low back pain.

Medical and social history

• Papillary thyroid cancer (diagnosed 2 years ago) by ultrasound-guided fine needle aspiration
• Total thyroidectomy plus central neck dissection

Stage and treatment

• Stage: T1bN1bM0
• Histopathology: pT1bN1bM0 papillary carcinoma, characterized by psammoma bodies, chromatin pallor, and nuclear grooving, with 3/4+ central nodes and 1+ supraclavicular node.
• Mutation analysis: negative for BRAF, RAS, RET, NTRK1, and VEGF; proficient mismatch repair, microsatellite stable
• Adjuvant therapy: RAI ablation plus levothyroxine to maintain thyroid-stimulating hormone concentration <1.5 mIU/L
• Postoperative thyroglobulin concentration: 17 ng/mL

20 Months Later:

Imaging Studies

• Follow-up chest CT: indicates disease recurrence in the upper lobe of left lung, unilateral cervical lymph nodes, and C6-C7 vertebrae
• Brain MRI: negative for evidence of central nervous system metastases

Evaluation

• Thyrogen^®-stimulated I¹³¹ Whole-Body Scan: no uptake in metastases
• Serum thyroglobulin: undetectable
• 18-F fludeoxyglucose (FDG) PET/CT: intensely avid FDG uptake in lung, lymph nodes, and cervical vertebrae

Diagnosis

• Metastatic RAI-refractory DTC

Targeted Oncology: What are the next steps for this patient with DTC?

Lori Wirth, MD: You're going to talk with your radiation oncologist. She's had a pretty thorough radiographic workup. We know what the thyroglobulin is. She's a pretty young woman so her performance status is good. We'll do the usual blood tests and liver function [tests] and so forth. I like that the brain MRI was done in this case; it's not [always] something that we think about in patients with advanced thyroid cancer as often as we should. In the SELECT trial [NCT01321554] with lenvatinib [Lenvima], for example, [approximately 15%] of those patients did have brain metastases,¹ and especially in this case—it's unusual for papillary thyroid cancer to cause bone metastases, and when there are unusual sites of disease, those patients are more likely to have brain metastases as well.

She had the whole-body RAI scan that didn't show any uptake. She had a PET scan and a brain MRI. Because of that C6-C7 metastasis seen on the CT scan, I think a PET/CT is a really good choice in this particular case, though with many of my patients with metastatic papillary thyroid cancer, I might do just a neck and a chest CT scan, and that's often all of it, because lung metastases are the most common sites of metastases. Bone metastases are pretty unusual.

If there is progression in the treated areas in 6 months or 12 months, which time period do you look at to decide if the patient’s DTC is refractory?

There are some thyroid cancers that will take up RAI but still progress anyway. The old guidelines said if there's progression within a year of RAI uptake, even if there was uptake in the lesions, that's RAI refractory disease, but that 1 year cut off point was removed from the current guidelines. The current guidelines give people a little bit more leeway to make an individualized decision. In this case, she progressed 20 months after the 17-ng/mL dose, and she had that test done so she has RAI-refractory disease. But even without that test dose...you can give her all the RAI you want, but it's not going to work. In the current era, most people would say she's RAI refractory, even though it was 20 months, not 1 year.

What are recommendations from the 2025 version of the American Thyroid Association guidelines for RAI-refractory DTC?

One of the recommendations is, if a patient has RAI-refractory disease, they shouldn't get more RAI.² That statement was made intentionally, because historically, when we didn't have other things to offer patients, patients got a lot of RAI, and there are real downsides to RAI: dry mouth, dry eyes, tearing, but there's also a slight increased risk of secondary malignancies from RAI, and the higher the cumulative dose, the higher the risk. We have other tools now, so we shouldn't be giving patients with RAI-refractory disease RAI.

Then there are stronger indicators of RAI-refractory disease. If there's disease that you know is there and it doesn't take up RAI, this is RAI refractory. Progression in less than 6 months after a treatment dose is clearly RAI refractory, and then no uptake on a diagnostic scan [is indicative]. Or if some lesions take up RAI, but not others; a patient like that might still benefit from RAI, as some lesions are taking it up.

_{DISCLOSURES: Wirth previously reported a consulting or advisory role with Merck, Eisai, Lilly, Bayer, Exelixis, Coherus Biosciences, METIS Precision Medicine, Tome Biosciences, EMD Serono, Ellipses Pharma, Illumina, and Nested.}

_References:

_{1. Gianoukakis AG, Dutcus CE, Batty N, Guo M, Baig M. Prolonged duration of response in lenvatinib responders with thyroid cancer. Endocr Relat Cancer. 2018;25(6):699-704. doi:10.1530/ERC-18-0049}

_{2. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid. 2025;35(8):841-985.}