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Radioiodine-Refractory Differentiated Thyroid Cancer

At a glance
  • Definition. RAI-refractoriness is decided on a post-therapy scan and by behaviour over time, never by a negative diagnostic scan alone.
  • Stop. Once disease is RAI-refractory, further empiric radioiodine adds radiation without benefit.
  • Pace. Many patients live for years on surveillance. Structural progression and symptoms, not a rising Tg alone, trigger treatment.
  • Test first. Before any systemic drug, send tumour tissue for a multigene NGS panel.
  • No driver. Lenvatinib first line, cabozantinib second line.
  • Driver found. NTRK, RET or ALK fusion: selective inhibitor first. BRAF V600E: lenvatinib first, BRAF-directed therapy next.
  • Few lesions. Oligometastatic or oligoprogressive disease is often best treated locally.

1. What makes DTC “radioiodine-refractory”?

Radioiodine works only while tumour cells still carry the sodium-iodide symporter (NIS). When they lose it, ¹³¹I stops reaching the tumour. The 2025 ATA guideline separates true refractoriness from disease that is merely less avid.

RAI-refractory (RAIR)

  • No ¹³¹I uptake on a post-therapy whole-body scan in disease confirmed on structural imaging or ¹⁸F-FDG PET/CT.
  • Or disease progression less than 6 months after an appropriate therapeutic RAI activity.

Reduced RAI sensitivity (not yet RAIR)

  • No uptake on a diagnostic ¹²³I or ¹³¹I scan despite detectable disease. The post-therapy scan may still be positive.
  • Uptake in some, but not all, lesions on the post-therapy scan.

The grey zone

  • Uptake in all known lesions, but disease persists (stable, not cured) after several therapeutic activities.
  • Whether to call this RAIR is debated; there are no randomised data. The chance of cure with more RAI is low.
  • Before another activity, weigh: the intensity of uptake on the last post-therapy scan, FDG avidity, and whether preparation was adequate (low-iodine diet, TSH stimulation, no recent iodinated contrast).
Three categories. Only the first ends radioiodine treatment.
Figure 1. Three categories. Only the first ends radioiodine treatment.
Two rules
  • RAIR cannot be diagnosed in a patient who has never received an ablative or therapeutic activity.
  • Patients with RAIR DTC should not receive further empiric RAI therapy.

2. Why tumours stop taking up iodine

  • Iodine trapping needs NIS, which is driven by TSH-receptor signalling and the thyroid transcription factors.
  • Loss of differentiation is tightly linked to constitutive MAPK signalling (RAS → BRAF → MEK → ERK).
  • BRAF V600E, present in about half of papillary cancers, represses NIS and other thyroid-specific genes (TSH-R, Tg, TPO).
  • As iodine avidity falls, glucose metabolism usually rises. That is why RAIR lesions are often FDG-avid (the “flip-flop” pattern).
  • The practical corollary: switching MAPK signalling off can switch NIS back on (redifferentiation, section 11).
How MAPK and PI3K activation switch off iodide uptake, and where each drug class acts.
Figure 2. How MAPK and PI3K activation switch off iodide uptake, and where each drug class acts.
Flip-flop: as a tumour dedifferentiates it loses iodine avidity and gains FDG avidity. TENIS = thyroglobulin elevated, negative iodine scintigraphy.
Figure 3. Flip-flop: as a tumour dedifferentiates it loses iodine avidity and gains FDG avidity. TENIS = thyroglobulin elevated, negative iodine scintigraphy.

3. Imaging in RAIR DTC

ModalityWhat it does in RAIR DTC
Post-therapy ¹³¹I scan with SPECT/CTThe scan that defines RAIR; shows which lesions still trap iodine
¹⁸F-FDG PET/CTFinds iodine-negative disease; FDG avidity weighs against further RAI and signals more aggressive disease; tracks progression and response
CT / MRIMeasures target lesions (RECIST) and follows disease not seen on iodine scans
Neck ultrasoundLong-term surveillance of small cervical nodal metastases
Nuclear medicine pearl
  • An FDG-avid, iodine-negative lesion in a patient with rising Tg is the flip-flop signature. Report it as such: it changes the next step from “more iodine” to surveillance, local or systemic therapy.

4. Management at a glance

Three questions drive every decision: how much disease, how fast is it growing, and is it causing (or about to cause) harm?

The management pathway. Patients move between lanes over time.
Figure 4. The management pathway. Patients move between lanes over time.

5. Active surveillance

  • Who: asymptomatic, stable or minimally progressive disease, or clinically significant comorbidities.
  • How: TSH-suppressive levothyroxine with serial imaging and thyroglobulin (with antibodies).
  • How often: every 3–12 months, set by disease burden, lesion location, histology and Tg doubling time.
Thyroglobulin is a prompt, not a trigger
  • A rising Tg alone, without structural progression, is not a reason to start systemic therapy.
  • An accelerating Tg should bring imaging forward to look for a structural correlate.

6. Before systemic therapy: test the tumour

  • Perform tissue-based biomarker testing before the first systemic drug to find actionable drivers.
  • A multigene NGS panel that also detects fusions is preferred over sequential single-gene tests.
  • PD-L1 immunohistochemistry is not a routine biomarker in RAIR DTC.
Histology (advanced disease)Treatment-directing alteration found
Papillary (PTC)85% (260/307)
Anaplastic (ATC)52% (68/130)
Poorly differentiated (PDTC)29% (16/55)
Follicular (FTC)2% (1/55)

Table 1. Yield of genomic profiling in 552 advanced thyroid carcinomas (Toda et al., Japanese national database).

Genotype-directed systemic therapy.
Figure 5. Genotype-directed systemic therapy.

7. Multikinase inhibitors: no actionable driver

DrugMain targetsPivotal trialMedian PFS vs placeboPlace
LenvatinibVEGFR1–3, FGFR1–4, PDGFRα, RET, KITSELECT, phase 3 (n = 392)18.3 vs 3.6 months; ORR 64.8%
Preferred 1st line
SorafenibVEGFR1–3, PDGFRβ, RET, RAF (incl. BRAF)DECISION, phase 3 (n = 417)10.8 vs 5.8 months1st-line alternative
CabozantinibVEGFR2, MET, RET, AXLCOSMIC-311, phase 3 (n = 187), after 1–2 prior VEGFR TKIsNot reached vs 1.9 months (HR 0.22)2nd line
  • Lenvatinib over sorafenib: there is no head-to-head trial, but network meta-analyses and real-world comparisons favour lenvatinib for PFS and response rate.
  • In DECISION, sorafenib improved PFS in every biomarker subgroup, irrespective of BRAF or RAS status.
  • Cabozantinib is FDA-approved for RAIR DTC that has progressed on prior VEGFR-targeted therapy.
Median PFS in placebo-controlled trials of first-line VEGFR kinase inhibitors.
Figure 6. Median PFS in placebo-controlled trials of first-line VEGFR kinase inhibitors.

When to start an MKI (lenvatinib preferred; sorafenib alternative)

  • Symptomatic RAIR DTC: start lenvatinib without delay.
  • Asymptomatic but now progressing: start lenvatinib earlier if disease control is the priority; deferring is reasonable if quality of life is the priority.
  • MKIs (lenvatinib, sorafenib, cabozantinib) are not curative and their toxicity affects daily life.
  • Overall survival is hard to judge because placebo patients crossed over in DECISION (sorafenib) and SELECT (lenvatinib). Exploratory SELECT analyses suggest a lenvatinib OS benefit in patients over 65 and in those with lung metastases ≥1 cm.

MKI dosing and monitoring

  • Lenvatinib: start at 24 mg once daily. In a randomised trial, starting at 18 mg gave a lower week-24 response rate (40.3% vs 57.3%, noninferiority not met) with similar grade ≥3 toxicity (57.1% vs 61.3%).
  • Lenvatinib: 14 mg once daily for severe renal impairment (creatinine clearance <30 mL/min) or severe hepatic impairment.
  • Sorafenib: 400 mg twice daily (the DECISION dose).
  • Cabozantinib: 60 mg once daily (the COSMIC-311 dose).
  • Monitoring (any MKI): review at baseline, at least every 2 weeks for the first 2 months, then every 1–2 months.

Other VEGFR inhibitors (not FDA-approved for RAIR DTC)

  • Sunitinib, pazopanib, axitinib and vandetanib: phase 2 activity only.
  • Apatinib (REALITY, phase 3, China): median PFS 22.2 vs 4.5 months, with an overall survival benefit.
  • Anlotinib (randomised phase 2, n = 113, China): median PFS 40.5 vs 8.4 months.

8. Living with an MKI: toxicity

Adverse effectPrevent / checkManage
Hypertension (commonest VEGFR class effect)Control BP before starting; daily home BPAntihypertensives; dose interruption or reduction if refractory
Hand–foot skin reaction (sorafenib > lenvatinib)Remove calluses before and during therapy; alcohol-free moisturisers; cushioned footwear; avoid sun exposure20–40% urea cream; topical or systemic steroids if severe; dose change
Diarrhoea (with anorexia, weight loss, stomatitis)Avoid trigger foods; high-protein, low-fat, low-fibre dietLoperamide; probiotics; hydration
Rising TSHTSH and free T4 periodicallyIncrease levothyroxine to hold the TSH target
ProteinuriaUrine protein monitoringInterrupt or reduce the dose if significant
QTc prolongation (class effect)ECG before starting and periodically; correct K⁺ and Mg²⁺Avoid other QT-prolonging drugs; interrupt if prolonged
Rare but life-threatening; know when to avoid a VEGFR MKI
  • Serious events: GI perforation, fistula, bleeding, arterial and venous thromboembolism, hepatic or renal toxicity, reversible posterior leukoencephalopathy.
  • Avoid or use with great caution in: poor cardiac function, recent acute coronary syndrome or stroke, uncontrolled hypertension, colitis or diverticulitis, recent bowel surgery or perforation, tumour invading the trachea, oesophagus or great vessels, haemoptysis, untreated brain metastases.

9. Targeted therapy for actionable drivers

DriverHow commonFirst choiceKey evidence
NTRK fusion~2% of adult PTC; far more common in children (up to ~25%)Larotrectinib (entrectinib alternative)Larotrectinib, thyroid cohort (n = 29): ORR 71%; 86% in PTC/FTC; 24-month PFS 69%; mostly grade 1–2 toxicity
RET fusionA minority of PTC; commoner in children and after radiation exposureSelpercatinib or pralsetinibSelpercatinib (LIBRETTO-001, n = 19): ORR 79%, 1-year PFS 64%. Pralsetinib (ARROW, n = 9): ORR 89%. No head-to-head trial
ALK fusionRare; commoner after radiation exposureCrizotinib, alectinib or lorlatinibCase reports and small series only, but responses can be striking
BRAF V600EAbout half of PTCLenvatinib first; BRAF-directed therapy after MKI progression or intoleranceVemurafenib: ORR 38.5% (MKI-naive). Dabrafenib vs dabrafenib + trametinib: RECIST ORR 35% vs 30%; the combination was not superior
  • Dabrafenib + trametinib holds a tumour-agnostic FDA approval for BRAF V600E solid tumours that have progressed after prior treatment.
  • BRAF-directed drugs are not for non-V600 BRAF alterations.
  • RAS (common in FTC, follicular-variant PTC and PDTC): no approved targeted drug. KRAS G12C inhibitors (sotorasib, adagrasib) could be considered if that exact mutation is found. HRAS (tipifarnib) and MEK (selumetinib) inhibition have shown little activity.
  • PI3K/AKT/mTOR: buparlisib gave no RECIST responses; single-agent everolimus 0–5%. Combinations remain investigational.
  • Other genotypes: lenvatinib first line.

10. Oligometastatic disease: treat locally

For a solitary metastasis or a few (oligometastatic) lesions, focal ablative treatment can control the sites, delay the need for systemic therapy, may prolong survival and, rarely, cures.

OptionBest suited toNotes
MetastasectomyResectable lung or bone lesionsNo randomised trials; complete (R0) resection is associated with excellent long-term survival
SBRT / SABRLesions unsuitable for surgery (lung, bone, spine)SABR-COMET (mixed primaries, randomised phase 2) improved overall survival versus standard care
Radiofrequency ablationSmall lesions (≤3 cm) away from large vesselsLess effective above 3 cm or next to large vessels (heat sink)
Microwave ablationLarger lesions (>3 cm)Heats faster and hotter than RFA
CryoablationLesions near nerves or other sensitive structuresFreezing; ice ball visible on CT
Oligoprogression
  • One or a few lesions grow while the rest stay controlled on a drug: treat the growing sites locally (surgery or SBRT) and continue the current systemic therapy, which can extend its useful life considerably.

11. Redifferentiation therapy

The aim is to use a short course of a MAPK-pathway inhibitor to switch NIS back on, then treat with ¹³¹I.

A typical redifferentiation protocol (schedules vary between trials).
Figure 7. A typical redifferentiation protocol (schedules vary between trials).
StudyDrugPatientsResult
Ho 2013Selumetinib (MEK), 4 weeks20 evaluableUptake increased in 12; 8 reached the dosimetry threshold (all 5 NRAS-mutant). After ¹³¹I: 5 PR, 3 SD
Rothenberg 2015Dabrafenib (BRAF V600E)10New uptake in 6; after ¹³¹I: 2 PR, 4 SD at 3 months
Dunn 2019Vemurafenib (BRAF)10 evaluable4 reached the threshold and were treated; all showed tumour regression at 6 months
MERAIODE, 2023Dabrafenib + trametinib (BRAF V600E)24 (21 evaluable)Scan uptake 5% at baseline, 65% on drug; 6-month PR 38%, SD 52%
ASTRA, 2022Selumetinib + adjuvant RAI (high risk, not genotyped)233Complete response at 18 months 40% vs 38%: negative
Where it fits
  • May be considered in selected patients with progressive, metastatic RAIR DTC and a targetable BRAF or RAS mutation.
  • Not recommended in the adjuvant setting for patients not selected by genotype (ASTRA).

Why it sometimes fails

  • MAPK rebound: BRAF or MEK inhibition up-regulates HER3, which reactivates MAPK and PI3K signalling.
  • Adding lapatinib, an EGFR/HER2 inhibitor that blocks HER3 activation, prevents this rebound and increases NIS expression more than BRAF/MEK inhibition alone in preclinical models.

12. Beyond first line: immunotherapy and chemotherapy

Immune checkpoint inhibitors

  • Single-agent pembrolizumab is disappointing in unselected RAIR DTC: ORR 9% in KEYNOTE-028 (n = 22) and 6.8% in KEYNOTE-158 (n = 103).
  • Consider only for TMB-high or MSI-high / mismatch-repair-deficient tumours, where pembrolizumab has tumour-agnostic approvals.
  • Lenvatinib + pembrolizumab: no clear advantage over lenvatinib alone in the first line; activity is modest when pembrolizumab is added at lenvatinib progression.

Cytotoxic chemotherapy

  • Low efficacy; not a standard treatment.
  • Reserved for rapidly progressive, imminently threatening disease (e.g. airway compromise) that cannot be controlled by other means.

13. On the horizon: new radioligand therapy

  • SSTR-targeted PRRT: thyroid cancers can over-express somatostatin receptors (SSTR2). In a meta-analysis (11 studies, 165 patients), ORR was 15.6% in DTC and 8.5% in MTC, with serious adverse events in about 3%; ¹⁷⁷Lu-based PRRT performed better than ⁹⁰Y-based PRRT. Select patients with SSTR PET.
  • FAP-targeted therapy: in a first-in-human dose-escalation study of ¹⁷⁷Lu-EB-FAPI (¹⁷⁷Lu-LNC1004) in 12 patients with metastatic RAIR thyroid cancer, ORR was 25% and disease control 83%; haematological toxicity limited the highest dose.
  • Both remain investigational: consider them in trials or after standard options are exhausted.

Summary

  1. Confirm RAIR on a post-therapy scan or by progression within 6 months of a therapeutic activity, then stop empiric RAI.
  2. Map the disease with FDG PET/CT and cross-sectional imaging; use Tg kinetics to time imaging, not to start drugs.
  3. Asymptomatic, slow disease: TSH suppression with imaging and Tg every 3–12 months.
  4. Few lesions, or one lesion growing: surgery, SBRT or thermal ablation.
  5. Progressive disease: NGS panel, then genotype-matched therapy (lenvatinib, then cabozantinib, if no driver).
  6. Redifferentiation, PRRT and FAP-targeted therapy are promising but not yet standard.

Test yourself

Five quick questions. Pick an answer to see the explanation.

1. Which finding establishes radioiodine-refractory DTC?
2. A 62-year-old has progressive, multifocal RAIR papillary cancer. NGS shows no actionable alteration. Preferred first-line therapy?
3. Progressive RAIR PTC harbours an ETV6::NTRK3 fusion. Best first-line systemic therapy?
4. What did the ASTRA trial show?
5. Which finding most strongly argues against starting a VEGFR multikinase inhibitor?

References

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  2. Filetti S, Durante C, Hartl DM, et al. ESMO Clinical Practice Guideline update on the use of systemic therapy in advanced thyroid cancer. Ann Oncol. 2022;33(7):674-84.
  3. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-28.
  4. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-30.
  5. Tahara M, Kiyota N, Hoff AO, et al. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2021;147:51-7.
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  8. Lin Y, Qin S, Li Z, et al. Apatinib vs placebo in patients with locally advanced or metastatic, radioactive iodine-refractory differentiated thyroid cancer: the REALITY randomized clinical trial. JAMA Oncol. 2022;8(2):242-50.
  9. Chi Y, Zheng X, Zhang Y, et al. Anlotinib in locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma: a randomized, double-blind, multicenter phase II trial. Clin Cancer Res. 2023;29(20):4047-56.
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  11. Waguespack SG, Drilon A, Lin JJ, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022;186(6):631-43.
  12. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-35.
  13. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021;9(8):491-501.
  14. Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272-82.
  15. Busaidy NL, Konda B, Wei L, et al. Dabrafenib versus dabrafenib + trametinib in BRAF-mutated radioactive iodine refractory differentiated thyroid cancer: results of a randomized, phase 2, open-label multicenter trial. Thyroid. 2022;32(10):1184-92.
  16. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368(7):623-32.
  17. Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015;21(5):1028-35.
  18. Dunn LA, Sherman EJ, Baxi SS, et al. Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers. J Clin Endocrinol Metab. 2019;104(5):1417-28.
  19. Leboulleux S, Do Cao C, Zerdoud S, et al. A phase II redifferentiation trial with dabrafenib-trametinib and 131I in metastatic radioactive iodine refractory BRAF p.V600E-mutated differentiated thyroid cancer. Clin Cancer Res. 2023;29(13):2401-9.
  20. Ho AL, Dedecjus M, Wirth LJ, et al. Selumetinib plus adjuvant radioactive iodine in patients with high-risk differentiated thyroid cancer: a phase III, randomized, placebo-controlled trial (ASTRA). J Clin Oncol. 2022;40(17):1870-8.
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  23. Lee DY, Kim YI. Peptide receptor radionuclide therapy in patients with differentiated thyroid cancer: a meta-analysis. Clin Nucl Med. 2020;45(8):604-10.
  24. Fu H, Huang J, Zhao T, et al. Fibroblast activation protein-targeted radioligand therapy with 177Lu-EB-FAPI for metastatic radioiodine-refractory thyroid cancer: first-in-human, dose-escalation study. Clin Cancer Res. 2023;29(23):4740-50.
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