Lenvatinib Restored Radioiodine Uptake in Refractory Thyroid Cancer, Case Report Shows

In a case report published in EJNMMI Reports, clinicians describe a 53-year-old woman whose radioiodine-refractory differentiated thyroid cancer, long invisible on radioactive iodine scans, regained the ability to take up radioactive iodine after nine months of treatment with the multikinase inhibitor lenvatinib. That restored uptake allowed the medical team to deliver an additional round of radioactive iodine therapy, which produced new imaging findings and a further decline in her tumor marker levels. To the authors’ knowledge, clinically meaningful restoration of radioiodine avidity in established radioiodine-refractory disease has not previously been reported after multikinase inhibitor therapy, making the observation noteworthy even though it rests on the experience of one patient.

The patient’s disease course began years earlier. In 2011 she underwent removal of the right lobe of her thyroid for a large lesion measuring approximately 5.1 by 4.4 centimeters, which pathology examination classified as a follicular adenoma, a benign tumor. After seven years of irregular follow-up, suspicious lymph nodes and bilateral pulmonary nodules prompted a more extensive operation: total thyroidectomy with dissection of central and right lateral neck lymph nodes. Pathology then confirmed invasive follicular variant papillary thyroid carcinoma involving both thyroid lobes, with lymph node metastases and tumor infiltration into the fibrous tissue surrounding the right internal jugular vein.

Staged as T4bN1bM1 and classified as high risk of recurrence, she received six cycles of radioactive iodine therapy within the following three years, for a cumulative dose of 35.15 gigabecquerels. Early on, the treatment appeared to work: her thyroglobulin level, a protein produced by thyroid tissue that serves as a tumor marker, initially declined. The first post-therapy whole-body scan showed multiple abnormal iodine-avid lesions in the thyroid bed, chest, back, thoracic spine region, right hip region, and left proximal thigh, consistent with pulmonary and bone metastases. But over successive treatment cycles the picture changed. Serial post-therapy scans showed a gradual loss of iodine uptake in previously avid lesions, and her thyroglobulin began to rise after the fourth cycle. A diagnostic whole-body scan performed six months after the sixth and final treatment showed no lesional uptake at all, confirming that the cancer had become radioiodine-refractory.

Radioiodine refractoriness is a pivotal turning point in differentiated thyroid cancer. It is associated with an increased risk of thyroid cancer-related mortality and generally reflects, at least in part, a process of tumor dedifferentiation, in which cancer cells lose the specialized molecular machinery, including the sodium/iodide symporter, that allows them to concentrate iodine. Once tumors can no longer take up radioactive iodine, further iodine therapy is futile, and management shifts toward surveillance or systemic therapy. Targeted drugs have become an important modality for controlling such disease, and in selected patients with specific molecular drivers, restoration of iodine uptake during targeted therapy can enable subsequent salvage radioiodine therapy, which adds a tumoricidal component through radiation-induced irreversible DNA damage beyond the continuous signaling inhibition that tyrosine kinase inhibitors provide on their own.

Such restoration has been achieved with selective kinase inhibitors targeting BRAF, RAS, RET, or NTRK alterations. Multikinase inhibitors such as lenvatinib, which target VEGFR, FGFR, and PDGFR and are established first-line systemic agents for progressive radioiodine-refractory disease, had not demonstrated clear restoration of iodine avidity at the clinical level. Notably, a prospective study called RESET specifically explored whether lenvatinib could re-induce iodine sensitivity, and the results were negative: no patient met dosimetry-based criteria for effective subsequent radioiodine therapy. Against that background, the new case stands out as a contrary observation.

After the refractory state was confirmed, the patient spent three years under active surveillance with continued thyrotropin suppression. Lenvatinib was then initiated because of a rapid rise in thyroglobulin suggesting biochemical progression, worsening scapular and back pain, and computed tomography findings of enlarged pulmonary metastases and newly developed multifocal osteolytic bone lesions, including the manubrium sterni and the tenth thoracic vertebra. Concurrent molecular testing revealed both an NRAS exon 3 mutation and a TERT promoter mutation, a combination that would later inform the authors’ interpretation of the response. Lenvatinib was started at 24 milligrams daily, but treatment-related adverse events, including hypertension, bilateral lateral cutaneous pain over the fifth toes, and mild morning epistaxis, required a modified schedule of five days on and two days off the drug.

The response was measurable on several fronts. After eight months of therapy, the size of the target pulmonary metastatic lesions had fallen by approximately 36.36 percent according to RECIST version 1.1, meeting the criteria for a partial response. Some bone lesions developed marginal sclerosis, suggesting osteoblastic repair of the destructive lytic lesions. Most strikingly, her thyroglobulin dropped from 7965.21 nanograms per milliliter to 454 nanograms per milliliter. Then, at nine months of treatment, the team performed a recombinant human thyroid-stimulating hormone-assisted diagnostic whole-body scan under strict iodine abstinence, undertaken with ethics approval to help tailor subsequent treatment given her adverse effects. The scan revealed iodine uptake in selected bone metastases involving the manubrium sterni and the seventh and tenth thoracic vertebrae.

The authors are careful about what this uptake means. The iodine-avid lesions might represent sites that had previously responded to several courses of radioiodine therapy but subsequently progressed, or lesions that newly developed during follow-up despite prior negative whole-body scans. Because most previous scans were planar and there was no clinical indication for an additional diagnostic scan immediately before lenvatinib initiation, lesion-specific changes in avidity cannot be reconstructed with certainty over such a long disease course. Nevertheless, the patient-level observation stands: disease that had evolved into an established refractory state with no discernible lesional uptake later showed reappearance of iodine-avid metastases. The restored uptake permitted salvage radioiodine therapy with 7.4 gigabecquerels, and the subsequent post-therapy scan showed additional avid bone lesions in the first thoracic vertebra, the right third and ninth posterior ribs, bilateral iliac bones, and the right pubis, with higher uptake intensity than before. Thyroglobulin declined further, from 677 to 482.13 nanograms per milliliter, corroborating a clinically meaningful biochemical response.

Why might this patient have responded when the prospective RESET study failed? The authors point to several converging factors. The restoration appeared after nine months of lenvatinib, roughly three times the treatment duration used in RESET, suggesting that later reassessment during multikinase therapy may still be informative in selected patients. The tumor’s biology also fits a favorable pattern: redifferentiation studies have shown that RAS-mutant and follicular-pattern tumors are particularly likely to regain iodine uptake, and in the cohort reported by Toro-Tobon and colleagues, in which genotype-directed redifferentiation therapy restored uptake in 57.6 percent of previously refractory patients, all RAS-mutant tumors redifferentiated. This may indicate that the iodine-handling machinery in such tumors is suppressed rather than completely lost. Preclinical work adds that lenvatinib may modulate iodine handling in sodium/iodide symporter-expressing thyroid cancer cells and may exert regulatory effects on the tumor immune microenvironment, although the mechanism remains to be fully elucidated. The predominance of restored uptake in bone metastases, the authors note, is better explained by interlesional heterogeneity, including differences in differentiation status, residual symporter function, vascularity, local microenvironment, and treatment response, than by any bone-specific redifferentiation mechanism, for which evidence is currently insufficient.

The authors emphasize that a single case does not constitute definitive proof of clinical redifferentiation. Still, the practical message is concrete: for patients with radioiodine-refractory differentiated thyroid cancer receiving multikinase inhibitor therapy, reassessment of iodine avidity warrants active clinical consideration when formulating subsequent treatment strategies, particularly when disease progresses or the metastatic pattern changes. A repeat recombinant human thyroid-stimulating hormone-assisted diagnostic scan may identify iodine-avid disease that reopens the possibility of salvage radioiodine therapy, and this approach avoids thyroid hormone withdrawal and the lesion-stimulating effects of sustained endogenous thyrotropin elevation. In this case, that reassessment converted a drug usually regarded as a disease-control agent into a bridge back to a therapy the patient’s cancer had seemingly abandoned.

Subject of Research: Restoration of radioiodine uptake after lenvatinib treatment in a patient with radioiodine-refractory differentiated thyroid cancer

Article Title: Restoration of radioiodine avidity after lenvatinib in NRAS- and TERT promoter-mutant radioiodine-refractory differentiated thyroid cancer: a case report

Article References: Chen, K., Zhao, Y., Shi, C., Li, Z., & Lin, Y. (2026). Restoration of radioiodine avidity after lenvatinib in NRAS- and TERT promoter-mutant radioiodine-refractory differentiated thyroid cancer: a case report. EJNMMI Reports, 10(1), Article 56. https://doi.org/10.1186/s41824-026-00334-3

Image Credits: AI Generated

DOI: 10.1186/s41824-026-00334-3

Keywords: differentiated thyroid cancer, radioiodine-refractory, lenvatinib, multikinase inhibitor, redifferentiation, NRAS mutation, TERT promoter mutation, salvage radioiodine therapy, thyroglobulin, case report, diagnostic whole-body scan, follicular variant papillary thyroid carcinoma