Redifferentiation Therapy Improves Radioactive Iodine Treatment in Some Thyroid Cancer Patients

Clinical Thyroidology®Vol. 35, No. 5 Thyroid CancerFree AccessRedifferentiation Therapy Improves Radioactive Iodine Treatment in Some Thyroid Cancer PatientsGiuseppe BarbesinoGiuseppe BarbesinoThyroid Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.Search for more papers by this authorPublished Online:12 May 2023https://doi.org/10.1089/ct.2023;35.205-207AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Weber M, Kersting D, Riemann B, Brandenburg T, Fuhrer-Sakel D, Grunwald F, Kreissl MC, Dralle H, Weber F, Schmid KW, Herrmann K, Jentzen W, Grafe H, Rischpler C, Theurer S, Bockisch A, Nagarajah J, Fendler WP 2022 Enhancing radioiodine incorporation into radioiodine-refractory thyroid cancer with MAPK inhibition (ERRITI): A single-center prospective two-arm study. Clin Cancer Res 28:4194–4202. PMID: 35594174.SUMMARYBackgroundFollicular thyroid cells are uniquely able to concentrate iodine up to 30- to 40-fold above its blood concentration in normal conditions, and even up to 400- to 500-fold higher under intense thyrotropin (TSH) stimulation (1). Trying to exploit this property and thus destroy residual cancer deposits, the radioactive isotope of iodine (131I is administered after total thyroidectomy to select differentiated thyroid cancer patients, with little radiation exposure for other tissues (2). Unfortunately, some thyroid cancers, especially the most advanced or aggressive ones, lose the ability to accumulate and/or retain iodine, and are therefore refractory to this therapy. The BRAF V600E and other mutations activate the MAPK-MEK pathway, which in turn inhibits genes involved in iodine uptake and retention, resulting in radioiodine refractoriness (3). This study assessed the action of tyrosine kinase inhibitors on mutated BRAF and/or MEK to restore iodine uptake and efficacy in patients with radioactive iodine–refractory thyroid cancer.MethodsThis prospective, single-center, 2-arm phase 2 study (4) included patients with unresectable or radioiodine-refractory thyroid cancer, with the latter defined as insufficient iodine accumulation in one or more lesions. Patients were also required to have associated structural disease, defined as at least one measurable lesion >15 mm, and available BRAF mutation status.The iodine refractoriness and disease measurements were assessed with a preliminary, TSH-stimulated 124I PET-CT scan. The patients were then treated for 3 weeks with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib if their tumor was BRAF-mutated or with trametinib alone if their tumor was BRAF wild-type. After the 3-week period, a TSH-stimulated 124I PET-CT was repeated. The primary end point was the recovery of meaningful iodine uptake at the end of treatment. Responsive patients were treated with personalized 131I treatment doses. Reduction in serum thyroglobulin and a response by RECIST 1.1 criteria were secondary end points.ResultsTwenty patients were included in the study—10 with papillary thyroid carcinoma, 7 with follicular thyroid carcinoma, and 3 with poorly differentiated thyroid carcinoma. Six patients had BRAF-mutated thyroid carcinoma, while 14 had BRAF wild-type cancers.Overall, 7 patients (35%) met imaging criteria for successful redifferentiation (36% of those with BRAF wild-type tumors and 33% of those with BRAF-mutated tumors). Patients who successfully achieved redifferentiation of their thyroid cancer were treated with high 131I activities, as dictated by dosimetry (mean dose, 300 mCi). The mean absorbed dosed per administered activity increased 9-fold after successful redifferentiation, from 0.03 Gy/mCi to 0.28 Gy/mCi. A drop in serum thyroglobulin was observed in 4 of the 7 cases. Although a decrease in the lesional diameter was observed in 6 of 7 patients, a drop greater than 30% was observed in only one patient. Interestingly, a post hoc analysis indicated that tumors with lower FDG uptake were more likely to respond. The treatment was well tolerated, with only two grade 3 or 4 events, and all were considered to be manageable.ConclusionsIn this phase 2 study of patients with advanced thyroid cancer, pretreatment inhibition of the MAPK-MEK cascade induced partial restoration of iodine uptake and retention in one third of the cohort. In the majority of these patients, subsequent treatment with high-dose 131I was then successful in achieving partial biochemical and structural responses.COMMENTARYRadioiodine has been used to treat thyroid cancer since the 1940s. However, among those patients not cured by surgery, many will not be cured by radioiodine either. Paradoxically, patients most likely to respond to radioactive iodine are the ones least in need of it—they are the ones with the smallest burden of disease and the least aggressive tumors (5). There is a negative correlation between iodine and glucose uptake in cancer cells, which in turn correlates with aggressive tumor behavior and prognosis (6,7). Temporarily targeting the specific alterations causing the dedifferentiation, followed by radioiodine, is a clever strategy to minimize the use of potentially toxic drugs and effectively treat unresectable disease.This study, together with others (8), shows the potential, but also the current limits, of this approach. About one third of patients in the cohort achieved sufficient iodine uptake, and structural responses to high doses of radioiodine were modest. These results may pave the way for further therapies in these patients with relatively limited options. In the near future, I hope to learn whether these protocols can be optimized to improve efficacy, whether multiple courses of treatment will add to the benefit seen, and whether they will result in improved life expectancy and/or delay the need for long-term systemic therapy.Disclosures: The author has no relevant conflicts of interest to declare.References1.Wolff J 1964 Transport of iodide and other anions in the thyroid gland. Physiol Rev 44:45–90. Crossref, Medline, Google Scholar2.Mazzaferri EL, Jhiang SM 1994 Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418–428. Crossref, Medline, Google Scholar3.Fagin JA, Wells SA Jr 2016 Biologic and clinical perspectives on thyroid cancer. N Engl J Med 375:1054–1067. 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