**6. Radioiodine refractory (RAI refractory)**

DTC cells can retain functions of follicular cells, such as iodide uptake and iodination, which allows RAI uptake for treating cancer [43]. Most DTC cases have a favorable prognosis after standard therapy, including total thyroidectomy, selective RAI therapy, and TSH suppressive therapy. NIS plays a role in the active transport of iodide into the thyroid follicular cells [9]. Functional NIS expression is regulated at the transcriptional and posttranslational levels, and TSH is primarily involved at the translational level [43]. Concerning posttranslational regulation, abundant NIS expression may mislocalize in the intracellular compartment rather than the cell membrane [43]. This mislocation targeting of NIS disturbs uptake and accumulation of radioiodine, inducing the failure of RAI therapy in DTC [10, 43]. The local recurrence and distant metastasis risk increase to 20% and 10%, respectively [10]. Among these cases, two-thirds show initial or gradual loss of the ability of iodine uptake due to the dysfunction, and even loss, of NIS expression in the basal membrane, indicating a status of dedifferentiation known as radioiodine-refractory (RAIR), which significantly reduces the 10-year survival rate less than 10% [9, 43].

Radioiodine refractory is when progressive dedifferentiation of the tumor cells leads to a loss of ability to accumulate RAI by non-functioning the sodium iodide symporter [43, 44]. The condition included is (a) tumor or metastatic site (one or multiple) that does not ever concentrate radioiodine (no avidity outside the thyroid bed on the initial post-therapy WBS); (b) tumor tissue that initially showed RAI avidity but lost the ability to concentrate on subsequent scans or treatments; (c) radioiodine is concentrated in some, but not all, sites of metastatic; (d) disease progression despite significant concentration of RAI (within 1 year of treatment) [10, 44].

Decreased NIS expression, diminished membrane targeting, or both, which are mainly caused by genetic and epigenetic alterations and dysregulated signaling pathways, are the primary mechanisms underlying RAIR [10]. Genetic alterations in MAPK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways by point mutations or chromosomal rearrangements are basic molecules in the pathogenesis of thyroid cancers and RAIR. Besides the signaling pathways, epigenetic and genetic alterations of other pathways, such as Wnt/ß-catenin and TGF-ß/Smad signaling pathways, are also related to the silencing of expression of thyroid-specific genes, resulting in RAIR [10, 28].

The evidence has demonstrated a strong association between the *BRAF*V600E mutation and RAI-avidity loss in PTC [43]. The *BRAF*V600E mutation can upregulate the expression of tumor-promoting genes, such as *TGFβ1,* mesenchymal-toepithelial transition factor [*MET*], vascular endothelial growth factor A [*VEGFA*], and thrombospondin 1 [*TSP1*]) [43, 45]. It can downregulate the expression genes of tumor suppressors such as tissue inhibitor of metalloproteinases 3 [*TIMP3*], death-associated protein kinase 1 [*DAPK1*]), and solute carrier family five-member 8 [*SLC5A8]*, [46]. *BRAF*V600E mutation induces the secretion of TGFβ, which can stimulate SMAD3 and impair PAX8, which cause a decrease in NIS expression [43]. Moreover, telomerase reverse transcriptase (*TERT*) promoter (TERTp) mutations are particularly prevalent in *BRAF*V600E mutation PTC. TERTp mutations were associated with aggressive tumor behavior and poor prognosis in thyroid cancer. They were also observed to be correlated with the reduction of RAI uptake in distant metastatic lesions of PTC [10, 43]. On the other hand, the RET/PTC rearrangement impacts the dedifferentiation of DTC remains limited. In vitro studies reported that alternation of RET/PTC could suppress the expression of thyroid differentiation markers (TPO, TSH receptor, thyroglobulin, and NIS) [47, 48]. Recently, oncogeneactivated signaling pathways have also been reported to control histone posttranslational modification affecting thyroid-specific genes' expression [10, 49]. This finding supports attempts to convert thyroid cancer into redifferentiated thyroid cancer by modulating histone acetylation and deacetylation [10, 43]. *BRAF*-activated NIS silencing could be influenced by histone deacetylation at critical regulatory regions of the *NIS* promoter [10].

## **7. Patient preparation**

The effectiveness of RAIT depends on patient preparation. Ideally, serum TSH levels reach ≥30 mU/L to optimize radioiodine uptake [50]. TSH elevation can be reached by waiting at least 3 weeks after thyroidectomy or 4–5 weeks after discontinuing treatment with levothyroxine (LT4). When thyroid hormone is withheld, it should be initiated or resumed 2 days after radioiodine administration [50]. Recombinant human thyrotropin (rhTSH) administration is an acceptable alternative to thyroid hormone withdrawal (TWH) based on ATA guidelines before remnant ablation or adjuvant treatment in low-risk and intermediate-risk DTC without extensive lymph node involvement. In extensive lymph node disease without distant metastasis, the rhTSH stimulation may be considered an alternative to THW before

*DOI: http://dx.doi.org/10.5772/intechopen.108481 Aspects Considered in Differentiated Thyroid Cancer for Radioiodine Therapy*

RAIT. The rhTSH is not approved yet by Food and Drug Administration (FDA) to treat distant metastases of DTC. The rhTSH stimulation is recommended for any patient with DTC regardless of the risk level if comorbidities exist that preclude THW [12]. Furthermore, patients should be advised to avoid iodine-containing medications (iodinated contrast agents, antiseptics, eye drops or amiodarone, and iodine-containing foods) for 4–6 weeks prior to RAIT to avoid competition with non-radioactive iodine. Moreover, a low-iodine diet (<50 μg/day), starting 1– 2 weeks prior to RAIT, is recommended optionally [50]. Patients are advised to avoid meals for at least 2 hours before and 2 hours after administering RAI because heavy meals can slow the absorption of RAI [16].

### **8. Follow-ups**

The follow-ups are carried out every 6 months (for the first 5 years after diagnosis), and if no pathological findings since the period, examinations are adequate annually [49, 51]. The follow-up assessment is based on the interview, clinical examination, cervical sonography, and determination of TSH and thyroid hormone levels, Tg, and Tg antibodies. When postoperative hypoparathyroidism occurs, substitution therapy is needed. A diagnostic WBS is obligatory 6–12 months after the initial RAIT, and the next WBS is needed if there is a relapse indication [12, 52]. Metastatic uptake on 131I-WBS confirms their capacity to concentrate RAI and the potential to respond to RAI in this condition as a permit for RAI activity to treat metastases.

The criteria for a disease-free (6–12 months) after initial therapy of DTC with total thyroidectomy and RAIT are no clinical signs of DTC and without pathological uptake in 131I-WBS (except the uptake showed after remnant ablation). A serum Tg is below the detection limit, and undetected Tg antibodies [12, 52]. In conditions with elevated/rising Tg serum levels and undetectable radioiodine uptake, F-18 fluorodeoxyglucose positron emission tomography (18FDG-PET) examination is recommended [49, 50, 53].

### **9. Conclusions**

The RAI administration aims at remnant ablation and adjuvant treatment for irradiating presumed foci of tumor cells to reduce the recurrence risk or treat persistent or recurrent disease. The risk stratification after thyroidectomy becomes pivotal in DTC management to offer an individualized therapy approach. The decisions should be taken depending on tumor features, patient-related factors, healthcare settings, and local team preferences. The local team was considered by interdisciplinary teams in the initial management of DTC patients, focusing on RAIT. Even though RAIT in the low-intermediate risk class is still debatable, RAIT is recommended in high-risk DTC without distant metastasis, showing improved outcomes and without controversial decisions.

### **Conflict of interest**

The author has no possible conflict of interest.
