Collateral Effects of 131I Therapy: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Peter Tang and Version 2 by Angela Spanu.

The most common thyroid cancer is differentiated thyroid cancer (DTC) which accounts for over 95% of cases. A suitable choice for the treatment of DTC is systemic administration of sodium 131 or potassium iodide. It is an effective tool used for irradiation of thyroid residues, microscopic DTCs, other unresectable or incompletely resectable DTCs, or for all purposes mentioned.

  • Differentiated Thyroid Cancer
  • personalized dosimetry
  • radioiodine therapy

1. Introduction

The most common thyroid cancer is differentiated thyroid cancer (DTC) which accounts for over 95% of cases [ 1 ][1]. It had become the most common cancer in women by the year 2020 after breast cancer, colorectal cancer, lung and cervical cancer [GLOBOCAN2020]. Although it represents only 1% of all human malignancies, it has been found in 5% of thyroid nodules and, in turn, has a prevalence of 20-30% in the general population [ 2 ][2]. The histological derivation is the follicular epithelium from which it maintains histological characteristics such as the expression of sodium iodide symporter (NIS) [ 3][3]. Thyroid follicular epithelial cells represent the embryological derivation of DTC. Classically, it can be divided into three histological types: papillary thyroid cancer (also known as PTC, the most common), follicular thyroid cancer (FTC, the second most common) and Hürthle cell thyroid cancer. The latter was considered a particular type of FTC, but due to the significant histopathological and molecular differences it was classified as an independent tumor type in 2017 by the World Health Organization. Hürthle cell carcinoma is thus defined as a derivation of follicular cell carcinoma of the thyroid and not a variant [ 4 ][4].
Although the causes of thyroid cancer are unknown, many studies have evaluated risk factors. High-risk factors in the development of DTC are radiation exposure to the head and neck region, chromosomal alterations such as mutations in the RAS and BRAF genes and expression of the PAX8 / PPARγ fusion protein, and hereditary conditions such as bone marrow cancer. thyroid, syndromic and non-syndromic familial non-medullary thyroid cancer. Low risk factors are thyroid imaging with iodine 131 ( 131I), iodine deficiency, elevated levels of thyroid stimulating hormone (TSH), autoimmunity, presence of thyroid nodules and environmental pollutants, but also lifestyle, diet and elevated BMI. It is unclear whether estrogen plays a role in increasing risk: some studies have reported an increasing risk associated with exogenous estrogen, while ovarian estrogen loss lowers it. Estradiol is considered a stimulator of benign and malignant neoplasms [ 5 , 6 ][5][6]. Last but not least, histological type, in particular high cell cancer and columnar cell cancer, but also vascular, lymphatic and distant metastasis are also considered risk factors contributing to a poor prognosis [ 7 ][7].

2. Risk classification

Regarding the prognosis, the risk of cancer death from DTC was estimated by the TMN classification. It has been established in classes V: Group I includes patients under the age of 55 with any T and N, Mo, and the cancer-related risk of death is <2%. Class II represents patients with any T and N except M1 or patients aged 55 years or older and TMN T1 / T2 N1 M0 or T3a / T3b classification, any N and M0. In this group the risk is 5%. Group III included patients aged 55 or older with T4a, any N and M0 with a 5-20% risk. Class IVa identifies subjects with at least 55 years of T4b, any N, M0 and a risk> 50%. Class IVb has a risk of death> 80%, with any T, any N and M1 [ 16 , 17 ] [8][9] (seeTable 1 ).
Table 1.
Risk of cancer-related death for DTC by TMN classification.

Class

Class

Age

T

N

Risk of Recurrence

Histology

M

Percentage Risk

ATA Recommendation for Therapy

I

<55 years

Any

low

<5%

PTC and well-differentiated and minimally invasive FTC

and

Any

No vascular invasion, no local and distant metastasis

M0

Not recommended

<2%

II

  

Any

intermediate

Any

M1

5–20%

Aggressive histology or vascular invasion (e.g., tall cell, insular, columnar cell carcinoma, Hurthle cell carcinoma, follicular thyroid cancer)

Or

Microscopic invasion into the perithyroidal soft tissues

Or

Cervical lymph node metastases

Or

131I uptake outside the thyroid bed on the post-treatment scan

Recommended

5%

high

>20%

Macroscopic tumor invasion

Or

Incomplete tumor resection with gross residual disease

Or

Distant metastasis

Recommended
More than 80% of patients are identified as low risk [19][12]. The risk influences therapy management: for ATA iodine therapy is not recommended for the residual ablation in low-risk DTC, while adjuvant therapy is recommended in intermediate-risk with activities between 30 mCi (1110 MBq) and 150 mCi (5550 MBq). In 70-year-old or older patients, activities up to 200 mCi (7400 MBq) of 131I are desirable to avoid possible adverse events.

3. Indications for 131I-Therapy

3.1. EAMN Recommendations

European Association of Nuclear Medicine (EANM) guidelines recommended 131I therapy only for the ablation of thyroid remnants as a post-surgical adjuvant procedure, for microscopic or incompletely resectable DTC, other non-resectable lesions, or both purposes (See Table 3).
Table 3.
EANM Indications, contraindications, and relative contraindications for RAIT.

Indications

Contraindications

Relative Contraindications

adjuvant treatment post-surgery of persistent or recurrent iodine avid lesions (DTC)

Pregnancy and breastfeeding (absolute contraindication)

bone marrow depression

less differentiated tumor histotypes, such as papillary tall-cell, columnar cell or diffuse sclerosing or follicular widely invasive, poorly differentiated, or Hürthle cell

unifocal papillary thyroid cancer ≤1 cm sized without metastasis

pulmonary function restriction

II

≥55 years

T1/T2

patients > 45 years

thyroid capsule invasion

N1

salivary gland function restriction

M0

5%

II

≥55 years

T3a/T3b

Intolerance to surgery

history of radiation exposure

Any

neurological symptoms

M0

5%

III

≥55 years

T4a

Any

M0

5-20%

Intolerance to other therapies (e.g., chemotherapy)

tall-cell, columnar cell, or diffuse sclerosing histotypes

VAT

≥55 years

T4b

Any

M0

>50%

IVb

  

Any

Any

M1

>80%
Hürthle cell, invasive FTC, tall cell, diffuse sclerosis variant, and columnar cell carcinomas are characterized by the worst prognosis due to their high vascularity and therefore a higher risk of hematogenic spread. It is common in patients with these histological types to have metastases at diagnosis [18][10]. Risk classification is a milestone for iodine treatment. The therapy of DTC is customized on the basis of histological classification and Tumor Nodes Metastasis (TNM) staging and risk of recurrence. In particular, the risk of structural recurrence has been valued by the American Thyroid Association (ATA) on the basis of histological characteristics such as capsular, lymph nodes, and vascular invasion, the presence of aggressive histologic type, the number of lymph nodes metastasis, and thyroglobulin serum levels. The patients are, therefore, classified at a low (recurrence risk <5%, it is the case of PTC and well-differentiated and minimally invasive FTC), intermediate (5–20%), or high (>20%) risk of recurrence [15][11] (See Table 2).
Table 2. ATA risk of recurrence classification and corresponding ATA recommendation for RAIT from 2015 ATA Management Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

Neurological damage (edema)
The administration of RAIT also for ATA and EANM ought to be limited to remnant ablation, adjuvant treatment, or treatment of known diseases such as locoregional metastasis and distant metastasis [20][13]. In particular, RAIT is recommended in microscopic DTC. It finds explication in better results of RAIT in microscopic or small macroscopic tumors than in larger lesions [12][14]. The intention of cure or palliation using RAIT should be considered case by case, which represents the best choice as adjuvant treatment post-surgery of persistent or recurrent DTC until the lesion is iodine avid. Lymph nodes, lung, and most tissue metastasis can be successfully treated by RAIT with or without the auxilium of surgery, while bone and brain metastasis does not have a high rate of cure [21][15]. Moreover, less differentiated RAIT tumor histotypes, such as papillary tall-cell, columnar cell or diffuse sclerosing or follicular widely invasive, poorly differentiated, or Hürthle cells, have a greater risk of relapse and a lower overall survival but, despite diminished NIS expression, such tumors may be responders to RAIT [22][16]. RAIT should be also considered in patients >45 years since the most aggressive forms are diffused in older age and have a reduced overall survival [15][11], but also in patients unable to tolerate surgery or other eventual other therapies such as chemotherapy. According to recent European guidelines, in addition to pregnancy and breastfeeding, exclusions for RAIT are patients with unifocal papillary thyroid cancer ≤1 cm sized without metastasis, thyroid capsule invasion, or a history of radiation exposure. Additionally, tall-cell, columnar cell, or diffuse sclerosing subtypes are excluded [3]. Relative exceptions are bone marrow depression, pulmonary function restriction, especially if lung metastasis is present, and salivary gland function restriction. It is also necessary to evaluate the presence of neurological symptoms or damage since inflammation and local edema due to RAIT effect on cerebral metastasis could result in severe compression effects. Furthermore, 18F-fluorodeoxyglucose (18F-FDG) uptake in metastases is an evident indicator of the presence of radioiodine non-avid disease and a considerable independent unfavorable prognostic indicator. Specifically, the numbers of FDG-avid lesions and the higher maximum standard uptake values (SUVmax) correlate with overall mortality [23][17]. Radioiodine therapy is commonly well tolerated even if it has been suggested to be a potential second primary malignancy superior to 30% in a study conducted on 13 types of cancers [24][18]. However, EAMN evaluated that risk to be inferior to 1% in a latency period of ≥5 years. More cases have been observed when cumulative radioiodine activities exceed 20–30 GBq [25,26][19][20]. To maximize therapeutic effects and minimize collateral events, the maximum activity allowed has been proposed. A single administration of 1–5 GBq is recommended for the ablation of post-surgical thyroid remnants, even if there are different clinical practices among centers. It remains controversial which activities between 1.11GBq, 1.85 GBq, or 3.7 GBq are the best option. A systematic review by Hackshaw et al. established that ablation success rates are similar using 1.11 GBq and 3.78 GBq of 131I [27][21]. The accepted dosimetry approach is the blood-based method that takes into account blood and the whole body as compartments under the assumption that a similar iodine concentration has been found in blood and red marrow [28][22]. Still, the presence of extended metastatic bone involvement represents a limitation for the method due to the underestimation of the absorbed dose in red marrow. Likewise, in the presence of diffuse pulmonary micro-metastases, this method should be applied with caution because the critical organ, in this case, is the lung and not red marrow so dosimetry could be applied to the lung [29,30][23][24].

3.2. ATA Recommendations

For ATA, adjuvant treatment after total thyroidectomy should be deemed in intermediate-risk and high-risk DTC using activities between 30 mCi (1110 MBq) and 150 mCi (5550 MBq) [31][25]. However, a common practice was determining the activity through empiric fixed doses chosen by physicians on the basis of experiences, convention, and patient parameters [32,33][26][27]. The method mostly used was Beierwaltes’s proposal [34][28]. It considers that the administered activity should not exceed 5.55–6.2 GBq for regional nodes that could not be removed by surgery, 6.2–7.4 GBq for pulmonary metastasis, and 7.4 GBq for skeletal metastasis. Other intermediate activities were used such as Schlumberger et al. [35][29], which used an initial activity of 3.7 GBq of 131I for pulmonary and bone metastasis every 3–6 months, and Menzel et al., which used a fixed activity of 11.1 GBq at 3-month intervals [36][30]. In this regard, a riveting study by Iizuka and collaborators makes a comparison between clinical outcomes of intermediate-high risk patients treated with high-dose and low-dose iodine therapy [37][31]. For low-dose therapy is intended the administration of 1100 MBq of 131I, while the high-dose is defined as 2960–3700 MBq of 131I administration. They collocated initial success with a thyroglobulin (Tg) level inferior to 2.0 ng/mL without thyroid-stimulating hormone administration and no 131I uptake in the thyroid region at 131I scintigraphy performed 6–12 months after RAIT. The conducted analysis established that the success rate of iodine therapy tended to be superior in high-risk patients treated with high-dose therapy even if no statistical differences have been found between the two groups in terms of success rate. These results reveal that in high-risk patients, a high-dose treatment is preferable. On the other side, Qu et al. evaluated the therapeutic response between low- and intermediate-risk patients treated with high-activity (3.7 MBq) and low-activity (1.1 MBq) [38][32]. The ablation and therapeutic results were similar between the two groups. Lymph node involvement and serum Tg seemed to influence ablation and therapeutic response, respectively. The success rate of ablation was lower for patients in the N1b stage than for patients in the N0 stage, while increased with lower serum Tg levels. In particular, they noted that a pre-treatment Tg level was associated with a higher better response: a level of 0.47 μg/L was a cut-off for predicting ablation results and a level of 3.09 μg/L for predicting therapeutic response. Thirty-two years of follow-up in DTC patients after RAIT was conducted by Martins-Filho and colleagues, to evaluate tumor behavior in correlation with cumulative iodine doses and survival. Patients with higher Tg serum levels had progressive disease and needed more frequent and higher doses of iodine treatment [39][33]. They observed that a patient with an age below 45 years had a 70% chance of complete remission with a cumulative activity of 100 mCi. If the activity ranges in 1 Ci, there is a 27% chance of stabilizing the disease. A high chance of progression was evident for cumulative activities of 600 mCi in a patient with an age above 45 years, and also for cumulative activities of 800 mCi or higher in a patient under 45 years. The data suggest a careful evaluation of further RAIT. There also is no common line of decision making for children since some centers set the activity by body weight or surface area or by age [40][34], while for German guidelines it should be adjusted according to the 24 h thyroid bed uptake and body weight: if uptake is <5%, the activity should be 50 MBq/kg, 5–10% uptake would assure an activity of 25 MBq/kg and 10–20% uptake an activity of 15 MBq/kg [41][35].

3.3. RAIT in Metastatic DTC

A field that needs standardized applications again is RAIT in metastatic DTC. There had been multiple differentiated approaches in the past and present among centers. First of all, the empiric proposals: Beierwalters et al. provided 6.48 GBq (175 mCi) for lung and 7.4 GBq (200 mCi) for bone [34][28]; Schlunmberger et al. used 3.7 GBq (100 mCi) every 3 months to 6 months until whole-body scan (WBS) was negative [31][25]; Petrich et al. used a therapeutic activity of 3.7 GBq (100 mCi) and if metastasis were still evident, they retreated the patient with 7.4 GBq (200 mCi) [42][36]; Brown et al. used 5.5 GBq (150mCi) every 3–4 months until the scan was negative of there was progression; Menzel et al. administered 11.1 GBq (300 mCi) every 3 months [36][30]; Durante et al. opted for 3.7 GBq (100 mCi) every 3–9 months during the first 2 years, once a year after until no metastasis was evident [12][14]; Hindle et al. used 3.7 GBq (100 mCi) every 6 months if there was lung uptake and chest radiography was negative, but if a cumulative activity of 18.5 GBq (500 mCi) was reached and lung uptake was present, reduced the therapy once a year and then every 2 years [43][37]. Again, Hindle et al. recommended the use of activity between 3.7 and 5.5 GBq (100–150 mCi) every 6 months when lung uptake was evident but also chest radiography was [44][38]. Ghachem et al. compared the ablation rate between patients treated with 1.1 to 1.85 GBq and patients treated with 3.7 GBq of 131I [45][39]. They had a similar ablation rate but the likelihood to have remission was 1.83 times greater for higher activity determining that mini dose protocol is not more effective in ablation than the higher dose protocol. 2013/59 EURATOM recommended for metastatic DTC that the optimal activity is the one that permits the best response rate and low toxicity even if it is still in debate and the same international guidelines do not suggest if it is preferable to use empiric or dosimetry-based therapies in these patients [46][40].

4. Collateral Effects of 131I Therapy

4.1. Bone Marrow Deficiency

The side effects of RAIT, especially on bone marrow, have been widely described even if the great majority of these studies do not evaluate them through dosimetry studies. In an intriguing review by Andresen et al. [47][41], adverse effects have been related to dose levels summarizing what was reported in the literature.
To exclude the possibility to have bone marrow damage, the absorbed dose to the blood should not exceed 2 Gy, and the whole-body retention after 48 h from the administration should not be superior to 4.4 or 3 GBq in the absence or presence of iodine-avid diffuse lung metastases, respectively [48,49][42][43].

4.2. Nausea, Neck Pain, Lacrimal and Salivary Disfuntion

The considered side effects such as nausea, neck pain, lacrimal and salivary dysfunction, and altered smell and taste seem to be acute effects that are more frequent in therapies with 100 mCi, and less frequent for dosages between 30 and 50 mCi (respectively, 13% vs. 4%, 17% vs. 7%, 10–24% vs. 8–20%, 5–16% vs. 6–13%, 6% vs. 0 and 2% vs. 0). Sialadenitis has a frequency between 2 and 67% and nasolacrimal duct obstruction 3.4% [50][44].
RAIT should be carefully evaluated in patients with restriction of salivary to minimize side effects (e.g., xerostomia) since salivary glands are the physiological site of iodine uptake. It happens because of the presence of NIS, a plasma membrane glycoprotein, that mediates active I(-) transport in various organs such as the thyroid, the previously written salivary glands, stomach, lactating breast, and small intestine [51][45]. Acute salivary gland swelling and pain decrease a few days after 131I-therapy in patients with DTC but, in some patients, the onset of these symptoms is slower. In other patients, the symptoms could lead to chronic radiation sialadenitis. These complications are clinically significant in 10–30% of subjects even if their frequency is not well known [52,53,54,55,56,57,58][46][47][48][49][50][51][52]. In particular, in the prospective cohort study by Hyer et al., patients were treated with an ablative activity of 3GBq and a further of 5.5 GBq in case of residual disease. Of the 79 patients examined, 26% developed salivary gland toxicity after iodine therapy, with a median onset of 48 h after 131I administration and a median duration of symptoms of 12 months. The reported symptoms were xerostomia in all cases, 2 patients were referred with an episode of swelling and pain, 6 patients had two episodes, and 8 subjects had three or more episodes. The submandibular gland was interested in 50% of subjects, parotid in 39%, and 11% of patients had both glands affected. Among these patients, 55% had lymph node metastasis while only 32% of patients without salivary gland involvement had lymphatic metastasis. The mean cumulative activities were 8.57 GBq in patients with salivary complications, 9.04 GBq for the others. These results demonstrated that repeated activities were more associated with the development of salivary gland toxicity. Conversely, cumulative doses seemed not to be related suggesting how it is more damaging repeated doses than a single dose [59][53]. Since sialadenitis is not always clinically evident, many other studies using 99mTC-pertechnetate scintigraphy were conducted to evaluate salivary gland function. Abnormalities at salivary gland scintigraphy were noted with activities of more than 18.5 GBq 131I [60][54], but also with activities between 3.7 GBq and 38.7 GBq of 131I [61][55]. As regards the timing of symptoms that arise, it was reported from months to years after RAIT [58[52][56],62], and in a study by Allweiss et al. [57][51], they continued up to 2.5 years later. It was also reported an increase of risk in developing salivary gland neoplasm such as pleomorphic adenoma, non-Hodgkin’s lymphoma, and mucoepidermoid carcinoma and it is proportional to the 131I dose [60][54]. Moreover, it seems that the administration of lemon candy post-therapy increases the risk of acute and chronic salivary gland toxicity. The rationale for using lemon candy after iodine administration is based on the concept that ascorbic acid increases the salivary flow and then iodine clearance. On the other flip, it enhances blood flow to rising 131I uptake. In the context of diminished glomerular filtration rate determined by hypothyroidism, the serum level of 131I is high. Additionally, the remnant or metastatic tissues are not so avid as the normal thyroid. Consequently, the continuous consumption of lemon candy could only improve this condition leading to a greater amount of dose to the salivary gland [63][57].

4.3. Sexual Sphere Side Effects

Male and female infertility have subacute latency, differently from the upper cited sialadenitis but also from nasolacrimal duct obstruction, and the onset of secondary malignancy that are late effects that seem to be evident only for 131I activity major to 100 mCi. Notably, in males, a transient decrease of follicle-stimulating hormone (FSH) levels and reduced sperm motility were evident while in women it has been observed lower birth rate in the age group between 35 and 39 years.
A potential impact has been pointed out by Bourcigaux et al. on exocrine and endocrine testicular function after 3.7 GBq iodine administration. They observed Sertoli cell function and induced sperm chromosomal abnormalities 3 months and 13 months after therapy [64][58].

4.4. Second Recurrences

According to literature from 30 to 40 years old, recurrences were thought to occur 10–20 years after RAIT. Today, thyroid cancer is presented at an earlier stage and has a lower recurrence rate of 3–10% [51,52,53,54][45][46][47][48]. Moreover, Carrillo et al. demonstrated that patients with DTC treated with 131I, which have a biochemical recurrence and no diagnostic WBS (DWBS) or extensive studies, have lower frequencies of second recurrence (SR) compared to the group that, prior RAIT, underwent a DWBS with 5 mCi of 131I and Magnetic Resonance Imaging (MRI) and/or 18F-FDG PET if DWBS was negative [55][49]. In a study by Rubino et al., second primary malignancies (SPM) and leukemia risk were evaluated. They selected a cohort of 6841 Swedish, Italian, and French patients with FTC or PTC diagnosed during the period 1934 and 1995 [25][19]. In total, 576 patients had SPM and among them, 13 presented a third malignant neoplasm less than 2 years after. The risk of cancer was globally increased by 27% compared to the general population of the same countries. The mean time between thyroid cancer diagnosis and SPM presentation was 15 years. No gender differences were observed. The cancer types with a significantly increased risk were cancers in the digestive tract, bone and soft tissue, skin melanoma, kidney, central nervous system, endocrine glands (excluded thyroid), leukemias, female breast cancer, and genital male malignancies. No association between SPM and external radiotherapy was observed, so no interactions between them could be described. In total, 13 cases of oral cancer were counted, and of them, 7 were caused by 131I administration. They also demonstrated a significant association between cumulative activities of 131I and the risk of solid cancer, with an increase of 4% per GBq.

4.5. The Stunning Fenomenon

Another noteworthy event to take into consideration for RAIT success is represented by the “stunning” phenomenon. It consists of the diminishing of iodine uptake due to the suboptimal therapeutic effects, biological effects, or both, caused by a previous diagnostic radioiodine administration. To avoid this phenomenon, it is suggested to shun unnecessary pre-therapeutic 131I administration, when the indications to RAIT are clear, or if necessary, to use lower radioiodine activities before RAIT. Hence, an activity of 3–10 MBq is recommended for uptake quantification and 10–185 MBq for WBS. An alternative could be opting for other tracers such as 123iodine (123I), 99mTechnetium (99mTc), or 124I in PET/CT. Dosimetry studies demonstrated that activities of 10–20 MBq represent a considerable radiation burden for thyroid cells. The stunning effect seems to be caused by direct radiation damage to thyrocytes [65,66,67,68,69,70,71,72,73][59][60][61][62][63][64][65][66][67]. This results in a diminishing in iodine transportation by 50% also with an absorbed dose of 3 Gy [74][68] and down-regulation in NIS expression [75][69]. These phenomena lead to a diminishing in iodine uptake [69][63]. In this regard, Verburg and collaborators compared two groups of patients, one undergone a pre-ablative 24 h uptake measurement with 40 MBq 131I and the other without pre-ablative diagnostic scintigraphy [65][59]. They demonstrated how the success rate of ablation was 2 times greater in the group without pre-ablative scintigraphy than in the group that underwent a pre-therapeutic uptake study. Similar results were cited in the papers: Jeevanram et al., who reported a decrease of 20–25% uptake when the activity of 111–185 MBq was used for pre-ablation scan [76][70]; Lassman et al., after 74 MBq [66][60]; Muratet et al., for 111 MBq [77][71]; Hu et al. and Lees et al., after using 185 MBq [67,78][61][72]; and Park et al., for 370 MBq [79][73]. No stunning events were observed in groups undergoing 37 MBq scans [77][71], with 123I or without any pre-therapeutic scans [78][72].

4.6. Reduced Kidney Function and Dosimetry Considerations

Notably, patients with reduced kidney function or hemodialysis reached higher bone marrow doses per unit of administered activity [33][27]. Recently, in low-risk cancer, the long-term cancer control rates were equivalent if therapeutic activities between 30–50 mCi or major or equal to 100 mCi were used [80][74]. In contrast, it was suggested that higher doses could better control cancer in intermediate- and high-risk patients [47,81][41][75]. In a recent phase III trials, Schlumberger et al. proved equivalent rates of thyroid remnant ablation with 30 versus 100 mCi [82][76]. Mallick et al., instead, asserted that low-dose using recombinant human thyrotropin alfa was as effective as high-dose radioiodine, but it has a lower rate of side effects [83][77]. In a paper by Khang et al., the mortality risk for SR is higher for patients with a cumulative 131I activity > 37 GBq. On the other hand, the risk of DTC-specific mortality is lower compared to the group which received a cumulative activity < 37 GBq and has similar all-cause mortality to low-activity RAIT patients [84][78]. In a study by Klubo-Gwiezdzinska et al., it was well demonstrated that the dosimetry approach has more efficacy compared to the empiric approach [85][79]. These considerations highlight how the dosimetry-based approach is more effective and represents a key role for a more personalized therapy, especially in patients with metastatic disease to minimize side effects.

References

  1. Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet 2016, 388, 2783–2795.
  2. Pacini, F.; Basolo, F.; Bellantone, R.; Boni, G.; Cannizzaro, M.A.; De Palma, M.; Durante, C.; Elisei, R.; Fadda, G.; Frasoldati, A.; et al. Italian consensus on diagnosis and treatment of differentiated thyroid cancer: Joint statements of six Italian societies. J. Endocrinol. Investig. 2018, 41, 849–876.
  3. Luster, M.; Clarke, S.E.; Dietlein, M.; Lassmann, M.; Lind, P.; Oyen, W.J.; Tennvall, J.; Bombardieri, E. Guide-lines for radioiodine therapy of differentiated thyroid cancer. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 1941–1959.
  4. Fariduddin, M.M.; Syed, W. Hurthle Cell Thyroid Carcinoma; StatPearls Publishing: Treasure Island, FL, USA, 2022.
  5. Luo, J.; Hendryx, M.; Manson, J.E.; Liang, X.; Margolis, K.L. Hysterectomy, Oophorectomy, and Risk of Thyroid Cancer. J. Clin. Endocrinol. Metab. 2016, 101, 3812–3819.
  6. Bogović Crnčić, T.; Ilić Tomaš, M.; Girotto, N.; Grbac Ivanković, S. Risk Factors for Thyroid Cancer: What Do We Know So Far? Acta Clin. Croat. 2020, 59, 66–72.
  7. Duntas, L.; Grab-Duntas, B.M. Risk and prognostic factors for differentiated thyroid cancer. Hell. J. Nucl. Med. 2006, 9, 156–162.
  8. Brierley, J.D.; Gospodarowicz, M.K.; Wittekind, C. TNM Classification of Malignant Tumours, 8th ed.; John Wiley & Sons: Hoboken, NJ, USA, 2017.
  9. Tuttle, R.M.; Haugen, B.; Perrier, N.D. Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (Eighth Edition): What Changed and Why? Thyroid 2017, 27, 751–756.
  10. Sciuto, R.; Romano, L.; Rea, S.; Marandino, F.; Sperduti, I.; Maini, C.L. Natural history and clinical outcome of differentiated thyroid carcinoma: A retrospective analysis of 1503 patients treated at a single institution. Ann. Oncol. 2009, 20, 1728–1735.
  11. Eustatia-Rutten, C.F.A.; Corssmit, E.P.M.; Biermasz, N.R.; Pereira, A.M.; Romijn, J.A.; Smit, J.W. Survival and Death Causes in Differentiated Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 2006, 91, 313–319.
  12. Haugen, B.R.; Alexander, E.K.; Bible, K.C.; Doherty, G.M.; Mandel, S.J.; Nikiforov, Y.E.; Pacini, F.; Randolph, G.W.; Sawka, A.M.; Schlumberger, M.; et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016, 26, 1–133.
  13. Tuttle, R.M.; Ahuja, S.; Avram, A.M.; Bernet, V.J.; Bourguet, P.; Daniels, G.H.; Dillehay, G.; Draganescu, C.; Flux, G.; Führer, D.; et al. Controversies, Consensus, and Collaboration in the Use of (131)I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medi-cine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid 2019, 29, 461–470.
  14. Durante, C.; Haddy, N.; Baudin, E.; Leboulleux, S.; Hartl, D.; Travagli, J.P.; Caillou, B.; Ricard, M.; Lum-broso, J.D.; De Vathaire, F.; et al. Long-term outcome of 444 patients with distant metastases from papil-lary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J. Clin. Endocrinol. Metab. 2006, 91, 2892–2899.
  15. Pelizzo, M.R.; Boschin, I.M.; Toniato, A.; Pagetta, C.; Piotto, A.; Bernante, P.; Casara, D.; Pennelli, G.; Rubello, D. Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): A mono-institutional 12-year experience. Nucl. Med. Commun. 2004, 25, 547–552.
  16. Besic, N.; Vidergar-Kralj, B.; Frkovic-Grazio, S.; Movrin-Stanovnik, T.; Auersperg, M. The role of radioactive iodine in the treatment of Hürthle cell carcinoma of the thyroid. Thyroid 2003, 13, 577–584.
  17. Robbins, R.J.; Wan, Q.; Grewal, R.K.; Reibke, R.; Gonen, M.; Strauss, H.W.; Tuttle, R.M.; Drucker, W.; Larson, S.M. Real-Time Prognosis for Metastatic Thyroid Carcinoma Based on 2-Fluoro-2-Deoxy-d-Glucose-Positron Emission Tomography Scanning. J. Clin. Endocrinol. Metab. 2006, 91, 498–505.
  18. Sandeep, T.C.; Strachan, M.W.; Reynolds, R.M.; Brewster, D.H.; Scélo, G.; Pukkala, E.; Hemminki, K.; An-derson, A.; Tracey, E.; Friis, S.; et al. Second primary cancers in thyroid cancer patients: A multination-al record linkage study. J. Clin. Endocrinol. Metab. 2006, 91, 1819–1825.
  19. Rubino, C.; De Vathaire, F.; Dottorini, M.E.; Hall, P.; Schvartz, C.; Couette, J.E.; Dondon, M.-G.; Abbas, M.T.; Langlois, C.; Schlumberger, M. Second primary malignancies in thyroid cancer patients. Br. J. Cancer 2003, 89, 1638–1644.
  20. De Vathaire, F.; Schlumberger, M.; Delisle, M.J.; Francese, C.; Challeton, C.; De La Genardiére, E.; Meunier, F.; Parmentier, C.; Hill, C.; Sancho-Garnier, H. Leukaemias and cancers following iodine-131 administration for thyroid cancer. Br. J. Cancer 1997, 75, 734–739.
  21. Hackshaw, A.; Harmer, C.; Mallick, U.; Haq, M.; Franklyn, J.A. 131I Activity for Remnant Ablation in Patients with Differentiated Thyroid Cancer: A Systematic Review. J. Clin. Endocrinol. Metab. 2007, 92, 28–38.
  22. Sgouros, G. Blood and bone marrow dosimetry in radioiodine therapy of thyroid cancer. J. Nucl. Med. 2005, 46, 899–900.
  23. Sgouros, G.; Song, H.; Ladenson, P.W.; Wahl, R.L. Lung toxicity in radioiodine therapy of thyroid carcinoma: Development of a dose-rate method and dosimetric implications of the 80-mCi rule. J. Nucl. Med. 2006, 47, 1977–1984.
  24. Song, H.; He, B.; Prideaux, A.; Du, Y.; Frey, E.; Kasecamp, W.; Ladenson, P.W.; Wahl, R.L.; Sgouros, G. Lung dosimetry for radioiodine treatment planning in the case of diffuse lung metastases. J. Nucl. Med. 2006, 47, 1985–1994.
  25. Ciarallo, A.; Rivera, J. Radioactive Iodine Therapy in Differentiated Thyroid Cancer: 2020 Update. Am. J. Roentgenol. 2020, 215, 285–291.
  26. Van Nostrand, D.; Atkins, F.; Yeganeh, F.; Acio, E.; Bursaw, R.; Wartofsky, L. Dosimetrically Determined Doses of Radioiodine for the Treatment of Metastatic Thyroid Carcinoma. Thyroid 2002, 12, 121–134.
  27. Verburg, F.A. Advantages of dosimetry in 131I therapy of differentiated thyroid carcinoma. Q. J. Nucl. Med. Mol. Imaging 2019, 63, 253–257.
  28. Beierwaltes, W.H. The treatment of thyroid carcinoma with radioactive iodine. Semin. Nucl. Med. 1978, 8, 79–94.
  29. Schlumberger, M.; Tubiana, M.; De Vathaire, F.; Hill, C.; Gardet, P.; Travagli, J.P.; Fragu, P.; Lumbroso, J.; Caillou, B.; Parmentier, C. Long-term results of treatment of 283 patients with lung and bone metastases from differen-tiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 1986, 63, 960–967.
  30. Menzel, C.; Grünwald, F.; Schomburg, A.; Palmedo, H.; Bender, H.; Späth, G.; Biersack, H.J. “High-dose” radio-iodine therapy in advanced differentiated thyroid carcinoma. J. Nucl. Med. 1996, 37, 1496–1503.
  31. Iizuka, Y.; Katagiri, T.; Ogura, K.; Mizowaki, T. Comparison between the different doses of radioactive iodine abla-tion prescribed in patients with intermediate-to-high-risk differentiated thyroid cancer. Ann. Nucl. Med. 2019, 33, 495–501.
  32. Qu, Y.; Huang, R.; Li, L. Low- and high-dose radioiodine therapy for low-/intermediate-risk differentiated thyroid cancer: A preliminary clinical trial. Ann. Nucl. Med. 2017, 31, 71–83.
  33. Martins-Filho, R.; Ward, L.S.; Amorim, B.J.; Santos, A.O.; Lima, M.C.; Ramos, C.D.; Matos, P.S.; Assump-ção, L.V.; Camargo, E.E.; Etchebehere, E.C. Cumulative doses of radioiodine in the treatment of differentiated thy-roid carcinoma: Knowing when to stop. Arq. Bras. Endocrinol. Metab. 2010, 54, 807–812.
  34. Jarząb, B.; Handkiewicz-Junak, D.; Włoch, J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: A qualitative review. Endocr. Relat. Cancer 2005, 12, 773–803.
  35. Franzius, C.; Dietlein, M.; Biermann, M.; Frühwald, M.; Linden, T.; Bucsky, P.; Reiners, C.; Schober, O. Procedure guideline for radioiodine therapy and 131iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer. Nucl. Med. 2007, 46, 224–231.
  36. Petrich, T.; Widjaja, A.; Musholt, T.J.; Hofmann, M.; Brunkhorst, T.; Ehrenheim, C.; Oetting, G.; Knapp, W.H. Outcome after radioiodine therapy in 107 patients with differentiated thyroid carcinoma and initial bone metastases: Side-effects and influence of age. Eur. J. Pediatr. 2001, 28, 203–208.
  37. Hindié, E.; Mellière, D.; Lange, F.; Hallaj, I.; de Labriolle-Vaylet, C.; Jeanguillaume, C.; Lange, J.; Perlemuter, L.; Askienazy, S. Functioning pulmonary metastases of thyroid cancer: Does radioiodine influence the prognosis? Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 974–981.
  38. Ylli, D.; Van Nostrand, D.; Wartofsky, L. Conventional Radioiodine Therapy for Differentiated Thyroid Cancer. Endocrinol. Metab. Clin. North. Am. 2019, 48, 181–197.
  39. Ghachem, T.B.; Yeddes, I.; Meddeb, I.; Bahloul, A.; Mhiri, A.; Slim, I.; Slimene, M.F.B. A comparison of low versus high radioiodine administered activity in patients with low-risk differentiated thyroid cancer. Eur. Arch. Otorhinolaryngol. 2016, 274, 655–660.
  40. Finessi, M.; Liberini, V.; Deandreis, D. Major limits of dosimetrically determined activities in advanced differentiated thyroid carcinoma. Q. J. Nucl. Med. Mol. Imaging 2019, 63, 258–266.
  41. Andresen, N.S.; Buatti, J.M.; Tewfik, H.H.; Pagedar, N.A.; Anderson, C.M.; Watkins, J.M. Radioiodine Ablation following Thyroidectomy for Differentiated Thyroid Cancer: Literature Review of Utility, Dose, and Toxicity. Eur. Thyroid J. 2017, 6, 187–196.
  42. Benua, R.S.; Cicale, N.R.; Sonenberg, M.; Rawson, R.W. The relation of radioiodine dosimetry to results and com-plications in the treatment of metastatic thyroid cancer. Am. J. Roentgenol. Radium Ther. Nucl. Med. 1962, 87, 171–182.
  43. Lassmann, M.; Hänscheid, H.; Chiesa, C.; Hindorf, C.; Flux, G.; Luster, M. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: Blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 1405–1412.
  44. Wang, L.; Ganly, I. Post-treatment surveillance of thyroid cancer. Eur. J. Surg. Oncol. 2017, 44, 357–366.
  45. Tuttle, R.M.; Tala, H.; Shah, J.; Leboeuf, R.; Ghossein, R.; Gonen, M.; Brokhin, M.; Omry, G.; Fagin, J.A.; Shaha, A. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: Using response to therapy variables to modify the initial risk estimates predicted by the new Ameri-can Thyroid Association staging system. Thyroid 2010, 20, 1341–1349.
  46. Durante, C.; Attard, M.; Torlontano, M.; Ronga, G.; Monzani, F.; Costante, G.; Ferdeghini, M.; Tumino, S.; Meringolo, D.; Bruno, R.; et al. Identification and Optimal Postsurgical Follow-Up of Patients with Very Low-Risk Papillary Thyroid Microcarcinomas. J. Clin. Endocrinol. Metab. 2010, 95, 4882–4888.
  47. Durante, C.; Montesano, T.; Torlontano, M.; Attard, M.; Monzani, F.; Tumino, S.; Costante, G.; Meringolo, D.; Bruno, R.; Trulli, F.; et al. Papillary thyroid cancer: Time course of recurrences during postsurgery surveillance. J. Clin. Endocrinol. Metab. 2013, 98, 636–642.
  48. Ito, Y.; Higashiyama, T.; Takamura, Y.; Kobayashi, K.; Miya, A.; Miyauchi, A. Prognosis of patients with papillary thyroid carcinoma showing postoperative recurrence to the central neck. World J. Surg. 2011, 35, 767–772.
  49. Carrillo, J.F.; Vázquez-Romo, R.; Ramírez-Ortega, M.C.; Carrillo, L.C.; Gómez-Argumosa, E.; Oñate-Ocaña, L.F. Prognostic Impact of Direct 131I Therapy After Detection of Biochemical Recurrence in Intermediate or High-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study. Front. Endocrinol. 2019, 10, 737.
  50. Portulano, C.; Paroder-Belenitsky, M.; Carrasco, N. The Na+/I− symporter (NIS): Mechanism and medical impact. Endocr. Rev. 2014, 35, 106–149.
  51. Allweiss, P.; Braunstein, G.D.; Katz, A.; Waxman, A. Sialadenitis following I-131 therapy for thyroid carcinoma: Concise communication. J. Nucl. Med. 1984, 25, 755–758.
  52. Alexander, C.; Bader, J.B.; Schaefer, A.; Finke, C.; Kirsch, C.M. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J. Nucl. Med. 1998, 39, 1551–1554.
  53. Hyer, S.; Kong, A.; Pratt, B.; Harmer, C. Salivary Gland Toxicity after Radioiodine Therapy for Thyroid Cancer. Clin. Oncol. (R Coll Radiol) 2007, 19, 83–86.
  54. Mandel, S.J.; Mandel, L. Radioactive Iodine and the Salivary Glands. Thyroid 2003, 13, 265–271.
  55. Malpani, B.L.; Samuel, A.M.; Ray, S. Quantification of salivary gland function in thyroid cancer patients treated with radioiodine. Int. J. Radiat. Oncol. Biol. Phys. 1996, 35, 535–540.
  56. Mandel, S.J.; Mandel, L. Persistent sialadenitis after radioactive iodine therapy: Report of two cases. J. Oral Maxillofac. Surg. 1999, 57, 738–741.
  57. Nakada, K.; Ishibashi, T.; Takei, T.; Hirata, K.; Shinohara, K.; Katoh, S.; Zhao, S.; Tamaki, N.; Noguchi, Y.; Noguchi, S. Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer? J. Nucl. Med. 2005, 46, 261–266.
  58. Bourcigaux, N.; Rubino, C.; Berthaud, I.; Toubert, M.E.; Donadille, B.; Leenhardt, L.; Petrot-Keller, I.; Brailly-Tabard, S.; Fromigué, J.; de Vathaire, F.; et al. Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma. Hum. Reprod. 2018, 33, 1408–1416.
  59. Verburg, F.A.; Verkooijen, R.B.; Stokkel, M.P.; van Isselt, J.W. The success of 131I ablation in thyroid cancer pa-tients is significantly reduced after a diagnostic activity of 40 MBq 131I. Nuklearmedizin. Nucl. Med. 2009, 48, 138–142.
  60. Lassmann, M.; Luster, M.; Hänscheid, H.; Reiners, C. Impact of 131I diagnostic activities on the biokinetics of thyroid remnants. J. Nucl. Med. 2004, 45, 619–625.
  61. Lees, W.; Mansberg, R.; Roberts, J.; Towson, J.; Chua, E.; Turtle, J. The clinical effects of thyroid stunning after diagnostic whole-body scanning with 185 MBq 131 I. Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 1421–1427.
  62. Leung, S.F.; Law, M.W.M.; Ho, S.K.W. Efficacy of low-dose iodine-131 ablation of post-operative thyroid remnants: A study of 69 cases. Br. J. Radiol. 1992, 65, 905–909.
  63. Lundh, C.; Nordén, M.M.; Nilsson, M.; Forssell-Aronsson, E. Reduced iodide transport (stunning) and DNA synthesis in thyrocytes exposed to low absorbed doses from 131I In Vitro. J. Nucl. Med. 2007, 48, 481–486.
  64. Luster, M.; Sherman, S.I.; Skarulis, M.C.; Reynolds, J.R.; Lassmann, M.; Hänscheid, H.; Reiners, C. Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1371–1377.
  65. Mariotti, S.; Barbesino, G.; Caturegli, P.; Marinó, M.; Manetti, L.; Pacini, F.; Centoni, R.; Pinchera, A. Assay of thyroglobulin in serum with thyroglobulin autoantibodies: An unobtainable goal? J. Clin. Endocrinol. Metab. 1995, 80, 468–472.
  66. McDougall, I.R. 74 MBq radioiodine 131I does not prevent uptake of therapeutic doses of 131I (i.e., it does not cause stunning) in differentiated thyroid cancer. Nucl. Med. Commun. 1997, 18, 505–512.
  67. Medvedec, M. Thyroid stunning In Vivo and In Vitro. Nucl. Med. Commun. 2005, 26, 731–735.
  68. Postgård, P.; Himmelman, J.; Lindencrona, U.; Bhogal, N.; Wiberg, D.; Berg, G.; Jansson, S.; Nyström, E.; Forssell-Aronsson, E.; Nilsson, M. Stunning of iodide transport by (131)I irradiation in cultured thyroid epithelial cells. J. Nucl. Med. 2002, 43, 828–834.
  69. Nordén, M.M.; Larsson, F.; Tedelind, S.; Carlsson, T.; Lundh, C.; Forssell-Aronsson, E.; Nilsson, M. Down-regulation of the Sodium/Iodide Symporter Explains 131I-Induced Thyroid Stunning. Cancer Res. 2007, 67, 7512–7517.
  70. Jeevanram, R.; Shah, D.; Sharma, S.; Ganatra, R. Influence of initial large dose on subsequent uptake of therapeutic radioiodine in thyroid cancer patients. Int. J. Radiat. Appl. Instrum. Part B 1986, 13, 277–279.
  71. Muratet, J.P.; Daver, A.; Minier, J.F.; Larra, F. Influence of scanning doses of iodine-131 on subsequent first ablative treatment outcome in patients operated on for differentiated thyroid carcinoma. J. Nucl. Med. 1998, 39, 1546–1550.
  72. Hu, Y.-H.; Wang, P.-W.; Wang, S.-T.; Lee, C.-H.; Chen, H.-Y.; Chou, F.-F.; Huang, Y.-E.; Huang, H.-H. Influence of 131I diagnostic dose on subsequent ablation in patients with differentiated thyroid carcinoma: Discrepancy between the presence of visually apparent stunning and the impairment of successful ablation. Nucl. Med. Commun. 2004, 25, 793–797.
  73. Park, H.-M.; Perkins, O.W.; Edmondson, J.W.; Schnute, R.B.; Manatunga, A. Influence of Diagnostic Radioiodines on the Uptake of Ablative Dose of Iodine-131. Thyroid 1994, 4, 49–54.
  74. Nixon, I.; Ganly, I.; Shah, J. Thyroid cancer: Surgery for the primary tumor. Oral Oncol. 2013, 49, 654–658.
  75. Shinohara, S.; Kikuchi, M.; Suehiro, A.; Kishimoto, I.; Harada, H.; Hino, M.; Ishihara, T. Characteristics and prognosis of patients with thyroglobulin-positive and radioactive iodine whole-body scan-negative differentiated thyroid carcinoma. Jpn. J. Clin. Oncol. 2015, 45, 427–432.
  76. Schlumberger, M.; Catargi, B.; Borget, I.; Deandreis, D.; Zerdoud, S.; Bridji, B.; Bardet, S.; Leenhardt, L.; Bastie, D.; Schvartz, C.; et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N. Engl. J. Med. 2012, 366, 1663–1673.
  77. Mallick, U.; Harmer, C.; Yap, B.; Wadsley, J.; Clarke, S.; Moss, L.; Nicol, A.; Clark, P.M.; Farnell, K.; McCready, R.; et al. Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer. N. Engl. J. Med. 2012, 366, 1674–1685.
  78. Khang, A.R.; Cho, S.W.; Choi, H.S.; Ahn, H.Y.; Yoo, W.S.; Kim, K.W.; Kang, K.W.; Yi, K.H.; Park, D.J.; Lee, D.S.; et al. The risk of second primary malignancy is increased in differentiated thyroid cancer patients with a cumulative131I dose over 37 GBq. Clin. Endocrinol. 2014, 83, 117–123.
  79. Klubo-Gwiezdzinska, J.; Van Nostrand, D.; Atkins, F.; Burman, K.; Jonklaas, J.; Mete, M.; Wartofsky, L. Efficacy of Dosimetric Versus Empiric Prescribed Activity of 131I for Therapy of Differentiated Thyroid Cancer. J. Clin. Endocrinol. Metab. 2011, 96, 3217–3225.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback