Role of 131I in low-risk differentiated thyroid cancer

Abstract

Differentiated thyroid cancer (DTC) is the most frequent endocrine neoplasm, with an increase in recent decades. Papillary carcinoma is the most frequent histological subtype and a large number of cases are related to tumors of small size and with little clinical repercussion, detected incidentally or as a consequence of the availability of diagnostic techniques. The "good prognosis" of the majority of cases has maintained for years the controversy in the approach to these patients, especially in two basic aspects of the therapeutic protocol: surgery and the administration of radioiodine. While in metastatic and high-risk patients, the administration of ¹³¹I therapy is widely accepted, in intermediate-low risk patients its use is highly questioned. In this paper we review the available evidence on radioiodine therapy in low-risk patients.

Resumen

El cáncer diferenciado de tiroides (CDT) representa la neoplasia endocrina más frecuente, registrándose un incremento en las últimas décadas. El carcinoma papilar es el subtipo histológico más frecuente y un gran número de casos se relaciona con tumores de pequeño tamaño y con poca repercusión clínica, detectados de manera incidental o como consecuencia de la disponibilidad de las técnicas diagnósticas. El “buen pronóstico” de la mayoría de los casos han mantenido desde hace años la controversia en el abordaje de estos pacientes, especialmente en dos aspectos básicos del protocolo terapéutico: la cirugía y la administración de radioyodo. Si bien en los pacientes metastásicos y de alto riesgo, la administración de terapia con ¹³¹I está ampliamente aceptada, en los pacientes de riesgo intermedio-bajo su uso está muy cuestionado. En este trabajo realizamos una revisión de la evidencia disponible sobre la terapia con radioyodo en los pacientes de bajo riesgo.

Differentiated thyroid cancer (DTC) is the most frequent endocrine neoplasia, with the incidence increasing in the last decades. Papillary carcinoma is the most frequent subtype and is related to small sized tumors with little clinical repercussion in a large number of cases. It is detected incidentally or as a consequence of the availability of diagnostic techniques.¹

Despite the increase in incidence, survival remains stable at around 98%.² Thus, because of the "good prognosis" of the majority of cases, for years the approach to these patients has remained controversial, especially in relation to two basic aspects of the therapeutic protocol: surgery and the administration of radioiodine.

Based on studies by the group of Mazzaferri, the recommended approach in DTC includes total thyroidectomy and lymph node dissection in patients with palpable adenopathies. In addition, radioiodine is administered post-operatively, following hormone deprivation in all tumors greater than 1.5 cm. The objective of treatment with iodine 131 (¹³¹I) in these patients is to destroy the remaining tissue (benign or malignant) showing ¹³¹I uptake. This approach reduces both the risk of recurrence and mortality in patients with high risk DTC without distant metastasis.³

The therapeutic objective of post-surgical administration of ¹³¹I can be standardized as ablation of thyroid remnants, adjuvant treatment or treatment of the known disease. Thus, following global evaluation including clinical-pathological, analytical and imaging aspects, radioiodine is administered to eliminate the normal remnant tissue in patients of low risk to ensure undetectable thyroglobulin levels or to reduce these levels to within a lower range (ablation of remnants). It is also administered to treat suspected or probable unknown localizations of neoplastic cells in patients with low or intermediate risk with the aim of reducing the risk of recurrence (adjuvant therapy). Finally, ¹³¹I is administered to treat persistent or recurrent disease in patients with demonstrated metastasis (treatment of the disease).⁴

Since the publication of the guidelines of the American Thyroid Association (ATA) for the management of adult patients with thyroid nodules and DTC in 2015,⁵ controversy regarding many aspects of the management of these patients has increased, especially in relation to the participation of nuclear medicine physicians in the care process of DTC in both the field of diagnosis and in therapy with radioiodine. This controversy has been described in documents of the European Association of Nuclear Medicine (EANM) and the American Society of Nuclear Medicine and Molecular Imaging (SNMMI), which refuse to endorse the ATA guidelines.⁶ In most cases, the objections are based on different interpretations of the evidence available.

The consequence of the recommendation of the ATA guidelines of implementing surgical techniques of less extension than total thyroidectomy in patients with tumors between 1 and 4 cm without extrathyroid extension or without clinical evidence of metastasis is that radioiodine is not administered following surgery. The direct implication of this is a change in daily practice since thyroglobulin would no longer have the important role it currently has in the follow-up and monitoring of patients with DTC.

There are many studies in the literature that support one decision or another in patients with low risk. Perhaps the most extreme position is that led by the group of the Mayo Clinic,⁷ which, since 1983, has questioned the efficacy of radioiodine in the post-operative management, promoting selective use based on the classification of the patients with the MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scoring system.⁸ In the ATA⁵ guidelines, the administration of radioiodine is considered an option that is definitively not recommended, but could be considered in determined situations. To the other extreme, the studies of Sawka⁹ have shown a statistically significant benefit in terms of reducing the rates of recurrence and a reduction in the appearance of metastasis in all patients with tumors greater than 1 cm. In addition, it has been demonstrated that the risk of lymph node or distant metastasis based on tumor diameter increases from 1 cm, and thus, the term “low risk” should not be deemed equivalent to “absence of risk”.¹⁰ A review of the literature published in the last decade supports post-surgical treatment with radioiodine in DTC in tumors larger than 1 cm.¹¹

The main handicap for decision making in regard to which protocol to use in a patient with DTC, especially in cases of low risk, is the lack of evidence, since up to now no randomized controlled studies with a long follow-up and comparing different therapeutic strategies with and without radioiodine administration in different scenarios have been published.

What is low risk differentiated thyroid cancer?

The main point in the argument of whether to treat or not patients with low risk lies in the definition of “low risk” itself. At present, different guidelines have established several definitions.^4,12–15

First of all, there is no agreement as to what “risk” should be evaluated - the risk of death related to DTC or the risk of recurrence. Different guidelines include different parameters to construct the classification, but most take into account tumoral size, the relation with the gland and lymph node involvement. Table 1 shows some examples of different requisites for considering a patient as having low risk.

Table 1.

Different classifications of low risk based on the different guidelines available in the literature.

8th edition of UICC/AJCC staging classification (16)		ATA 2015 (5)	ETA 2006 (12)	SNMMI 2012 (14)
<55 years	>55 years	Papillary thyroid carcinoma • No metastasis • No macroscopic remnants • No invasion in locoregional tissues or structures • No aggressive histology (tall cell, hobnail variant, columnar cells) • No uptake of radioiodine outside thyroid bed • No vascular invasion • Encapsulated follicular variant, intrathyroidal • Well differentiated tumor, intrathyroidal, with capsular invasion without or with minimum vascular invasion (< 4 foci) • Papillary microcarcinoma, intrathyroidal, unifocal or multifocal, including BRAFV600E mutation	Very low risk	Very low risk
Stage I: Any T or N M0Stage II: Any T or N, M1	T2, N/N0, M0Any T with N1, M0T3, Any N, M0		T1(≤1 cm) N0M0	T1-2 N0M0MACIS<6
			Low risk	Low risk
			T1(>1 cm) N0M0T1(m)N0M0T2N0M0	<45 years: T1-2, No-1ª, M0<45 years: MACIS<6>45 years: T2N0M0 and MACIS <6No aggressive histology

UICC, Union for International Cancer Control; AJCC, American Joint Committee on Cancer; ATA, American Thyroid Association; ETA, European Thyroid Association; SNMMI, American Society of Nuclear Medicine and Molecular Imaging; MACIS, distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size.

The classification of the tumor, node metastasis (TNM) system was modified in 2018 with a reclassification of a significant number of patients, and a global trend to a reduction in staging.¹⁷ This system is the most widely used in tumor staging, but it is based on the risk of death and is, therefore, not the most adequate in the context of DTC since the risk of recurrence and not of mortality should be considered in these patients. The 2015 ATA guideline⁵ bases its classification on the risk of recurrence, which in the case of patients classified as low risk is less than 5%. The main strength of this system is that it estimates the risk of recurrence versus others that are predictors of specific survival. However, not all the parameters included in the classification are globally accepted. For example, after reclassification according to the 8th edition of the TNM system, minimum extrathyroidal extension was no longer included as T3, thereby reclassifying many patients as having low risk. In the evaluation of 177,497 patients with classical papillary carcinoma included in the National Cancer Database. It was found that patients with minimal extrathyroidal extension had a worse survival compared to those without invasion (10-year survival 89.3% vs. 93.1%). Likewise, all the levels of extrathyroidal extension were associated with the risk of lymph node involvement and metastasis.¹⁸

To improve the classification of patients, the use of molecular alterations of the tumor should also be included in the different guidelines, since beyond histology these alterations induce changes in behavior and, thus, in the prognosis of the patient. Alterations in BRAF, RAS or RET/PET and even in the determination of microRNA will play an important role in the management of patients with DTC in the future.¹⁹

A new, recently published histological classification of thyroid tumors includes changes in the terminology, new types, subtypes and grading system.²⁰

Indications for treatment with radioiodine

The 2015 ATA guideline⁵ recommends routine use of adjuvant treatment with radioiodine in patients with high risk following thyroidectomy. In cases of intermediate risk, it indicates that this treatment should be considered as an option, but in cases of low risk it is not recommended in routine treatment. The guideline adds that in cases of low risk the personal characteristics of the patient that could modify the risk of recurrence and have implications in the follow-up should be considered as well as the preferences of the patient. Thus, the well established indication for treatment with radioiodine is limited to patients with macroscopic extrathyroid invasion, incomplete tumor resection, distant metastasis, thyroglobulin levels in disagreement with morphological findings, lymph node involvement >3 cm or follicular thyroid cancer with extensive vascular invasion. On the other hand, it only indicates that “therapy with radioiodine should be considered” in patients with T1-3 and limited lymph node disease.

In the British guideline, selective and personalized use is recommended in T1b, T2 and N1, including tumor size, extrathyroid extension, unfavorable or invasive histology, multiple or large lymph node metastases, an elevated ratio between positive and negative lymph nodes and extracapsular lymph node involvement in the consideration. It is not indicated in either unifocal or multifocal tumors ≤1 cm in diameter, tumors with a classical histology or minimally invasive follicular neoplasia without angioinvasion or without invasion of the thyroid capsule.¹³

The position of the SNMMI^21,22 considers that it is possible to increase the survival rates of patients with low or very low risk and should be an option for evaluation in cases with lesions greater than 1 cm or even in smaller sizes when there are concurrent risk factors (aggressive histology, lymphatic or vascular invasion, lymph node or distant metastasis, multifocality, capsule invasion or rupture, perithyroidal involvement, elevation of antithyroglobulin antibodies).

The recent consensus of the European Thyroid Association (ETA)²³ states that the decision for therapy with radioiodine should be made based on initial prognostic indicators for mortality related to thyroid cancer and recurrence, including histological and surgical reports, serum thyroglobulin results (>2 ng/mL with suppressive therapy or >5−10 ng/mL after stimulation with recombinant human thyroid‐stimulating hormone [rhTSH]) and post-surgical cervical ultrasonography. The expected benefits of therapy with ¹³¹I depend on the individual risk of the patient. It is important to note that the result of post-surgical cervical ultrasonography (between 2 weeks and 2 months) and the determination of thyroglobulin levels, preferably after 6 weeks, play a fundamental role in the decision to treat with radioiodine.²⁴ The challenge is to identify the patients who would benefit from radioiodine treatment and avoid those who would potentially not benefit.

According to the EANM, radioiodine treatment should be administered to all patients with DTC following thyroidectomy, except in cases with sizes less than 1 cm, with no evidence of metastasis, without thyroid capsule invasion, without a previous history of irradiation and without an unfavorable histology. It is also essential to consider other factors of risk such as the family history, tumor size, the proximity of the thyroid capsule and the presence of vascular invasion.¹⁵

With respect to microcarcinomas, some studies have described benefits in overall survival (204.3 vs. 197.5 months) following treatment with radioiodine in papillary microcarcinomas according to data extracted from the Surveillance, Epidemiology and End Results (SEER) database that included 7818 patients.²⁵ The Al-Qahtani study described improvement in progression-free survival at 5–10 years in patients who received radioiodine compared to those who did not (97.5% vs. 92.2% progression free at 5 years and 90.9% vs. 84% progression free at 10 years).²⁶

A recent study,²⁷ from the study of the National Cancer Database, including 4518 patients with aggressive histologies, did not show an improvement in survival in patients with tumors ≤2 cm, although there were differences in the case of tumors between 21 and 40 mm in size (83.4% vs. 70.0%, p = 0.04).

The meeting of experts of the ATA, EANM, SNMMI and ETA in Martinica⁴ led to the development and publication of nine principles related to the controversy about DTC. Principle 5 states that the selection of patients for radioiodine therapy should include multiple factors beyond post-surgical status and the staging of risk. It emphasizes that the data collected in the literature indicate great heterogeneity in the selection of patients and the results of treatment and should, thus, be carefully analyzed. It recommends evaluating the opinion of the patient following objective information of the pros and cons of the administration of ¹³¹I, focused on their individual situation.

The SNMMI/EANM²⁸ guidelines underline that an absolute threshold of thyroglobulin levels to identify patients who do not require therapy with ¹³¹I cannot be established but rather they should be managed for the selection of the activity to administer. An undetectable thyroglobulin value may lead to delayed diagnosis of residual tumoral tissue in a group of patients, especially in those in whom lymph node dissection was not performed or who have additional risk factors.²⁹ A recent study³⁰ showed that post-surgical thyroglobulin values <1 ng/mL do not exclude metastatic disease.

A controversial subject in the group of patients with low risk is the consideration of ablative treatment. In most clinical settings of low risk, lymph node dissection is not systematically performed in order to reduce morbidity during surgery. Thus, considering the probability of lymph node involvement, even in patients with pT1a tumors (12–50% according to the British guideline¹³), in most cases, treatment with radioiodine is intended as adjuvant rather than ablative therapy.³¹

Activity of ¹³¹I in post-surgical treatment

The ATA⁵ guidelines recommend the use of activities of 30 mCi (1.1 GBq) if it is decided to perform treatment in patients with low or intermediate risk with characteristics of low risk.

Several non-randomized studies have demonstrated no inferiority in the results of the use of low (1.1 GBq) and high doses (3.7 GBq).^32,33 The simultaneous publication of the two randomized clinical trials ESTIMABL1³⁴ and HiLo,³⁵ with a non-inferiority design, justifies the use of low doses (1.1 GBq) together with rhTSH stimulation as the procedure of choice. No ocular or salivary complications were observed in these two studies and the whole body dosimetry was less than in cases of high doses.

In the evaluation at 5 years, non-inferiority of the option of low dose was maintained in both studies,^36,37 with the difference that in the English study (HiLo) there was a greater need for new treatments in the group treated with low doses compared to the high dose group. This might be explained by the different inclusion criteria, the extension of the surgery and the parameters used to define complete ablation.

Therefore, if it is decided to treat patients with low risk with radioiodine following thyroidectomy, the procedure should consist in the administration of 30 mCi (1.1 GBq) of ¹³¹I after stimulation with two intramuscular doses of recombinant thyrotropin alfa.³⁸

In all the cases in which it is decided to perform treatment, it is recommended to carry out a post-therapy scan with the aim of confirming the presence and extension of the thyroid remnant and exclude or confirm the presence of other unsuspected foci. The role of single photon emission computerized tomography/computerized tomography is rising, especially in the distinction of whether the activity in the cervical bed only corresponds to remnants or includes activity in the locoregional lymph nodes.²³

Treat or not treat: ESTIMABL2

The ESTIMABL2³⁹ study has recently been published. This is an open, randomized, phase III, non-inferiority study including patients with low risk (pT1aNxMx and pT2NxMx) treated with thyroidectomy with or without lymph node dissection. The patients were randomized into two groups - one which received 1.1 GBq of ¹³¹I post-surgically and another that did not receive treatment with radioiodine.

Most of the patients included had a histology of papillary thyroid cancer and, thus, the results cannot be extrapolated to other histopathological subgroups. The patients underwent total thyroidectomy and complete resection (R0) confirmed by ultrasound. It also included an important group of patients who had undergone central dissection and some had even undergone dissection of the lateral compartment. This surgical approach can increase the collateral effects of surgery and reduce the potential benefits of ¹³¹I.⁴⁰ In this group of patients, the guidelines^5,13 recommend that total thyroidectomy should be avoided since lobectomy could be sufficient, although this subject is controversial, especially in patients with tumors greater than 1 cm or with risk factors.

The design of a non-inferiority study seeks to increase statistical efficiency, allowing to reduce the number of patients and the follow-up time with respect to whether the objective would have been to find significant differences in a context of low risk in which the events of recurrence and progression are limited. The study has different weak points that should be considered before extrapolating the results to clinical practice: the definition of events, comparison of the results by ultrasound, differences in the measurement of thyroglobulin (stimulation in the group treated with radioiodine and no stimulation in those not treated), different cut-off levels of thyroglobulin or the evaluation of antithyroglobulin antibodies.⁴⁰

In my opinion, beyond the design of the study itself, the main limitation is the short follow-up time (3 years) used to evaluate recurrences. In the context of patients with low risk with excellent rates of survival and progression-free time, the follow-up time should be prolonged to at least 5–10 years.

Side effects of therapy with radioiodine

There are increasingly more publications and concern about the theoretical immediate as well as medium- and long-term side effects of radioiodine. The most worrisome effects include nausea and vomiting, post-radiation thyroiditis (due to abundant thyroid remains) and more rarely, sialoadenitis and xerostomia, bone marrow suppression, gonadal dysfunction, second neoplasia and the possibility of pulmonary fibrosis in cases of extensive lung involvement.⁴²

The controversy in the literature is extensive; while some groups describe an increase in the risk of a second neoplasia related to the administration of radioiodine, others do not report the same results. A recent meta-analysis⁴³ found the publications on this subject to be of low quality, together with a small relative effect of the administration of radioiodine on the appearance of second tumors, suggesting that the indication of treatment with ¹³¹I should not be restricted based on the risk of developing a second tumor or hematological neoplasia.

In general the risk of treatment has tended to be increased compared to the benefits.⁴⁴

Evaluation of therapeutic response

The combination of the determination of thyroglobulin, cervical ultrasound and the whole body scan with ¹³¹I at 6–12 months after therapy is the preferred method for assessing therapeutic response and restaging risk. In cases with an elevation of thyroglobulin levels a whole body scan with ¹³¹I should also be performed. Studies with ¹⁸F-FDG PET/CT should be carried out in cases with suspicion of disease without avidity for the radioiodine^45,46 and in cases with an elevation of thyroglobulin with a diagnostic scan with negative ¹³¹I.

Conclusions

In view of the current opinion of not systematically treating patients with low risk DTC with radioiodine, the proposal is a personalized and individualized decision, including as many factors as possible (as well as molecular tests if available) for decision making.

Multiple factors should be taken into account in the decision to administer or not to perform post-surgical treatment with radioiodine in patients with DTC of low risk. This decision should include both the patient and their specific situation, the context in which the patient is evaluated, the expected impact, and of course, the opinion of the patient following the receipt of objective information.

It is difficult to think that retrospective studies in the context of risk as low as 2–3 % can demonstrate improvements in terms of disease-free survival. The recent review of the literature in the last decade,⁴⁷ that shows coincidences with the meta-analysis of Sawka,⁹ indicates that when large series with a long follow-up period are analyzed, it is more likely to find benefits with the administration of radioiodine.

Conflict of interest

The authors have no conflicts of interest to declare.