Radioiodine Remnant Ablation for Differentiated Thyroid Cancer

Key Points

Question

Is treatment with low-activity radioactive iodine (RAI) comparable with high-activity RAI regarding recurrence rates in well-differentiated thyroid carcinoma?

Findings

In this systematic review and meta-analysis of 10 studies that included 3821 patients, there was no difference in successful ablation or recurrence rates when comparing low-activity RAI with high-activity RAI.

Meaning

This study suggests that low-activity RAI is comparable with high-activity RAI regarding recurrence rates and thus should be considered because of its similar efficacy but lower morbidity.

Abstract

Importance

Postoperative radioactive iodine (RAI) remnant ablation for differentiated thyroid cancer (DTC) facilitates the early detection of recurrence and represents an adjuvant therapy that targets persistent microscopic disease. The optimal activity of RAI in low- and intermediate-risk DTC remains controversial.

Objective

To evaluate the long-term cure rate of different RAI activities in low- and intermediate-risk DTC. Secondary outcomes included successful remnant ablation, adverse effects, and hospital length of stay.

Data Source

A systematic search of the databases PubMed, Cochrane Collaboration, Embase, Scopus, and Web of Science was performed to identify randomized clinical trials (RCTs) and observational studies that compared long-term outcomes (>12 months) for American Thyroid Association–classified low- and intermediate-risk DTC based on receipt of either low-activity or high-activity RAI postoperatively.

Study Selection

All RCTs or observational studies evaluating patients with low- and intermediate-risk DTC who were treated initially with total/near-total thyroidectomy, followed by remnant RAI ablation with either low or high activities. Eligible studies had to present odds ratio, relative risk (RR), or hazard ratio estimates (with 95% CIs), standard errors, or the number of events necessary to calculate these for the outcome of interest rate.

Data Extraction

Two investigators reviewed the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Dichotomous variables were pooled as risk ratios and continuous data as weighted-mean differences. Quality assessment of the included studies was performed using the Newcastle-Ottawa and Jadad scales.

Main Outcomes and Measures

Disease recurrence was the primary outcome. Secondary outcomes included successful ablation, adverse effects, and length of stay.

Results

Ten studies that included 3821 patients met inclusion criteria, including 6 RCTs and 4 observational studies. There was no difference in long-term cure recurrence rates (RR, 0.88; 95% CI, 0.62-1.27, P = .50) or successful remnant ablation (RR, 0.95; 95% CI, 0.87-1.03; P = .20) between low-activity and high-activity RAI.

Conclusions and Relevance

In this systematic review and meta-analysis, low-activity RAI was comparable with high-activity RAI regarding successful ablation and recurrence rates. This suggests that low-activity RAI is preferable to high-activity in low- and intermediate-risk DTC because of its similar efficacy but reduced morbidity.

Trial Registration

PROSPERO Identifier: CRD42020166780

This systematic review and meta-analysis examines the long-term cure rate of different radioactive iodine activities in low- and intermediate-risk differentiated thyroid cancer.

Introduction

Thyroid cancer is the most frequently occurring endocrine cancer.^1,2 Most cases are differentiated thyroid cancers (DTCs), which predominantly consist of papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC).² Differentiated thyroid cancer is associated with an excellent prognosis; reported 10-year survival rates typically exceed 95%,³ partially owing to increased incidental detection of small PTC in recent years.^4,5 Within the DTC paradigm, near-total or total thyroidectomy remains the mainstay of curative-intent therapy. In many cases, patients are subsequently indicated to undergo postoperative radioactive ¹³¹iodine (¹³¹I/RAI) therapy. Radioactive iodine ablates residual thyroid tissue, facilitating the detection of metastatic disease on posttreatment RAI whole-body scans, as well as allowing for serological surveillance with thyroglobulin (Tg) testing. Radioactive iodine also treats microscopic (ie, occult) persistent disease, fulfilling the role of adjuvant therapy. However, there remains much controversy around both indications for use and appropriate dosage in this context.^3,6,7,8,9

The American Thyroid Association (ATA) guidelines for managing DTC have stratified patients into 3 well-defined disease recurrence risk categories: low, intermediate, and high risk.³ Low-risk DTC comprises intrathyroidal cancers with 5 or fewer lymph node micrometastases of 0.2 cm or less, while intermediate-risk DTC describes cancers with aggressive histology, minor extrathyroidal extension, vascular invasion, or greater than 5 involved lymph nodes (0.2-3.0 cm in size).³ Given the excellent prognosis in low- and intermediate-risk groups,¹⁰ the prevention of recurrent disease has become the main focus. However, while postoperative RAI therapy improves disease-free and disease-specific survival in high-risk patients,¹¹ the survival advantages for low- and intermediate-risk patients are less obvious.^2,3,8,9

Moreover, further uncertainty remains concerning the RAI activity requirement for effective ablation, with conflicting results published by previous meta-analyses.^2,7,12,13,14 Regimens vary from low activities of 0.8 to 1.1 GBq (22-30 mCi) to high activities of 3.7 GBq (100 mCi), or even 5.5 GBq (149 mCi). While it might be assumed that there is a higher efficacy with higher doses,^12,15 clinicians should remain cognizant of the disadvantages of higher-activity RAI, including patient isolation, increased length of hospital stay, cost, and the well-documented higher adverse event and toxicity rates associated with higher activities.¹⁶ Furthermore, the association of RAI activity with recurrence and long-term patient outcomes in low- and intermediate-risk DTC is no longer valid following the long-term results of 2 large phase 3 trials that failed to demonstrate a difference in recurrence rates after 5 years between low- and high-activity RAI.^17,18 Accordingly, the primary aim of this meta-analysis was to evaluate the long-term cure rate of different RAI activities in low- and intermediate-risk DTC.

Methods

This meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses¹⁹ and Meta-Analyses and Systematic Reviews of Observational Studies²⁰ guidelines. Institutional review board approval was not required.

Population, Intervention, Comparison, and Primary and Secondary Outcomes

The population comprised patients with primary low- and intermediate-risk DTC as defined by the ATA (defined as either PTC or FTC variants) who were undergoing primary total or near-total thyroidectomy. The intervention was low-activity (≤3 GBq) RAI remnant ablation, which was compared with high-activity (>3 GBq) RAI remnant ablation. The primary outcome was disease recurrence at a follow-up period of at least 12 months, and secondary outcomes included successful remnant ablation, adverse events, length of hospital stay, and quality of life (QOL).

Literature Retrieval

Two individual investigators (D.L.J and D.P.H) performed independent searches of the Cochrane Library, Medline, Embase, Scopus, and Google Scholar electronic databases. The latest search was performed in March 2020 by combining the following search terms using the Boolean AND/OR operators: radioiodine, radioiodide, remnant ablate (to cover ablation, ablative, and ablate), differentiated thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer. English language limitations were set. All titles were scanned for relevance before relevant abstracts were scanned. Full texts of studies of interest were then reviewed. In cases of multiple records using the same patient cohort, end point data were extracted from the report with the longest follow-up. Each reviewer extracted the following data variables: title and reference details (first author, journal, year, and country), study population characteristics (number in study; operative approach, number treated by high and low activities; sex and age), disease characteristics (histopathological type, low/intermediate risk), and outcome data (length of follow-up, successful ablation, need for further treatment, recurrence, length of stay [LOS], and adverse effects).

All data were recorded independently by both reviewers and were compared following completion of the reviewing process to limit selection bias. In cases of discrepancies of opinion, a third reviewer (É.J.R) arbitrated. First author name and the year of publication were used for article identification.

Study Selection and Inclusion/Exclusion Criteria

Relevant data were extracted using standard data extraction forms from all included studies. Studies were included for analysis if they met the following criteria: (1) all randomized clinical trials (RCTs) or observational studies with a retrospective or prospective design that evaluated patients with low- and intermediate-risk DTC; (2) studies evaluating clinical outcomes from adult patients (at least age 16 years) with DTC; (3) patients must have undergone total or near-total thyroidectomy for primary treatment for DTC; (4) patients must have undergone ¹³¹I RAI ablation initially within 3 months postsurgery and had assessment for ablation success at 6 to 12 months after treatment; (5) presented odds ratio (OR), relative risk (RR), or hazard ratio (HR) estimates (with 95% CI), standard errors, or the number of events necessary to calculate these for the outcome of interest rate; (6) included at least 10 patients who were treated with DTC in each arm; and (7) reported on a previously unreported group. Exclusion criteria were (1) any publication that did not meet the previously described inclusion criteria; (2) review articles, opinion pieces, letters to the editor, study protocols, abstracts, and conference proceedings; (3) studies that included patients with high-risk DTC; and (4) studies that included children younger than 16 years.

Risk of Bias and Quality Assessment

The risk of bias and quality in each eligible RCT was assessed by 2 independent reviewers (D.L.J. and M.G.D.) using the Cochrane risk of bias tool.²¹ The following 7 areas were included: random sequence generation, allocation concealment, masking of participants and personnel, masking of outcome assessment, incomplete outcome data, selective reporting, and other biases. A risk of bias graph was drawn, and risk of bias summary was compiled. The quality of RCTs and observational studies was also assessed using the Jadad scale²² and the Newcastle-Ottawa scale (NOS),²³ respectively. A Jadad scale score of 3 or more or a NOS score of 7 or more represented studies of high quality.

Statistical Analysis

Statistical analysis was performed using the Review Manager software (version 5.3; The Nordic Cochrane Centre). Forest plots were generated for dichotomous variables (disease recurrence, successful ablation, and adverse effects), and for 1 continuous variable (LOS). Dichotomous variables were analyzed using the Mantel–Haenszel RRs (with 95% CIs), while continuous variables were analyzed using weighted-mean differences. In the unavailability of means and standard deviations, estimates were derived from study data by the methods described by Hozo et al²⁴ and Luo et al.²⁵ Heterogeneity between studies was assessed using the Cochrane χ² value and the extent of inconsistency by I² value. A fixed-effects model was used for calculations unless significant heterogeneity existed (I² > 50%), in which case a random-effects model was used. A P value of <.05 was considered statistically significant. A sensitivity analysis that excluded each study 1 at a time, including nonrandomized studies exclusively, and studies with shorter median follow-ups (<5 years) exclusively was performed to ensure the results from the main analysis were robust and account for any significant heterogeneity. We defined long-term median follow-up to be greater than 5 years.

Results

Search Overview

Our literature search yielded 2310 studies; 2254 were excluded following title or abstract review. A further 46 were excluded following full text review. A total of 10 studies were considered eligible according to the predefined criteria, including 6 RCTs.^{17,18,26,27,28,29} Figure 1 depicts the Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart of our search strategy.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses Flow Diagram.

Study Characteristics

The 10 included studies were conducted in centers throughout Europe, Asia, Australia, and the US. The number of participants in the included studies ranged from 158 (low activity, n = 81 [51.3%], and high activity, n = 77 [48.7%]) to 726 (low activity, n = 363 [50%]; high activity, n = 363 [50%]) patients. Four studies were observational retrospective cohort studies^30,31,32,33 and 6 were prospective RCTs.^{17,18,26,27,28,29} Four of the 6 RCTs had a Jadad score of 3 of 5, while 1 scored a 2 of 5,²⁸ with 1 achieving full marks.²⁶ In the nonrandomized observational studies, the NOS rating ranged from 5 to 9, with 2 studies^30,33 considered to have a high ratings (NOS score, ≥7). Four studies^18,28,29,33 reported on patients with low-risk DTC, 3 on intermediate-risk exclusively,^30,31,32 and 4 on both low- and intermediate-risk DTC.^17,26,27 The characteristics of the included RCTs and observational studies are illustrated in the Table.^{17,18,26,27,28,29,30,31,32,33}

Table. Characteristics of Included Studies.

Source	Type of study	Country	Sex, female/male	Histopathology, PTC/FTC	TNM staging	TSH preparation method	Activity (GBq)	Follow-up time, mean, mo	Criteria for successful ablation	Criteria for recurrence
Castagna et al,30 2013	Observational	Italy	166/59	213/12	T1-3, N1-3, M0	TSH withdrawal or recombinant TSH	Low activity: 85 (1.1 GBq-1.85 GBq); high activity: 140 (3.7 GBq)	50-83	−ve US; −ve WBS; sTg <1 ng/mL	sTg >1 ng/mL and radiological evidence
Dehbi et al,17 2019	RCT	UK	326/88	Not specified	T1-3, N1-3, M0	TSH withdrawal or recombinant TSH	Low activity: 217 (1.1 GBq); High activity: 217 (3.7 GBq)	78	−ve WBS; sTg <2 ng/mL	Radiological evidence of recurrence
Fallahi et al,26 2012	RCT	Iran	286/55	326/15	T1-3, N1-3, M0	TSH withdrawal	Low activity: 171 (1.1 GBq); high activity: 170 (3.7 GBq)	12	−ve WBS; sTg <2 ng/mL	+ve WBS; sTg >2 ng/mL
Han et al,31 2014	Observational	South Korea	169/7	173/1 (2 = FVPTC)	T1-3, N1-3, M0	TSH withdrawal	Low activity: 96 (1.1 GBq); high activity: 80 (5.5 GBq)	40-113	−ve WBS; sTg <1 ng/mL	Cytologically/pathologically confirmed lesion; radiological evidence; sTg <1 ng/mL
Jeong et al,32 2016	Observational	Korea	184/20	194/6 (3 = FVPTC)	T1-3, N1-3, M0	TSH withdrawal	Low activity: 80 (1.1 GBq); high activity: 124 (3.7-5.5 GBq)	120	−ve WBS; sTg <1 ng/mL	Cytologically/pathologically confirmed lesion; sTg >1 ng/mL
Kruijff et al,33 2013	RCT	Australia	937/234	1171/0	T1-3, N0, M0	TSH withdrawal or recombinant TSH	Low activity: 153 (<3 GBq); High activity: 817 (>3 GBq)	50	Tg <0.9 ng/mL; 2 consecutive negative scans of −ve WBS	Cytologically/pathologically; confirmed lesion; sTg >2 ng/mL
Kukulska et al,28 2010	Observational	Poland	285/24	265/44	T1-3, N1-3, M0	TSH withdrawal	Low activity: 214 (1.1 GBq or 2.2 GBq); high activity: 95 (3.7 GBq)	24-120	−ve WBS; sTg <10 mg/mL	sTg >1 ng/mL; radiological evidence
Ma et al,29 2017	RCT	China	199/79	268/7 (3 = FVPTC)	T1-3, N1-3, M0	TSH withdrawal	Low activity: 155 (1.85 GBq); high activity: 123 (3.7 GBq)	24-36	−ve WBS; sTg <2 ng/mL	+ve WBS; +ve neck US; sTg >2 ng/mL
Mäenpää et al,27 2008	RCT	Finland	128/32	146/11 (3 = FVPTC)	T1-3, N1-3, M0	TSH withdrawal	Low activity: 81 (1.1 GBq); high activity: 77 (3.7 GBq)	18-77	−ve WBS; sTg <1 ng/mL	+ve WBS; sTg >1 ng/mL
Schlumberger et al,18 2018	RCT	France	590/162	693/58	T1-3, N0, M0	TSH withdrawal or recombinant TSH	Low activity: 363 (1.1 GBq); high activity: 363 (3.7 GBq)	6-110	−ve US; sTg <1 ng/mL	Radiological evidence of disease; Tg >1 ng/mL or less if receiving levothyroxine treatment

Abbreviations: FTC, follicular thyroid cancer; FVPTC, follicular variant of papillary thyroid carcinoma; PTC, papillary thyroid cancer; RCT, randomized clinical trial; sTg, stimulated thyroglobulin levels; TNM, tumor, node, metastasis; TSH, thyroid-stimulating hormone; ve US, ultrasonography; ve WBS, whole-body scan.

SI conversion factor: To convert Tg to μg/L, multiply by 1.

Patient Characteristics

A total of 3821 patients were included for qualitative and quantitative analysis (Table). The low-activity group included 1615 patients (42%) vs 2206 (58%) in the high-activity group. There were 3102 female participants (81.2%). A total of 3449 patients (90.3%) received a diagnosis of PTC, 154 (4%) received a diagnosis of FTC, and 218 (5.7%) were not specified. All patients were considered either low or intermediate risk based on their tumor, node, and metastasis staging.

Primary Outcomes

Recurrence Rates

All 10 studies described recurrence data. There was no heterogeneity (I² = 0%; P = .48), so a fixed-effects model was used. No statistical difference was observed for long-term cure recurrence rates between low- and high-RAI activities (RR, 0.88; 95% CI, 0.62-1.27; P = .50) (Figure 2).

Figure 2. Forest Plots Comparing Recurrence Rates Between Low-Activity and High-Activity Radioactive Iodine (RAI), Including a Randomized Clinical Trial (RCT) Subgroup Analysis.

M-H indicates Mantel-Haenszel.

Exclusion of Study by Study and Subgroup of RCTs Only

Exclusion of any specific study did not significantly alter the findings from the main analysis. In an analysis of RCT data exclusively, there was no difference in recurrence rates between activities (RR, 1.09; 95% CI: 0.70-1.70; P = .69) (Figure 2).

Subgroup of Studies With a 5-Year Follow-up

Six studies provided long-term follow-up data.^{17,18,28,30,31,32} There was no difference in recurrence rates in this subgroup (RR, 1.10; 95% CI, 0.68-1.79; P = .70; I² = 0%; P = .92).

Subgroup of Studies Based on ATA Classifications of Risk and Recurrence

There was no difference in recurrence rates in studies with low risk only (RR, 0.56; 95% CI, 0.29-1.08; P = .08) or in those with intermediate risk only (RR, 1.20; 95% CI, 0.54-2.68; P = .66). Furthermore, there was no difference observed when applying the ATA classification of recurrence (RR, 1.21; 95% CI, 0.70-2.09; P = .51).

Subgroup Analysis Based on RAI Preparation Methods

There was no difference when comparing preparation methods for RAI. No difference between low and high activities was observed in those who used traditional thyroid-stimulating hormone (TSH) withdrawal^{26,27,28,29,31,32,33} (RR, 0.72; 95% CI, 0.42-1.22; P = .22) or those who used TSH withdrawal or recombinant TSH^17,18,30,33 (RR, 1.11; 95% CI, 0.68-1.81; P = .68).

Secondary Outcomes

Successful Ablation

All 10 studies were included in this analysis. While there was a trend favoring high- vs low-activity RAI in achieving successful ablation (71.5% vs 67.4%), meta-analysis demonstrated no significant difference in successful ablation between RAI activities (RR, 0.95; 95% CI, 0.87-1.03; P = .20; I² = 79%) (Figure 3A). In an analysis of RCTs only, no significant difference in ablation between activities was observed (RR, 0.91; 95% CI, 0.88-1.00; P = .05) (Figure 3A).

Figure 3. Forest Plots Comparing Ablation.

A, Comparison of successful ablation rates between low-activity and high-activity radioactive iodine (RAI), including a randomized clinical trial (RCT) subgroup analysis. B, Comparison of the need for further ablation. M-H indicates Mantel-Haenszel.

There was no difference in the risk of requiring further RAI treatment between the activities (RR, 1.37; 95% CI, 0.80-2.35; P = .25) (Figure 3B); however, a subgroup analysis of RCT data exclusively demonstrated that those who received low-activity RAI were more likely to receive further treatment (RR, 1.55; 95% CI, 1.15-2.09; P = .04) (Figure 3B). No difference was observed in the subgroup analysis of studies that reported the ATA classification of successful ablation (RR, 1.03; 95% CI, 0.95-1.15; P = .67).

Length of Stay

Three RCTs reported data concerning LOS. There was no difference in LOS between the different RAI activities (weighted-mean difference, −3.91; 95% CI, −25.90 to 18.08; P = .73; I² = 99%)

Risk of Bias

Overall, the methodological quality of the included studies was good. A risk of bias summary and graph for the included studies are included in Figure 4. Given the observational nature of 4 studies,^30,31,32,33 there was a high risk of selection and performance bias. However, there was a low risk of reporting, attrition, and other bias.

Figure 4. Risk of Bias Graph and Summary.

Discussion

Several recent studies have compared low-activity and high-activity RAI to evaluate their efficacy concerning rates of successful ablation; however, only recently have long-term recurrence rates been considered.^17,18 To our knowledge, this is the first meta-analysis that compares long-term oncologic outcomes based on RAI remnant ablation. The most significant result demonstrated in this meta-analysis is the data supporting the noninferiority of low-activity RAI to high-activity RAI regarding disease recurrence and rates of successful ablation for those being treated for low- to intermediate-risk DTC. Second, patients who were undergoing low-activity treatment trended toward a shorter LOS and are recognized as having less costs as those receiving high-activity treatment.³⁴ In tandem, these results suggest that low-activity RAI may be used to supplement surgical resection in DTC in a more cost-effective manner while minimizing treatment-associated toxic effects.

To reiterate, DTC has an excellent prognosis, with a 5-year overall survival exceeding 95%.³ Of the 3821 patients who were evaluated in this analysis, only 15 disease-specific mortalities (0.39%) were reported, one-third of whom were in the low-activity group and two-thirds the high-activity group. These excellent clinical outcomes allow the focus to shift toward disease control and QOL within the DTC paradigm. Although there is a clear survival advantage for RAI use in high-risk patients, the advantages for patients with low- to intermediate-risk DTC appear less clear in previous oncological literature.^2,3,8,9 Orosco and colleagues³⁵ determined that radioactive iodine therapy was protective in association with cancer-specific mortality in high-risk patients following their evaluation of more than 250 000 patients who received a diagnosis DTC from the Surveillance, Epidemiology and End Results and National Cancer Database databases. However, findings for intermediate-risk patients were less informative.³⁵

Within cancer care, patient QOL scoring remains an extremely important consideration.^36,37 While 2 recent, included, large phase 3 RCTs compared QOL scores using the Medical Outcomes Study 36-Item Short Form Health Survey,^17,18 difficulties detailing QOL outcomes ensued because of the heterogeneity and scarcity of reported data. We wish to reiterate the clinical importance of QOL indices in modern cancer care, which were limited within this meta-analysis.

One may question the clinical use of RAI within the scope of low- and intermediate-risk DTC given their excellent survival outcomes as described in this analysis, which were disease-specific survival rates in excess of 99% following median follow-up. However, RAI ablation has multiple critical purposes in the management of this malignancy from a treatment and surveillance perspective. First, RAI destroys residual thyroid cells that may progress to malignancy and eradicates occult carcinoma foci. Second, the destruction of these cells leads to undetectable serum Tg levels, increasing the specificity of ¹³¹I scanning, which facilitates biochemical and structural disease recurrence surveillance. If ablation is successful, as determined by undetectable serum Tg levels and negative imaging results, the risk of disease recurrence is as low as 1% in some series.^3,38 However, the correct RAI activity required for successful remnant ablation remains uncertain.^7,12,13

Inconsistencies in defining successful ablation add further complexity to DTC management. The ATA classifies successful ablation as no clinical, biochemical (stimulated Tg <1 ng/mL [to convert to μg/L, multiply by 1]), or structural evidence of disease,³ while 3 studies considered stimulated Tg levels less than 2 ng/mL as successful^17,26,29 and another considered levels less than 10 ng/mL successful.²⁸ The reproducibility of defining oncological parameters and biomarkers is paramount in achieving the best clinical and oncological outcomes. In this analysis, the subgroup analysis was performed with studies with contrasting definitions excluded, and no difference in successful ablation was observed between RAI activities. This suggests that current contrasting guidelines may be arbitrary, and we propose clarity surrounding successful ablation may be incorporated into best practice guidelines.

The ATA criteria for excellent therapy response, or lack of recurrence, are multifactorial. Clinical eradication of the tumor, no evidence of tumor recurrence detected by RAI imaging, and negligible serum stimulated Tg levels (<1 ng/mL) are incorporated into ATA guidelines.³ Four studies included consider recurrence as stimulated Tg levels of greater than 1 ng/mL in radiological evidence of tumor, whereas the remaining considered either higher Tg levels^{17,26,28,29,33} or cytological/pathological diagnosis.³² Again, these inconsistencies in criteria for recurrence render informative conclusions that may be drawn in association with RAI ablation difficult. Subgroup analysis of studies that considered Tg levels of less than 1 ng/mL and radiology evidence of recurrence failed to detail differences in recurrence rates, which suggests low-activity RAI may be favorable in this setting.

In this analysis, methods pertaining to TSH stimulation failed to affect ablation success or recurrence rates. These results align with a previous metanalysis.³⁹ Radioactive iodine–related morbidity is largely due to iatrogenic toxic effects due to secondary ¹³¹I uptake in glands other than the targeted remnant thyroid tissue; lacrimal and salivary glands are therefore most commonly affected, with taste disturbance, xerostomia, dysphagia, neck pain, and swelling reported.¹⁶ Prescription of a lower initial dose limits the radiation exposure, lessening the adverse effects associated with acute toxic effects.^7,40 Although some trials report adverse reactions, it was inconsistent, and the data were too heterogenous to compare. In the HiLo trial, a higher rate of short-term adverse effects was seen in the high-activity group.⁴⁰ Similarly, Mäenpää and colleagues²⁷ reported less nausea, neck pain, and taste disturbance in the low-activity group. Ma et al²⁹ reported similar levels of liver and kidney dysfunction in both groups.²⁹ Limiting the toxic effects that are associated with therapy is a pertinent issue in thyroid oncology, and we advocate for future work surrounding treatment-related toxic effects. Furthermore, several reports suggest a dose-dependent risk of developing secondary malignancies⁴¹; however, no secondary malignancies were reported in the 3821 patients included in this pooled analysis.

Limitations

Inconsistencies surrounding the definition of low- and high- activity RAI limit the conclusions that can be drawn from this meta-analysis. In clinical practice, varying ¹³¹I ablative doses are prescribed; in our study, low activity ranges from 1.1 GBq to 3 GBq, and high activity ranges from 3 GBq to 5.5 GBq. For the purpose of our study, we chose 3 GBq as the cutoff between low- and high-RAI activities. Twelve-month follow-up limits the likelihood of disease recurrence rates; however, 6 of the included studies had a mean follow-up of 5 years or more, and a subgroup analysis failed to illustrate differences in low- vs high-activity RAI. This analysis also included 4 observational studies, leading to inherent selection bias as well as moderate levels of evidence. Finally, discrepancies in successful thyroid remnant ablation or recurrence criteria limit the meaningful conclusions that may be drawn; however, the subgroup analysis was performed to eradicate ambiguity surrounding results.

Conclusions

This analysis has evaluated all available data comparing oncologic outcome and remnant ablation for patients with DTC who were treated with surgery and RAI based on RAI activities. These data demonstrate the comparability of low-activity and high-activity RAI regarding recurrence rates, successful ablation, and adverse effects for patients with low- to intermediate-risk DTC. These results suggest that the prescription of low-activity RAI is preferable to high-activity RAI in low- to intermediate-risk DTC because of its similar efficacy and reduced morbidity.