The Optimal Activity of Radioactive Iodine for Remnant Ablation in Low/Intermediate Risk Differentiated Thyroid Carcinoma: A Continuous Controversy and Meta-Analysis

Radioactive iodine (RAI) is widely used for remnant ablation in low/intermediate differentiated thyroid carcinoma (DTC). However, the optimal effective dose that overweighs the benefits over unwanted side effects is a matter of controversy. This meta-analysis aimed to assess low versus high doses of RAI activity for DTC remnant ablation. Two authors independently searched PubMed and Cochrane Library using the keywords low dose radioactive iodine, high dose radioactive iodine, low-risk/intermediate risk, differentiated thyroid carcinoma, and remnant ablation. Two hundred and twenty references were identified when limiting the engine to controlled trials in English and during the period from January 2010 to December 2020. Nine trials (five from Europe and four from Asia) including 3137 patients fulfilled the inclusion and exclusion criteria. The data were then entered in an extraction sheet detailing the trial information including the author's name, year of publication, country, and type of surgery, preparation for RAI, the patients and control number in the low and high-dose groups, follow-up period, and the results. Out of 220 articles retrieved, nine controlled trials were included (follow-up period range, six months to 12 years, 3137 patients, and low risk of bias). The analysis favored the high dose for remnants ablation, odd ratio, 0.73, 95% CI, 0.50-1.07; P-value for the overall effect was 0.10. However, the results were limited due to the significant heterogeneity observed (56%, P-value 0.03). High-dose RAI was better for DTC remnants ablation. Further studies focusing on intermediate-risk DTC and adjusting for preoperative and postoperative factors are recommended.


Introduction
Drafting a review about the radioactive iodine effective dose is triggered by the controversy surrounding it. The controversy starts from the name: is it a dose? So that it can be viewed like chemotherapy or an activity calculated from the given patients' characters and imaging factors. The arena of the activity against the dose ended in the controversy regarding the protective effects of radioactive iodine (RAI) on solid tumors and the induction of hematological malignancies aside from multiple myeloma [1]. The second reason is the substantial fear stocked among the patients who might be candidates for RAI [2]. Importantly, these gaps were not sufficiently addressed to alleviate the patient's anxiety. Also, the goal of RAI might be hazy in most of the previous studies (remnants ablation, adjuvant, or for metastatic disease) [3]. The previous metaanalyses retrieved add to the above controversy; some showed the superiority of the high dose [4], other studies suggested high doses for incomplete thyroid surgery in certain parts of the World [5][6], the rest showed no differences between high and low doses [7][8][9]. Besides, no recent updates regarding this important issue. Given the above and the increasing focus on RAI's side effects, including craniofacial and psychosocial effects [10], we conducted this meta-analysis to compare high-and low-dose RAI for low/intermediate differentiated thyroid carcinoma remnants ablation. The current review thought to address the type of surgery, preparation for RAI, and the postoperative assessment methods ignored by previous studies.

Inclusion criteria according to Population, Intervention, Comparison, Outcomes, and Study (PICOS)
Studies were included if they are randomized control trials in the English language and comparing lowdose and high-dose radioactive iodine. The studies should have been carried out among adults with low/intermediate-risk differentiated thyroid carcinoma (DTC). Methodologies other than controlled trials, not specifying the dose, and carried on other thyroid disorders (thyrotoxicosis, non-differentiated thyroid carcinoma, and high-risk DTC) were excluded. Studies were approached if they stated at least two postoperative follow-up measures to assess the outcomes.

Patients
Adults with the diagnosis of DTC and followed for at least six months, children, and pregnant women who might not be candidates for radioactive iodine were not included. We included patients with total or neartotal thyroidectomies with possible lymph node dissection. Thyroid hormone withdrawal with and without recombinant thyroid-stimulating hormone (TSH) was accepted. However, we did not control for TSH levels before the administration of RAI. The patients must be followed by at least two postoperative investigations to assess the outcomes (thyroid ultrasonography, neck scan, whole-body scan, stimulated thyroglobulin, and thyroglobulin antibodies). In the present meta-analysis, both 1100 and 1850 MBq were considered low doses while 3700 was considered a high dose [11]. An example is Kukulska et al. [10], whose study was in two stages: first comparing 30 mCi and 60 mCi and in the second, the authors assessed 60 vs 100 mCi and showed no differences. Thus, we combined 30 mCi and 60 mCi as low doses.

Literature search
The search engine was set to controlled trials in English in PubMed and the Cochrane Library. The keywords used were low dose radioactive iodine, high dose radioactive iodine, low-risk differentiated thyroid carcinoma, intermediate-risk differentiated thyroid carcinoma, and remnant ablation. The systematic literature search was limited to the period from January 2010 to December 2020. We identified 220 references (204 in PubMed and 16 in the Cochrane library), of the 11 studies, which fulfilled the inclusion and exclusion criteria, and two were excluded (purchase is a need). Thus, nine full texts were included in the final metaanalysis. The results were exported to a data analysis sheet including the author's names, year of publication, country, type of surgery, preparation for RAI, the patients and controls numbers in the low and high doses groups, the follow-up period, and the results. A modified Cochrane risk of bias tool was used to assess the quality of the included trials ( Figure 1, Table 1) [12].

Data analysis
The dichotomous data were manually entered in the Revman system (version 5.4, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) for reviews with a 95% confidence interval. The mean difference and heterogeneity estimation were conducted. The fixed or random effects were applied depending on the level of heterogeneity observed (> 50% was considered as high). P <0.05 was considered significant. A funnel plot assessed sensitivity.

Results
In the present data, six out of the nine included trials [10,[13][14][15][16][17] were on the side of the higher radioactive iodine for low/intermediate differentiated thyroid carcinoma remnants ablation while three [18][19][20] were neutral or favored the low dose. The trials were from Europe (five) and Asia (four) and included 3137 patients followed for six months to 12 years. The included studies were assessed by a modified Cochrane system and showed low risk regarding selection, attrition, and reporting while one study (Dehbi et  Of the eight studies included, seven showed that low and high-dose RAI activity was equally effective and one showed the superiority of the high dose. In the present meta-analysis, there were 758 and 775 total events in the interventional and control groups, respectively. Due to the significant heterogeneity observed (56%, P-value 0.03), the random effect was chosen. The chisquare value was 15.98, Tau2 0.15, and df. 7. The P-value for the overall effect was 0.10, odds ratio 0.73, 95% CI, 0.50-1.07. The results imply that the high dose is more efficacious. The funnel plot showed marked lateralization (Tables 1-3, Figure 2).

Discussion
The current finding of the superiority of the high dose radioactive iodine for low/intermediate-risk differentiated thyroid carcinoma remnants ablation might enrich and upgrade the available evidence. The management of DTC with radioactive iodine requires further clarification; the debate is living continuously due to the development in technology [21]. The current finding is in line with Song et al. [4] and Shengguang et al. [6] who compared 1.1 GBq and 3.7 GBq; also, the later study restricted its observations to Europe and following incomplete thyroid surgery. A strength of this meta-analysis is that we defined both 1100 and 1850 MBq as a low dose [11]. Besides, we included both thyroxine withdrawal and recombinant TSH for RAI preparation due to the comparable efficacy [22][23]. A further strength of our data is specifying at least two methods for postoperative assessment due to the limitations and less reliability. Neck ultrasound is operator dependent and less sensitive in the central compartment, a thyroglobulin assay lacks a precise value and is prone to interference by thyroglobulin antibodies, while neck scintigraphy uses different isotopes with varying sensitivity and specificity [3,24]. The current findings were different from previous meta-analyses that recommended low-dose activity [7][8]. Importantly, Ma et al. included only three trials under recombinant human thyrotropin (rhTSH) stimulation [7]. The pooling of both low and intermediate-risk DTC might explain the discrepancy observed between different meta-analyses. Furthermore, DTC is not uniform (a follicular variant of papillary thyroid carcinoma versus the classical variant and Hurthle cell carcinoma may behave differently). Thus, pooling these sub-groups may affect the results. An important issue that may affect RAI outcomes and inform physicians is the thyroglobulin/TSH ratio. Currently, a TSH of ≥30 mIU/L is suggested for thyroglobulin estimation, however, a great doubt was thrown and this threshold has been questioned. The thyroglobulin/TSH ratio from 0.126 to 0.034 shown by previous studies is wide and needs further adjustments due to its importance to RAI outcomes. Besides, further studies focusing on different DTC sub-types and concentrating on intermediate-risk patients are needed.

Conclusions
High-dose RAI is recommended for low/intermediate DTC remnant ablation. However, the results were limited by the high heterogeneity observed. Further studies assessing the different DTCs and controlling for TSH levels and postoperative assessment methods are recommended.

Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no