How important is the timing of radioiodine ablation in differentiated thyroidal carcinomas: a referral Centre experience

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Original Article

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How important is the timing of radioiodine ablation in differentiated thyroidal carcinomas: a referral Centre experience

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F.Selcuk Simsek ∗ , T.Ansal Balci, Y. Donder, K. Ugur, F. Kilinc

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Pamukkale university, Kınıklı mahallesi Pamukkale üniversitesi Hastanesi Nükleer Tıp Anabilim, 20500 Denizli, Türkiye, Turkey

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Article history: Received 2 June 2019 Accepted 28 August 2019 Available online xxx

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Keywords: Thyroid neoplasms Iodine-131 Surgery

Introduction: It is difficult to make a scientific, evidence-based approach about the timing of radioiodine remnant ablation (RRA) in patients with differentiated thyroid carcinomas (DTCs). Primary aim of the study was to reveal whether timing of RRA relates to achievement of non- structurally incomplete response (non-SIR) in low/intermediate and high-risk patients. Another aim was to reveal the correlation of timing with non-SIR status in reproductive-age women. Materials and Methods: Records of 279 low, intermediate, and high-risk patients were analysed, retrospectively. Number of days between surgery and RRA is referred to as timing. Low/intermediate-risk patients, high-risk patients, and low/intermediate-risk reproductive-age women were divided into nonSIR and SIR groups, according to 2015 American Thyroid Association guidelines for therapy response. The relationship between timing and therapy response was analysed statistically. Results: We could not find any significant relationship in patients with low/intermediate risk between timing and non-SIR, including women between 18 and 49 years of age (p > 0.1). For high-risk patients, we found a statistically significant relationship between timing and non-SIR response. According to ROC analysis, RRA ≤ 58 days was found as a cut-off value. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated as 83.3%, 70.0%, 2.78, and 0.24, respectively. Conclusion: RRA must be initiated within 58 days after surgery in patients with high-risk DTCs. Under this approach, risk of SIR and associated mortality risk may be reduced. RRA timing for women in reproductive ages with low/intermediate risk groups may be planned according to their pregnancy/breastfeeding intent. For other low/intermediate risk groups, they can safely proceed according to the capacity of the medical facility and related logistical considerations. © 2019 Sociedad ˜ ˜ S.L.U. All rights reserved. Espanola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espana,

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Introducción: Es difícil adoptar un enfoque científico basado en la evidencia con respecto al intervalo de aplicación de la ablación de restos con yodo radiactivo (RRA) en pacientes con carcinoma diferenciado de tiroides (DTC). El objetivo principal del estudio fue revelar si el intérvalo de aplicación de la RRA está relacionado con la obtención de una respuesta no estructuralmente incompleta (no SIR) en pacientes de bajo/intermedio y alto riesgo. Otro objetivo era revelar la correlación entre el plazo de aplicación y el estado no SIR en las mujeres en edad reproductiva. Materiales y métodos: Se analizaron retrospectivamente los registros de 279 pacientes de bajo, intermedio y alto riesgo. El «intérvalo de aplicación» se refiere al número de días entre la cirugía y la RRA. Las pacientes de bajo/intermedio riesgo, las pacientes de alto riesgo y las mujeres en edad reproductiva de bajo/intermedio riesgo se dividieron en grupos SIR y no SIR, de acuerdo con las directrices de 2015 de la Asociación Estadounidense de la Tiroides para la respuesta terapéutica. Se analizó estadísticamente la relación entre el intérvalo de aplicación y la respuesta terapéutica. Results: No se observó ninguna relación significativa en pacientes con riesgo bajo/intermedio entre el ˜ de edad (p > 0,1). Para intérvalo de aplicación y la respuesta no SIR, incluidas las mujeres de 18 a 49 anos los pacientes de alto riesgo, se encontró una relación estadísticamente significativa entre el intérvalo de aplicación y la respuesta no SIR. Según el análisis de ROC, se encontró que el valor límite era RRA ≤ 58 días. Se calcularon la sensibilidad, especificidad, cociente de probabilidad positivo y cociente de probabilidad negativo en 83,3 %, 70,0 %, 2,78 y 0,24, respectivamente. Conclusión: La RRA debe comenzar dentro de los 58 días después de la cirugía en pacientes con DTC de alto riesgo. De este modo, se puede reducir el riesgo de SIR y el riesgo de mortalidad asociado. Para las mujeres en edad reproductiva con grupos de riesgo bajo/intermedio, se puede planificar el plazo de aplicación de la RRA de acuerdo con los planes que tengan en cuanto al embarazo o la lactancia.

∗ Corresponding author. E-mail address: [email protected] (F.Selcuk Simsek). ˜ ˜ S.L.U. All rights reserved. 2253-8089/© 2019 Sociedad Espanola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espana,

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Para otros grupos de riesgo bajo/intermedio, pueden proceder con seguridad de acuerdo con la capacidad de la instalación médica y las consideraciones logísticas relacionadas. ˜ de © 2019 Sociedad Espanola ˜ S.L.U. Todos los derechos reservados. Medicina Nuclear e Imagen Molecular. Publicado por Elsevier Espana,

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Introduction Differentiated thyroid carcinomas (DTCs) are the most common malignancies of the endocrine system. The incidence of the disease has been increasing 1 . Although low/intermediate-risk cases account for the majority of DTCs, high-risk cases are also relatively common 2 . The therapy is based on risk stratification; it basically consists of total thyroidectomy (TT), followed by radioiodine remnant ablation (RRA), and thyroid stimulating hormone (TSH) suppression. Decreasing the recurrence and mortality is the main goal of the treatment 3 . In patients with low/intermediaterisk DTCs, this can be more easily achieved, while it may be more challenging in high-risk cases. RRA, which is the second treatment step in most patients after TT, has two main advantages. The first is the ablation of all remnant thyroglobulin-producing tissues. Thus, thyroglobulin monitoring can be performed more accurately and the specificity for detecting recurrence/relapse can be increased. The second is the ablation of remaining malignant tissues. This decreases the recurrence/relapse or mortality rates. For decision-making about the RRA, risk stratification systems are used which are provided by various guidelines 4–7 . According to these guidelines, risk assessment is based on numerous clinical, histopathological, and biochemical parameters. However, there are not any specific recommendations provided in the guidelines for the timing of post-surgery RRA. In addition, to the best of our knowledge, the number of studies addressing the timing of post-surgery RRA is also extremely limited. As a result, it is difficult to make scientific, evidence-based determinations about the timing of post-surgery RRA in patients. This can lead to various problems for the patients and treatment centres. Firstly, although DTCs are considered curable, the diagnosis of malignancy is psychologically difficult for most of the patients. Many patients may want to receive RRA therapy as soon as possible. According to our clinical experience, some patients may develop intense anxiety regarding the treatment, if rapid initiation of RRA is not possible. Another problem related to the timing of RRA in women of reproductive ages. For some patients, diagnosing of DTCs during this period, pregnancy plan has to be postponed; or breastfeeding has to be discontinued which, is extremely important in terms of child and maternal health, for the administration of radioiodine therapy. For others, the radioiodine therapy is postponed for pregnancy or breastfeeding. It is very difficult for most patients to choose among these options. However, the scarcity of scientific data in timing poses some challenges to the physician. The first is the difficulty of decision-making about the timing according to risk stratification. The second relates to the advice given to women of reproductive ages who are diagnosed with DTCs and planning for pregnancy/breastfeeding. The third relates to the difficulty of treatment centres to prioritise patient groups according to facility logistics. To address these challenges, the main point to consider is the category of therapy response. According to 2015 American Thyroid Association (ATA) guidelines, among the patients in the structural incomplete response (SIR) category, disease specific mortality rates range between 11 and 50%. On the other hand, this rate has been reported as <1% for each of the excellent, indeterminate, and biochemical incomplete responses 7 . Due to similar disease specific mortality rates, we grouped these three categories as non-SIR response. Its clinical significance was also explained in a recent study 8 .

The primary aim of our study was to reveal whether the timing of RRA relates to the achievement of non-SIR category in low/intermediate, and high-risk patients. Another aim was to reveal the correlation of timing with non-SIR status in women in reproductive ages as a special group. The first intended benefit of the study is to enable more accurate timing of RRA. The second benefit is the possibility of providing data-based advice to women who are breastfeeding or planning for pregnancy. In terms of treatment centres, the main benefit is more accurate logistical planning for prioritized patients. To the best of our knowledge, this is the first study to evaluate timing of RRA in patients with different risk groups, according to non-SIR response category. Materials and methods

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The medical records of 602 patients with DTCs, who were treated/followed up in our department, between April 2011 and January 2018 were retrospectively evaluated. The 271 patients whose RRA timing could not be found from the records were excluded from the study. 52 patients who received RRA were excluded due to the fact that RRA was not recommended by 2015 ATA guidelines. The records of the remaining 279 low, intermediate, and high-risk patients were analysed. The Ethics Committee approval for the study was obtained. The study was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments. Consent forms were signed by all patients before the procedures. Total thyroidectomy was performed by thyroid surgeons with at least ten years of experience. If the patient had biopsy-proven lymph node metastasis before the surgery, unilateral or bilateral cervical lymph node dissection was performed. If the patient had suspicious findings on pre-operative ultrasound or if abnormal lymph nodes were found during surgery, these lymph nodes were examined by frozen section. Central, unilateral, or bilateral cervical lymph node dissection was performed in case of metastasis. All resected tissues were examined histopathologically. Before the ablation therapy, thyroid hormone withdrawal (THW), and iodine-poor diets were administered according to the ATA guidelines 6,7 . As a routine procedure in our nuclear medicine clinic, pre-ablation ultrasound was performed at least ten days before the RRA. When necessary, we also performed preablation neck MRI and/or unenhanced chest CT. Stimulated Tg (sTg), antithyroglobulin (anti-Tg), and thyroid stimulating hormone (TSH) levels from venous blood samples were measured approximately four hours before the 131 I therapy. For the biochemical analyses, Siemens analysers were used with appropriate commercial kits based on the chemiluminescence method and international standards. Low-risk, intermediate-risk, and high-risk patients received 100 millicuries (mCi), 150 mCi, and 200 mCi of 131 I, respectively. None of our patients had paraplegia from cord compression, or airway compromisation due to extensive local disease. None of our patient received radiotherapy before the RRA. Iodine-131 whole body imaging (131 I WBI) was performed between days 5 and 10 after the RRA for re-staging, and between 6 and 12 months after the ablation therapy for RRA response evaluation, with a dual-head SPECT gamma camera (Infinia 2; General Electric, Tel Aviv, Israel; Scan speed was 10 cm/min). At the same time sTg, anti-Tg and TSH levels were measured. In cases where we could not decide if the lesion seen in the postabla-

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Fig. 1. ROC analysis of the timing in high risk patients according to non-SIR response category.

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tion/response evaluation 131 I WBIs was lymph node metastasis, distant metastasis or not a metastasis at all, we correlated them with neck MRI, unenhanced chest CT, or whole body bone scintigraphy. If none of the imaging methods were able to detect lesions in spite of sTg elevation in therapy response 131 I WBI, we performed 18 Fluoro-deoxyglukose Positron emission tomography/computed tomography. The risk stratification of the patients treated after January 2016 was performed according to 2015 ATA guidelines. The risk stratification of the patients, who received treatment before this date were retrospectively re-designated according to 2015 ATA guidelines. Due to the high number of patients in low/intermediate-risk group, they were divided into four subgroups according to timing. The first, second, third and fourth groups were divided into ≤90 days, 90–180 days, 181–270 days and >270 days, respectively. This approach was also used for low/intermediate-risk women of reproductive ages as an additional group. Reproductive age was defined as being between 18–49 years old. The correlation between timing and non-SIR was analysed. Data analysis was conducted by IBM SPSS Statistics 22.0 (IBM Corp., Armonk, New York, USA). Descriptive statistics included numbers (n), percentages (%), median and mean ± standard deviation values. The relationship between categorical variables was examined by the Chi-square test for low/intermediate-risk patients and Fisher exact test for highrisk patients. The difference between the independent variables was analysed by independent samples t-test. The receiver operating characteristic (ROC) curve method was used for diagnostic tests and for the calculation of cut-off values (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018). The sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated. A p-value <0.05 was considered as statistically significant.

Results

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Of the 279 patients, 77.8% (n = 217) were female; 9.3% of the patients (n = 26) were in the high-risk group and 90.7% (n = 253) were in the low/intermediate-risk group. The mean patient age was 45.5 ± 12.9 years in the low/intermediate-risk group and 45.0 ± 15.4 years in the high-risk group. The median postoperative RRA timing was 68 days in the low/intermediate- risk patients and 59 days in the high-risk patients. Of the low/intermediate-risk patients, 89.1% (n = 223) had a diagnosis of papillary carcinoma and 11.9% (n = 30) had a follicular carcinoma; the corresponding values were 84.6% (n = 22) and 15.4% (n = 4) in the high-risk patients, respectively. In the low/intermediate-risk group, the median sTg was 4.8 ng/dl. In the high-risk group, the corresponding value was 181 ng/dl. The mean size of largest primary tumour was 2.2 ± 1.5 cm in the low/intermediate-risk patients and 3.5 ± 2.3 cm in the highrisk patients. There were not any significant differences between the low/intermediate-risk and high-risk groups in terms of age, sex, histopathological type, and timing (p > 0.1). However, the difference between the groups with respect to sTg and tumour size was significant, as expected (p < 0.05). The cohort of women with low/intermediate risk and between the ages of 18 and 49 years consisted of 107 patients (38.3% of all patients). In this group, the median timing was 68 days. According to ROC analysis RRA ≤58 days was found as a cut-off value for timing in high-risk patients. The sensitivity, specificity, PLR, and NLR were calculated as 83.3%, 70.0%, 2.78, and 0.24, respectively. Area under the ROC curve was 0.673, 95% CI was 0.47–0.84, SD was ±0.12. ROC analysis was shown in Fig. 1. There were no differences between subgroups of high-risk patients in terms of age, sex, histopathological type, radioiodine dose, median sTg level, tumour size, focality, lympho-

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Fig. 2. Comparison of the two similar high risk patients’ therapy response in terms of timing 38-year-old female patient diagnosed with papillary carcinoma with extrathyroidal invasion. Before the RRA her sTg was 270 ng/ml and TSH level was >75 uIu/ml. After the 200 mCi I-131 therapy 5 days I-131 WBI was shown residual thyroidal tissue in the neck, and upper mediastinal lymph node metastasis. Her RRA timing was 137 days (a) 11 months later 5 mCi 131 I WBI shown right cervical thyroidal tissue as well as middle mediastinal 131 I activity (arrow) with sTg 10.8 ng/ml (b). Therapy response evaluated as SIR. 49 years old female patient diagnosed with papillary carcinoma with extrathyroidal invasion. Before the RRA her sTg was 240 ng/ml and TSH level was 62 uIu/ml. After the 200 mCi I-131 therapy 6 days 131 I WBI was shown residual thyroidal tissue in neck and upper mediastinal lymph node metastasis. Her RRA timing was 47 days (c) 7 months later her sTg was <0.2 ng/ml and 5 mCi 131 I WBI shown cure (d). Therapy response evaluated as non-SIR. Although, second patient had many more metastatic sites, and therapy response was evaluated 4 months earlier, she could achieve excellent response compared to first patient. Table 1 Comparisons of demographic, histopathologic and biochemical parameters between subgroups of high risk patients.

Age (years) Sex (Male/Female) Histopathological type (F/P) Mean radioiodine doses(mCi) Tumour size (cm) Focality (Unifocal/multifocal) LVI (+/−) Capsular invasion (+/−) ETI (+/−) Perineural invasion (+/−) Margin positivity (+/−) LNM (+/−) LNM size (cm) Distant metastasis (+/−) Median stimulated Tg (ng/ml)

≤59 days

>59 days

P value

Timing (days)

≤90

90–180

181–270

>270

45.4 ± 15.3 2/11 3/10 165 ± 41 3.4 ± 2.0 5/8 6/2 5/3 5/1 2/4 6/2 10/3 3.3 ± 1.9 4/9 101

45.7 ± 15.5 3/10 1/12 153 ± 32 3.7 ± 2.7 5/8 5/4 5/3 4/1 3/4 8/3 9/4 2.9 ± 1.6 4/9 104

>0.1 >0.1 >0.1 >0.05 >0.1 > 0.1 > 0.1 > 0.1 > 0.1 > 0.1 > 0.1 > 0.1 >0.1 > 0.1 > 0.1

Non-SIR SIR

139 (85.8%) 23 (14.2%)

61 (91.0%) 6 (9.0%)

12 (92.3%) 1 (7.7%)

10 (90.9%) 1 (9.1%)

ATA, American Thyroid Association; F, follicular, P, papillary, LVI, lymph vascular invasion, ETI, extra thyroidal invasion, LNM, lymph node metastasis, Tg, thyroglobulin.

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Table 2 The non-SIR/SIR response ratios of subgroups of low/intermediate risk patients, according to RRA timing.

vascular/capsular/extrathyroidal invasion, lymph node metastasis, lymph node metastasis size, and presence of distant metastasis. Results were summarized in Table 1. Five patients who received RRA for ≤58 days had extrathyroidal invasion. Three of them had gross invasion, while two of them had minimal invasion. Four of the patients who received RRA for >58 days had extrathyroidal invasion. Two of them had gross invasion, two had minimal invasion. Four patients who received RRA for ≤58 days had distant metastasis. Three of them had lung metastasis, and one of them had lung metastasis together with bone metastasis. Four patients who received RRA for >58 days had distant metastasis. Two of them had lung metastasis. One lung metastasis was seen together with bone

Table 3 The non-SIR/SIR response ratios of subgroups of low/intermediate risk women patients in reproductive ages, according to RRA timing. Timing (days)

≤90

90–180

181–270

>270

Non-SIR SIR

68 (89.4%) 8 (11.6%)

22 (91.6%) 2 (8.4%)

4 (100%) 0 (0%)

3 (100%) 0 (0%)

metastasis. The last patient had lung, bone, and liver metastasis at the same time (Fig. 2). For low/intermediate-risk patients, we did not find any significant relationship between timing and non-SIR (p > 0.1). The non-SIR response ratio of patients who received RRA in the first, second, third, and fourth subgroups were found as 85.8%, 91.0%, 92.3%, and 90.9%, respectively. Results are summarized in Table 2. Similarly, for the female patients with low/intermediate-risk in the reproductive ages, we did not find any significant relationship between timing and non-SIR (p > 0.1). The ratio of patients who received RRA in the first, second, third, and fourth subgroups were found as 89.4%, 91.6%, 100%, and 100%, respectively. Results are summarized in Table 3. There were not any statistically differences between subgroups of all low/intermediate risk patients in terms of age, sex, histopathological type, radioiodine dose, sTg level, tumour size, focality, lymph node metastasis, lymph node metastasis size, and lymphovascular/capsular/extrathyroidal invasion. Results were shown in Table 4.

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Table 4 Comparisons of Demographic, Histopathologic and Biochemical Parameters between subgroups of low/intermediate Risk Patients. Timing (Days)

≤90

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181–270

>270

P value

Age (years ± SD) Sex (Male/Female) 2015 ATA (Low/intermediate) Histopathological type (F/P) Mean radioiodine doses (mCi ± SD) Mean tumour size (cm ± SD) Focality (Unifocal/multifocal) LVI (+/−) Capsular invasion (+/−) ETI (+/−) Perineural invasion (+/−) Margin positivity (+/−) LNM (+/−) Mean LNM size (cm ± SD) Median stimulated Tg (ng/ml)

45.1 ± 12.1 39/120 69/90 21/138 106.2 ± 16.6 2.1 ± 1.5 63/60 26/71 34/58 10/46 6/40 10/54 38/121 1.8 ± 0.8 6.5

47.7 ± 14.2 12/53 20/45 6/59 109.5 ± 19.8 2.2 ± 1.2 26/15 8/32 12/26 5/17 1/12 3/13 18/47 2.1 ± 0.8 7.0

50.7 ± 13.5 3/13 5/11 2/14 107.1 ± 18.1 2.1 ± 1.5 6/5 4/6 9/5 1/5 1/5 1/5 3/13 2.3 ± 0.9 4.7

41.3 ± 7.0 3/10 3/10 1/12 115.3 ± 24.0 1.8 ± 1.2 4/5 1/4 3/5 0/3 0/3 0/3 2/11 2.7 ± 1.1 3.8

>0.1 >0.1 >0.1 >0.1 >0.1 >0.1 >0.1 P = 0.09 >0.1 >0.1 >0.1 >0.1 >0.1 >0.1

ATA, American Thyroid Association; F, follicular; P, papillary; LVI, lymphovascular invasion; ETI, Extrathyroidal invasion; LNM, lymph node metastasis; Tg, thyroglobuline.

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Discussion The decision about radioiodine ablation is made according to various guidelines 4–7 . However, none of them have not mentioned about the time interval between TT and RRA. One of the most important reasons for this is that the studies on the timing of RRA have only recently been started and the literature on this subject is very limited. In contrast, thyroid surgeons have long been aware of the negative results of delaying the surgery for more than 12 months in DTCs 9 . The emergence of similar literature on the time interval between TT and RRA can be useful in clinical practice. In a previous large patient series, if the RRA therapy was initiated after more than 180 days postoperatively in the high-risk group, risk of death increased approximately 4.2 times 10 . In that study, the mean RRA timing was reported as 844.6 days. Another recently published study reported that, no significant correlation was found between persistent disease and timing among highrisk patients receiving and not receiving RRA therapy within six months 11 . In the study by Tsirona et al. where they investigated 107 stage 1 patients; unlike those previously mentioned, persistent disease occurred in 12% of the patients who received RRA within 4.7 months. Authors found a 1.8% persistent and 7% recurrent disease rate among patients who received RRA after 4.7 months 12 . In a study reported by Suman et al., the correlation between timing and overall survival was investigated in low- and intermediate-risk patients. In that study, 5-year overall survival rate was 98.7% in lowrisk patients who received RRA within 3 months and it was 99.1% in those who received RRA between 3 and 12 months. Furthermore, in their intermediate-risk cases, the 5-year overall survival rate was calculated as 98.4% for RRA applied within 3 months, and 98.6% for RRA between 3 and 12 months. Neither comparison was reported as significant. Similarly, when both groups were evaluated together, the correlation between timing and overall survival could not be found 3 . In our study, the likelihood of non-SIR was significantly higher at the one-year follow- up in high-risk patients who received RRA ≤58 days. According to ROC analysis of the patients in the highrisk group who received RRA >58 days had 2.78 times higher SIR risk compared to those who received RRA ≤58 days. Our results differ from the findings reported by Scheffel et al 11 . A possible reason for this difference is that the previous study was an analysis of the correlation between persistent disease and timing, whereas we analysed the correlation between non-SIR and timing. The results we obtained are consistent with the correlation between timing and mortality which were reported by Higashi et al. 10 . Considering the low mortality rate among the non-SIR response category 7 , this similarity was expected. However, the value of greater than

180 days which was given by Higashi et al were quite different from the value of greater than 58 days in our study. High-risk patients received RRA therapy much earlier in our study compared to that by Higashi et al. The authors also mentioned their long-time interval between surgery and RRA 10 . The timing we obtained appears to be closer to most other centres worldwide 13 . On the other hand, we could not find a significant correlation between timing and nonSIR in low/intermediate-risk patients, unlike the high risk ones (p > 0.1). Our results were similar to the absence of correlations between persistent disease, OS, and timing in low/intermediate risk cases reported by other researchers 3,11,12 . Similarly, we could not find a correlation in the low/intermediate risk category when women between the ages of 18 and 49 were analysed as a special group. In our study, a relatively large number of patients and their follow-up with the same procedure at the same centre was an advantage. We believe that this increases the validity of our findings. However, our study had some limitations. Firstly, the analysis was retrospective and it has inherently some limitations about data collection. However, we think that the relatively large number of patients were sufficient to provide useful information. Secondly, although certain parameters of some patients were missing, the absence of statistically significant differences of other parameters except time interval between the subgroups might be an advantage. Thirdly, more than 90% of patients’ surgeries were performed by two referral centres’ thyroid surgeons, this may be considered as a limitation. Low number of high-risk patients might be another limitation, despite of the statistically significant result. Due to this reason we think that it is too early to mention a definitive conclusion for this group. Additionally, in our study, BRAFV 6◦◦vE and TERT mutations were not evaluated. In a comprehensive meta-analysis, the sensitivity of BRAFV600E mutation was calculated as 65% for recurring patients. In addition, according to this analysis the PPV of recurrence prediction was found as only 25% 14 . As stated in the 2015 ATA guidelines, since the clinical effects of the BRAFV V ◦◦vE mutation were not clear, it was not routinely recommended for the initial postoperative risk stratification. Similarly, it has been reported that, although TERT mutation status may be helpful, however it must be confirmed 7 . Finally, we did not study women in the reproductive ages in the high-risk category. Nonetheless, we think that, our results can also be applied to them.

Conclusion

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Initiation of the RRA therapy within 58 days after the TT in patients with high-risk DTCs might be an appropriate approach to achieve non-SIR category. With this approach, the risk of SIR associated mortality may be reduced. On the other hand, the RRA timing

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for women in reproductive ages with low/intermediate risk group may be planned according to their pregnancy and breastfeeding intent. The RRA therapy planning for other low/intermediate risk groups can safely proceed according to the capacity of the medical facility and related logistical considerations. Of course, close followup is necessary for these two groups. This approach may facilitate more effective and efficient use of health centres’ resources. At the same time, it can provide clearer information about the timing of RRA for patients. We think large scale, prospective, and multicentre studies are required to clarify this issue further, especially for high-risk patients.

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Ethics approval and consent to participate

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The Ethics Committee approval for the study was obtained. Firat University Non-invasive Ethics Committee Consent for publication

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We have patient’s consent form. If you may request, we can share to a copy at any stage (including after publication). However, we did not send right now, because there is patient’s name in it.

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Availability of data and materials

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The datasets generated and/or analysed during the current study are not publicly available due to patient privacy but are available from the corresponding author on reasonable request.

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Funding section

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None Conflict of interests

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The authors have no conflicts of interest to declare. Acknowledgement None.

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