ABSTRACT

Conclusion:

Ablation with 30-50 mCi can be safely applied in DTC patients who are in the ATA 2015 low-risk group and are planned for RAI ablation treatment.

Results:

According to the first-year follow-up, 15 patients were accepted as indeterminate response and 85 patients as excellent response. Three (5.5%) of the patients who were accepted as indeterminate response were in group 1 and 12 (26%) were in group 2. According to the third year follow-up, 1 patient in group 1 and 3 patients in group 2 were accepted as indeterminate response. No biochemical incomplete response or recurrent disease was detected. In the chi-square analysis performed to investigate the relationship between the first-year treatment response and RAI activities, a significant relationship was found (p=0.004). In the Mann-Whitney U test performed to investigate the parameters that may be effective in the treatment response, only the preablative serum thyroglobulin value was shown to have a significant difference between the two groups (p=0.01). In the long-term follow-up of the patients, based on the third year treatment response data, chi-square analysis was performed to evaluate the two groups in terms of treatment responses, and no statistically significant relationship was found (p=0.73).

Methods:

Between February 2016 and August 2018, 100 patients who received RAI treatment in our clinic after total thyroidectomy and who were in the low-risk group DTC were included in this retrospective study. These patients were divided into 2 groups: low-activity (30-50 mCi) (group 1) and high-activity (100 mCi) (group 2). While 54 patients were treated with low activity, 46 patients received high activity RAI. The 2 groups were compared according to the 1^st- and 3^rd-year treatment response status.

Objectives:

The aim of this study was to compare the treatment responses after ablation with 30-50 mCi radioactive iodine (RAI) and 100 mCi RAI in patients with differentiated thyroid cancer (DTC) who were in the low-risk group according to 2015 American Thyroid Associations Classification (ATA 2015) criteria.

Introduction

Differentiated thyroid carcinomas (DTC) usually show a slow course of progression and patients diagnosed with DTC have a long life expectancy. A significant increase has been observed in the incidence of DTC with the widespread use of imaging modalities recently (1,2). An important reason for this is thought to be the incidental detection of small-sized nodules, which would not normally cause any symptoms in the patient, in imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (USG), and positron emission tomography (PET)/CT applied to the patient for other reasons. This has led to a significant increase in the incidence of especially low-risk thyroid cancer through the early diagnosis of slow-progressing malignant thyroid nodules.

According to the 2015 American Thyroid Associations Classification (ATA 2015), patients without risk factors such as extrathyroidal extension, distant metastasis, or aggressive histological subtype are defined as low-risk (3). In these patients, the recurrence of the disease or disease-related mortality after treatment is extremely rare. It has been reported that when patients with DTC undergo successful radioactive iodine (RAI) remnant ablation after total thyroidectomy, less than 1-4% of patients have disease recurrence (4,5,6,7). The very slow course of the disease and the very low rate of recurrence have led to the emergence of very different clinical approaches, and there is no consensus among physicians yet on the necessity of RAI in these patients and the activity to be administered if necessary. This situation often leads to overtreatment of these patients, resulting in undesirable results such as unnecessary radiation exposure, an increase in the frequency of side effects and secondary malignancies, and cost increase (8,9). The aim of this study was to compare the treatment responses after ablation with low-activity (30-50 mCi) RAI and high-activity (100 mCi) RAI in patients with DTC who were in the low-risk group according to ATA 2015 criteria.

Materials and Methods

Results

Of the 100 patients included in the study, 79 were female and 21 were male. The mean age of the patients was 47±13 (range 19-75 years), while the mean tumor diameter was 19.40±10.68 millimeters. The mean preablative Tg value was calculated as 2.92 (0.04-82.55) in all patients in the study group. While there were 7 T1a, 38 T1b, 8 T2, 1 T3 stage patients in group 1, which consisted of patients who received low-activity (30-50 mCi) RAI treatment, there were 3 T1a, 21 T1b, 19 T2, 3 T3 stage patients in group 2, which consisted of patients who received high- activity (100 mCi) RAI treatment. In group 1, 25 patients had unifocal and 29 patients had multifocal disease, while in group 2, 23 patients had unifocal and 23 patients had multifocal disease. While the mean primary tumor diameter was 21.62±7.39 (4-45) mm in group 1, it was 23.11±12.69 (3-65) mm in group 2. Preablative serum Tg value was 1.81 (0.04-34) ng/mL in group 1 and 4.25 (0.05-82.55) ng/mL in group 2. The demographic and clinical features of the patients in this study are summarized in Table 1.

Table 1

According to the first-year follow-up, 15 patients were accepted as indeterminate response and 85 patients as an excellent response. Three (5.5%) of the patients who were accepted as indeterminate response were in group 1 and 12 (26%) were in group 2. According to the 3^rd year follow-up, 1 patient in group 1 and 3 patients in group 2 were accepted as indeterminate response. No biochemical incomplete response or recurrent disease was detected in any patient in either patient group. The treatment responses of the patients at the end of the 1^st and 3^rd years according to the administered RAI activities are summarized in Table 2.

Table 2

In the chi-square analysis performed to investigate the relationship between the first-year treatment response and RAI activities, a significant relationship was found (p=0.004). Accordingly, group 2 had significantly more patients who were accepted as indeterminate response than group 1 at the end of the first year. It was investigated which parameters had a statistically significant difference between patients with excellent response and patients with indeterminate response. In the Mann-Whitney U test performed for this purpose, only the preablative serum Tg value was shown to have a significant difference between patients with excellent and indeterminate response (p=0.010), and tumor size, patient age, and preablative anti-Tg levels were found to be not statistically significant factors (p=0.083; 0.38; 0.80; respectively).

The mean preablative serum Tg value was 2.14 (0.04-85.55) ng/mL in patients with excellent response at 1^st year after treatment and 6.21 (0.83-41) ng/mL in patients with indeterminate response. In the long-term follow-up of the patients, based on the third year treatment response data, chi-square analysis was performed to evaluate the two groups in terms of treatment responses, and no statistically significant relationship was found (p=0.73).

Discussion

The ATA 2015 guideline does not recommend routine RAI ablation in low-risk thyroid cancer patients but recommends the application of low-activity RAI if ablation is required. Similarly, there are multiple studies that have shown that a low activity of RAI is as effective as a high activity for thyroid remnant ablation in low- and intermediate-risk patients. However, due to changes in definitions of response to treatment and patient selection criteria, the rate of ablation success may differ between these studies.

In this study, we found that 85 out of 100 patients with low-risk DTC showed excellent response to treatment 1 year after RAI treatment. Similarly, in a single-center randomized study by Dong et al. (10), it was found that RAI ablation was successful at 6 months after RAI in 412 of the 474 (87.5%) low-intermediate risk patients. In the same study, it was reported that the successful ablation rates between the patients who received high- and low-activity RAI were similar (87.5% vs. 86.5%; respectively). Comparably, in another study that included 34 patients by Yasmin et al. (11), it was reported that no statistically significant difference concerning the treatment response was found between high- and low-activity RAI receiving patients at 1 year after RAI treatment [82% vs. 76%, respectively (p=0.671)]. As opposed to these studies, in the present study, there was a statistically significant difference between the two groups 1 year after RAI treatment. In this study, the successful ablation rates 1 year after treatment were 94.5% at low- and 74% at high-activity RAI receive patients (p=0.004). This variability among these past studies and this study could be due to different study populations and different definitions of treatment response. In the Mann-Whitney U test performed to investigate the parameters that may be effective in the significant difference in treatment responses in the current study, only the preablative serum Tg value was shown to have a significant difference between the two groups (p=0.01); and tumor size, patient age, preablative anti-Tg levels were found to be not statistically significant factors (p=0.083; 0.38; 0.80; respectively).

In the present study, the mean preablative serum Tg value was 2.14 (0.04-85.55) ng/mL in patients with excellent response at 1^st year after treatment and 6.21 (0.83-41) ng/mL in patients with indeterminate response. In a different study by Ha et al. (12), it was reported that 121 of 176 (68.8%) patients with low-risk DTC had successful ablation after receiving low-activity RAI. Although the successful ablation rate was lower in the study by Ha et al. (12), it was also discovered similarly to our study that the pre-ablative serum Tg levels were the only independent factor related to the treatment response (1.2±2.3 ng/mL in successful, vs. 6.2±15.2 ng/mL in unsuccessful ablation, p=0.027).

In two major open-label, randomized, controlled trials, there was no statistically significant correlation found between high- and low-activity RAI receiving low-intermediate risk patients, considering the treatment response in long-term follow-up. In the HiLo study including 434 patients by Dehbi et al. (13), the successful ablation rates were similar between the high- and low-activity RAI groups at 3-5 years after treatment (98.5% vs. 97.9% at 3 years and 97.9% vs. 97.3% at 5 years after RAI, respectively). Likewise, in the ESTIMABL1 study including 752 patients by Schlumberger et al. (14), 98% of the low-risk DTC patients had excellent response to treatment at 5 years after RAI. Of the 11 patients who showed evidence of disease 5 years after RAI, 5 had previously received high-activity and 6 had received low-activity RAI treatment. Similar to these studies, in this study, no statistically significant difference was found between the high- and low-activity RAI groups at 3 years after treatment (98% vs. 87%, respectively, p=0.73).

Conclusion

In conclusion, although the data obtained in our study revealed that there was a statistically significant difference between the high- and low-activity RAI groups at the end of the first year, there was no statistically significant difference in long-term follow-up. Therefore, considering the unwanted effects of high-activity RAI treatment such as side effects, cost increase, and secondary malignancy, ablation with 30-50 mCi can be safely applied in DTC patients who are in the ATA 2015 low-risk group and are planned for RAI ablation treatment.

Patients

Between February 2016 and August 2018, 100 patients (97 patients with papillary, and 3 patients with follicular carcinoma) who received RAI treatment in our clinic after total thyroidectomy and who were in the low-risk group DTC were included in this retrospective study.

The inclusion criteria were as follows: age at diagnosis ≥18 years; patients undergoing total or near-total thyroidectomy; low-risk DTC; and primary RAI therapy after surgery. The exclusion criteria were the presence of aggressive histologic subtypes, high preablative serum anti-thyroglobulin (anti-Tg) levels, vascular invasion, microscopic or gross extrathyroidal extension, metastatic lymph nodes of any size, any RAI-avid metastatic foci outside the thyroid bed on the first posttreatment whole-body RAI scan indicating distant metastasis, and secondary malignancy. These patients were divided into two groups: low-activities (30-50 mCi) (group 1) and high-activity (100 mCi) (group 2). While 54 patients were treated with low activity (6 patients with 30 mCi and 48 with 50 mCi), 46 patients received high activity RAI. The 2 groups were compared according to the 1^st- and 3^rd-year treatment response status.

Radioactive Iodine Administration

Patients admitted to our clinic in the 1-6 months postoperative period were prepared with thyroid hormone withdrawal for 4 weeks and a low-iodine diet for 2 weeks. Patients with thyroid-stimulating hormone (TSH) level ≥30 mU/L were evaluated for RAI activity determination by serum Tg and anti-Tg levels, neck USG, and technetium-99m pertechnetate thyroid scintigraphy. Four to 7 days after RAI treatment, a post-therapy I-131 whole-body scan (WBS) was performed using a Mediso Anyscan SC-SN-3s-60R high energy parallel hole collimator. Scan images were reviewed by 2 consultant nuclear physicians before reporting.

Response to Therapy

The ATA 2015 guideline has a dynamic risk assessment system that classifies the patient based on the response to therapy (excellent, indeterminate, biochemical incomplete, and structural incomplete response) using serum Tg level, anti-Tg antibodies, USG, diagnostic wholebody scan, CT, PET/CT, and MRI (3). In this study, response to therapy assessment was performed twelve months and three years after RAI treatment based on the ATA 2015 risk assessment system.

Thus, an excellent response was defined as negative imaging with TSH-stimulated Tg <1 ng/mL or suppressed Tg <0.2 ng/mL.

Meanwhile, an incomplete response was defined as one of the following:

1. Biochemical incomplete response was defined as negative imaging with abnormal suppressed Tg (≥1 ng/mL) and/or stimulated Tg values (≥10 ng/mL) or rising anti-Tg.

2. Structural incomplete response was defined as locoregional or distant metastases on USG and/or WBS (independent of Tg and anti-Tg).

Lastly, indeterminate response was defined as non-specific findings on imaging studies, non-stimulated Tg between 0.2 and 1 ng/mL, stimulated Tg between 1 and 10 ng/mL, or anti-Tg stable or declining in the absence of structural or functional disease.

University of Health Sciences Turkey, Prof. Dr. Cemil Taşcıoğlu City Hospital Ethics Committee approval was obtained on 09.05.2022 with decision number 147 for this clinical study, which was designed retrospectively.

Statistical Analysis

Data were analyzed using IBM SPSS Statistics 26.0 for Windows. Results were expressed as mean ± standard deviation. Comparisons of the data were performed by Mann-Whitney U and chi-square tests. Results were considered statistically significant when the two-tailed p value was less than 0.05.

Study Limitations

The limitations of this study were the retrospective design, limited number of patients, and relatively short follow-up time of 3 years. As previously stated, DTC is a disease that can progress over a long period of time. Thus, extending this period may have some positive impacts on patient outcome.

References

Stewart B, Wild CP: World cancer report 2014. World: 2015. http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer- Report-2014

Dal Maso L, Tavilla A, Pacini F, Serraino D, van Dijk BAC, Chirlaque MD, Capocaccia R, Larrañaga N, Colonna M, Agius D, Ardanaz E, Rubió-Casadevall J, Kowalska A, Virdone S, Mallone S, Amash H, De Angelis R; EUROCARE-5 Working Group. Survival of 86,690 patients with thyroid cancer: a population-based study in 29 European countries from EUROCARE-5. Eur J Cancer 2017;77:140-152.

Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1-133.

Rosario PW, Mineiro Filho AF, Prates BS, Silva LC, Calsolari MR. Postoperative stimulated thyroglobulin of less than 1 ng/ml as a criterion to spare low-risk patients with papillary thyroid cancer from radioactive iodine ablation. Thyroid 2012;22:1140-1143.

Soyluk O, Boztepe H, Aral F, Alagol F, Özbey NC. Papillary thyroid carcinoma patients assessed to be at low or intermediary risk after primary treatment are at greater risk of long term recurrence if they are thyroglobulin antibody positive or do not have distinctly low thyroglobulin at initial assessment. Thyroid 2011;21:1301-1308.

Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin JA, Shaha A. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 2010;20:1341-1349.

Pelttari H, Välimäki MJ, Löyttyniemi E, Schalin-Jäntti C. Post-ablative serum thyroglobulin is an independent predictor of recurrence in low-risk differentiated thyroid carcinoma: a 16-year follow-up study. Eur J Endocrinol 2010;163:757-763.

Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer 2011;117:4439-4446.

Haymart MR, Banerjee M, Stewart AK, Koenig RJ, Birkmeyer JD, Griggs JJ. Use of radioactive iodine for thyroid cancer. JAMA 2011;306:721-728.

Dong P, Wang L, Qu Y, Huang R, Li L. Low - and high-dose radioiodine ablation for low-/intermediate-risk differentiated thyroid cancer in China: large randomized clinical trial. Head Neck 2021;43:1311-1320.

Yasmin T, Adnan S, Younis MN, Fatima A, Shahid A. Comparing high and low-dose radio-iodine therapy in thyroid remnant ablation among intermediate and low-risk papillary thyroid carcinoma patients-single centre experience. Dose Response 2021;19:15593258211062775.

Ha S, Oh SW, Kim YK, Koo do H, Jung YH, Yi KH, Chung JK. Clinical Outcome of remnant thyroid ablation with low dose radioiodine in korean patients with low to intermediate-risk thyroid cancer. J Korean Med Sci 2015;30:876-881.

Dehbi HM, Mallick U, Wadsley J, Newbold K, Harmer C, Hackshaw A. Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial. Lancet Diabetes Endocrinol 2019;7:44-51.

Schlumberger M, Leboulleux S, Catargi B, Deandreis D, Zerdoud S, Bardet S, Rusu D, Godbert Y, Buffet C, Schvartz C, Vera P, Morel O, Benisvy D, Bournaud C, Toubert ME, Kelly A, Benhamou E, Borget I. Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial. Lancet Diabetes Endocrinol 2018;6:618-626.

Comparison of Radioactive Iodine Activities in Terms of Short- and Long-term Results in Ablation Therapy in Patients with Low-risk Differentiated Thyroid Cancer