Radioiodine (I-131) Ablation in Outpatient After Total Thyroidectomy for the Differentiated Thyroid Cancer

Objective To evaluate the clinical significance of I-131 ablation in patients with differentiated thyroid cancer. Subjects and Methods Forty-three postoperative (total thyroidectomy) patients with differentiated thyroid cancer were studied. Thirty-one patients received total thyroidectomy for thyroid cancer (Primary operation group) and 12 patients had total thyroidectomy as a second operation (Reoperation group : subtotal thyroidectomy was performed at first operation for thyroid cancer). All patients received I-131 30 mCi ablation and SPECT/ CT scans were performed to assess the thyroid bed accumulation of I-131 to evaluate the efficacy of ablation. Thyroglobulin levels were measured before and 6 months after I-131 ablation. Results Ablation success rate was 64.3% in Primary operation group and 42.8% in Reoperation group. Thyroid cancer recurrence rate after ablation was 3.2% in Primary operation group and 33.3% in Reoperation group (p<0.05). Serum Tg level tended to be higher in Reoperation group than that in Primary operation group at 6 months after ablation. Thyroid cancer recurrence was observed in 3 of 4 patients with ablation failure in Reoperation group. Serum Tg level was higher in patients with recurrent disease (±) compared to those without recurrence (±). Conclusion


Introduction
It is estimated that 1,900 of 100,000 people (1.9%) will develop thyroid cancer in their lifetime and 800 (0.8%) will die from it [1].
The 20-year survival rate of differentiated thyroid cancer varies from 99% in low-risk patients to 57% in high-risk patients [2].
Common treatments for thyroid cancer include surgery, such as total and subtotal thyroidectomy, chemotherapy, and molecular targeted therapy. I-131 ablation is specifically aimed to ablate the thyroid bed that remains following total thyroidectomy to prevent local recurrence and consequently reduces the metastasis and recurrence rates following thyroidectomy [3]. Various recent studies demonstrate that the effective rate of I-131 ablation using 30mCi is equivalent to 100 mCi [4][5][6]. This finding was supported further by a meta-analysis that demonstrated that there was no significant difference between the administration of 30 mCi and 100 mCi of I-131 in terms of its efficacy [7].
Another study advocated that there were no significant intergroup differences in outcome among patients receiving 25-50 mCi of I-131 [8]. However, there are no studies to date that have compared the efficacy of I-131 ablation-naïve patients who had previously received subtotal thyroidectomy for thyroid cancer and required total thyroidectomy due to recurrent disease and those who underwent total thyroidectomy after the initial diagnosis of thyroid cancer. Accordingly, the efficacy of low-dose (30 mCi) I-131 ablation was evaluated in patients who received total thyroidectomy after the initial diagnosis of thyroid cancer and those who underwent total thyroidectomy as a second operation (received subtotal thyroidectomy at the first operation for thyroid cancer).

Patients
A total of 43 patients with differentiated thyroid cancer who received total thyroidectomy and not having any metastases to lymph nodes and other organs between July 2011 and July 2018 were

Assessment of Low-Dose I-131 Ablation
To assess the efficacy of ablation, follow-up I-131 scintigraphy was performed 4 to 6 months after ablation in patients who had a residual thyroid bed identified in the initial scintigraphy. The efficacy of ablation was assessed visually based on the follow-up scintigram. Disappearance of the thyroid bed was defined as a success and the presence of residual uptake was defined as a failure.

Measurement of Tg And Anti-Tg Antibody
As serum thyroglobulin (Tg) is a tumor marker for thyroid cancer used to detect postoperative recurrence as well as the efficacy of I-131 ablation, the relation between the serum Tg level and recurrence of thyroid cancer following ablation was examined.
The serum Tg and anti-Tg antibody levels were measured just before the ablation (baseline Tg), following the pre-treatment protocol (stimulated Tg), and at 6 months after the ablation (follow-up Tg).
High Tg level (high-Tg case) was defined as Tg ≥ 2 ng/mL and low Tg level (low-Tg case) was defined as < 2 ng/mL at 6-month follow-up, irrespective of the baseline Tg level. However, patients with high anti-Tg antibody (> 28 U/mL) were excluded from this grouping since Tg level could not be measured accurately.

Follow-Up After Low-Dose I-131 Ablation
During the follow-up period, chest and abdominal CT was performed every 6 months, and FDG-PET/CT was performed every year after total thyroidectomy to examine the presence of recurrent thyroid cancer. Recurrence of thyroid cancer was defined as appearance of new gross lesions on follow-up CT and FDG-PET/CT.

Statistical Analysis
Differences between the 2 groups were analyzed using the Student's t-test for continuous variables and the Fisher's exact test for categorical variables. The log-rank test was used to determine the rate of thyroid cancer recurrence using Tg levels (baseline, stimulated, and follow-up Tg) during the follow-up period. MINITAB 14 (Minitab Inc., State College, PA, USA) was used for the analyses, and a significance level of < 5% (p<0.05) was considered significant.

Recurrence Rate
The recurrence rate of thyroid cancer following ablation was 3.2% in PO group and 33.3% in RO group; the difference significant  Table 3).     (Figure 2a). The serum Tg level is abnormally high 6 months after ablation (42.5 ng/mL), and FDG-PET/CT shows metastasis in the right 10th rib (Figure 2b). External-beam radiotherapy with 30 Gy was performed to target the metastatic lesion in September 2014. The serum Tg level decreases from 64.8 ng/mL before externalbeam radiotherapy to 5.7 ng/mL after external-beam radiotherapy. The patient is currently being followed-up with no signs of metastatic disease to date.

c)
A hot spot is seen in the neck region on the maximum intensity projection (MIP) image (white arrowhead). d) Significant FDG uptake is observed in the right side of the trachea on the fusion image (white arrow), indicating local recurrence following surgery for thyroid cancer.

Serum Tg Levels
Baseline Tg and follow-up Tg were measured in 37 patients, while stimulated Tg was measured in 31 patients. Six patients had high level of anti-Tg antibody at baseline. Follow-up Tg level was ≥ 2ng/mL in 10 patients and < 2 ng/mL in 27 patients. There was no significant difference in baseline Tg levels and stimulated Tg levels between PO and RO groups. There were no significant differences in baseline Tg and stimulated Tg levels between the patients with and without recurrence of thyroid cancer. Follow-up Tg level tended to be higher in RO group than in PO group, and in patients with recurrent disease than in those without (Figure 4).  (Table 4). Among the 12 patients who had successful ablation, 5 were classified as having high-Tg and 7 were classified as having low-Tg. All 12 patients who had successful ablation had no recurrence of thyroid cancer during the follow-up period. Among the 9 patients who did not respond to ablation, 3 were classified as having high-Tg and 6 were classified as having low-Tg. All 3 high-Tg cases had recurrence of thyroid cancer and were in RO group (Table 4).

Discussion
Up to 90% of patients who receive total thyroidectomy are reported to have residual thyroid tissue [9]. The present study demonstrated that 32 of 43 patients (74.4%) had residual thyroid tissue following surgery. The possibility of having residual thyroid tissue following total thyroidectomy is thought to depend largely on the skill of the surgeons and may vary in different institutions.
In this study, a relatively high proportion of patients had residual thyroid tissue, suggesting a difficulty in removing thyroid tissue completely with a single total thyroidectomy. It is well known that I-131 ablation after total thyroidectomy significantly lowers the rates of metastasis and recurrence of differentiated thyroid cancer.
Many studies demonstrated that there is no clear difference in the efficacy rate of I-131 ablation between 30 mCi and 100 mCi I-131 [4][5][6]. We found 57.1% had a successful I-131 ablation, which is in accordance with previous studies demonstrating that 50-63% respond to treatment with 30 mCi of I-131 [5,6,10]. The present study demonstrated that the rate of postoperative recurrence of thyroid cancer was significantly higher in RO group (33.3%) than The postoperative recurrence rate in patients with differentiated thyroid cancer who did not receive ablation ranges from 6.6 to 35.4%, depending on the duration of follow-up period and whether the initial surgery was radical [11]. The present study demonstrated that only 3.1% of patients in the PO group had postoperative recurrence of differentiated thyroid cancer, whereas the recurrence rate was high (33.3%) in RO group. This could be attributed to the possibilities that tumors in the RO group may have had dedifferentiation or anaplastic transformation at the time of ablation, or presence of small metastatic lesions that could not be detected by imaging. Differentiated thyroid cancer is known to undergo anaplastic transformation during its progression and the prognosis of such differentiated cancers that have undergone anaplastic transformation is poor. Furthermore, papillary and follicular cancers may exist within non-malignant lesions and undergo anaplastic transformation [12]. Previous studies have reported that 1-3% of differentiated thyroid cancers undergo anaplastic transformation during progression [13,14]. Although the underlying mechanisms of anaplastic transformation of differentiated thyroid cancer have not been fully elucidated, BRAF and N-RAS mutations may be involved in terms of molecular biology and that anaplastic transformation is preceded by dedifferentiation [15,16].
Furthermore, the degree of differentiation is reported to be reduced in a relatively high proportion (11-13%) in patients with recurrent thyroid cancer [11,17]. Tumors become increasingly poorly differentiated after repeated episodes of recurrence with a rate ranging from 7% for the first recurrence and 21% for the second recurrence, indicating that recurrent lesions of differentiated thyroid cancer are likely to undergo anaplastic transformation at a relatively high rate [17]. In the present study, all the patients in RO group had a history of recurrence of thyroid cancer prior to ablation. Therefore, it is possible that they had lesions that had undergone dedifferentiation or anaplastic transformation at the time of ablation. Differentiated thyroid cancer arises from follicular epithelial cells of the thyroid that have become cancerous and acquire the ability to take up iodine (dependent on the NaI symporter), and ablation with I-131 take advantage of this ability.
However, approximately 30% of patients with differentiated thyroid cancer are reported to lack the ability to take up iodine. If small metastatic lesions that do not express NaI symporter exist at the time of ablation, these lesions would not be detected by scintigraphy and would likely contribute to subsequent recurrence.
In the present study, as time from the initial surgery to ablation was longer in the RO group than in the PO group, it is highly likely that anaplastic transformation and micro-metastasis may have occurred during this period leading to a low efficacy rate to ablation.
Tg is a tumor marker used to detect recurrence of thyroid cancer following total thyroidectomy and previous studies demonstrated that it is a highly specific marker for thyroid cancer [18,19].
However, the level of serum Tg is not necessarily specific to cancer but depends on the amount and activity of thyroid tissue, which increases in Graves' disease and in non-malignant thyroid tumors as the mass of thyroid tissue and tumor size increase [20]. There were no significant differences in the Tg and stimulated Tg levels at baseline between PO and RO groups, and between patients with and without recurrence of thyroid cancer. These data suggest that serum Tg alone is limited in predicting postoperative recurrence of differentiated thyroid cancer. On the other hand, the follow-up Tg levels were higher in RO group than in PO group and in patients with recurrent disease compared with those without recurrent disease. All 5 patients who had recurrent disease had high serum Tg levels (9.6-48.7 ng/mL) at 6 months after ablation.
Three patients who did not respond to ablation had high levels of follow-up Tg and developed recurrence of thyroid cancer during the follow-up period, specifically local recurrences in the neck.
In contrast, there was no recurrence in patients who responded to ablation and serum Tg level was low (<2 ng/mL) at 6 months after ablation. Although, there is an individual difference in terms of the efficacy of ablation since it depends on the uptake of I-131 in the thyroid tissue and whether the iodine intake was properly restricted prior to ablation, the present findings suggest that the risk of local recurrence is high in patients with residual thyroid bed with high serum Tg level at 6 months after the initial ablation. Thus, ablation with radioactive iodine is recommended following total thyroidectomy for differentiated thyroid cancer who are at risk of recurrence. Based on the present findings, we recommend active consideration of multidisciplinary treatment 6 months after initial ablation to prevent local recurrence.

Conclusion
Low-dose I-131 ablation is recommended following total thyroidectomy in patients with high risk differentiated thyroid cancer. However, low-dose (30mCi) I-131 ablation may not be effective for patients who had received surgery for differentiated thyroid cancer and have previously had recurrent disease.