Radioiodine Uptake and Thyroglobulin-Guided Radioiodine Remnant Ablation in Patients with Differentiated Thyroid Cancer: A Prospective,Randomized,Open-Label,Controlled Trial

Abstract

Background:

Radioiodine (¹³¹I) remnant ablation (RRA) has become a key step in the postoperative treatment of differentiated thyroid cancer (DTC). However, inadequate or excessive ¹³¹I is common using fixed activities. This study was designed to explore the feasibility of radioiodine uptake and thyroglobulin (RAIU-Tg)-guided RRA.

Methods:

A total of 277 patients were randomized to the RAIU-Tg-based activity group or a fixed activity of 3.7 GBq group at a ratio of 4:1. The RAIU-Tg-based activity was established based on four levels of RAIU (≤2%, 2–5%, 5–15%, and >15%) and Tg levels (≤2, 2–5, 5–10, and >10 ng/mL). Based on this, ¹³¹I activities of 1.1, 1.85, 3.7, and 5.55 GBq were administered. If the levels for RAIU and Tg were not in the same category, the higher activity determined by either RAIU or Tg was administered. Successful RRA was defined as negative diagnostic whole-body scan and Tg <1 ng/mL (anti-Tg antibody negative) or negative diagnostic whole-body scan (anti-Tg antibody positive) under thyrotropin stimulation six months or more post RRA.

Results:

There was no statistically significant difference in baseline characteristics between the RAIU-Tg-based activity group (n = 207) and the fixed activity group (n = 58). The activity of ¹³¹I used in the RAIU-Tg-based activity group (3.26 ± 1.54 GBq) was significantly lower than that used in the fixed activity group (p < 0.0001), whereas the rate of successful RRA in the RAIU-Tg-based activity group was significantly higher than the rate in the fixed activity group (94.2% vs. 70.7%; p < 0.0001). The rates of successful RRA in the four subgroups of the RAIU-Tg-based activity group were comparable (p = 0.543). Although there was no statistically significant difference in the incidence of total/short-term adverse effects between the RAIU-Tg-based activity group and the fixed activity group, a significantly lower incidence of intermediate adverse effects, which predominantly consisted of xerostomia, was reported in the RAIU-Tg-based activity group.

Conclusions:

Compared to a fixed activity of 3.7 GBq, RAIU-Tg-guided dosimetry can improve the success rate and decrease the incidence of intermediate side effects of RRA in postoperative patients with DTC.

Introduction

The incidence of thyroid cancer has increased dramatically in the past three decades in the United States and China (1,2). It is projected that by 2030, thyroid cancer will be the second leading cancer diagnosis in women and the ninth leading cancer diagnosis in men (3). The most common types of thyroid cancer stem from follicular cells, which account for 90–95% of cases, and are referred to as differentiated thyroid cancers (DTCs) (4). Despite differences in their biologic behavior, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are collectively classified as DTC and are treated with similar therapeutic regimens. The primary options for the initial management of DTC are surgery followed by radioiodine (¹³¹I) remnant ablation (RRA) and/or therapy of potential residual thyroid cancer or metastatic disease and thyrotropin (TSH) suppression therapy. These therapies tend to be associated with a favorable prognosis, as reflected by 10-year survival rates of about 90% (5).

RRA is a form of orally administered ¹³¹I therapy intended to eradicate normal thyroid tissue and microscopic cancer cells that remain after gross thyroidectomy of DTC, thereby facilitating the detection of recurrent disease, reducing recurrence risk, and facilitating initial staging by examinations such as thyroglobulin (Tg) measurements and post-therapeutic whole-body scanning (RxWBS). If RRA is successful, recurrence rates are usually 1–4% and disease-specific death <1%, resulting in a decrease in the frequency of follow-up and the degree of TSH suppression (6).

Unfortunately, the debate about the optimal activity of ¹³¹I required for RRA continues (7,8). Over the past several years, several randomized controlled trials have been published to evaluate the effectiveness of fixed activities (9 –12), adding more information on this subject matter. In these reports, some studies have demonstrated no difference in outcomes between low and high activities of ¹³¹I (9,10), whereas other investigations have shown that high activities of ¹³¹I have resulted in higher RRA success rates (11,12). These inconsistent results regarding the fixed activities of ¹³¹I prescribed for RRA were the driver to analyze further the optimal ¹³¹I activity for RRA. Each of the above-mentioned studies used fixed activities, which may yield an inadequate or excessive ¹³¹I activity in the background of individualized surgery for thyroid cancer (11,12).

Radioactive iodine uptake (RAIU), which correlates to some extent with thyroid remnant weight and the activity of the sodium–iodide symporter, has been approved by the American College of Radiology and Society of Nuclear Medicine and Molecular Imaging to estimate the mass of thyroid remnant (13). Tg is produced by thyroid tissue, and an elevated Tg serum level is indicative of the presence of thyroid remnants or metastasis of thyroid cancer (13,14). Thus, postoperative TSH-stimulated serum Tg has been recognized as a reliable marker for remnant thyroid tissue when residual or recurrent disease and metastases have been excluded (8).

This prospective, randomized, open-label, controlled trial was conducted to investigate the feasibility of RRA with regard to the stratification by RAIU combined with Tg (RAIU-Tg) under TSH stimulation.

Methods

Study conduct

All of the patients provided written informed consent prior to the initiation of the trial. The protocol was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Shanghai, P.R. China). The authors vouch for the completeness and accuracy of the data and analyses.

Patients

Patients with DTC who underwent total, near-total, or sub-total thyroidectomy and who were referred for RRA were enrolled. After the initial surgery, all of the patients were staged with the tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer Seventh Edition and stratified into three groups (low, intermediate, and high risk) according to the 2015 American Thyroid Association (ATA) guidelines (8). Patients underwent thyroid hormone withdrawal (THW) and were on a low-iodine diet for four weeks prior to RAIU and serum tests preceding RRA. Patients with persistent/recurrent locoregional disease or distant metastases identified by imaging modalities, such as computed tomography (CT), ultrasonography (US), and technetium-99m methylene diphosphonate single-photon emission tomography/CT (^99mTc-SPECT/CT), were excluded. RAIU was measured 24 hours after the administration of 0.185 MBq of ¹³¹I by a gamma counter, immediately followed by RRA. TSH, Tg, and anti-Tg antibody (TgAb) levels were measured by an electrochemiluminescence immunoassay on the Cobas analyzer (Roche Diagnostics Gmbh, Roche Ltd., Basel, Switzerland). All of the RRA patients were randomly assigned to either the RAIU-Tg-based activity group or the fixed activity group (3.7 GBq) at a ratio of 4:1. RxWBS was performed three days after ¹³¹I administration. All of the adverse effect information was recorded using standard questionnaires before and after RAI treatment.

RAIU-Tg-based activity

RAIU-Tg-based activity was determined by four levels of RAIU (≤2%, 2–5%, 5–15%, and >15%), and Tg concentrations (≤2, 2–5, 5–10, and >10 ng/mL). Based on this, ¹³¹I activities of 1.1, 1.85, 3.7, and 5.55 GBq, respectively, were administered. If the levels for RAIU and Tg were not in the same category, the higher activity determined by either RAIU or Tg was administered (Fig. 1). Prednisone (20 mg, t.i.d., per os) was given to patients with RAIU >15% before ¹³¹I administration and was continued for a total of five days.

FIG. 1.

Radioiodine (¹³¹I) dosing strategies for ¹³¹I remnant ablation based on stratification of radioactive iodine uptake (RAIU) and thyroglobulin (Tg).

Outcome assessment

The primary outcome was the success rate of RRA, which was assessed six months or more after RRA using serum Tg and a diagnostic whole-body scan (DxWBS), with 185 MBq of ¹³¹I determined four weeks after THW. The secondary outcomes were short-term (≤1 month) and intermediate (about one year) adverse effects. RRA was considered successful if the levels of TSH-stimulated Tg were ≤1 ng/mL (TgAb level ≤100 IU/mL) and if the DxWBS was negative at follow-up. In cases where Tg antibodies were positive (TgAb level >100 IU/mL), successful RRA was defined as the absence of visible RAI uptake on DxWBS. To estimate the interference of TgAb, stratified analyses in patients with TgAb ≤10, 10–100, and >100 IU/mL were also performed using the defined criteria of successful RRA described above.

Statistical analyses

Descriptive quantitative data are expressed as means ± standard deviations; qualitative data are expressed as percentages. Primary and secondary comparisons were performed in the two main groups (RAIU-Tg-based activity group and fixed activity group) and four subgroups (1.1, 1.85, 3.7, and 5.55 GBq) in the RAIU-Tg-based activity group, respectively. Statistically significant differences of continuous variables were determined by independent samples t-test, Mann–Whitney U-test, or analysis of variance test as appropriate. Categorical variables were compared with Pearson's chi-square test or Fisher's exact test. The difference in observed rates of successful RRA and its bilateral confidence interval are also presented. Statistical analyses were performed using IBM SPSS Statistics for Window v24.0 (IBM Corp., Armonk, NY).

Results

Patient characteristics before RRA

In total, 277 patients were enrolled between 2013 and 2017. After the exclusion of 12 patients (five patients with distant metastases, four patients lost to follow-up, and three patients because of TSH levels <30 mIU/L), there were 265 eligible subjects with data that could be evaluated between the two groups and among the four subgroups in the RAIU-Tg-based cohort (Fig. 2). Most patients were female (77.4%) with a mean age of 42.8 ± 10.8 years. Most patients had undergone total thyroidectomy (87.5%). Sub-total and near -total thyroidectomies were performed in 6.8% and 5.7% of patients, respectively. PTCs accounted for 88.7% of all of the eligible patients. After surgery and before THW, patients received thyroid hormone therapy at a mean dose of 1.9 ± 0.4 μg/kg. Four weeks after THW, TSH levels reached >100, 60–100, and 30–60 mIU/L in 65.7%, 20.4%, and 14.0% of all of the eligible patients, respectively. Tg and RAIU ranged from <0.04–150.1 ng/mL and 0.1–40.6%, respectively. Tg levels ≤2, 2–5, 5–10, and >10 ng/mL were found in 41.1%, 23.4%, 21.1%, and 14.3% of patients, respectively. RAIU ≤2%, 2–5%, 5–15%, and >15% was found in 35.1%, 26.4%, 25.7%, and 12.8% of patients, respectively. Baseline characteristics before RRA in the RAIU-Tg-based activity and fixed activity groups are described in Table 1. In addition to the histologic subtype of DTC, the distribution of age, sex, dose of administered thyroxin before THW, interval between RRA and follow-up, operation type, and ATA risk stratification between the two groups were comparable. Furthermore, in the analyses of the characteristics of the four subgroups in the RAIU-Tg-based activity group, significant differences in the dose of administered thyroxin before THW, histologic subtype of DTC, ATA risk stratification, and stimulated TSH, Tg, and RAIU four weeks after THW were found (Table 2).

FIG. 2.

Algorithm for the inclusion and exclusion of the studied patients.

Table 1.

Baseline Characteristics of Patients Before Radioiodine Remnant Ablation with Regard to Dosing Strategy (n = 265)

Characteristic	RAIU-Tg-based activity group (n = 207)	Fixed activity group (n = 58)	p
Age (years)	42.2 ± 10.7	45.2 ± 10.8	0.473
Female, n (%)	163 (78.7)	42 (72.4)	0.309
Operation type, n (%)
Total thyroidectomy	184 (88.9)	48 (82.8)	0.438
Sub-total thyroidectomy	12 (5.8)	6 (10.3)	0.176
Near-total thyroidectomy	11 (5.3)	4 (6.9)	0.282
Histologic subtype of differentiated thyroid cancer, n (%)
Papillary	202 (97.6)	55 (94.1)	0.109
Follicular	5 (2.4)	3 (5.2)	0.109
T stage, n (%)
T1a	95 (45.9)	26 (44.8)	0.552
T1b	47 (22.7)	13 (22.4)	0.885
T2	33 (15.9)	10 (17.2)	0.812
T3	32 (15.5)	9 (15.5)	0.991
N stage, n (%)
N0	107 (51.7)	28 (48.3)	0.646
N1a	63 (30.4)	19 (32.8)	0.735
N1b	37 (17.9)	11 (19.0)	0.983
ATA risk stratification, n (%)
Low risk	130 (62.8)	34 (58.6)	0.562
Intermediate risk	77 (37.2)	24 (41.4)	0.562
Administered thyroxin before THW (μg/kg)	1.9 ± 0.4	2.0 ± 0.3	0.144
TSH (mIU/L) 4 weeks after THW, n (%)
≥30–60	26 (12.6)	11 (19.0)	0.214
>60–100	42 (20.3)	12 (20.7)	0.998
>100	139 (67.1)	35 (60.3)	0.371
Tg (ng/mL) 4 weeks after THW, n (%)
≤2	86 (41.5)	23 (39.7)	0.796
>2–5	49 (23.7)	13 (22.4)	0.842
>5–10	43 (20.8)	13 (22.4)	0.724
>10	29 (14.0)	9 (15.5)	0.699
RAIU 4 weeks after THW, n (%)
≤2%	72 (34.8)	21 (36.2)	0.841
>2–5%	56 (27.1)	14 (24.1)	0.656
>5–15%	52 (25.1)	16 (27.6)	0.704
>15%	27 (13.0)	7 (12.1)	0.845

T stage and N stage were evaluated based on American Joint Committee on Cancer 7th Edition/Tumor-Node-Metastasis Classification System for Differentiated Thyroid Carcinoma.

RAIU, radioiodine uptake; Tg, thyroglobulin; THW, thyroid hormone withdraw; ATA, American Thyroid Association.

Table 2.

Baseline Characteristics of Patients in RAIU-Tg-Based Activity Subgroups Before Radioiodine Thyroid Ablation Categorized by Administered ¹³¹I Activity (n = 207)

	¹³¹I activity (GBq)
Characteristic	1.1 (n = 52)	1.85 (n = 45)	3.7 (n = 57)	5.55 (n = 53)	p
Age (years)	43.1 ± 11.4	42.7 ± 12.3	42.1 ± 9.8	40.8 ± 9.5	0.373
Female, n (%)	46 (88.5)	34 (75.6)	44 (77.2)	39 (73.6)	0.248
Operation type, n (%)
Total thyroidectomy	48 (92.3)	43 (95.6)	50 (87.7)	43 (81.1)	0.114
Sub-total Thyroidectomy	3 (5.8)	2 (4.4)	3 (5.3)	5 (9.4)	0.548
Near-total Thyroidectomy	1 (1.9)	1 (2.2)	4 (7.0)	5 (9.4)	0.282
Histologic subtype of differentiated thyroid cancer, n (%)
Papillary	52 (100.0)	45 (100.0)	56 (98.2)	49 (92.5)	0.040
Follicular	0	0	1 (1.8)	4 (7.5)	0.040
T stage, n (%)
T1a	25 (48.1)	21 (46.7)	29 (50.9)	20 (37.7)	0.552
T1b	14 (26.9)	10 (22.2)	12 (21.1)	11 (20.8)	0.865
T2	8 (15.4)	8 (17.8)	9 (15.8)	8 (15.1)	0.985
T3	5 (9.6)	6 (13.3)	7 (12.3)	14 (26.4)	0.078
N stage, n (%)
N0	33 (63.5)	25 (55.6)	27 (47.4)	22 (41.5)	0.123
N1a	13 (25.0)	12 (26.7)	18 (31.6)	20 (34.0)	0.494
N1b	6 (11.5)	8 (17.8)	12 (21.1)	11 (20.8)	0.862
ATA risk stratification, n (%)
Low risk	40 (76.9)	30 (66.7)	35 (61.4)	25 (47.2)	0.016
Intermediate risk	12 (23.1)	15 (33.3)	22 (38.6)	28 (52.8)	0.016
Administered thyroxin before THW (μg/kg)	2.0 ± 0.3	2.1 ± 0.4	1.9 ± 0.5	1.7 ± 0.4	0.022
TSH (mIU/L) 4 weeks after THW, n (%)
≤30–60	4 (7.6)	4 (8.9)	5 (8.8)	13 (24.5)	0.025
>60–100	8 (15.4)	7 (15.5)	10 (17.5)	17 (32.1)	<0.0001
>100	40 (88.9)	34 (75.6)	42 (73.7)	23 (43.4)	0.0001
Thyroglobulin (ng/mL) 4 weeks after THW, n (%)
≤2	52 (100)	15 (33.3)	16 (28.1)	3 (5.7)	<0.0001
>2–5	0	30 (66.7)	15 (26.3)	4 (7.5)	<0.0001
>5–10	0	0	26 (45.6)	17 (32.1)	<0.0001
>10	0	0	0	29 (54.7)	<0.0001
24 h RAIU 4 weeks after THW, n (%)
≤2%	52 (100)	11 (24.4)	5 (8.8)	4 (7.5)	<0.0001
>2–5%	0	34 (75.6)	13 (22.8)	9 (17.0)	<0.0001
>5–15%	0	0	39 (68.4)	13 (24.5)	<0.0001
>15%	0	0	0	27 (50.9)	<0.0001

T stage and N stage were evaluated based on AJCC 7th Edition/TNM Classification System for Differentiated Thyroid Carcinoma.

TSH, thyrotropin.

Efficacy analyses of RRA

Three days post ¹³¹I administration, RxWBS showed ¹³¹I uptake in the thyroid bed in 97.1% patients in the RAIU-Tg-based activity group and in 100% of patients in the fixed activity group (p = 0.173). To analyze efficacy at follow-up, the evaluation of efficacy was performed at 11.6 ± 4.4 months (5.4–29.5 months) after RRA. TSH-stimulated Tg levels ≤1, 1–10, and 10–100 ng/mL were found in 239, 19, and 6 patients, respectively. TgAb ≤10, 10–100, and >100 IU/L were found in 72, 179, and 17 patients, respectively. The DxWBS showed an absence of ¹³¹I uptake in the neck in 93.2% of all of the eligible patients. There was no statistically significant difference in the time interval between RRA and efficacy evaluation between the two groups and among the four subgroups (Tables 3 and 4).

Table 3.

Outcome Analyses After Radioiodine Remnant Ablation with Regard to Dosing Strategy (n = 265)

Characteristic	RAIU-Tg-based activity group (n = 207)	Fixed activity group (n = 58)	p
Interval between RRA and follow-up (months)	11.4 ± 4.5	12.5 ± 3.8	0.135
Tg (ng/mL), n (%)
≤1	196 (94.7)	43 (74.1)	<0.0001
>1–10	9 (4.3)	10 (17.2)	0.002
>10–100	2 (1.0)	4 (6.9)	0.022
>100	0	1 (1.7)	0.219
TgAb (IU/L), n (%)
≤10	57 (27.5)	15 (25.9)	0.800
>10–100	138 (66.7)	38 (65.5)	0.870
>100	12 (5.8)	5 (8.6)	0.305
¹³¹I uptake in RxWBS, n (%)			0.173
Positive in neck	201 (97.1)	58 (100)
Negative	6 (2.9)	0
DxWBS, n (%)			<0.0001
Success	200 (96.6)	47 (81.0)
Fail	7 (3.4)	11 (19.0)
Analysis based on the given definition of successful RRA, n (%)			<0.0001
Success	195 (94.2)	41 (70.7)
Fail	12 (5.8)	17 (29.3)
Stratified analysis based on TgAb (IU/mL), n (%)
≤10			0.002
Success	54 (94.7)	9 (60.0)
Fail	3 (1.4)	6 (40.0)
>10–100			0.019
Success	131 (94.9)	31 (81.6)
Fail	7 (5.1)	7 (18.4)
>100			0.033
Success	9 (75.0)	1 (20.0)
Fail	3 (25.0)	4 (80.0)
Persistent disease, metastasis and retreatment in the follow-up, n (%)
Local persistent disease	2 (1.0)	3 (5.2)^a	0.063
Distant metastasis	2 (1.0)	2 (3.4)^a	0.209
Retreatment	3 (1.4)	4 (7.7)	0.043

Both local recurrence and distant metastasis were found in one patient.

TgAb, antithyroglobulin; RRA, radioiodine remnant ablation; RxWBS, post-therapeutic whole-body scan; DxWBS, diagnostic whole-body scan.

Table 4.

Outcome Analyses of RAIU-Tg-Based Activity Subgroups After Radioiodine Remnant Ablation Categorized by Administered ¹³¹I Activity (n = 207)

	¹³¹I activity (GBq)
Characteristic	1.1 (n = 52)	1.85 (n = 45)	3.7 (n = 57)	5.55 (n = 53)	p
Interval between RRA and follow-up (months)	11.7 ± 4.9	10.1 ± 3.9	11.8 ± 4.4	11.6 ± 4.6	0.813
Tg (ng/mL), n (%)
≤1	51 (98.1)	42 (93.3)	55 (96.5)	48 (90.6)	0.330
>1–10	1 (1.9)	3 (6.7)	1 (1.8)	4 (7.5)	0.365
>10–100	0	0	1 (1.8)	1 (1.9)	0.978
TgAb (IU/L), n (%)
≤10	10 (19.2)	4 (8.9)	24 (42.1)	19 (35.8)	0.001
>10–100	39 (75.0)	36 (80)	31 (54.4)	32 (60.4)	0.018
>100	3 (5.8)	5 (11.1)	2 (3.5)	2 (3.8)	0.487
¹³¹I uptake in RxWBS, n (%)					0.095
Positive in neck	48 (92.3)	44 (97.8)	57 (100)	52 (98.1)
Negative	4 (7.7)	1 (2.2)	0	1 (1.9)
DxWBS					0.129
Success	51 (98.1)	43 (95.6)	56 (98.2)	50 (94.3)
Fail	1 (1.9)	2 (4.4)	1 (1.8)	3 (5.7)
Analysis based on the given definition of successful RRA, n (%)					0.245
Success	51 (98.1)	43 (95.6)	54 (94.7)	47 (88.7)
Fail	1 (1.9)	2 (4.4)	3 (5.3)	6 (11.3)
Stratified analysis based on TgAb (IU/mL), n (%)
≤10					0.665
Success	10 (100.0)	4 (100.0)	23 (95.8)	17 (89.5)
Fail	0	0	1 (4.2)	2 (10.5)
>10–100					0.301
Success	38 (97.4)	36 (100.0)	30 (96.8)	28 (87.5)
Fail	1 (2.6)	0	1 (3.2)	4 (12.5)
>100					0.591
Success	3 (100.0)	3 (60.0)	1 (50.0)	2 (100.0)
Fail	0	2 (40)	1 (50.0)	0
Local persistent disease, n (%)	0	1 (2.2)	0	1 (1.9)	0.470
Distant metastasis, n (%)	0	0	1 (1.8)	1 (1.9)	0.980
Retreatment, n (%)	0	0	1 (1.8)	2 (3.8)	0.004

Total success rate in the RAIU-Tg-based activity group was significantly higher than the fixed activity group (94.2% vs. 70.7%; p < 0.0001), including patients with negative and positive TgAb levels. After the exclusion of patients with positive TgAb, RRA was considered successful in 89.4% patients in the RAIU-Tg-based activity group and in 69.0% of patients in the fixed activity group (p = 0.001). Table 3 summarizes the outcome of RRA in the 265 eligible patients with regard to dosing strategy. Moreover, equivalent success rates of 98.1%, 95.6%, 94.7%, and 88.7% were achieved in the four subgroups using the RAIU-Tg-based dosing strategy (p = 0.245). Table 4 shows the analysis of the main characteristics of the 207 eligible patients in the RAIU-Tg-based activity group with regard to administered activity of ¹³¹I.

Local disease, distant metastases, and retreatment

Upon follow-up, local disease and distant metastases were found in four patients in the RAIU-Tg-based activity group: one, one, and two patients had local disease or distant metastasis after RRA with activities of 1.85, 3.7, and 5.55 GBq, respectively. Three of these patients underwent ¹³¹I retreatment due to the identification of ¹³¹I-avid local disease (n = 2) and pulmonary metastases (n = 1). In the fixed activity group, two patients underwent ¹³¹I retreatment due to local disease, one had distant metastases, and one had both local disease and distant metastases. The distribution of local disease, distant metastases, and retreatment in the RAIU-Tg-based activity and fixed activity groups is detailed in Table 3, and Table 4 shows the findings in the four subgroups in the RAIU-Tg-based activity group.

Adverse effects of RRA

The incidence of total adverse effects of RRA was comparable between the RAIU-Tg-based activity group and fixed activity group within similar follow-up time (11.4 ± 4.5 vs. 12.5 ± 3.8 months; p = 0.135), and it was mainly comprised of short-term adverse effects. However, the incidence of intermediate adverse events and xerostomia was lower in the RAIU-Tg-based dosimetry group (Table 5). The incidence of intermediate adverse effects, xerostomia, xerophthalmia, and total adverse effects were activity dependent among the four subgroups in the RAIU-Tg-based activity group (Table 6).

Table 5.

Comparison of Adverse Events After Radioiodine Remnant Ablation with Regard to Dosing Strategy (n = 265)

Adverse events, n (%)	RAIU-Tg-based activity group (n = 207)	Fixed activity group (n = 58)	p
Short term	35 (16.9)	9 (15.5)	0.801
Neck pain	14 (6.7)	4 (6.9)	0.972
Neck swelling	1 (0.4)	0	0.781
Hoarseness	1 (0.4)	0	0.781
Nausea	15 (7.2)	5 (8.6)	0.454
Vomiting	10 (4.8)	2 (3.4)	0.490
Poor appetite	1 (0.4)	1 (1.7)	0.390
Stomachache	2 (1.0)	0	0.610
Acid reflux	1 (0.4)	1 (1.7)	0.390
Rhinitis	2 (1.0)	0	0.610
Intermediate	27 (13.0)	15 (25.9)	0.018
Xerostomia	19 (9.2)	11 (19.0)	0.038
Xerophthalmia	10 (4.8)	5 (8.6)	0.331
Amenorrhea	1 (0.4)	0	0.781
All	44 (21.3)	19 (32.8)	0.069

Table 6.

Comparison of Adverse Events After Radioiodine Remnant Ablation Among RAIU-Tg-Based Activity Subgroups Categorized by Administered ¹³¹I Activity (n = 207)

	¹³¹I activity (GBq)
Adverse events, n (%)	1.1 (n = 52)	1.85 (n = 45)	3.7 (n = 57)	5.55 (n = 53)	p
Short term	4 (7.7)	6 (13.3)	12 (21.1)	13 (24.5)	0.180
Neck pain	1 (1.9)	3 (6.7)	7 (12.3)	3 (5.7)	0.196
Neck swelling	0	1 (2.2)	0	0	0.217
Hoarseness	0	0	0	1 (1.9)	0.725
Nausea	0	3 (6.7)	5 (8.8)	7 (13.2)	0.377
Vomiting	2 (3.8)	1 (2.2)	3 (5.3)	4 (7.5)	0.190
Poor appetite	0	0	1 (1.8)	0	0.924
Stomachache	0	0	1 (1.8)	1 (1.9)	0.936
Acid reflux	0	0	0	1 (1.9)	0.725
Rhinitis	1 (1.9)	0	1 (1.8)	0	0.469
Intermediate	2 (3.8)	1 (2.2)	10 (17.5)	14 (26.4)	<0.0001
Xerostomia	0	1 (2.2)	8 (14.0)	10(18.9)	0.001
Xerophthalmia	1 (1.9)	0	3 (5.3)	6 (11.3)	0.045
Amenorrhea	1 (1.9)	0	0	0	0.469
All	5 (9.6)	4 (8.9)	14 (24.6)	21 (39.6)	<0.0001

Discussion

¹³¹I has been used in the treatment of thyroid disease for more than seven decades. RRA is one of the key steps in the initial management of appropriately selected DTC patients, and its main objective is the complete destruction of normal or cancerous thyroid tissue to make Tg a more reliable marker and radioiodine scanning a more accurate imaging modality, and to improve therapeutic outcomes (8,15). In the era of precision medicine, an individualized administration of ¹³¹I may be of value.

Traditionally, fixed activities of 1.1 and 3.7 GBq of ¹³¹I have been commonly prescribed, but they may be insufficient or excessive if the remnant is not appropriately evaluated (9 –12). Although previous studies comparing the efficacy of RRA with fixed ¹³¹I activities of 1.1 and 3.7 GBq in DTC patients using either recombinant TSH or THW have demonstrated non-inferiority of the low ¹³¹I activity and recombinant TSH, only patients who underwent a total or near-total thyroidectomy were enrolled. Notably, the second ablation was needed in >10% of these patients (9,10). An individualized surgical approach aimed at eradicating the tumor while reducing the risk of complications, such as hypoparathyroidism and damage of the recurrent laryngeal nerve, are widely used. For patients who have only been subjected to sub-total thyroidectomy, higher administered activities may be needed, especially for patients with larger remnants (8). In the present study, an individualized RAIU-Tg-based dosimetry was used, and it is demonstrated that this regimen is more precise in determining the prescribed activity for RRA, as it could significantly improve success rates and decrease the incidence of intermediate adverse effects. The findings are in line with the pooled data from 11 studies from a meta-analysis, which revealed that treatment with higher activities of ¹³¹I is significantly more efficient for remnant ablation, particularly after less-than-total thyroidectomy (16).

Calculated and RIAU-based activities were recently compared to traditionally fixed activities (17,18). Since the usefulness of a calculated activity has not been confirmed by clinical outcome data, an exploratory RAIU-based RRA protocol has been created (1.1 GBq for RAIU ≤5%, 1.85 GBq for RAIU 5–10%, and 2.8 GBq for RAIU >10%) and compared with fixed activities of 3.7 and 5.55 GBq. However, the success rate of 43% in the RAIU-based activity group versus 56% in the fixed activity group was disappointing (17). The present study stratified the RAIU group into more subgroups (≤2, 2–5, 5–15, and >15%), used higher activities (1.1, 1.85, 3.7, and 5.55 GBq), and considered the Tg concentration, which allowed higher activities to be administered to 26.6% of patients. This modified protocol resulted in a much higher success rate of 94.2% compared to the aforementioned study. Thus, the findings suggest that the combination of RAIU and Tg concentration can be helpful in characterizing the thyroid remnant and predicting the optimal activity for successful RRA. Moreover, this RAIU-Tg-based approach may pave a new way for thyroid remnant eradication in patients in whom complete thyroidectomy is contraindicated. Additionally, it seems that the success rate in each subgroup of the RAIU-Tg-based activity group was higher than in the fixed activity group, suggesting that accurate assessment of thyroid remnant and discriminatory treatment via this RAIU-Tg-based stratification may be of value. Notably, upon further stratification of patients in the RAIU-Tg-based activity group to subgroups based on the levels of RAIU and Tg, it was observed that the baseline characteristics in each subgroup differed in comparison to the fixed activity group. Thus, comparisons between the fixed activity group and each subgroup in the RAIU-Tg-based activity group were not performed.

Although the incidence of total adverse effects of RRA was comparable between the RAIU-Tg-based groups and the fixed activity group, the incidence of intermediate adverse effects, such as xerostomia, was significantly lower in the RAIU-Tg-based activity group than in the fixed activity group. It is well known that damage to the salivary glands is the most frequent intermediate adverse effect of RRA, since the salivary glands physiologically concentrate ¹³¹I, resulting in radiation. In this study, the occurrence of intermediate adverse events, total adverse events, xerostomia, and xerophthalmia correlated with the ¹³¹I activity, which is consistent with previous studies (9,19). Similarly, short-term adverse effects were more frequently observed in patients who received a higher activity of ¹³¹I, which is also in accordance with previous studies (20,21). Although 13.0% of patients in the RAIU-Tg-based activity group had an RAIU >15%, the incidence of neck pain was only 5.7%, which may be attributed to the prophylactic use of prednisone.

In the 2015 ATA guidelines, criteria for successful RRA involving low TSH-stimulated Tg together with negative TgAb and DxWBS were defined (8). Although negative US has been occasionally adopted as an additional criterion for successful ablation (9,10,22,23), the still existing nonviable and nonfunctioning post-ablation remnants detected by US do not necessarily mean a failure (Fig. 3). Currently, a defined cutoff for TgAb positivity is lacking. In this study, TgAb levels ≤100 IU/mL were considered as negative and >100 IU/mL as positive according to the experience of the authors' group and others (24).

FIG. 3.

¹³¹I whole-body scan and neck ultrasonography of a 34-year-old male patient with papillary thyroid carcinoma post sub-total thyroidectomy. Whole-body scintigraphy three days after the administration of ¹³¹I (5.55 GBq) showed robust ¹³¹I uptake in the thyroid remnant (A), which could not be visualized in the follow-up ¹³¹I whole body scan seven months later (B). Meanwhile, ultrasonography just before radioiodine ablation showed thyroid remnant measuring 19 mm × 15 mm × 36 mm (C), which shrank to 12 mm × 12 mm × 17 mm (D), 9 mm × 11 mm × 17 mm (E), and 6 mm × 8 mm × 13 mm (F) at two, five, and seven months post radioiodine ablation, respectively.

Stunning is defined as decreased ¹³¹I uptake and efficacy mainly due to prior ¹³¹I administration (25). To reduce the possibility of stunning, the pre-therapeutic ¹³¹I activity used for diagnostic procedures should be as low as possible. In this study, only 0.185 MBq of ¹³¹I was used for the RAIU test, which is not thought to result in relevant stunning, but a pre-therapeutic DxWBS was not performed (26). Admittedly, the downside of not performing a pre-therapy scan is recognized, which is associated with the risk of not identifying patients with distant metastases prior to the first ¹³¹I treatment. To avoid for this limitation, the majority of the patients with local disease or distant metastases (high risk) had been identified by Tg testing in combination with other medical imaging modalities and excluded before RRA. Distant metastases were identified in only four (1.5%) patients by post-therapy scan, which may in part be due to the fact that a pre-therapy scan was not performed.

Other imaging modalities, especially evaluation with ¹⁸F-FDG-PET/CT, ¹²⁴I PET/CT, ^99mTc-SPECT/CT, or ¹³¹I-SPECT/CT, may provide more accurate postoperative assessments and facilitate planning for RRA (27 –29). It is also important to mention that the proposed RAIU-Tg-based activity determination may not be informative for complex clinical situations such as patients with renal insufficiency (30), children (31), and older individuals (32). Further studies are still needed to optimize this regimen of RRA using a neural network model, wherein the neural layers receive patient characteristics traveling from the input (characters) to the output layer (outcomes) to form a character-aided calculation flow for individualized dosing (33). Moreover, compared to the other subgroups, a relatively lower success rate of RRA (88.7%) was achieved in the RIAU >15% subgroup, despite the high activity of ¹³¹I (5.55 GBq) with concomitant administration of prednisone. Whether the administration of glucocorticoids has an impact on the ablation rate is currently unclear. Lastly, multicenter studies with a larger sample size and longer periods of follow-up are required to confirm the current findings and explore factors correlating with levels of Tg and RAIU.

In conclusion, the data suggest that compared to a fixed activity (3.7 GBq) approach, the application of the RAIU-Tg-guided RRA dosing strategy is feasible in patients with DTC, and it is associated with improved success rates and with decreased intermediate adverse effects.

Footnotes

Acknowledgments

This study was sponsored by the National Natural Science Foundation of China (grant nos. 81671711 and 81701731) and Shanghai Key Discipline of Medical Imaging (grant no. 2017ZZ02005).

Author Disclosure Statement

None of the authors have any conflicts of interest to declare.

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