Long-term clinical outcomes and prognostic factors for patients with papillary thyroid carcinoma with other organ invasions after adjuvant radioactive iodine

Papillary thyroid carcinoma (PTC) with other organ invasions is directly related to patient prognosis and quality of life; however, studies on the clinical outcomes of adjuvant radioactive iodine (RAI) for PTC with other organ invasions are limited. This study aimed to clarify the clinical outcomes and prognostic factors for patients with PTC with other organ invasions after adjuvant RAI. Patients with PTC with other organ invasions without distant metastases who underwent surgery and adjuvant RAI were retrospectively reviewed. We evaluated the initial responses based on the American Thyroid Association guidelines and survival rates. Prognostic factors for locoregional recurrence-free survival (LRRFS) were analyzed. Between January 2005 and December 2019, 102 patients were included in the study. Their median age was 55 years. The median follow-up duration was 92 months (range; 30–231 months). The excellent response rate after RAI was 42%. The 7-year overall survival, LRRFS, and recurrence-free survival rates were 100%, 75%, and 75%, respectively. Metastatic lymph node size, resection margin status, and post-RAI suppressed thyroglobulin level were the independent prognostic factors for LRRFS. We demonstrated that 75% of patients with PTC with other organ invasions could achieve long-term survival without recurrence after adjuvant RAI. Future development of effective treatment strategies for large metastatic lymph nodes, gross residual tumors, and high serum thyroglobulin levels is warranted.


Introduction
Papillary thyroid carcinoma (PTC) is the most frequent endocrine malignancy. Its incidence has been increasing over the past several decades [1]. Thyroidectomy followed by adjuvant radioactive iodine (RAI) and the suppression of thyroid-stimulating hormone (TSH) is the standard management for patients with PTC at the American Thyroid Association (ATA) high-risk disease [2]. The ATA guidelines and National Comprehensive Cancer Network recommend a fixed administered activity of 100-200 and 50-150 mCi for adjuvant RAI if the residual microscopic disease is suspected or an aggressive histological variant of PTC is present, respectively [3,4]. However, this recommendation is based on expert opinion, and there is little evidence to suggest that increasing the administered activities of adjuvant RAI is necessarily associated with improved clinical outcomes for patients with ATA high-risk disease without evidence of persistent disease [5][6][7][8][9][10][11]. Moreover, no study focused on patients with PTC with other organ invasions.
Some locally advanced PTC cases of unresectable or gross residual disease will be unamenable to further resection [12]. The structural disease recurrence rate is 30-40%, with grossly positive margins and gross extra-thyroidal extensions [2]. Locoregional disease progression in patients with PTC with other organ invasions can significantly affect their morbidity and quality of life because of the proximity of the thyroid to critical organs, including the larynx, trachea, esophagus, and cervical or mediastinal vessels [13,14].
Therefore, identifying clinical outcomes and prognostic factors for the recurrence of PTC with other organ invasions could lead to the development of potent treatments. This study was designed to clarify the clinical outcomes and prognostic factors for patients with PTC with other organ invasions after adjuvant RAI.

Materials and methods
This retrospective study protocol was reviewed and approved by the Institutional Review Board of Kanaji Thyroid Hospital as a collective review (approval number: 20). Written informed consent was obtained from all patients. This study was conducted according to the Declaration of Helsinki.

Patient selections
Patients with PTC who underwent total thyroidectomy with central and/or lateral lymph node dissection and adjuvant RAI at Kanaji Thyroid Hospital were retrospectively reviewed. The eligibility criteria were as follows: patients aged ≥20 years; those with PTC with other organ invasions requiring adjuvant RAI; and those without distant metastasis based on the Union for International Cancer Control-TNM Classification, Eighth Edition [15]. Patients who received adjuvant external-beam radiotherapy (EBRT) or those with recurrent tumors large enough to be detected by imaging studies or physical examination during adjuvant RAI were excluded.

Method of RAI and assessment
The prescribed initial dose of RAI was 60, 100, or 120 mCi. In Japan, adjuvant RAI for PTC requires admission to a dedicated treatment facility with strict radiation precautions. Due to the current shortage of treatment beds and long admission waitlist, we administered doses of 60 mCi until 2017 to treat more patients. The dose was increased to 100 or 120 mCi in 2018 when the dosing guidelines were changed to 100-150 mCi in our country [16].
A strict iodine-controlled diet was required for 2 weeks before RAI. We discontinued thyroxine (dose range 100-200 μg per day) in 42 (41%) patients undergoing thyroid hormone withdrawal to raise TSH levels 4 weeks before RAI. Consecutively, all the patients were switched to triiodothyronine (dose range: 30-50 μg per day) for 2 weeks. Beginning in 2013, 60 (59%) patients were administered thyrotropin alfa via intramuscular injection (0.9 mg) 2 days before RAI to stimulate TSH release. The elevation of TSH levels to ≥30 mU/L was considered satisfactory for subsequent RAI. Then, 4-7 days after RAI, whole-body I-131 scintigraphy was performed using a gamma camera with high-energy collimators. Furthermore, the concentration of serum thyroglobulin (Tg) was measured, and 6-12 months after adjuvant RAI, I-131 scintigraphy was performed to evaluate whether RAI was successful. Excellent response to RAI was defined as the absence of I-131 accumulation as detected on I-131 scintigraphy, no evidence of disease in imaging studies, and serum concentration of suppressed Tg < 0.2 ng/ml, as mentioned in the ATA guidelines [2]. Furthermore, RAI was provided if necessary depending on the patient's situation, such as the presence of residual I-131 accumulation.
After treatment completion, the patients were followed up with 3-month intervals for the first 12 months and with 3-6-month intervals thereafter. Follow-up evaluations included history taking and physical examination, blood tests, ultrasonography, computed tomography, and bone scintigraphy.

Statistical analysis
The overall survival (OS) and locoregional recurrence-free survival (LRRFS) rates from the surgery were measured using the Kaplan-Meier method. Death from any cause was defined as an event for calculating the OS. Disease recurrence at the primary or regional lymph node site or death from any cause was defined as an event for calculating the LRRFS. Differences in the LRRFS in univariate analysis were assessed using the log-rank test. Prognostic factors statistically significant in the univariate analysis were further analyzed in a multivariate analysis. All statistical analyses were performed using EZR, version 1.54 [17], and p values of <0.05 (twosided) were used to denote statistical significance.

Patient characteristics
Between January 2005 and December 2019, 128 patients with PTC with other organ invasions received adjuvant RAI at our hospital. Of the 128 patients, 26 (20%) were excluded because of receiving adjuvant EBRT, and 102 (80%) were evaluated in this study. Table 1 shows the baseline characteristics of the patients. Of the 102 patients, 99 (97%) involved other organs from the primary tumor, and 3 (3%) involved other organs from an extra-capsular extension (ECE) of lymph node metastases. The median follow-up time for all patients was 92 months (range, 30-231 months).

Outcomes
The median interval time from surgery to RAI was 3 months (range, 1-12 months). All patients completed adjuvant RAI without severe toxicities. Table 2 shows the treatment details of RAI.

Prognostic factors for LRRFS
In the univariate analysis of the LRRFS, primary tumor size (≤2 cm), metastatic lymph node size (≤3 cm), the absence of extra-capsular extension of lymph nodes, the absence of gross residual disease, and post-RAI suppressed Tg level (<0.2 ng/ml) were associated with a significantly better   (Table 4).

Discussion
This study was designed to understand the long-term clinical outcomes and prognostic factors for patients with PTC with other organ invasions after adjuvant RAI. In this study, the excellent response rate was 42%, and the 7-year OS and LRRFS rates were 100% and 75%, respectively. Metastatic lymph node size, resection margin status, and post-RAI suppressed Tg level were the independent prognostic factors for LRRFS. There are reports of adjuvant RAI for high-prognostic thyroid cancer [8][9][10][11]. Although the T4 disease rate (range; 1-40%) in these studies was lower, and the follow-up period was shorter (range; 34-92 months), our recurrence rate was favorable compared with those in previous studies (range; 3-53%).
There was no evidence to recommend increasing the initial and total administered activities of RAI for patients with PTC with other organ invasions in this study. However, we found that surgical margin status in high-risk thyroid cancer was related to treatment outcomes, and increasing the administered activities of adjuvant RAI may be preferred for microscopically positive marginal cases. For example, Watanabe et al. reported that patients with microscopically positive tumor margins could benefit from RAI at a dose of 100 mCi compared with RAI at 30 mCi [10]. In contrast, Jeong et al. reported that the recurrence rates in patients with complete resection did not differ between those who received 100 mCi and those who received 150 mCi [9]. These findings were associated with our results, where resection margin status was an independent prognostic factor for the LRRFS.
Watanabe et al. reported that the most common relapse location was the lymph nodes, and no patients with microscopic positive margins relapsed [10]. A recent metaanalysis did not find a statistically significant association between microscopically positive surgical margins and local recurrence [18]. In this study, all local recurrences relapsed from areas considered as gross residual disease. Thus, adjuvant RAI alone may be insufficient for treating and preventing local recurrence from gross residual disease. Some retrospective studies showed evidence of long-term RAI radioactive iodine, Tg thyroglobulin Fig. 1 Kaplan-Meier estimates of survival locoregional control using EBRT in patients with gross residual disease, and EBRT is recommended by the ATA and the American Head and Neck Society [2,[19][20][21][22]. Metastatic lymph node sizes >3 cm are at a high risk of recurrence, which is supported by this study's results [2]. A few studies have reported that the recurrence rate was 27-32% if any metastatic lymph node was >3 cm [23,24]. The 5-year LRRFS rate for metastatic lymph nodes >3 cm in this study was worse at 52%, probably because of another prognostic factor, such as T4 disease.
The serum level of suppressed Tg as a marker of response to adjuvant RAI was found to be a strong predictor of eventual disease recurrence, and this was supported by a previous study [25]. The serum level of suppressed Tg may be a surrogate for patients with PTC with a longer time to event [26].
This study has limitations associated with its retrospective design. First, the number of patients who received RAI at doses of 100-120 mCi was small, and the follow-up period was short. These may have been the causes of the non-statistically significant differences compared with 60 mCi for adjuvant RAI. Long-term follow-up studies to evaluate the prognosis in patients treated with these two approaches are needed, and our group is also planning to conduct a long-term follow-up study. Second, the initial response to adjuvant RAI was evaluated in only half of the patients. The main reason was that the rate of receiving I-131 scintigraphy for diagnosis was low. Implementing a strict iodine-controlled diet is difficult in our country because of the excessive iodine intake from seafood, and the benefit of treatment outweighs the effort required to provide a strict iodine-controlled diet before I-131 scintigraphy for diagnosis. Therefore, we selected post-RAI suppressed Tg level as an independent variable for LRRFS rather than the initial response to RAI in this study.
In conclusion, we identified the long-term clinical outcomes and prognostic factors for PTC with other organ invasions after adjuvant RAI directly related to patient prognosis and quality of life. Metastatic lymph node size, resection margin status, and post-RAI suppressed Tg level were independent prognostic factors for the LRRFS. Randomized trials and large-scale studies on potent treatments, such as EBRT, are desirable for these patients at a high risk of recurrence.

Data availability
Raw data of this analysis are available from the corresponding author upon request.

Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethical approval All procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent to be included in the study was obtained from all  ECE extra-capsular extension, RAI radioactive iodine, Tg thyroglobulin patients. The study protocol was approved by the participating centers' institutional review boards.