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

doi:10.21203/rs.3.rs-2106764/v1

Purpose: 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.

Methods: Patients with PTC with other organ invasions without distant metastases who underwent surgery and adjuvant RAI were retrospectively reviewed. The initial response based on the American Thyroid Association guidelines and survival rates were evaluated. Prognostic factors for locoregional recurrence-free survival (LRRFS) were analyzed.

Results: 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.

Conclusion: We confirmed 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.

Extra-capsular extension

Positive tumor margin

Radioiodine therapy

Thyroidectomy

Thyroid cancer

Papillary thyroid carcinoma (PTC) is the most frequent endocrine malignancy. Its worldwide 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 if 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 improvement in clinical outcomes for patients at the ATA high-risk disease without evidence of persistent disease [5–11]. Moreover, no study focused on patients with PTC with other organ invasions.

Inevitably, some locally advanced PTC cases of unresectable disease or gross residual disease will be unamenable to further resection [12]. The structural disease recurrence rate is 30–40% with the presence of gross 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, the identification of 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.

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. Before the introduction of increasing the administered activities of 100–120 mCi for adjuvant RAI in 2018, the patients were treated with adjuvant RAI at a dose of 60 mCi.

A strict iodine-controlled diet was required for 2 weeks before RAI. The patients were administered with thyrotropin alfa via intramuscular injection (0.9 mg) 2 days before RAI to stimulate the release of TSH. Thyroxine (dose range 100–200 μg per day) in patients undergoing thyroid hormone withdrawal to raise TSH levels was discontinued 4 weeks before RAI and was switched to triiodothyronine (dose range: 30–50 μg per day) for 2 weeks. The elevation of TSH levels to ≥ 30 mU/L was regarded as 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.

Statical analysis

The overall survival (OS), locoregional recurrence-free survival (LRRFS), and recurrence-free survival (RFS) 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. Disease recurrence at any site or death from any cause was defined as an event for calculating the RFS. 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 [16], and p-values of < 0.05 (two-sided) 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.

Of the 102 patients, 27 (26%) did not undergo I-131 scintigraphy for diagnosis 6–12 months after adjuvant RAI, 15 (15%) were present with anti-thyroglobulin antibody, 1 (1%) was not evaluated for the serum suppressed Tg, 6 (6%) were not evaluated because of multiple reasons, and the remaining 53 (52%) were evaluated for the response to RAI. Twenty-two (42%) patients achieved an excellent response to RAI. The 5- and 7-year OS, LRRFS, and RFS rates for all patients were 100%, 82%, and 82% and 100%, 75%, and 75%, respectively (Fig. 1). Of the 26 patients with recurrence, 7 (27%) had local recurrence, 13 (50%) had regional lymph node metastasis, 4 (15%) had local recurrence and regional lymph node metastasis, 1 (4%) had lung metastasis, and 1 (4%) had local recurrence and lung metastasis. All local recurrences were relapsed from areas considered gross residual disease.

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 prognosis (p = 0.023, p < 0.001, p = 0.014, p < 0.001, and p < 0.001, respectively) (Table 3). In the multivariate analysis, metastatic lymph node size (hazard ratio [HR], 6.99, 95% confidence interval [CI], 1.76–27.9), resection margin status (HR, 3.04, 95% CI, 1.005–9.19), and post-RAI suppressed Tg level (HR, 14.6, 95% CI, 2.74–78.04) were the independent prognostic factors (Table 4).

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, LRRFS, and RFS rates were 100%, 75%, and 75%, respectively. Metastatic lymph node size, resection margin status, and post-RAI suppressed Tg level were the independent prognostic factors for LRRFS.

Table 5 shows a literature review of studies that included adjuvant RAI for high-prognostic thyroid cancer [8-11]. Although the rate of T4 disease in this study was higher, and the follow-up period in this study was longer than that in previous studies. The response and recurrence rates were generally favorable compared with those in previous studies.

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 marginal 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. 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 a dose of 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 meta-analysis did not find a statistically significant association between microscopically positive surgical margins and local recurrence [17]. 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 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, 18-21].

Metastatic lymph node sizes > 3 cm are at a high risk of recurrence, and this fact is supported by the results of this study [2]. A few studies have reported that the recurrence rate was 27%–32% if any metastatic lymph node was > 3 cm [22, 23]. 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 [24]. The serum level of suppressed Tg may be a surrogate for patients with PTC with a longer time to event [25].

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 for this 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.

ATA, American Thyroid Association, CI, confidence interval, CT, computed tomography, EBRT, external-beam radiotherapy, ECE, extra-capsular extension, HR, hazard ratio, LRRFS, locoregional recurrence-free survival, OS, overall survival, PTC, papillary thyroid carcinoma, RAI, radioactive iodine, RFS, recurrence-free survival, Tg, thyroglobulin, TSH, thyroid-stimulating hormone

Ethics Statement

All procedures were in accordance with 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 patients. The study protocol was approved by the participating centers’ institutional review boards.

Conflict of Interest

The authors declare no conflict of interest.

Funding

None.

Acknowledgments

None.

Data Statement

Raw data of this analysis is available from the corresponding author upon request.

Author Contributions

TK prepared the manuscript and conducted the literature search, TK reviewed and edited the manuscript, and TK, NS, TF, MH, and TY reviewed the manuscript. All authors have read and approved the final manuscript.

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Table 1 baseline characteristics of patients according to post-operation
	no. (%)
Age, year
Median (range)	55 (22–89)
< 55	50 (49)
≥ 55	52 (51)
Gender
Male	15 (15)
Female	87 (85)
ECOG PS
0	91 (89)
1	11 (11)
Presence of TgAb
Yes	20 (20)
No	82 (80)
Preoperative median Tg level, ng/mL (range)	72.4 (5.4–1751)
Postoperative median suppressed Tg level, ng/mL (range)	0.69 (0.04–57)
Extent of surgery
TT + CND	15 (15)
TT + CND + Unilateral MRND	75 (73)
TT + CND + Bilateral MRND	12 (12)
Resection margin
Negative (R0)	24 (23)
Microscopic residual disease (R1)	19 (19)
Gross residual disease (R2)	38 (37)
Unknown (RX)	21 (21)
Extracapsular invasion site
Larynx	5 (5)
Trachea	63 (62)
Esophagus	24 (24)
Vessels	17 (17)
Recurrent laryngeal nerve	68 (67)
Median primary tumor size, cm (range)	2.1 (0.4–7.5)
Primary tumor size, cm
> 2	51 (50)
≤ 2	51 (50)
Number of metastatic lymph node
> 3	60 (59)
≤ 3	42 (41)
Presence of ECE in metastatic lymph node
Yes	12 (12)
No	90 (88)
Metastatic lymph node size, cm
> 3	21 (21)
≤ 3	81 (79)
T factor
T3b	3 (3)
T4a	99 (97)
pN factor
0	15 (15)
1a	18 (18)
1b	69 (67)
Stage no. (%)
I	50 (49)
III	52 (51)

CND, central neck dissection; ECE, extra-capsular extension; ECOG PS, eastern cooperative oncology group performance status; MRND, modified radical neck dissection; Tg, thyroglobulin; TgAb, anti-thyroglobulin antibody; TT, total thyroidectomy.

Table 2 Treatment details of RAI
	no. (%)
Initial dose of RAI, mCi
60	91 (89)
100	3 (3)
120	8 (8)
Post-RAI median suppressed Tg level, ng/mL (range)	0.19 (0.04–56)
Post-RAI suppressed Tg level, ng/mL
< 0.2	41 (50)
0.2–1	16 (20)
≥ 1	25 (30)
Accumulation 6–12 months after RAI
Yes	17 (25)
No	52 (75)
Number of RAI administration before recurrence
1	84 (82)
2	14 (14)
≥ 3	4 (4)
Total median dose of RAI before recurrence, mCi (range)	60 (60–500)

RAI, radioactive iodine; Tg, thyroglobulin.

Table 3 Univariate analysis of LRRFS
Factor	Group	no.	5y-LRRFS (%)	p-value
Age, year	≥ 55	52	80	0.28
	< 55	50	84
Gender	Male	15	67	0.1
	Female	87	85
ECOG PS	0	91	83	0.28
	1	11	71
Primary tumor size, cm	> 2	51	75	0.023
	≤ 2	51	88
pN factor	0	15	100	0.065
	1a	18	100
	1b	68	73
Number of metastatic lymph node	> 3	60	75	0.35
	≤ 3	42	92
Presence of ECE in metastatic lymph node	Yes	12	58	0.014
	No	90	85
Metastatic lymph node size, cm	> 3	21	52	< 0.001
	≤ 3	81	90
Resection margin	R0, 1, X	64	92	< 0.001
	R2	38	64
Interval time from surgery to RAI, month	≥ 6	22	86	0.5
	< 6	80	81
Initial dose of RAI, mCi	60	91	83	0.14
	100, 120	11	66
Number of RAI dosing before recurrence	1	84	81	0.28
	≥ 2	18	83
Post-RAI suppressed Tg level, ng/mL	≥ 0.2	41	69	< 0.001
	< 0.2	41	98

ECE, extra-capsular extension; ECOG PS, eastern cooperative oncology group performance status; LRRFS, locoregional recurrence-free survival; RAI, radioactive iodine; Tg, thyroglobulin.

Table 4 Multivariate analysis of LRRFS
Factor	HR	95% CI	p-value
Primary tumor size, cm (> 2 vs. ≤ 2)	2.07	0.75–5.68	0.16
Metastatic lymph node size, cm (> 3 vs. ≤ 3)	6.99	1.76–27.9	0.006
Presence of ECE in metastatic lymph node (Yes vs. No)	0.35	0.085–1.44	0.15
Resection margin status (R2 vs. R0, 1, X)	3.04	1.005–9.19	0.049
Post-RAI suppressed Tg level, ng/mL (≥ 0.2 vs. < 0.2)	14.6	2.74–78.04	0.002

ECE, extra-capsular extension; RAI, radioactive iodine; Tg, thyroglobulin.

Table 5 Literature review of studies that included adjuvant RAI for high-risk thyroid cancer
Author	Year	Initial median dose of RAI, mCi	no.	Median age	Gender Male/Female (%)	T factor T1-3/4 (%)	Median tumor size, cm	N factor N0/1 (%)	M factor M0/1 (%)	Incomplete tumor resection (%)	Excellent response rate (%)	Recurrence rate during the follow-up period (%)	Median follow-up period (months)
Gray⁸	2019	100	66	51	6/94	-	2.6	-	98/2	55	-	36	54
Gray⁸	2019	150	66	47	38/62	-	2.4	-	95/5	55	-	20
Jeong⁹	2019	100	128	46	24/76	66/34	1.8	8/92	100/0	0	47	7	34
Jeong⁹	2019	150	125	47	22/78	70/30	1.5	6/94	100/0	0	63	10	57
Watanabe¹⁰	2020	30	17	67	35/65	77/23	-	18/82	100/0	100 (R1)	-	53	36
Watanabe¹⁰	2020	100	31	60	29/71	48/52	-	3/97	100/0	100 (R1)	-	23	44
Kim¹¹	2021	100	45	48	27/73	100/0	-	9/91	100/0	-	-	4	92
Kim¹¹	2021	150	39	50	22/78	95/5	-	26/74	100/0	-	-	3
Our report	2022	60	102	55	15/85	3/97	2.1	15/85	100/0	56	42	24	92

R1, microscopic residual disease; RAI, radioactive iodine.

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

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Abstract

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Introduction

Materials And Methods

Results

Discussion

Abbreviations

Declarations

References

Tables

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