Long-term outcomes and prognostic factors of patients with lung metastases from differentiated thyroid cancer after radioiodine therapy in Japan

Abstract

Long-term survival in patients with differentiated thyroid cancer (DTC) and lung metastasis remains unexplored in Japan. This study aimed to investigate the long-term survival and prognostic factors of radioiodine therapy (RIT) in a University Hospital setting. This retrospective study included 62 patients with lung metastases from DTC who received RIT between March 2005 and December 2016. According to the ¹³¹I whole-body scan and chest computed tomography results, lung metastases were classified as ¹³¹I-avid or non-¹³¹I-avid, and miliary, micronodular, or macronodular metastases. The 5- and 10-year overall survival (OS) rates from the initial RIT were calculated by the Kaplan–Meier method, and a proportional hazard fit analysis was performed to determine prognostic factors. With a median follow-up of 7.9 years, the 5- and 10-year OS rates from the initial RIT were 93% and 72%, respectively. Univariable and multivariable analyses of patient subgroups revealed that macronodular lung metastases (defined as nodules >1 cm), older age at initial RIT, and high thyroglobulin values (>400 ng/mL) at initial RIT predicted low OS. The 5- and 10-year OS rates of DTC patients with lung metastases were similar to those in previous Japanese reports, which included a smaller sample size compared with ours. Patients with ≤1 cm lung metastases, aged ≤55 years, and a thyroglobulin level of ≤400 ng/mL at the initial RIT had favorable outcomes.

DIFFERENTIATED THYROID CANCER (DTC) is comprised of papillary and follicular carcinomas. DTC has a relatively good prognosis, with a 5-year overall survival (OS) rate of 98.4% [1]. However, distant metastases occur in 4%–34% of patients, with the lungs and bones as the most common sites [2-6]. Distant metastasis is a poor prognostic factor and a significant cause of death [7]. Radioiodine therapy (RIT) is the standard method for treating patients with lung metastases. However, RIT is not effective in all patients [8], and those who respond poorly are classified as “radioiodine refractory.” Hence, patients refractory to RIT require other treatment options such as surgical treatment, external-beam radiation, and molecular-targeted agents.

Reports from Asian countries on the long-term prognosis of patients with lung metastases from DTC treated with RIT indicate several poor prognostic factors, including older age, lack of ¹³¹I accumulation in lung metastases, presence of other distant organ metastases, and the presence of lung metastases >1 cm [9-12]. In Japan, previous reports on the prognosis of patients with lung metastases from DTC have focused mostly on short-term outcomes; however, even in studies on long-term outcomes, only patients with ¹³¹I accumulation in lung metastasis were investigated [8, 13]. Only a few studies have investigated the long-term prognosis of Japanese patients with DTC and lung metastases that included those with and without ¹³¹I accumulation. Therefore, we aimed to determine the long-term prognosis and prognostic factors after RIT in patients with lung metastases from DTC in Japan. Since Kanazawa University Hospital is a major center for radioisotope treatment in Japan, we retrospectively surveyed patients with DTC and summarized the long-term OS rates and poor prognostic factors in patients with lung metastases after RIT for DTC.

Materials and Methods

Patients

Overall, 402 patients with DTC underwent RIT at Kanazawa University Hospital from March 1, 2005 to December 31, 2016; 109 (27.1%) of these patients subsequently developed lung metastases. Using medical charts, the outcome was confirmed in 62 of 109 (56.9%) patients and they were included in this retrospective cohort study.

The present study was approved by the ethics committee of Kanazawa University (2021–271 [113920]). Due to this study’s retrospective nature, written informed consent from each patient was waived by opting out.

Diagnostic criteria for lung metastasis from DTC

Clinical examinations and imaging, including radiography, computed tomography (CT), ¹³¹I scintigraphy, serum thyroglobulin (Tg), and anti-Tg antibody (TgAb) levels, were used to diagnose lung metastasis. Pathological examination of the diagnosis was limited to 5 enrolled patients. Patients who met any of the following conditions were diagnosed as having lung metastasis: i) confirmation by pathological examination; ii) scintigraphic accumulation of ¹³¹I in lungs (¹³¹I-avid) with or without nodules on chest radiography or CT regardless of serum Tg level; and iii) nodules on chest radiography or CT without ¹³¹I accumulation in lungs (non-¹³¹I-avid) associated with an elevated serum Tg level or TgAb level.

Patients were divided into three groups according to the size of the lung nodules: i) patients with negative chest radiography or CT results but positive ¹³¹I accumulation (defined as “miliary metastases”), ii) patients with lung nodules ≤1 cm (defined as “micronodular metastases”), and iii) patients with lung nodules >1 cm (defined as “macronodular metastases”). Regarding the time of diagnosis of lung metastasis, patients were also classified as “initial” or “developed” if diagnosed ≤6 or >6 months after primary thyroid surgery, respectively.

Radioiodine therapy

A total of 26 patients (42%) underwent total thyroidectomy, while the remaining 36 patients underwent lobectomy followed by total thyroidectomy. All patients reached a hypothyroid state (serum thyroid stimulating hormone [TSH] level of >30 mIU/L) after more than 2 weeks of thyroid hormone withdrawal and iodine restriction. Thereafter, they received radioiodine (range, 1,110–12,950 MBq) after Tg and TgAb measurements. Serum Tg and TgAb levels were determined by electrochemiluminescence immunoassay. A post-therapy whole-body scan (WBS) was performed days after ¹³¹I administration, with an additional WBS 7 days after administration only in patients who received the initial treatment. Anterior and posterior WBS were acquired at a speed of 15 cm/min with a 256 × 1,024 matrix using ¹³¹I energy of 364-keV photopeak and a 20% window. Board-certified nuclear medicine physicians confirmed the sites of ¹³¹I accumulation using post-therapy WBS. Additional RIT was administered 6–12 months later to patients with ¹³¹I-avid metastases. Subsequent RIT was completed when ¹³¹I accumulation disappeared in lesions, new lesions appeared, or the attending physician decided to discontinue RIT due to the patient’s condition.

Evaluation data and follow-up

Clinical data including sex, pathological type, operation method (lobectomy followed by completion of total thyroidectomy or total thyroidectomy), age at initial surgery (age at diagnosis of primary DTC), age at diagnosis of lung metastasis, age at initial RIT, time of diagnosis of lung metastasis (initial or developed), size of lung nodules, site of distant metastasis, and serum Tg and TgAb levels after TSH stimulation at the time of RIT, were collected from medical records. Follow-up included determination of serum Tg and TgAb levels on L-thyroxine and radiological examinations once or twice a year. The follow-up period was based on the date of death or the most recent contact as of December 31, 2021.

Data analysis and statistics

All data were presented as median, range, proportions, or absolute numbers. A univariable Cox proportional hazard model was used for identifying predictors and calculating hazard ratio for OS from the initial RIT. A proportional hazard fit analysis was used to determine the contribution of predictive factors to OS. Survival curves were generated using the Kaplan–Meier method and the log-rank test. These analyses were first performed for all patients (n = 62), then after excluding those with a TgAb level of >28.0 IU/mL (n = 45). Statistical analysis was performed using JMP Pro version 16 (SAS Institute, Cary, NC, USA). A p-value <0.05 was considered to indicate statistical significance.

Results

Clinical and demographic characteristics of the patients with lung metastases are shown in Table 1. Of the 62 patients, 19 (30.6%) were men and 43 (69.4%) were women. The pathological types of primary DTC were papillary, follicular, both (papillary and follicular), and unknown in 50 (80.6%), 9 (14.5%), 2 (3.2%), and 1 (1.6%) patients, respectively. The median age at diagnosis of primary DTC (age at initial surgery) was 52.5 years (range, 10–74 years) and that of lung metastases was 62 years (range, 18–78 years). The median age at initial RIT was 60.5 years (range, 23–76 years). A total of 24 and 38 patients had ¹³¹I-avid and non-¹³¹I-avid lung metastases, respectively. Abnormal accumulation in lung metastases disappeared in 8 out of 24 patients during follow-up evaluations after RIT.

Table 1 Clinical characteristics of patients with differentiated thyroid cancer and lung metastases

Characteristics	Data	Percentage
Patient number	62
Male	19	30.6%
Female	43	69.4%
Pathological type of primary thyroid tumor
Papillary thyroid carcinoma	50	80.6%
Follicular thyroid carcinoma	9	14.5%
Papillary + follicular thyroid carcinoma	2	3.2%
Unknown	1	1.6%
Operation method
Total thyroidectomy	26	41.9%
Lobectomy or subtotal thyroidectomy + completion thyroidectomy	36	58.1%
Time of diagnosis of lung metastasis
Initial	15	24.2%
Developed	47	75.8%
Site of distant metastasis
Lung only	39	62.9%
Lung + other organs*	23	37.1%
The maximum size of lung metastases
X-ray CT negative and 131I avid	3	4.8%
≤1 cm	42	67.7%
>1 cm	17	27.4%
Age at initial surgery
Median (range)	52.5 (10–74)
≤55 years	36	58.0%
>55 years	26	42.0%
Age at diagnosis of lung metastases
Median (range)	62 (18–78)
≤55 years	22	35.4%
>55 years	40	64.6%
Age at initial 131I therapy
Median (range)	60.5 (23–76)
≤55 years	24	38.7%
>55 years	38	61.3%
Thyroglobulin value at initial 131I therapy
≤400 ng/mL	36	58.1%
>400 ng/mL	26	41.9%
131I uptake on lung metastases
Positive	24	38.7%
Negative	38	61.3%

* Other organ metastases include bone (n = 16), liver (n = 4), spleen (n = 1), kidney (n = 2), adrenal glands (n = 2), brain (n = 3), and skin and soft tissue (n = 3).

RIT was administered 146 times (Table 2). The doses per treatment ranged from 1.11 to 12.95 GBq; the most common doses were 3.7 GBq (35.4%), 5.55 GBq (36.8%), and 7.4 GBq (22.9%). The number of RIT administrations ranged from 1 to 9 times; a total of 53 patients (85.6%) were treated ≤3 times.

Table 2 ¹³¹I therapy details during the study period

Administration dose per treatment (GBq)	Number (%)
1.11	3 (2.1)
1.85	2 (1.4)
3.7	51 (35.4)
5.55	53 (36.8)
7.4	33 (22.9)
11.1	1 (0.7)
12.95	1 (0.7)
Total administration dose (GBq)	Number (%)
1.11	2 (3.2)
3.7	5 (8.1)
5.55	12 (19.4)
6.66	1 (1.6)
7.4	8 (12.9)
9.25	3 (4.8)
11.1	12 (19.4)
12.95	2 (3.2)
14.8	3 (4.8)
16.65	4 (6.5)
20.35	1 (1.6)
22.2	5 (8.1)
38.85	1 (1.6)
40.7	2 (3.2)
55.5	1 (1.6)
Number of 131I therapy	Number (%)
1	20 (32.3)
2	21 (33.9)
3	12 (19.4)
4	4 (6.5)
5	3 (4.8)
6	1 (1.6)
9	1 (1.6)

The median follow-up period was 13.6 years (range, 2.0–49.2 years), 7.3 years (range, 0.1–23.0 years), and 7.9 years (range, 0.5–23.0 years) from the initial surgery, from the diagnosis of lung metastases, and from the initial RIT, respectively. At the end of the study, 18 patients (29.0%) had died: 11 from thyroid cancer and 7 from unknown causes. The median OS was 34.4 years from the initial surgery. The 5- and 10-year OS rates from the initial surgery were 98% and 86%, respectively. The median OS from the diagnosis of lung metastases was 12.8 years. The 5- and 10-year OS rates from the diagnosis of lung metastases were 89% and 71%, respectively. The median OS from the initial RIT was 14.3 years. The 5- and 10-year OS rates after the initial RIT were 93% and 72%, respectively (Fig. 1).

Fig. 1

Overall survival from initial ¹³¹I therapy. Survival rates at 5 and 10 years were 93% and 72%, respectively.

The results of univariable and multivariable hazard models are shown in Table 3. The univariable analysis for all patients showed that the prognosis was determined by macronodular metastases (hazard ratio [HR] 3.44, p = 0.016), distant metastases other than to the lungs (HR 2.83, p = 0.037), and higher Tg values (>400 ng/mL) at initial RIT (HR 2.85, p = 0.045). However, multivariate analysis using the five significant factors (pathological type, time of diagnosis of lung metastasis, distant metastases other than lung, macronodular metastases, and Tg value at initial RIT) showed that none of them had a significant impact on OS rates from initial RIT.

Table 3 Univariable and multivariable analyses for overall survival from initial ¹³¹I therapy

Variables	Total patients (n = 62)		Subset excluding patients with TgAb elevation (n = 45)
	Univariable analysis		Univariable analysis		Multivariable analysis
	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
Pathological type of primary thyroid tumor (Follicular thyroid carcinoma/Papillary thyroid carcinoma)	3.04 (0.94–9.86)	0.064	2.19 (0.46–10.50)	0.33
Operation method (Total thyroidectomy/Lobectomy or subtotal thyroidectomy + completion thyroidectomy)	1.10 (0.43–2.81)	0.84	1.00 (0.32–3.08)	1.00
Time of diagnosis of lung metastasis (Initial/Developed)	2.32 (0.85–6.30)	0.099	2.43 (0.73–8.08)	0.15
Site of distant metastasis (Lung + other organs*/Lung only)	2.83 (1.06–7.50)	0.037	2.58 (0.80–8.30)	0.11
The maximum size of lung metastases
>1.0 cm/≤1.0 cm	3.44 (1.26–9.39)	0.016	3.22 (0.97–10.68)	0.056	3.61 (1.04–12.50)	0.043
>1.5 cm/≤1.5 cm	1.82 (0.51–6.44)	0.35	2.75 (0.72–10.47)	0.14
>2.0 cm/≤2.0 cm	2.81 (0.36–22.07)	0.33	4.37 (0.54–35.67)	0.17
Age at initial surgery (>55 years/≤55 years)	1.02 (0.37–2.77)	0.97	1.15 (0.36–3.67)	0.81
Age at the diagnosis of lung metastases (>55 years/≤55 years)	1.42 (0.53–3.79)	0.49	2.87 (0.63–13.02)	0.17
Age at initial RIT (>55 years/≤55 years)	1.85 (0.68–5.07)	0.23	4.18 (0.90–19.52)	0.069	5.47 (1.11–26.98)	0.037
Thyroglobulin value at initial 131I therapy (>400 ng/mL/≤400 ng/mL)	2.85 (1.02–7.91)	0.045	4.82 (1.26–18.40)	0.022	4.91 (1.25–19.32)	0.042
131I uptake on lung metastases (Negative/Positive)	0.68 (0.27–1.74)	0.43	0.73 (0.24–2.21)	0.58
Total 131I doses (>15 GBq/≤15 GBq)	1.75 (0.66–4.61)	0.26	1.27 (0.37–4.33)	0.70

* Other organ metastases include bone (n = 16), liver (n = 4), spleen (n = 1), kidney (n = 2), adrenal glands (n = 2), brain (n = 3), and skin and soft tissue (n = 3) in total patients (n = 62). In the subset (n = 45), other organ metastases include bone (n = 13), liver (n = 3), spleen (n = 1), kidney (n = 2), adrenal (n = 2), brain (n = 3), and skin soft tissue (n = 3).

HR, hazard ratio; CI, confidence interval; TgAb, anti-thyroglobulin antibody.

Since elevated TgAb levels could affect Tg measurements, univariable and multivariable analyses were performed for a subgroup of 45 patients; 17 patients with elevated TgAb levels were excluded. Univariable analysis revealed that a higher Tg level at initial RIT was significantly associated with shorter OS (HR 4.82, p = 0.022). Macronodular metastases and higher age at initial RIT also tended to worsen the outcome, although these were statistically significant (p = 0.056 and 0.069, respectively). Multivariable analysis that included the three significant factors showed that all were significantly independent poor prognostic factors. Fig. 2 presents the prognostic significance of each factor for OS as evaluated by the Kaplan–Meier method. The log-rank test showed that patients with micronodular lung metastases, younger age (≤55 years), and lower Tg level (≤400 ng/mL) exhibited significantly longer long-term survival.

Fig. 2

Significant risk factors related to a lower overall survival rate are the maximum size of lung metastases (A, p = 0.0433), age at initial ¹³¹I therapy (B, p = 0.0496), and thyroglobulin level at initial ¹³¹I therapy (C, p = 0.0115).

Discussion

The current study summarized a long-term survival analysis in a clinical setting of patients with lung metastases in a University Hospital in Japan. We found only two Japanese reports on patients with lung metastasis from DTC with long-term follow-ups of >10 years [13, 14]. The two reports were from the same institution specializing in thyroid diseases. When compared with the results of the two previous studies, our 5-year survival rates were comparable. However, the 10-year survival rates were different, and our results were in between the other two studies (Table 4). The two previous studies included fewer patients with distant metastases other than to the lungs when compared with our study. Additionally, the study by Ohkuwa et al. included only patients with ¹³¹I-avid lung metastases [13], and the study by Matsuzu et al. included only patients with papillary carcinomas [14]. In contrast to the previous studies, the present work included a more comprehensive patient population, and the patient backgrounds in our study demonstrate the wide range of patients with DTC: 37% of patients had distant metastases other than lung metastases, 15% of patients had follicular carcinoma, and 61% of patients had non-¹³¹I-avid lung metastases. Furthermore, our study calculated OS from the initial RIT, while the previous two studies calculated cause-of-death-specific survival (CSS). These differences in patient backgrounds and the type of calculated survival rates may have contributed to the differences in the 10-year survival rates.

Table 4 Comparison of survival rate and characteristics with previous Japanese studies on long-term prognosis of lung metastases from DTC

	n	Papillary carcinoma (%)	Age at initial surgery (median, year)	Age at diagnosis of lung metastasis (median, year)	Macronodular metastasis (%)	131I-avid lung metastasis (%)	Lung only (%)	Survival rate (%)
								5 years	10 years
Ohkuwa et al. [13]	123	68	41	47	43	100	90	92a	90a
Matsuzu et al. [14]	64*	100	58	58	14	43	92	87b	68b
Akatani et al. (present study)	62	81	52.5	62	27	39	63	93c	72c

* Among the 64 patients, 56 patients received ¹³¹I therapy.

^a Cause-of-death-specific survival from diagnosis of lung metastasis, ^b Cause-of-death-specific survival from initial surgery, ^c Overall survival from initial ¹³¹I therapy.

DTC, differentiated thyroid cancer.

Our results showed that the presence of macronodular lung metastases decreased OS from the initial RIT. Several reports have demonstrated that macronodular metastasis is a prognostic factor for poor outcomes. Additionally, the maximum size of lung metastases is the most important factor predicting poor clinical outcomes and survival in patients with metastatic DTC confined to the lungs [15]. Macronodular metastasis is also a predictor of shorter progression-free survival and CSS in patients with DTC and lung-only metastases [10]. Cho et al. reported that the size of lung metastases was associated with significantly shortened progression-free survival in a study of 152 patients with lung metastases, 13.8% of whom had both lung and bone metastases [9]. Although our study included a higher percentage of patients (37%) with metastases other than to the lungs as compared with the study by Cho et al. [9], macronodular metastasis was still significantly associated with shorter OS. Thus, when lung metastases <1 cm are detected during follow-up, timely intervention before metastasis growth may improve outcomes.

As reported in previous studies, the age at initial surgery and at the diagnosis of lung metastases are associated with prognosis [9-12]. In this study, higher age at initial RIT (>55 years) was a significant factor that predicted poor outcomes. In recent years, many reports have set 55 years old as the cutoff value for age, and the AJCC/UICC TNM system also uses 55 years as the cutoff age for upstage patients [10, 16, 17]. Huang et al. and Yang et al. reported that the mortality risk in patients with DTC and distant or lung metastases increased by 5.6%–6.3% per year [11, 12].

Our study demonstrated that a higher Tg level at initial RIT (>400 ng/mL) was also a significant poor prognostic factor. The serum Tg level is a useful tumor marker for decision-making in the risk assessment and management of thyroid cancer [18]. The Tg level correlates with tumor burden; approximately 1 g of neoplastic thyroid tissue increases the serum Tg level by 1 μg/L during thyroxin treatment and by 2–10 μg/L following stimulation by TSH [19, 20]. Huang et al. showed that a low TSH-stimulated Tg level (<400 μg/L) at the time of metastasis discovery is an independent predictor of survival in patients with DTC and distant metastases [11]. Thus, the classic evaluation method using Tg measurements remains an important prognostic indicator.

As RIT is assumed to be effective when radioiodine accumulates in DTC lesions, ¹³¹I avidity has often been reported to be prognostically relevant [9, 10, 12]; however, ¹³¹I avidity was not associated with OS in this study. Among patients with ¹³¹I-avid distant metastases, the 10-year survival rate was 92% for patients who achieved negative imaging studies (negative WBS and radiological abnormalities), compared with 29% for patients with persistent abnormal accumulation [21]. Although accumulation in lung metastases could be necessary, considering that the disappearance of abnormal accumulation may also impact the prognosis, the low rate of 30% in this study (8 of 24 patients achieved disappearance of abnormal accumulation in lung metastases) may have led to a lack of statistical power.

There are several limitations to this study. First, this was a retrospective study that included a small number of patients with DTC treated with ¹³¹I at a single University Hospital in Japan; a multicenter prospective study is necessary to confirm our findings. Second, subsequent treatments have not been confirmed in all patients, which may have affected the OS rates. Third, recent studies revealed genetic abnormalities related to the development and prognosis of DTC [22-24]; however, this retrospective study did not include information on genetic mutations.

In conclusion, the OS rates in patients with DTC with lung metastases were similar to previous reports, even if we included a more comprehensive patient population. Patients with macronodular metastases had worse OS than patients with micronodular or miliary metastases. Younger patients (≤55 years) and patients with lower Tg values (≤400 ng/mL) at the time of initial RIT exhibited significantly longer long-term survival.

Disclosure

KN and SW belong to an endowed department partly funded by PDRadiopharma (Tokyo, Japan), which supplies ¹³¹I for RIT in Japan. Others declare no financial conflict of interest.

Funding

This research received no specific grant from any funding agency.

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