Vol 74, No 3 (2023)
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Hazard ratios of second primary malignancy after radioiodine for differentiated thyroid carcinoma: a large-cohort retrospective study

Weiming Wu1, Shujie Li1, Ke Xu2, Zhaowei Meng1
Pubmed: 37335064
Endokrynol Pol 2023;74(3):260-270.

Abstract

Introduction: The objective of this study is to evaluate the benefits of radioactive iodine (RAI) treatment and the risk of second primary malignancy (SPM) in RAI-treated patients.

Material and methods: The cohort for this analysis consisted of individuals diagnosed with a first primary differentiated thyroid carcinoma (DTC), reported by the Surveillance, Epidemiology, and End Results (SEER) database in 1988–2016. Overall survival (OS) difference was estimated by Kaplan-Meier curves and log-rank test, and hazard ratios (HR) were obtained by Cox proportional-hazards model to evaluate the association between RAI and SPM.

Results: Among 130,902 patients, 61,210 received RAI and 69,692 did not, and a total of 8604 patients developed SPM. We found that OS was significantly higher in patients who received RAI than in those who did not (p < 0.001). DTC survivors treated with RAI had increased risk of SPM in females (p = 0.043), particularly for SPM occurring in the ovary (p = 0.039) and leukaemia (p < 0.0001). The risk of developing SPM was higher in the RAI group than in the non-RAI group and the general population, and the incidence increased with age.

Conclusions: Increased risk of SPM occurs in female DTC survivors treated with RAI, which become more obvious with increasing age. Our research findings were beneficial to the formulation of RAI treatment strategies and the prediction of SPM for patients with thyroid cancer of different genders and different ages.

Original paper

Endokrynologia Polska

DOI: 10.5603/EP.a2023.0028

ISSN 0423–104X, e-ISSN 2299–8306

Volume/Tom 74; Number/Numer 3/2023

Submitted: 14.01.2023

Accepted: 02.03.2023

Early publication date: 29.05.2023

Hazard ratios of second primary malignancy after radioiodine for differentiated thyroid carcinoma: a large-cohort retrospective study

Weiming Wu*1Shujie Li*1Ke Xu2Zhaowei Meng1
1Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, China
2Tianjin Key Laboratory of Lung Cancer Metastasis and Tumour Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
*These authors contributed equally.

Ke Xu, PhD, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China, Anshan Road No. 154, Heping District, Tianjin 300052, P.R.China, tel: 86-15822889439, fax: 86-022-27813550; e-mail: ke_xu@hotmail.com
Zhaowei Meng MD PhD, Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, P.R. China, tel: 86-18622035159, fax: 86-022-27813550; e-mail: zmeng@tmu.edu.cn or jamesmencius@163.com

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Introduction: The objective of this study is to evaluate the benefits of radioactive iodine (RAI) treatment and the risk of second primary malignancy (SPM) in RAI-treated patients.
Material and methods: The cohort for this analysis consisted of individuals diagnosed with a first primary differentiated thyroid carcinoma (DTC), reported by the Surveillance, Epidemiology, and End Results (SEER) database in 1988–2016. Overall survival (OS) difference was estimated by Kaplan-Meier curves and log-rank test, and hazard ratios (HR) were obtained by Cox proportional-hazards model to evaluate the association between RAI and SPM.
Results: Among 130,902 patients, 61,210 received RAI and 69,692 did not, and a total of 8604 patients developed SPM. We found that OS was significantly higher in patients who received RAI than in those who did not (p < 0.001). DTC survivors treated with RAI had increased risk of SPM in females (p = 0.043), particularly for SPM occurring in the ovary (p = 0.039) and leukaemia (p < 0.0001). The risk of developing SPM was higher in the RAI group than in the non-RAI group and the general population, and the incidence increased with age.
Conclusions: Increased risk of SPM occurs in female DTC survivors treated with RAI, which become more obvious with increasing age. Our research findings were beneficial to the formulation of RAI treatment strategies and the prediction of SPM for patients with thyroid cancer of different genders and different ages. (Endokrynol Pol 2023; 74 (3): 260–270)
Key words: differentiated thyroid carcinoma; second primary malignant; radioactive iodine; cox proportional hazard model; hazard ratio

Introduction

For the past 20 years, the incidence of thyroid cancer has been increasing in the world. In 2018, the number of new cases of thyroid cancer was about 586,000 in the world, ranking 9th among all cancers [1, 2]. The incidence of thyroid cancer has increased more than 300% over the past 4 decades in the United States [1–3]. Differentiated thyroid carcinoma (DTC), accounting for more than 90% of all thyroid cancers, has a 10-year overall survival (OS) exceeding 90% [4]; it is the most common endocrine malignancy, which consists of papillary and follicular thyroid cancers.

Surgery, radioactive iodine (RAI), and thyroid hormone-suppressive therapy is currently recognized as the standard treatment for patients with DTC [5]. With this approach, the survival time of most patients with thyroid cancer is excellent. RAI therapy plays an important role in reducing the risk of disease recurrence and tumour-related death, as well as good prognosis. Despite a favourable prognosis, the scope of treatment for many patients with thyroid cancer is controversial, including the extent of surgery as well as the use and dose of RAI therapy [6–8]. The side effects of RAI treatment are considered minimal, but RAI may cause some acute or chronic effects [5]. Moreover, the most important concern is whether RAI will benefit survival and increase potential risk of second primary malignancy (SPM) [9, 10]. Studies have shown that 19% of patients develop second malignancy after surviving a primary carcinoma [11]. The reasons include continued lifestyle, genetic susceptibility, and treatment modality (radiotherapy and chemotherapy) [12–14]. It is difficult to estimate the incidence of second primary malignancies in patients with DTC after treatment with RAI because there are multiple factors that predispose the patients to SPM.

It has been reported that DTC survivors who received RAI treatment had increased risk of SPM [4, 15], and the SPM risk increased with increasing cumulative RAI activity [16, 17]. Some studies have also reported an increased incidence of SPM of certain organs for sensitivity to radioactivity [18, 19]. In contrast, another study suggested that the risk of second cancer was not related to RAI treatment [14]. Another study utilizing Surveillance, Epidemiology, and End Results (SEER) data included DTC patients for a total of 13 years from 1988 to 2001 (n = 18,882) and reported that RAI treatment was not associated with an increased risk of SPM [20]. Therefore, it is important to recognize the need for risk-benefit balance for DTC patients treated with RAI [21]. Previous studies using SEER tend to have a small sample size, short research time, or short follow-up time [4, 10]. In contrast, our study included DTC patients for nearly 30 years, with a longer period, more patients, and longer follow-up time.

This study aimed to determine whether there was a relationship between RAI treatment and the risk of developing SPM in DTC patients, whether gender was predicted by RAI treatment, and whether there was a relationship between RAI and non-radio-induced cancer. The effect of RAI treatment on OS was estimated by Kaplan-Meier curves. The relationship between the risk of SPM and some variables, including race, gender, age group, year of diagnosis, histological type, SEER stage, and tumour size, and whether to use RAI was assessed using the Cox proportional hazards regression model. This study is the largest study to date to analyse the all-cause and prognostic survival of RAI in DTC patients.

Material and methods

Data

The study population was from the SEER database of the United States National Cancer Institute (NCI). The SEER database collects cancer incidence data from population-based cancer registries covering a large proportion of the U.S. population. The SEER registries contain information on patient demographics, primary tumour site, tumour morphology, stage at diagnosis, treatment, and status. The SEER database is updated once a year to ensure high-quality data. The SEER*Stat software (SEER*Stat 8.3.9, available at https://seer.cancer.gov/seerstat/) was used to obtain information about patients’ demographic, pathologic, and clinical characteristics.

Inclusion and exclusion criteria

The baseline cohort for this analysis consisted of individuals diagnosed with a first primary thyroid cancer identified by International Classification of Diseases (ICD) code ICD-O-3:C73.9, reported to the SEER 18 database between 1988 and 2016. Considering the association between chemo patients and increased risk of SMP [13] and radiation therapies other than RAI that the SEER registries encode, such as beam radiation and radioactive interstitial implants, we excluded patients who were treated with both chemotherapy and RAI completely, and we excluded those who received radiation therapy other than RAI from the SEER database before extracting the data. Individuals were followed up through the developed second primary cancer, death, or the end of the study period.

The inclusion and exclusion criteria were outlined in Figure 1. A total of 37,935 people were excluded from our analysis due to one or more of the following 6 reasons:

  • 1 the study limited tumour histology to papillary and follicular thyroid cancer, defined as International Classification of Diseases for Oncology third edition histology codes 8052, 8130, 8260, 8330-8332, 8335, 8340–8344, and 8450 [15]. Patients with other histologic subtype from analysis were excluded (n = 10,870);
  • 2 patients whose survival time was missing were excluded (n = 598);
  • 3 patients diagnosed with SPM within 12 months of the thyroid cancer diagnosis were excluded (n = 1272) [22]
  • 4 the aim of this study was to evaluate the association between RAI and risk of second primary malignancy other than thyroid cancer; hence, patients with recurrent thyroid cancer were excluded (n = 335) [23]
  • 5 patients younger than 18 years of age were excluded (n = 1646);
  • 6 patients with missing data were excluded (n = 14,640).
179638.png
Figure 1. Inclusion and exclusion criteria for first primary thyroid cancer and second primary cancer in Surveillance, Epidemiology, and End Results (SEER) data, 1988–2016. DTC differentiated thyroid carcinoma; RAI radiation iodine

Finally, 130,902 patients were included in total. Additional variables analysed were sex, race (white, black, and other [American Indian/AK Native, Asian/Pacific Islander]), age (< 45 years, 45–54 years, 55–64 years, and 65 years) [5, 24], year of diagnosis (1988–2016), SEER stage (localized, regional, and distant), tumour size (0–10 mm and > 10 mm), and RAI therapy (yes or no). The end point of the study was set as 31 December 2016. The enrolled DTC patients were divided into 2 cohorts: those who received RAI and those who did not.

Statistical analysis

The data were extracted with SEER*Stat software and imported into MATLAB (available at https://www.mathworks.com/). In the study, MATLAB software was used for processing data, deleting missing values, and quantifying data. Patients’ clinicopathological characteristics were expressed as mean ± standard deviation (SD) for continuous variables, and number with percentage for categorical variables. The chi-square test was used to compare the differences of clinicopathological characteristics between patients who received RAI and those who did not. The chi-square test was performed using IBM SPSS software version 25.

In this study the OS difference was estimated by Kaplan-Meier curves and the log-rank test. Survival time was defined as the time after the diagnosis until death or last follow-up. In addition, a Cox proportional hazard model was performed to assess hazard ratios (HR) and 95% confidence interval (CI), with the occurrence of second primary cancer regarded as an outcome variable in the model. The endpoint was defined as the time from the date of DTC diagnosis to death or last follow-up or diagnosis date of the second malignancy, whichever came first. Univariate analyses were performed for each variable between patients who received RAI and those who did not. In this step, a total of 8 variables were evaluated including race, gender, age group, year of diagnosis, histological type, SEER stage, tumour size, and whether to use RAI. To explore whether each variable still had a higher HR value with statistical significance when other variables existed [25], we used 6 variables including race, age group, year of diagnosis, SEER stage, tumour size, and whether to use RAI in the adjusted Cox model for multivariable analyses. The statistical level of significance was set at p < 0.05, and all p value were 2 sided. All statistical analyses were performed using R 4.0.0 software, and the Cox proportional hazard model was conducted using the “Survival” package (R Project, version: 3.6.2, available at https://cran.r-project.org/mirrors.html).

Results

Clinicopathological characteristics

The clinicopathological characteristics of the study population are shown in Tab. 1. A total of 130,902 DTC patients were enrolled during the period 1988–2016. Among these patients, 61,210 received RAI and 69,692 did not; 102,773 (78.5%) were female and 28,129 (21.5%) were male. Statistically significant differences were found in gender, race, age, year of diagnosis, SEER stage, histological type, tumour size, and vital status. The median duration of follow-up of all patients with DTC was 79 months, in RAI therapy patients it was 85 months, and in non-RAI therapy patients it was 72 months. The median time of SPM development for all cases, cases with RAI treatment, and cases without RAI treatment was 128 months, 126.5 months, and 129 months, respectively.

Table 1. Clinicopathological characteristics of differentiated thyroid carcinoma (DTC) patients with radiation iodine (RAI) or without RAI

Variables

First Primary (n = 130,902)

RAI (n = 61,210)

non-RAI (n = 69,692)

p-value

SPM (n = 8604)

RAI SPM (n = 4154)

non-RAI SPM (n = 4450)

p-value

N

%

N

%

N

%

N

%

N

%

N

%

Gender

Male

28,129

21.5

14,605

23.9

13,524

19.4

< 0.001

2322

27

1228

29.6

1094

24.6

< 0.001

Female

102,773

78.5

46,605

76.1

56,168

80.6

6282

73

2926

70.4

3356

75.4

Race

White

107,622

82.2

50,130

81.9

57,492

82.5

< 0.001

7240

84.1

3437

82.7

3803

85.4

< 0.001

Black

8379

6.4

3248

5.3

5131

7.4

533

6.2

223

5.4

310

7.0

Other

14,901

11.4

7832

12.8

7069

10.1

831

9.7

494

11.9

337

7.6

Age [y]

< 45

56,395

43.1

28,661

46.8

27,734

39.8

< 0.001

1937

22.5

1007

24.3

930

20.9

< 0.001

45–54

32,037

24.5

14,901

24.3

17,136

24.6

2198

25.5

1113

26.8

1085

24.4

55–64

23,684

18.1

10,184

16.7

13,500

19.4

2260

26.3

1060

25.5

1200

27.0

≥ 65

18,786

14.3

7464

12.2

11,322

16.2

2209

25.7

974

23.4

1235

27.7

Year of diagnosis

1988–1996

9758

7.5

4566

7.5

5192

7.4

< 0.001

1,587

18.4

735

17.7

852

19.2

0.198

1997–2006

37,170

28.4

18,515

30.2

18,655

26.8

4031

46.9

1974

47.5

2057

46.2

2007–2016

83,974

64.2

38,129

62.3

45,845

65.8

2986

34.7

1445

34.8

1541

34.6

Stage

Localized

91,496

69.9

33,013

53.9

58,483

83.9

< 0.001

6074

70.6

2335

56.2

3739

84.0

< 0.001

Regional

37,582

28.7

26,930

44.0

10,652

15.3

2387

27.7

1711

41.2

676

15.2

Distant

1,824

1.4

1267

2.1

557

0.8

143

1.7

108

2.6

35

0.8

Histological

FTC

124,557

95.2

57,933

94.6

66,624

95.6

< 0.001

8077

93.9

3872

93.2

4205

94.5

0.013

PTC

6,345

4.8

3277

5.4

3068

4.4

527

6.1

282

6.8

245

5.5

Tumour size

0–10 mm

51,747

39.5

13,586

22.2

38,161

54.8

< 0.001

3542

41.1

1042

25.1

2500

56.2

< 0.001

> 10 mm

79,155

60.5

47,624

77.8

31,531

45.2

5062

58.9

3112

74.9

1950

43.8

Vital status

Alive

121,725

93.0

57,248

93.5

64,477

92.5

< 0.001

6168

71.6

3005

72.4

3163

71.1

0.194

Overall death

9177

7.0

3962

6.5

5215

7.5

2436

28.4

1149

27.6

1287

28.9

Cancer-specific death

1776

1.4

1051

1.7

725

1.0

< 0.001

238

2.7

152

3.6

86

1.9

< 0.001

Median follow-up (months) (IQR)

79 (34–137)

85 (41-141)

72 (29–133)

128 (81–183)

126.5 (82–182)

129 (79–183)

Prognostic impact of RAI on OS

During the study period, 9177 (7.01%) patients died, 3962 (3.03%) patients received RAI, and 5215 (3.98%) did not receive RAI. The OS for patients received RAI was significantly higher than those who did not (see Fig. 2A, log-rank test, both p < 0.001). Gender group analysis demonstrated that RAI had a significant impact on the OS, and the OS among females was significantly higher than for males (see Fig. 2BC, log-rank test, both p < 0.001).

179743.png
Figure 2. Overall survival difference for differentiated thyroid carcinoma (DTC) patients according to treatment. A. Total overall survival; B. Male overall survival; C. Female overall survival. RAI radiation iodine

Prognostic impact of RAI on CSM

More of those who received RAI died of thyroid cancer compared to those who did not receive RAI (1.6% vs. 1.0%, p < 0.001). Thyroid cancer-specific mortality (CSM) by RAI usage is provided in Table 2. CSM was higher in males treated with RAI than in males not treated with RAI [3% (n = 444) vs. 1.9% (n = 258), p < 0.001], and a consistent result was also observed in females, race subgroups, age subgroups, 1988-1996 Y, 1997-2006 Y, localized, FTC, and 0-10 mm subgroups. RAI was associated with reduced CSM value in patients with regional [RAI: 2.2% (n = 592), non-RAI: 2.6% (n = 279), p = 0.015] and distant [RAI: 21.2% (n = 269), non-RAI: 31.1% (n = 173), p < 0.001].

Table 2. Thyroid cancer specific mortality by radiation iodine (RAI) usage

Variables

RAI (%)

non-RAI (%)

p-value

Gender

Male

444 (3.0)

258 (1.9)

< 0.001

Female

607 (1.3)

467 (0.8)

< 0.001

Race

White

825 (1.6)

569 (1.0)

< 0.001

Black

69 (2.1)

56 (1.1)

< 0.001

Other

157 (2.0)

100 (1.4)

0.006

Age [y]

< 45

94 (0.3)

42 (0.2)

< 0.001

45–54

194 (1.3)

110 (0.6)

< 0.001

55–64

290 (2.8)

142 (1.0)

< 0.001

≥ 65

473 (6.3)

431 (3.8)

< 0.001

Year of diagnosis

1988–1996

295 (6.5)

191 (3.7)

< 0.001

1997–2006

512 (2.8)

279 (1.5)

< 0.001

2007–2016

244 (0.6)

255 (0.6)

0.116

Stage

Localized

190 (0.6)

273 (0.5)

0.026

Regional

592 (2.2)

279 (2.6)

0.015

Distant

269 (21.2)

173 (31.1)

< 0.001

Histological

FTC

902 (1.6)

604 (0.9)

< 0.001

PTC

149 (4.5)

121 (3.9)

0.234

Tumour size [mm]

0–10

102 (0.8)

141 (0.4)

< 0.001

>10

949 (2.0)

584 (1.9)

0.160

Univariate analysis

We performed a univariate Cox regression model to estimate the HRs for different variables including demographic characteristics, histological type, SEER stage, tumour size, and whether using RAI, with the endpoint defined as the time from the date of DTC diagnosis to diagnosis date of the second malignancy (see Tab. 3). In univariate Cox regression analyses, most of the variables showed statistical significance (p < 0.05), except for histological type. In both male and female groups, patients older than 65 years had the highest HR value, and the most recent period (2007 to 2016) had the highest elevation; the HR regional value was lower than that of the localized value. In the female group, HR of the black participants were higher than that of the white participants, other races’ HRs were lower than that of the whites, and the use of RAI was a significant predictor of SPM, whereas in the male group, HR value among black persons and therapy were not significant.

Table 3. Univariate survival analysis for demographic, histological type, tumour size, and therapy

Variables

Male

Female

HR (95% CI)

p-value

HR (95% CI)

p-value

Race

White

Reference

Reference

Black

1.14 (0.94–1.37)

0.190

1.11 (1.00–1.22)

0.049

Other

0.80 (0.69–0.94)

0.005

0.87 (0.81–0.95)

0.001

Age [y]

< 45

Reference

Reference

45–54

3.13 (2.72–3.61)

< 0.001

2.23 (2.09–2.39)

< 0.001

55–64

5.78 (5.05–6.63)

< 0.001

3.57 (3.33–3.83)

< 0.001

≥ 65

8.99 (7.84–10.31)

< 0.001

4.92 (4.58–5.29)

< 0.001

Year of diagnosis

1988–1996

Reference

Reference

1997–2006

1.14 (1.00–1.29)

0.045

1.26 (1.17–1.37)

< 0.001

2007–2016

1.23 (1.07–1.42)

0.003

1.49 (1.36–1.63)

< 0.001

Stage

Localized

Reference

Reference

Regional

0.85 (0.78–0.93)

< 0.001

0.93 (0.88–0.99)

0.021

Distant

1.20 (0.94–1.53)

0.141

1.10 (0.88–1.39)

0.392

Histological

FTC

Reference

Reference

PTC

1.07 (0.92–1.25)

0.38

1.02 (0.92–1.14)

0.665

Tumour size

0–10 mm

Reference

Reference

> 10 mm

0.78 (0.72–0.85)

<0.001

0.84 (0.80–0.88)

< 0.001

Therapy

Non-RAI

Reference

Reference

RAI

0.93 (0.86–1.02)

0.116

0.95 (0.91-1.00)

0.048

Multivariable analysis

In multivariable Cox regression analyses (see Fig. 3), a significant difference was found between the RAI and non-RAI groups. Receiving RAI treatment was a significant predictor of SPM in the female group of DTC survivors. Furthermore, adjusted HR increased with age for both males and females and the group over 65 years old, and still showed the highest HR value among all variables – the same as the result of univariate analysis. The adjusted HR of tumours larger than 10 mm and other races was lower than the reference, both in males and females. Moreover, we observed that there was no significant difference between the year of diagnosis and SEER stage in the male group, while the HR values in 1997–2008 and 2009–2016 were 1.14 versus 1.22, respectively, (p < 0.001), and the adjusted HR of the SEER stage was higher in patients with regional disease as compared to localized (adjusted HR = 1.07, p = 0.036) in the female group. In the multivariable analysis, we further verified the result that RAI treatment was a significant predictor of SPM for females.

179782.png
Figure 3. Hazard ratio (HR) difference for differentiated thyroid carcinoma (DTC) patients according to treatment (*p0.05, **p0.01, ***p0.001). A. Male HR value in multivariable Cox regression analysis; B. Female HR value in multivariable Cox regression analysis

Incidence of SPM

A total of 8604 patients developed SPM after a primary thyroid cancer. Among them, 2322 (27%) patients were male and 6282 (73%) patients were female. Table 4 presents the distribution of the different second primary malignancy sites. In the males, the incidence of all malignancy in the RAI group and non-RAI group were 8.41% (n = 1228) and 8.09% (n = 1,094); whereas in females the RAI group and non-RAI group were 6.27% (n = 2,926) and 5.97% (n = 3356). The incidence of SPM in females was lower than in the male group (see Fig. 4A, p < 0.05). In terms of different types of SPM, the most common sites were in the cecum and rectum, lung and bronchus, melanoma of the skin, breast, prostate, kidney and renal pelvis, and haematopoietic system, both in the RAI and non-RAI group. The incidence of prostate cancer was highest among SPM in the male group, and the incidence of RAI and non-RAI were 2.43% (n = 355) and 2.58% (n = 349), respectively, followed by melanoma of the skin. In females, the incidence of breast cancer group was highest among SPM, and the RAI group had a higher incidence (2.32%, 1,081) than the non-RAI group (2.27%, 1,276). In particular, DTC survivors treated with RAI in the female group had increased risk of SPM compared to the non-RAI group in certain types of malignancies, including ovarian cancer (0.17% vs. 0.12%, 80 vs. 69, p = 0.039) and leukaemia (0.22% vs. 0.12%, 104 vs. 68, p < 0.001), which showed greater sensitivity to radioactivity.

Table 4. The distribution of the different second primary malignancy sites

Second primary site

Male

Female

RAI (14,605)

non-RAI (13,524)

RAI (46,605)

non-RAI (56,168)

N

%

N

%

p

N

%

N

%

p

Salivary gland

10

0.07

7

0.05

0.564

25

0.05

18

0.03

0.090

Other oral cavity and pharynx

26

0.18

23

0.17

0.864

23

0.05

21

0.04

0.351

Digestive system

Stomach

15

0.10

24

0.18

0.095

31

0.07

32

0.06

0.530

Cecum and rectum

78

0.53

67

0.50

0.638

195

0.42

225

0.40

0.633

Liver

16

0.11

9

0.07

0.224

22

0.05

16

0.03

0.118

Others

60

0.41

38

0.28

0.063

100

0.21

129

0.23

0.627

Respiratory system

Lung and Bronchus

98

0.67

90

0.67

0.936

245

0.53

284

0.51

0.658

Others

8

0.05

5

0.04

0.484

8

0.02

14

0.02

0.402

Skin excluding basal and squamous

Melanoma of the skin

137

0.94

120

0.89

0.638

203

0.44

260

0.46

0.539

Others

6

0.04

9

0.07

0.359

11

0.02

8

0.01

0.269

Breast

4

0.03

4

0.03

-

1,081

2.32

1276

2.27

0.566

Female genital system

Ovary

80

0.17

69

0.12

0.039

Corpus uteri

158

0.34

185

0.33

0.767

Others

54

0.12

76

0.14

0.393

Male genital system

Prostate

355

2.43

349

2.58

0.461

Others

10

0.07

5

0.04

0.250

Urinary system

Kidney and renal pelvis

94

0.64

67

0.50

0.097

102

0.22

126

0.22

0.872

Others

73

0.50

66

0.49

0.872

41

0.09

52

0.09

0.819

Brain and other nervous system

Brain

20

0.14

16

0.12

0.655

32

0.07

38

0.07

0.940

Other nervous system

16

0.11

25

0.18

0.101

120

0.26

120

0.21

0.141

Other endocrine excluding thyroid

18

0.12

14

0.10

0.617

33

0.07

37

0.07

0.753

Haematopoietic system

Lymphoma

59

0.40

62

0.46

0.500

118

0.25

121

0.22

0.203

Leukaemia

55

0.38

31

0.23

0.025

104

0.22

68

0.12

< 0.0001

Myeloma

11

0.08

17

0.13

0.184

27

0.06

49

0.09

0.088

Others

59

0.40

46

0.34

0.373

113

0.24

132

0.24

0.788

Total

1,228

8.41

1,094

8.09

0.332

2,926

6.27

3,356

5.97

0.043

179831.png
Figure 4. Second primary malignant (SPM) incidence difference for differentiated thyroid carcinoma (DTC) patients according to treatment (*p0.05, **p0.01, ***p0.001). A. SPM incidence difference in gender subgroups; B. SPM incidence difference in age subgroups; C. Male SPM incidence difference in age subgroups; D. Female SPM incidence difference in age subgroups. RAI radiation iodine

The incidence of SPM increased with age both in the RAI group and in the non-RAI group, and incidence in the RAI group in all age subgroups demonstrated higher incidence than the non-RAI group. There were statistically significant differences among age subgroups of 41–50, 51–60, 61–70, and > 70 years of age between the RAI group and the non-RAI group (see Fig. 4B). The incidence of SPM increased with age in both females and males, and the incidence of SPM in men was higher than in women over 40 years old (see Fig. 4C–D). There were statistically significant differences in age subgroups of only 61–70 years for the male group and age subgroups of 41–50, 61–70, and > 70 years for the female group.

Discussion

In the current study, a retrospective large cohort analysis based on SEER was performed, and the risk of SPM after DTC was analysed in a series of 130,902 patients treated over almost 30 years, among whom 61,210 received RAI. We found that the use of RAI for DTC patients could increase OS, and the OS of females was significantly higher than for males. The result of this study was consistent with a previous National Cancer Database (NCDB) study which suggested that RAI was associated with improved OS in patients with DTC [26]. Moreover, a large number of studies indicate that RAI treatment could reduce the risk of recurrence of thyroid cancer and improve the survival for intermediate-risk, well-differentiated thyroid carcinoma patients [10, 27, 28]. Wang et al. proposed several factors to explain these different results, including racial differences, length of follow-up, and different treatment protocols, which might have an important impact on the recurrence rate of thyroid cancer and survival [10]. Overall, RAI is a key component of postoperative treatment of thyroid cancer, which can destroy thyroid cancer tissue by producing high-energy b-rays, remove latent foci, remove postoperative residual thyroid tissue such as metastatic or unresectable lesions, and reduce recurrence of thyroid cancer and improve the OS.

However, focusing just on thyroid cancer CSM, we found that a larger proportion of patients who received RAI specifically died of their thyroid cancer compared to non-RAI individuals [1.7% (n = 1,051) vs. 1.0% (n = 725), p < 0.001]. This result was consistent with a previous SEER study that showed a negative CSM association in patients with T1a disease [29]. Du et al. showed that the mortality of thyroid cancer increased both in intermediate-term (1–10 years) and long-term (10 years) survivors after RAI, while the mortality reduced in short-term (≤ 1 year) survivors, which is possibly due to the association between radiation exposure and thyroid cancer in a dose-dependent manner [30]. We excluded SPM diagnosed within 12 months of the thyroid cancer diagnosis, which may be another important cause. In addition, patients in the RAI group with regional or distant stage had lower CSM compared to those in the non-RAI group, especially in patients with distant metastatic thyroid cancer. These results indicate that RAI treatment may improve thyroid CSM, it was consistent with previous studies [31, 32]. We found that the mortality rate after RAI treatment was higher than that of non-RAI in all subgroups except for regional and distant metastasis. We speculate that this may be because DTC patients treated with RAI were more inclined to be high risk and intermediate risk.

In addition to the above aspects of survival, previous studies have found that RAI treatment was associated with a higher risk of SPM [4, 33, 34], which is a clinical concern regarding risks of adverse effects from this treatment. Several studies showed that primary thyroid cancer survivors treated with RAI were at increased risk of developing SPMs than those who did not receive RAI [15, 23, 35, 36], and a linear correlation was found between the risk of SPM and the RAI. RAI under a standard activity of 3.7 GBq (100 mCi) will induce in excess of 53 solid cancers and 3 leukaemias every 10 years in 10,000 patients [17]. The 2015 ATA Management Guidelines indicated that the risk of SPM increased significantly when patients received high-dose cumulative activity greater than 600 mCi, suggesting a dose–effect relationship [5]. In Iran, 973 patients followed for a median of 6 (3–26) years did not show significantly increased overall rate of SPM after a 3-year interval from the first RAI treatment, but a cumulative dose of RAI more than 40 GBq (1.08 Ci) considerably increased the risk of SPM [37]. The risk of SPM may be radically increased in patients with high cumulative activities. In contrast, Berthe et al. suggested that the risk of second cancer was not related to RAI treatment [14]. One study utilizing SEER data reported that RAI treatment was not associated with an increased risk of SPM; it was not statistically significant on multivariable analysis between RAI and SPM [20].

It was found that the HR value was higher in female patients with DTC after treatment with RAI after adjusting for different covariates. The HR value increased with the year of diagnosis in the multivariable analysis. The reason for this finding might have been due to their lifestyle exposures, including frequent use of imaging modalities [e.g. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT or CT)] and cosmic radiation, and genetic predisposition. In addition, our results suggested that the incidence of SPM after treatment appeared to increase steadily with the age of DTC patients. Age was an important risk factor for SPM, and mean age of RAI patients was less than that of non-RAI patients (46.44 vs. 49.15). Thus, a recommendation of lifelong follow-up of DTC survivors could be made. We found that the adjusted HR of SEER stage was higher in patients with regional disease as compared to those with localized disease.

Our study suggested the following:

  • the most common SPM were colorectal (e.g. cecum and rectum), lung and bronchus, melanoma of the skin, breast, kidney, and renal pelvis both in RAI and non-RAI groups, which is in agreement with the results of other studies [4, 12, 14, 15, 38, 39];
  • DTC survivors treated with RAI in the female group had a significantly increased risk of developing SPM, which mainly included ovarian cancer and leukaemia, when comparing with cases without RAI therapy. Although the 2015 American Thyroid Association (ATA) Management Guidelines indicated an increased risk of leukaemia due to RAI treatment, the absolute increase in the risk of other malignancies was considered small. In this study, the number of developing SPM was largest in breast, prostate, melanoma of the skin, lung and bronchus, and colorectal cancers, which may be due to the use of RAI treatment and other factors such as genetic susceptibility of DTC patients, lifestyle, and environmental exposures that we did not include in analyses. In addition, this result was consistent with a previous report that suggested that female breast cancer was the most diagnosed cancer throughout the world, ranking first among all cancers, closely followed by lung, prostate, and colorectal cancer [2]. A previous study showed that lifestyle interventions after treatment, such as quitting smoking or regular exercise, may help to reduce the incidence of SPM [40].

We identified moderate evidence that the first primary thyroid cancer survivors were at increased risk of developing malignancies in the ovaries and haematopoietic system. This was consistent with a previous study that suggested that RAI was associated with increased risk of second cancer in the female reproductive system [14]. Sandeep et al. found that there was a 59% increased risk of developing ovarian cancer in comparison with the general population [18]. A previous study showed that acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) were complications of cytotoxic therapy [41]. Another study showed that the majority of patients with AML after treatment with RAI harboured high-risk cytogenetic abnormalities like therapy-related myeloid leukemia (t-AML)/treatment-related MDS arising after other cytotoxic anticancer treatments [42]. In most patients this occurred 3 to 10 years after radiation or chemotherapy and was associated with loss of chromosomes 5 or 7 and TP53 gene mutation, which increased the risk that cells would harbour leukaemia-causing genetic defects.

Our study has several limitations. The first and most important limitation is that our study is retrospective, intrinsic selection biases exist, and although the SEER database is updated once a year, there may be coding errors and incomplete variables. Second, the SEER database is unable to obtain details about the dose and duration of RAI therapy for DTC survivors; thus, we could not calculate the correlation between the dosage and the incidence of SPM. Third, the SEER database does not record certain information on the patient’s clinical characteristics, such as postoperative biochemical data (e.g. thyroglobulin, thyroid-stimulating hormone, and thyroxine levels) and whole-body scanning. Fourth, it is also important to adjust for other risk factors for various SPM, such as lifestyle-related factors (e.g. family history, obesity, smoking, alcohol, consumption of red meat or processed meat), but these factors are not recorded in the SEER database.

Conclusion

RAI treatment was a risk factor for SPM in female DTC patients, and there was significant increase in the risk of SPM in radiation-sensitive organs. Gender, age, disease stage, and RAI therapy may all play important roles as predictors for the development of SPM in DTC survivors. Therefore, we recommend regular cancer screening for female DTC survivors.

References

  1. Yang Z, Wei X, Pan Y, et al. A new risk factor indicator for papillary thyroid cancer based on immune infiltration. Cell Death Dis. 2021; 12(1): 51, doi: 10.1038/s41419-020-03294-z, indexed in Pubmed: 33414407.
  2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249, doi: 10.3322/caac.21660, indexed in Pubmed: 33538338.
  3. Toumi A, DiGennaro C, Vahdat V, et al. Trends in Thyroid Surgery and Guideline-Concordant Care in the United States, 2007-2018. Thyroid. 2021; 31(6): 941–949, doi: 10.1089/thy.2020.0643, indexed in Pubmed: 33280499.
  4. Uprety D, Khanal A, Arjyal L, et al. The risk of secondary primary malignancy in early stage differentiated thyroid cancer: a US population-based study. Acta Oncol. 2016; 55(11): 1375–1377, doi: 10.1080/0284186X.2016.1196829, indexed in Pubmed: 27579851.
  5. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016; 26(1): 1–133, doi: 10.1089/thy.2015.0020, indexed in Pubmed: 26462967.
  6. Sutton W, Canner JK, Segev DL, et al. Treatment Variation in Older Adults With Differentiated Thyroid Cancer. J Surg Res. 2020; 254: 154–164, doi: 10.1016/j.jss.2020.04.013, indexed in Pubmed: 32445931.
  7. Patel SS, Goldfarb M. Well-differentiated thyroid carcinoma: the role of post-operative radioactive iodine administration. J Surg Oncol. 2013; 107(6): 665–672, doi: 10.1002/jso.23295, indexed in Pubmed: 23192391.
  8. Wallner LP, Banerjee M, Reyes-Gastelum D, et al. Use of radioactive iodine for thyroid cancer. JAMA. 2011; 306(7): 721–728, doi: 10.1001/jama.2011.1139, indexed in Pubmed: 21846853.
  9. Li W, Xiao H, Xu X, et al. The Impact of Radiotherapy on the Incidence of Secondary Malignancies: A Pan-Cancer Study in the US SEER Cancer Registries. Curr Oncol. 2021; 28(1): 301–316, doi: 10.3390/curroncol28010035, indexed in Pubmed: 33435562.
  10. Wang X, Zhu J, Li Z, et al. The benefits of radioactive iodine ablation for patients with intermediate-risk papillary thyroid cancer. PLoS One. 2020; 15(6): e0234843, doi: 10.1371/journal.pone.0234843, indexed in Pubmed: 32542018.
  11. Morton LM, Onel K, Curtis RE, et al. The rising incidence of second cancers: patterns of occurrence and identification of risk factors for children and adults. Am Soc Clin Oncol Educ Book. 2014: e57–e67, doi: 10.14694/EdBook_AM.2014.34.e57, indexed in Pubmed: 24857148.
  12. Adly MH, Sobhy M, Rezk MA, et al. Risk of second malignancies among survivors of pediatric thyroid cancer. Int J Clin Oncol. 2018; 23(4): 625–633, doi: 10.1007/s10147-018-1256-9, indexed in Pubmed: 29492793.
  13. Dracham CB, Shankar A, Madan R. Radiation induced secondary malignancies: a review article. Radiat Oncol J. 2018; 36(2): 85–94, doi: 10.3857/roj.2018.00290, indexed in Pubmed: 29983028.
  14. Berthe E, Henry-Amar M, Michels JJ, et al. Risk of second primary cancer following differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2004; 31(5): 685–691, doi: 10.1007/s00259-003-1448-y, indexed in Pubmed: 14747959.
  15. Marti JL, Jain KS, Morris LGT. Increased risk of second primary malignancy in pediatric and young adult patients treated with radioactive iodine for differentiated thyroid cancer. Thyroid. 2015; 25(6): 681–687, doi: 10.1089/thy.2015.0067, indexed in Pubmed: 25851829.
  16. Reinecke MJ, Ahlers G, Burchert A, et al. Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma a critical review and evaluation of the existing evidence. Eur J Nucl Med Mol Imaging. 2022; 49(9): 3247–3256, doi: 10.1007/s00259-022-05762-4, indexed in Pubmed: 35320386.
  17. Rubino C, de Vathaire F, Dottorini ME, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer. 2003; 89(9): 1638–1644, doi: 10.1038/sj.bjc.6601319, indexed in Pubmed: 14583762.
  18. Sandeep TC, Strachan MWJ, Reynolds RM, et al. Second primary cancers in thyroid cancer patients: a multinational record linkage study. J Clin Endocrinol Metab. 2006; 91(5): 1819–1825, doi: 10.1210/jc.2005-2009, indexed in Pubmed: 16478820.
  19. Endo M, Liu JB, Dougan M, et al. Incidence of Second Malignancy in Patients with Papillary Thyroid Cancer from Surveillance, Epidemiology, and End Results 13 Dataset. J Thyroid Res. 2018; 2018: 8765369, doi: 10.1155/2018/8765369, indexed in Pubmed: 30046434.
  20. Bhattacharyya N, Chien W. Risk of second primary malignancy after radioactive iodine treatment for differentiated thyroid carcinoma. Ann Otol Rhinol Laryngol. 2006; 115(8): 607–610, doi: 10.1177/000348940611500806, indexed in Pubmed: 16944659.
  21. McDonald AM, Lindeman B, Bahl D. Radioactive Iodine: Recognizing the Need for Risk-Benefit Balance. J Clin Oncol. 2022; 40(13): 1396–1399, doi: 10.1200/JCO.22.00013, indexed in Pubmed: 35298297.
  22. Schonfeld SJ, Morton LM, Berrington de González A, et al. Risk of second primary papillary thyroid cancer among adult cancer survivors in the United States, 2000-2015. Cancer Epidemiol. 2020; 64: 101664, doi: 10.1016/j.canep.2019.101664, indexed in Pubmed: 31884334.
  23. Sawka AM, Thabane L, Parlea L, et al. Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis. Thyroid. 2009; 19(5): 451–457, doi: 10.1089/thy.2008.0392, indexed in Pubmed: 19281429.
  24. Cooper DS, Doherty GM, Haugen BR, et al. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009; 19(11): 1167–1214, doi: 10.1089/thy.2009.0110, indexed in Pubmed: 19860577.
  25. Zhang R, Xu M, Liu X, et al. Establishment and validation of a nomogram model for predicting the survival probability of differentiated thyroid carcinoma patients: a comparison with the eighth edition AJCC cancer staging system. Endocrine. 2021; 74(1): 108–119, doi: 10.1007/s12020-021-02717-x, indexed in Pubmed: 33822318.
  26. Ruel E, Thomas S, Dinan M, et al. Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab. 2015; 100(4): 1529–1536, doi: 10.1210/jc.2014-4332, indexed in Pubmed: 25642591.
  27. Creach KM, Siegel BA, Nussenbaum B, et al. Radioactive iodine therapy decreases recurrence in thyroid papillary microcarcinoma. ISRN Endocrinol. 2012; 2012: 816386, doi: 10.5402/2012/816386, indexed in Pubmed: 22462017.
  28. Lee J, Song Y, Soh EY. Prognostic significance of the number of metastatic lymph nodes to stratify the risk of recurrence. World J Surg. 2014; 38(4): 858–862, doi: 10.1007/s00268-013-2345-6, indexed in Pubmed: 24305921.
  29. Orosco RK, Hussain T, Noel JE, et al. Radioactive iodine in differentiated thyroid cancer: a national database perspective. Endocr Relat Cancer. 2019; 26(10): 795–802, doi: 10.1530/ERC-19-0292, indexed in Pubmed: 31443087.
  30. Du B, Wang F, Wu L, et al. Cause-specific mortality after diagnosis of thyroid cancer: a large population-based study. Endocrine. 2021; 72(1): 179–189, doi: 10.1007/s12020-020-02445-8, indexed in Pubmed: 32770440.
  31. Elsamna ST, Suri P, Mir GS, et al. The Benefit of Primary Tumor Surgical Resection in Distant Metastatic Carcinomas of the Thyroid. Laryngoscope. 2021; 131(5): 1026–1034, doi: 10.1002/lary.29053, indexed in Pubmed: 32865854.
  32. Goffredo P, Sosa JA, Roman SA. Differentiated thyroid cancer presenting with distant metastases: a population analysis over two decades. World J Surg. 2013; 37(7): 1599–1605, doi: 10.1007/s00268-013-2006-9, indexed in Pubmed: 23525600.
  33. Kim C, Bi X, Pan D, et al. The risk of second cancers after diagnosis of primary thyroid cancer is elevated in thyroid microcarcinomas. Thyroid. 2013; 23(5): 575–582, doi: 10.1089/thy.2011.0406, indexed in Pubmed: 23237308.
  34. Pasqual E, Schonfeld S, Morton LM, et al. Association between radioactive iodine treatment for pediatric and young adulthood differentiated thyroid cancer and risk of second primary malignancies. J Clin Oncol. 2022; 40(13): 1439–1444, doi: 10.1200/JCO.21.01841, indexed in Pubmed: 35044839.
  35. Iyer NG, Morris LGT, Tuttle RM, et al. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 2011; 117(19): 4439–4446, doi: 10.1002/cncr.26070, indexed in Pubmed: 21432843.
  36. Lang BHH, Lo CY, Wong IO, et al. Impact of second primary malignancy on outcomes of differentiated thyroid carcinoma. Surgery. 2010; 148(6): 1191–6; discussion 1196, doi: 10.1016/j.surg.2010.09.022, indexed in Pubmed: 21134551.
  37. Fallahi B, Adabi K, Majidi M, et al. Incidence of second primary malignancies during a long-term surveillance of patients with differentiated thyroid carcinoma in relation to radioiodine treatment. Clin Nucl Med. 2011; 36(4): 277–282, doi: 10.1097/RLU.0b013e31820a9fe3, indexed in Pubmed: 21368600.
  38. Molenaar RJ, Sidana S, Radivoyevitch T, et al. Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer. J Clin Oncol. 2018; 36(18): 1831–1839, doi: 10.1200/JCO.2017.75.0232, indexed in Pubmed: 29252123.
  39. Joseph KR, Edirimanne S, Eslick GD. The association between breast cancer and thyroid cancer: a meta-analysis. Breast Cancer Res Treat. 2015; 152(1): 173–181, doi: 10.1007/s10549-015-3456-6, indexed in Pubmed: 26058757.
  40. Travis LB, Demark Wahnefried W, Allan JM, et al. Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol. 2013; 10(5): 289–301, doi: 10.1038/nrclinonc.2013.41, indexed in Pubmed: 23529000.
  41. Knight JA, Skol AD, Shinde A, et al. Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility. Blood. 2009; 113(22): 5575–5582, doi: 10.1182/blood-2008-10-183244, indexed in Pubmed: 19299336.
  42. Schroeder T, Kuendgen A, Kayser S, et al. Therapy-related myeloid neoplasms following treatment with radioiodine. Haematologica. 2012; 97(2): 206–212, doi: 10.3324/haematol.2011.049114, indexed in Pubmed: 21993688.