Int J Thyroidol.  2023 May;16(1):101-110. 10.11106/ijt.2023.16.1.101.

Second Primary Malignancy after Radioiodine Treatment of Thyroid Disease: Current Status

• Lee J
• Hong CM
• Ha JH

• KMID: 2543014
• DOI: http://doi.org/10.11106/ijt.2023.16.1.101

Abstract

Radioiodine has been effectively applied for the management of hyperthyroidism and differentiated thyroid cancers in most countries of the world. The majority of thyroid cancers are differentiated thyroid cancer that has an overall excellent prognosis, which attributed to appropriate treatment of the disease including administration of radioiodine, I-131. I-131 therapy has usually been undertaken for the ablation of remnant tissue or adjuvant treatment after surgical resection of the thyroid. I-131 therapy was routinely recommended for patients with high-risk disease, and should be considered for intermediate-risk disease as an adjuvant purpose. Several latest studies refute worries of increase cancer risk with I-131 treatment for thyroid cancer. Thus, recent ATA guidelines have shifted toward a more individual and stratified approach, because of benign nature of the differentiated thyroid cancer as well as awareness of side effects including potential increasing incidence of second primary malignancy after I-131 treatment. While some retrospective studies also pointed out that potential increases in cancer development after I-131 treatment for hyperthyroidism recently. Treatment decisions regarding the use of radioiodine therapy should consider the balance of risks and benefits for individual patients with low risk differentiated thyroid cancer and hyperthyroidism, if it is true. Thus, we will review current understanding for the association of increased secondary malignancy and I-131 treatment of thyroid diseases.

Keyword

Radioiodine; Differentiated thyroid cancer; Hyperthyroidism; Secondary primary malignancy

Reference

References

1. Hong JY, Han K, Jung JH, Kim JS. 2019; Association of exposure to diagnostic low-dose ionizing radiation with risk of cancer among youths in South Korea. JAMA Netw Open. 2(9):e1910584. DOI: 10.1001/jamanetworkopen.2019.10584. PMID: 31483470. PMCID: PMC6727680.

2. Guiu-Souto J, Neira-Castro S, Sanchez-Garcia M, Lopez Pouso O, Pombar-Camean M, Pardo-Montero J. 2018; Adaptive biokinetic modelling of iodine-131 in thyroid cancer treatments: implications on individualised internal dosimetry. J Radiol Prot. 38(4):1501–11. DOI: 10.1088/1361-6498/aae44e. PMID: 30255851.

3. Kolbert KS, Pentlow KS, Pearson JR, Sheikh A, Finn RD, Humm JL, et al. 2007; Prediction of absorbed dose to normal organs in thyroid cancer patients treated with 131I by use of 124I PET and 3-dimensional internal dosimetry software. J Nucl Med. 48(1):143–9.

4. Clement SC, Peeters RP, Ronckers CM, Links TP, van den Heuvel-Eibrink MM, Nieveen van Dijkum EJ, et al. 2015; Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review. Cancer Treat Rev. 41(10):925–34. DOI: 10.1016/j.ctrv.2015.09.001. PMID: 26421813.

5. Silva-Vieira M, Carrilho Vaz S, Esteves S, Ferreira TC, Limbert E, Salgado L, et al. 2017; Second primary cancer in patients with differentiated thyroid cancer: does radioiodine play a role? Thyroid. 27(8):1068–76. DOI: 10.1089/thy.2016.0655. PMID: 28614983.

6. Brown AP, Chen J, Hitchcock YJ, Szabo A, Shrieve DC, Tward JD. 2008; The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 93(2):504–15. DOI: 10.1210/jc.2007-1154. PMID: 18029468.

7. Hirsch D, Shohat T, Gorshtein A, Robenshtok E, Shimon I, Benbassat C. 2016; Incidence of nonthyroidal primary malignancy and the association with (131)I treatment in patients with differentiated thyroid cancer. Thyroid. 26(8):1110–6. DOI: 10.1089/thy.2016.0037. PMID: 27302111.

8. Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, et al. 2003; Second primary malignancies in thyroid cancer patients. Br J Cancer. 89(9):1638–44. DOI: 10.1038/sj.bjc.6601319. PMID: 14583762. PMCID: PMC2394426.

9. Sawka AM, Thabane L, Parlea L, Ibrahim-Zada I, Tsang RW, Brierley JD, et al. 2009; Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis. Thyroid. 19(5):451–7. DOI: 10.1089/thy.2008.0392. PMID: 19281429.

10. Hakala TT, Sand JA, Jukkola A, Huhtala HS, Metso S, Kellokumpu-Lehtinen PL. 2016; Increased risk of certain second primary malignancies in patients treated for well-differentiated thyroid cancer. Int J Clin Oncol. 21(2):231–9. DOI: 10.1007/s10147-015-0904-6. PMID: 26410770.

11. Khang AR, Cho SW, Choi HS, Ahn HY, Yoo WS, Kim KW, et al. 2015; The risk of second primary malignancy is increased in differentiated thyroid cancer patients with a cumulative (131)I dose over 37 GBq. Clin Endocrinol (Oxf). 83(1):117–23. DOI: 10.1111/cen.12581. PMID: 25115234.

12. Teng CJ, Hu YW, Chen SC, Yeh CM, Chiang HL, Chen TJ, et al. 2016; Use of radioactive iodine for thyroid cancer and risk of second primary malignancy: a nationwide population-based study. J Natl Cancer Inst. 108(2):djv314. DOI: 10.1093/jnci/djv314. PMID: 26538627.

13. Yu CY, Saeed O, Goldberg AS, Farooq S, Fazelzad R, Goldstein DP, et al. 2018; A systematic review and meta-analysis of subsequent malignant neoplasm risk after radioactive iodine treatment of thyroid cancer. Thyroid. 28(12):1662–73. DOI: 10.1089/thy.2018.0244. PMID: 30370820.

14. Pasqual E, Schonfeld S, Morton LM, Villoing D, Lee C, Berrington de Gonzalez A, et al. 2022; Association between radioactive iodine treatment for pediatric and young adulthood differentiated thyroid cancer and risk of second primary malignancies. J Clin Oncol. 40(13):1439–49. DOI: 10.1200/JCO.21.01841. PMID: 35044839. PMCID: PMC9061144.

15. Molenaar RJ, Sidana S, Radivoyevitch T, Advani AS, Gerds AT, Carraway HE, et al. 2018; Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol. 36(18):1831–9. DOI: 10.1200/JCO.2017.75.0232. PMID: 29252123. PMCID: PMC8462524.

16. Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen P. 2007; Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer. 109(10):1972–9. DOI: 10.1002/cncr.22635. PMID: 17393376.

17. Kitahara CM, Berrington de Gonzalez A, Bouville A, Brill AB, Doody MM, Melo DR, et al. 2019; Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. JAMA Intern Med. 179(8):1034–42. DOI: 10.1001/jamainternmed.2019.0981. PMID: 31260066. PMCID: PMC6604114.

18. Gronich N, Lavi I, Rennert G, Saliba W. 2020; Cancer risk after radioactive iodine treatment for hyperthyroidism: a cohort study. Thyroid. 30(2):243–50. DOI: 10.1089/thy.2019.0205. PMID: 31880205.

19. Shim SR, Kitahara CM, Cha ES, Kim SJ, Bang YJ, Lee WJ. 2021; Cancer risk after radioactive iodine treatment for hyperthyroidism: a systematic review and meta-analysis. JAMA Netw Open. 4(9):e2125072. DOI: 10.1001/jamanetworkopen.2021.25072. PMID: 34533571. PMCID: PMC8449277.

20. Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, et al. 2007; Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res. 168(1):1–64. DOI: 10.1667/RR0763.1. PMID: 17722996.

21. Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, et al. 1994; Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res. 137(2 Suppl):S68–97. DOI: 10.2307/3578893.

22. Furukawa K, Preston D, Funamoto S, Yonehara S, Ito M, Tokuoka S, et al. 2013; Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure. Int J Cancer. 132(5):1222–6. DOI: 10.1002/ijc.27749. PMID: 22847218. PMCID: PMC3910094.

23. Grant EJ, Brenner A, Sugiyama H, Sakata R, Sadakane A, Utada M, et al. 2017; Solid cancer incidence among the life span study of atomic bomb survivors: 1958-2009. Radiat Res. 187(5):513–37. DOI: 10.1667/RR14492.1. PMID: 28319463.

24. Muirhead CR, O'Hagan JA, Haylock RG, Phillipson MA, Willcock T, Berridge GL, et al. 2009; Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers. Br J Cancer. 100(1):206–12. DOI: 10.1038/sj.bjc.6604825. PMID: 19127272. PMCID: PMC2634664.

25. Radivoyevitch T, Sachs RK, Gale RP, Molenaar RJ, Brenner DJ, Hill BT, et al. 2016; Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation. Leukemia. 30(2):285–94. DOI: 10.1038/leu.2015.258. PMID: 26460209.

26. Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, Oyen WJ, et al. 2008; Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 35(10):1941–59. DOI: 10.1007/s00259-008-0883-1. PMID: 18670773.

27. Pacini F, Fuhrer D, Elisei R, Handkiewicz-Junak D, Leboulleux S, Luster M, et al. 2022; 2022 ETA Consensus Statement: what are the indications for post-surgical radioiodine therapy in differentiated thyroid cancer? Eur Thyroid J. 11(1):e210046. DOI: 10.1530/ETJ-21-0046. PMID: 34981741. PMCID: PMC9142814.

28. Tuttle RM, Ahuja S, Avram AM, Bernet VJ, Bourguet P, Daniels GH, et al. 2019; Controversies, consensus, and collaboration in the use of (131)I therapy in differentiated thyroid cancer: a joint statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid. 29(4):461–70. DOI: 10.1089/thy.2018.0597. PMID: 30900516.

29. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2016; 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. 26(1):1–133. DOI: 10.1089/thy.2015.0020. PMID: 26462967. PMCID: PMC4739132.

30. Luster M, Aktolun C, Amendoeira I, Barczynski M, Bible KC, Duntas LH, et al. 2019; European perspective on 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: proceedings of an Interactive International Symposium. Thyroid. 29(1):7–26. DOI: 10.1089/thy.2017.0129. PMID: 30484394.

31. James DL, Ryan EJ, Davey MG, Quinn AJ, Heath DP, Garry SJ, et al. 2021; Radioiodine remnant ablation for differentiated thyroid cancer: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 147(6):544–52. DOI: 10.1001/jamaoto.2021.0288. PMID: 33792650. PMCID: PMC8017484.

32. Hong CM, Shin JY, Kim BI, Song HC, Yoon JK, Won KS, et al. 2022; Incidence rate and factors associated with the development of secondary cancers after radioiodine therapy in differentiated thyroid cancer: a multicenter retrospective study. Eur J Nucl Med Mol Imaging. 49(5):1661–70. DOI: 10.1007/s00259-021-05608-5. PMID: 34773164.

33. Ruel E, Thomas S, Dinan M, Perkins JM, Roman SA, Sosa JA. 2015; Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab. 100(4):1529–36. DOI: 10.1210/jc.2014-4332. PMID: 25642591. PMCID: PMC4399282.

34. Hawkins M, Bhatia S, Henderson TO, Nathan PC, Yan A, Teepen JC, et al. 2020; Subsequent primary neoplasms: risks, risk factors, surveillance, and future research. Pediatr Clin North Am. 67(6):1135–54. DOI: 10.1016/j.pcl.2020.07.006. PMID: 33131538.

35. Mei X, Yao X, Feng F, Cheng W, Wang H. 2021; Risk and outcome of subsequent malignancies after radioactive iodine treatment in differentiated thyroid cancer patients. BMC Cancer. 21(1):543. DOI: 10.1186/s12885-021-08292-8. PMID: 33980182. PMCID: PMC8117631.

36. Reinecke MJ, Ahlers G, Burchert A, Eilsberger F, Flux GD, Marlowe RJ, et al. 2022; 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. 49(9):3247–56. DOI: 10.1007/s00259-022-05762-4. PMID: 35320386. PMCID: PMC9250458.

37. Seo GH, Cho YY, Chung JH, Kim SW. 2015; Increased risk of leukemia after radioactive iodine therapy in patients with thyroid cancer: a nationwide, population-based study in Korea. Thyroid. 25(8):927–34. DOI: 10.1089/thy.2014.0557. PMID: 26133388.

38. Kitahara CM, Preston DL, Sosa JA, Berrington de Gonzalez A. 2020; Association of radioactive iodine, antithyroid drug, and surgical treatments with solid cancer mortality in patients with hyperthyroidism. JAMA Netw Open. 3(7):e209660. DOI: 10.1001/jamanetworkopen.2020.9660. PMID: 32701159. PMCID: PMC7378755.

39. Cho YY, Lim J, Oh CM, Ryu J, Jung KW, Chung JH, et al. 2015; Elevated risks of subsequent primary malignancies in patients with thyroid cancer: a nationwide, population-based study in Korea. Cancer. 121(2):259–68. DOI: 10.1002/cncr.29025. PMID: 25223713.

40. Ahn HY, Min HS, Yeo Y, Ma SH, Hwang Y, An JH, et al. 2015; Radioactive iodine therapy did not significantly increase the incidence and recurrence of subsequent breast cancer. J Clin Endocrinol Metab. 100(9):3486–93. DOI: 10.1210/JC.2014-2896. PMID: 26147607.

41. Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. 2011; Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 117(19):4439–46. DOI: 10.1002/cncr.26070. PMID: 21432843. PMCID: PMC3155861.

42. Kim C, Bi X, Pan D, Chen Y, Carling T, Ma S, et al. 2013; The risk of second cancers after diagnosis of primary thyroid cancer is elevated in thyroid microcarcinomas. Thyroid. 23(5):575–82. DOI: 10.1089/thy.2011.0406. PMID: 23237308. PMCID: PMC3643257.

43. Ko KY, Kao CH, Lin CL, Huang WS, Yen RF. 2015; (131)I treatment for thyroid cancer and the risk of developing salivary and lacrimal gland dysfunction and a second primary malignancy: a nationwide population-based cohort study. Eur J Nucl Med Mol Imaging. 42(8):1172–8. DOI: 10.1007/s00259-015-3055-0. PMID: 25900274.

44. Fallahi B, Adabi K, Majidi M, Fard-Esfahani A, Heshmat R, Larijani B, et al. 2011; Incidence of second primary malignancies during a long-term surveillance of patients with differentiated thyroid carcinoma in relation to radioiodine treatment. Clin Nucl Med. 36(4):277–82. DOI: 10.1097/RLU.0b013e31820a9fe3. PMID: 21368600.

45. Lang BH, Wong IO, Wong KP, Cowling BJ, Wan KY. 2012; Risk of second primary malignancy in differentiated thyroid carcinoma treated with radioactive iodine therapy. Surgery. 151(6):844–50. DOI: 10.1016/j.surg.2011.12.019. PMID: 22341041.

46. Molenaar RJ, Pleyer C, Radivoyevitch T, Sidana S, Godley A, Advani AS, et al. 2018; Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia. 32(4):952–9. DOI: 10.1038/leu.2017.323. PMID: 29104287.

47. Tulchinsky M, Baum RP, Bennet KG, Freeman LM, Jong I, Kairemo K, et al. 2018; Well-founded recommendations for radioactive iodine treatment of differentiated thyroid cancer require balanced study of benefits and harms. J Clin Oncol. 36(18):1887–8. DOI: 10.1200/JCO.2018.78.5972. PMID: 29723091.

48. Verburg FA, Giovanella L, Iakovou I, Konijnenberg MW, Langsteger W, Lassmann M, et al. 2018; I-131 as adjuvant treatment for differentiated thyroid carcinoma may cause an increase in the incidence of secondary haematological malignancies: an "inconvenient" truth? Eur J Nucl Med Mol Imaging. 45(13):2247–9. DOI: 10.1007/s00259-018-4184-z. PMID: 30298378.

49. Sadetzki S, Mandelzweig L. 2009; Childhood exposure to external ionising radiation and solid cancer risk. Br J Cancer. 100(7):1021–5. DOI: 10.1038/sj.bjc.6604994. PMID: 19337255. PMCID: PMC2669984.

50. Seo GH, Kong KA, Kim BS, Kang SY, Moon BS, Yoon HJ, et al. 2021; Radioactive iodine treatment for children and young adults with thyroid cancer in South Korea: a population-based study. J Clin Endocrinol Metab. 106(7):e2580–e8. DOI: 10.1210/clinem/dgab192. PMID: 33755732.

51. Kim S, Bang JI, Boo D, Kim B, Choi IY, Ko S, et al. 2022; Second primary malignancy risk in thyroid cancer and matched patients with and without radioiodine therapy analysis from the observational health data sciences and informatics. Eur J Nucl Med Mol Imaging. 49(10):3547–56. DOI: 10.1007/s00259-022-05779-9. PMID: 35362796.

52. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. 2012; Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 44(11):1179–81. DOI: 10.1038/ng.2413. PMID: 23001125. PMCID: PMC3483435.

53. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. 2014; Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 371(26):2477–87. DOI: 10.1056/NEJMoa1409405. PMID: 25426838. PMCID: PMC4290021.

54. Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. 2017; Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 35(14):1598–605. DOI: 10.1200/JCO.2016.71.6712. PMID: 28068180. PMCID: PMC5455707.

55. Gulec SA, Ahuja S, Avram AM, Bernet VJ, Bourguet P, Draganescu C, et al. 2021; A joint statement from the American Thyroid Association, the European Association of Nuclear Medicine, the European Thyroid Association, the Society of Nuclear Medicine and Molecular Imaging on current diagnostic and theranostic approaches in the management of thyroid cancer. Thyroid. 31(7):1009–19. DOI: 10.1089/thy.2020.0826. PMID: 33789450.

56. Lassmann M, Hanscheid H, Chiesa C, Hindorf C, Flux G, Luster M, et al. 2008; EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 35(7):1405–12. DOI: 10.1007/s00259-008-0761-x. PMID: 18491092.

57. Stokke C, Gabina PM, Solny P, Cicone F, Sandstrom M, Gleisner KS, et al. 2017; Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force. EJNMMI Phys. 4(1):27. DOI: 10.1186/s40658-017-0194-3. PMID: 29164483. PMCID: PMC5698234.

58. Yang Z, Flores J, Katz S, Nathan CA, Mehta V. 2017; Comparison of survival outcomes following postsurgical radioactive iodine versus external beam radiation in stage IV differentiated thyroid carcinoma. Thyroid. 27(7):944–52. DOI: 10.1089/thy.2016.0650. PMID: 28446057.

59. Goldman MB, Maloof F, Monson RR, Aschengrau A, Cooper DS, Ridgway EC. 1988; Radioactive iodine therapy and breast cancer. a follow-up study of hyperthyroid women. Am J Epidemiol. 127(5):969–80. DOI: 10.1093/oxfordjournals.aje.a114900. PMID: 3358416.

60. Holm LE, Hall P, Wiklund K, Lundell G, Berg G, Bjelkengren G, et al. 1991; Cancer risk after iodine-131 therapy for hyperthyroidism. J Natl Cancer Inst. 83(15):1072–7. DOI: 10.1093/jnci/83.15.1072. PMID: 1875414.

61. Saenger EL, Thoma GE, Tompkins EA. 1968; Incidence of leukemia following treatment of hyperthyroidism. Preliminary report of the cooperative thyrotoxicosis therapy follow-up study. JAMA. 205(12):855–62. DOI: 10.1001/jama.1968.03140380059014. PMID: 5695509.

62. Dobyns BM, Sheline GE, Workman JB, Tompkins EA, McConahey WM, Becker DV. 1974; Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: a report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab. 38(6):976–98. DOI: 10.1210/jcem-38-6-976. PMID: 4134013.

63. Ron E, Doody MM, Becker DV, Brill AB, Curtis RE, Goldman MB, et al. 1998; Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group. JAMA. 280(4):347–55. DOI: 10.1001/jama.280.4.347. PMID: 9686552.

64. Taylor PN, Okosieme OE, Chatterjee K, Boelaert K. Executive Committees of the Society for Endocrinology and the British Thyroid Association. 2020; Joint statement from the Society for Endocrinology and the British Thyroid Association regarding 'Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism'. Clin Endocrinol (Oxf). 92(3):266–7. DOI: 10.1111/cen.14136. PMID: 31788839.

65. Anderson C, Mayer DK, Nichols HB. 2021; Trends in the proportion of second or later primaries among all newly diagnosed malignant cancers. Cancer. 127(15):2736–42. DOI: 10.1002/cncr.33558. PMID: 33823564.

66. Shimada K, Kai M. 2021; Lifetime risk assessment of lung cancer incidence for nonsmokers in Japan considering the joint effect of radiation and smoking based on the life span study of atomic bomb survivors. J Radiat Prot Res. 46(3):83–97. DOI: 10.14407/jrpr.2020.00255.