Weighing the pros and cons of treatment is a constant topic in the clinic, especially in today's era of precision medicine and personalized treatment.
In the past 10 years, with the deepening of understanding of the disease, the treatment concept of some thyroid cancers with a lower degree of malignancy, such as differentiated thyroid cancer (DTC), has shifted from radical to mild, which includes not only a reduction in the scope of surgical resection, but also a change in the population adapted to radioactive iodine therapy (RAI) [1].
At present, there is a consensus that patients with differentiated thyroid cancer with monofocal microcarcinoma (≤10 mm in diameter) do not need radioactive iodine therapy [2]. For other patients with low-risk differentiated thyroid cancer, the latest clinical studies have shown that patients who do not receive RAI have a better long-term prognosis than those who receive RAI [3]. In these patients, RAI not only does not improve prognosis, but may pose an additional risk of hematologic tumors such as leukemia [4]. However, the effect of RAI on the risk of a second primary malignancy (SPM) in solid entities remains inconclusive [5].
Recently, a team of Professor Cari M. Kitahara from the National Cancer Institute assessed the risk of solid SPM in differentiated thyroid cancer patients who received RAI before the age of 45 by using the SEER database.
The results of the study showed that RAI treatment was associated with a 23% increased risk of solid SPM, and the younger the age, the greater the risk of solid SPM in the future, and the results of the relevant research were published in the Journal of Clinical Oncology (JCO)[6].
Screenshot of the first page of the article
Since the 1940s, RAI has become one of the main treatments for thyroid cancer due to its high tissue specificity, improving the prognosis of thyroid cancer patients [7].
Patients tolerate RAI better than conventional radiation therapy, but in the long run many patients suffer from complications such as salivary gland dysfunction, conjunctivitis, and infertility [8], and the risk of secondary malignancy after radiation exposure is particularly worrying, especially in younger patients. Therefore, exploring the risk of RAI secondary malignancy in young differentiated thyroid cancer populations will help weigh the pros and cons of RAI treatment.
Professor Cari M. Kitahara's team included in the SEER database, patients diagnosed with differentiated thyroid cancer (papillary or follicular carcinoma) in the United States between 1975 and 2017 before the age of 45, and excluded cases of distant metastases at the time of diagnosis, assessing the risk of developing solid SPM 5 years after the diagnosis of differentiated thyroid cancer.
A total of 36,311 young patients with non-metastatic differentiated thyroid cancer were included in the study, of whom 81% were women and 45% were treated with RAI. The use of RAI in male patients (50%) was higher than in female patients (44%), and more than half (55%) of patients under 15 years of age received RAI treatment.
Overall, the use of RAI increased from 9% to 55% between 1975 and 2009, then gradually declined, falling to 39% in 2017. In patients with tumor < 1 cm and ≥ 1 cm, the use of RAI showed the same trend of change.
Changes in RAI use in patients with differentiated thyroid cancer between 1975 and 2017
The researchers primarily analyzed the risk of solid SPM in patients 5 years after the diagnosis of differentiated thyroid cancer (27,050 people with separable data). The results showed that during the follow-up period (median follow-up time of 15.6 years), 1524 people suffered from real SPM, and RAI treatment was associated with an increased risk of solid SPM (RR= 1.23, 95% CI: 1.11-1.37).
The cumulative incidence of solid SPM in patients receiving RAI and not receiving RAI was 5.6% (95% CI, 5.0-6.0) and 5.0% (95% CI: 4.6-5.4), respectively, 20 years after the diagnosis of differentiated thyroid cancer. This difference increased with the length of follow-up, with cumulative incidences of solid SPM in patients receiving RAI and patients not treated with RAI 12.5% (95% CI, 11.3 to 13.8) and 10.2% (95% CI, 9.5 to 11.0) in patients receiving RAI and not receiving RAI treatment, respectively, 30 years after diagnosis.
In organs with high radiation exposure (≥0.5 Gy), the risk of RAI treatment associated with salivary adenocarcinoma (RR 2.15, 95% CI: 0.91-5.08), gastric cancer (RR 1.61, 95% CI: 0.70-3.69), and kidney cancer (RR 1.34, 95% CI: 1.14-2.09) was higher.
For organs with relatively low radiation exposure (
Relationship between RAI treatment and solid SPM risk
Younger patients had a higher RR of solid SPM compared to older patients (P=0.07). The RR was 1.60 (95% CI, 1.07-2.40) for patients before the age of 25 years, compared with 1.16 (95% CI, 1.02-1.33) for patients aged 35 to 45 years. As the follow-up time after the diagnosis of differentiated thyroid cancer increased, the RR of the affected solid SPM increased (P=0.07).
Stratification of solid SPM risk in patients with differentiated thyroid cancer
Professor Cari M. Kitahara's team also analyzed the effect of RAI treatment on the risk of hematologic tumors in patients with differentiated thyroid cancer. Two years after being diagnosed with differentiated thyroid cancer, 146 people were diagnosed with hematologic SPM during follow-up (median follow-up time of 13 years).
RAI therapy increased the risk of leukemia (RR 1.92, 95% CI: 1.04 to 3.56), particularly non-lymphocytic leukemia (RR = 2.17, 95% CI: 1.03 to 4.55). The risk of Hodgkin or non-Hodgkin lymphoma was not increased by RAI treatment.
Relationship between RAI treatment and hematologic SPM risk
Although the study had limitations, such as not considering the interaction between RAI therapy and cancer risk factors such as smoking and obesity, and not including patients with differentiated thyroid cancer over the age of 45, it showed that RAI treatment would carry higher solid SPM-related risks, particularly in china
The result of the study is that doctors are weighing whether to give RAI treatment to patients with differentiated thyroid cancer an important reference basis, on the basis of correctly identifying patients who are most likely to benefit from RAI treatment, they also need to consider the adverse effects of the treatment on patients, and make medical decisions after comprehensive analysis, which is the real precision medicine and personalized treatment.
Thinking of the previous "New England Journal of Medicine" that RAI treatment has not improved the prognosis outcome of low-risk differentiated thyroid cancer patients, coupled with the fact that RAI will increase the risk of SPM in patients, I think the answer has been called out, RAI treatment will gradually no longer be the main treatment for low-risk differentiated thyroid cancer patients, and the indications for RAI treatment will be further strictly controlled.
bibliography
1.Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M 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.
2.Verburg FA, Flux G, Giovanella L, van Nostrand D, Muylle K, Luster M: Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade. Eur J Nucl Med Mol Imaging 2020, 47(1):78-83.
3.Leboulleux S, Bournaud C, Chougnet CN, Zerdoud S, Al Ghuzlan A, Catargi B, Do Cao C, Kelly A, Barge ML, Lacroix L et al: Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer. N Engl J Med 2022, 386(10):923-932.
4.Molenaar RJ, Sidana S, Radivoyevitch T, Advani AS, Gerds AT, Carraway HE, Angelini D, Kalaycio M, Nazha A, Adelstein DJ et al: Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer. J Clin Oncol 2018, 36(18):1831-1839.
5.Yu CY, Saeed O, Goldberg AS, Farooq S, Fazelzad R, Goldstein DP, Tsang RW, Brierley JD, Ezzat S, Thabane L et al: A Systematic Review and Meta-Analysis of Subsequent Malignant Neoplasm Risk After Radioactive Iodine Treatment of Thyroid Cancer. Thyroid 2018, 28(12):1662-1673.
6.Pasqual E, Schonfeld S, Morton LM, Villoing D, Lee C, Berrington de Gonzalez A, Kitahara CM: Association Between Radioactive Iodine Treatment for Pediatric and Young Adulthood Differentiated Thyroid Cancer and Risk of Second Primary Malignancies. J Clin Oncol 2022:JCO2101841.
7.Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM: Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. JAMA 2017, 317(13):1338-1348.
8.Piek MW, Postma EL, van Leeuwaarde R, de Boer JP, Bos AME, Lok C, Stokkel M, Filipe MD, van der Ploeg IMC: The Effect of Radioactive Iodine Therapy on Ovarian Function and Fertility in Female Thyroid Cancer Patients: A Systematic Review and Meta-Analysis. Thyroid 2021, 31(4):658-668.
Responsible editor 丨IoTalker