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Original Investigation
April 16, 2020

Association of Patient Age With Progression of Low-risk Papillary Thyroid Carcinoma Under Active Surveillance: A Systematic Review and Meta-analysis

Author Affiliations
  • 1University of Toronto Endocrinology Fellowship, Toronto, Ontario, Canada
  • 2University Health Network Library and Information Services, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 3Department of Endocrine Surgery, Nippon Medical School, Tokyo, Japan
  • 4Division of Head and Neck, Cancer Institute Hospital of Japanese Foundation of Cancer Research, Tokyo, Japan
  • 5Department of Surgery, Kuma Hospital, Kobe, Japan
  • 6Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
  • 7Department of Otolaryngology, Head and Neck Surgery, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • 8Joint Department of Medical Imaging, University Health Network–Mount Sinai Hospital–Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada
  • 9Division of Endocrinology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada
JAMA Otolaryngol Head Neck Surg. 2020;146(6):552-560. doi:10.1001/jamaoto.2020.0368
Key Points

Question  Is age associated with the risk of tumor progression (ie, tumor enlargement or incident metastatic disease) in individuals with small, low-risk papillary thyroid carcinoma under active surveillance?

Findings  In this systematic review and meta-analysis including data from 5 studies, the risk ratio for tumor growth of 3 mm or more in maximal diameter was reduced by about half in individuals aged 40 to 50 years or older compared with younger individuals. The risk of incident metastatic disease was low at all ages.

Meaning  Advancing age may be associated with reduced risk of papillary thyroid tumor enlargement under active surveillance.

Abstract

Importance  Active surveillance is sometimes considered as a disease management option for individuals with small, low-risk papillary thyroid carcinoma.

Objective  To assess whether patient age is associated with progression of low-risk papillary thyroid carcinoma (tumor growth or incident metastatic disease) in adults under active surveillance.

Evidence Review  Eight electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Emcare, PsycINFO, Web of Science, and ClincalTrials.gov) were searched from inception to March 2019, supplemented with a hand search. Two investigators independently screened citations, reviewed full-text articles, and abstracted data. Additional data were sought from authors. Random-effects meta-analyses were performed using incidence data (statistically adjusted for confounders and crude rates).

Findings  A total of 1658 unique citations were screened, and 62 full-text articles were reviewed, including 5 studies. Three studies included exclusively microcarcinomas and 2 included tumors up to 2 cm in maximal diameter. The mean age of participants was 51.0 to 55.2 years in 4 studies reporting this value. The mean or median follow-up was 5 years or more in 3 studies and approximately 2 years in 2 studies. The pooled risk ratio for tumor growth of 3 mm or more in maximal diameter in individuals aged 40 to 50 years or older compared with younger individuals was 0.51 when adjusted for confounders (95% CI, 0.29-0.89; 1619 patients, 2 studies), and the unadjusted risk ratio of this outcome for individuals 40 years or older was 0.55 (95% CI, 0.36-0.82; 2097 patients, 4 studies). In adults aged 40 to 45 years or older, the unadjusted risk ratio for any tumor volume increase compared with younger individuals was 0.65 (95% CI, 0.51-0.83; 1232 patients, 4 studies). The pooled risk ratio for incident nodal metastases in individuals 40 years or older was 0.22 (95% CI, 0.10-0.47; 1806 patients, 3 studies); however, in a secondary analysis, the risk difference was not significantly different. There was no statistically significant heterogeneity in any of the meta-analyses. There were no thyroid cancer–related deaths nor incident distant metastases.

Conclusions and Relevance  This study suggests that older age may be associated with a reduced risk of primary papillary thyroid carcinoma tumor growth under active surveillance. Incident metastatic disease is uncommon during active surveillance.

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    1 Comment for this article
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    commentary:Association of Patient Age With Progression of Low-risk Papillary Thyroid Carcinoma Under Active Surveillance
    jingming zhang, MD | Department of oncology, Zhengzhou University First Affliated Hospital, Zhengzhou, Henan, China
    To the editor:
    We deeply read with a recent article by Anna M et al about the association of patient age with progression of papillary thyroid carcinoma[1]. Through meta-analysis of 5 published studies, the authors found older age may be associated with a reduced risk of primary papillary thyroid carcinoma tumor growth under active surveillance. However, there are some critical issues remain to be explored.

    Firstly, this article found aged 40 to 50 years or 40 to 45 years may reduce risk of primary thyroid carcinoma tumor growth under active surveillance, which is hard to suggest that elder age
    may be associated with reduced risk of thyroid carcinoma tumor growth. Because there was no comparison of tumor growth in aged older than 50 years, such as age 60, 70 and so on. Although aged 40 or older was related with reduced risk of thyroid carcinoma, this result did not adjust for confounders. Therefore, this article can only obtain conclusion that aged 40 to 50 years was associated with reduced risk of primary thyroid carcinoma tumor growth, but not the older age may be associated with reduced risk of thyroid carcinoma tumor growth.

    Secondly, previous studies demonstrated that pregnant and high thyroid-stimulating hormone (TSH) levels were associated with progression of papillary thyroid carcinoma. The percentage of female patients ranged from 75% to 90%, pregnant is an important confounder and it is more appropriate to bring in pregnant to adjust[2]. Moreover, only one study required normal TSH level at baseline in this meta-analysis, TSH levels were another critical confounder which should be adjusted[3].

    We really appreciate the authors’ work and we look forward to the authors’ response to these issues.



    1. Koshkina A, Fazelzad R, Sugitani I, Miyauchi A, Thabane L, Goldstein DP, Ghai S, Sawka AM: Association of Patient Age With Progression of Low-Risk Papillary Thyroid Carcinoma Under Active Surveillance: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg 2020, 146:552-560.
    2. Shindo H, Amino N, Ito Y, Kihara M, Kobayashi K, Miya A, Hirokawa M, Miyauchi A: Papillary thyroid microcarcinoma might progress during pregnancy. Thyroid 2014, 24:840-844.
    3. Kim HI, Jang HW, Ahn HS, Ahn S, Park SY, Oh YL, Hahn SY, Shin JH, Kim JH, Kim JS, et al: High Serum TSH Level Is Associated With Progression of Papillary Thyroid Microcarcinoma During Active Surveillance. J Clin Endocrinol Metab 2018, 103:446-451.
    CONFLICT OF INTEREST: None Reported
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