Association Between Serum Thyrotropin and Cancer Recurrence in Differentiated Thyroid Cancer: A Population-Based Retrospective Cohort Study

Background: Levothyroxine to suppress thyrotropin (TSH) to <0.5 mIU/L following thyroidectomy in differentiated thyroid cancer (DTC) may reduce recurrence in higher-risk DTC. However, there is limited evidence to support guideline recommendations to maintain TSH in the low-normal range of 0.5-2 mIU/L to reduce recurrence in patients with lower risk DTC. The primary objective was to assess the association between exposure to high normal serum TSH (2-4 mIU/L) as compared with low normal TSH (0.5-2 mIU/L) target ranges and cancer recurrence in patients with DTC after thyroidectomy. Methods: This population-based retrospective cohort study used linked, administrative health care databases from Ontario, Canada, to follow patients with DTC post-thyroidectomy from 2007 to 2018. The exposure was time updated, serum TSH, treated as a cumulative and instantaneous exposure. Multivariable cause-specific proportional hazard regression analyses were performed to determine time to DTC recurrence from index date, defined as a composite of repeat neck surgery, radioactive iodine (RAI) treatment, and/or DTC-specific death. Results were also stratified by initial treatment as a marker of baseline recurrence risk in a sensitivity analysis. Results: This cohort of 26,336 individuals (78% female) with DTC and a median age of 50 years were followed for a median of 5.9 (interquartile range 3.6-8.6) years; 40.9% were initially treated with a hemi-thyroidectomy only and 38.2% received a total thyroidectomy and RAI. Compared with exposure to TSH 0.5 to ≤2 mIU/L, DTC recurrence rate was similar for each additional 3 months of exposure to TSH >2 to ≤4 mIU/L (adjusted cause specific [cs] hazard ratio [HR] 0.99 [confidence interval or CI 0.97-1.02]) but was significantly increased with each additional 3 months of exposure to TSH >4 mIU/L (adjusted csHR 1.07 [CI 1.04-1.09]). Results were similar across baseline treatment groups. Conclusion: There was no difference in clinically significant recurrence in those with low-risk DTC maintained with a TSH of 0.5-2 mIU/L compared with 2-4 mIU/L. Guidelines should consider liberalizing target TSH level post thyroidectomy in low-risk cohorts. These results cannot be applied to patients with high-risk DTC.