How long does thyroid hormone need to be withdrawn in preparation for RAI remnant ablation / treatment or diagnostic scanning?

• American Thyroid Association Recommendation # 53:
  • If thyroid hormone withdrawal is planned prior to radioactive iodine (RAI) therapy or diagnostic testing:
    • Levothyroxine (LT4) should be withdrawn for 3 to 4 weeks
    • Liothyronine (LT3) may be substituted for LT4 in the initial weeks if LT4 is withdrawn for 4 or more weeks:
      • In such circumstances, LT3 should be withdrawn for at least 2 weeks
  • Serum thyroid stimulating hormone (TSH) should be measured prior to radioisotope administration to evaluate the degree of TSH elevation:
    • A goal TSH of greater than 30 mIU/L has been generally adopted in preparation for RAI therapy or diagnostic testing:
      • But there is uncertainty relating to the optimum TSH level associated with improvement in long-term outcomes
    • Thyrotropin stimulation before RAI remnant ablation / therapy or scanning has been a long-established standard of care because early observational research suggested that:
      • A TSH greater than 30 mIU/L was required for incompletely resected thyroid tumors to significantly concentrate 131I
    • There have been two RCTs comparing various thyroid hormone withdrawal protocols prior to therapeutic or diagnostic iodine radioisotope administration:
      • Lee et al. reported on an open-label, single-center study, in which 291 patients with well-differentiated thyroid cancer (TNM stage T1 to T3, N0 / N1a, M0) were randomized to either with- drawal LT4 for 4 weeks (n = 89), or withdrawal of LT4 for 4 weeks with substitution of LT3 for the first 2 weeks (n = 133), or recombinant human TSH (rhTSH; with withdrawal of LT4 for a few days from the time of the first rhTSH injection to radioisotope administration) (n = 69):
        • In this trial, all patients received 30 mCi of 131I for remnant ablation and were prescribed a 2-week low-iodine diet (LID) pre-ablation
        • Although the randomization method was unclear, the baseline characteristics (including pre-ablation urinary iodine measurements) were well balanced among groups
        • Furthermore, the pre-ablation TSH was greater than 30 in all patients in all groups in this trial, with no significant difference in mean pre- ablation TSH levels
        • Moreover, the primary outcome, which was the rate of successful remnant ablation at 12 months:
          • Was not significantly different among groups:
            • Range 91.0% to 91.7% among groups
        • Upon administration of questionnaires in a double-blind fashion, there was no significant difference in quality of life during preparation for RAI ablation, between the LT4 withdrawal group and the LT4 withdrawal with LT3 substitution group:
          • However, quality of life in both withdrawal groups prior to remnant ablation was significantly worse than after rhTSH preparation
        • Long-term outcome data from this trial were not reported
      • In a single-center trial, Leboeuf et al. randomized 20 individuals with well-differentiated thyroid cancer awaiting RAI remnant ablation or diagnostic scanning to:
        • LT4 withdrawal and either substitution of LT3 for 21 days, followed by 2 weeks off LT3, or identical-appearing placebo for LT3 for 21 days
        • In both groups, either the LT3 or placebo was withdrawn for another 2 weeks, and weekly measurements were performed for serum TSH, free thyroxine, and free triiodothy- ronine
      • The primary outcome was the hypothyroidism symptom score (Billewicz scale), which was ascertained in a double-blind fashion at time of LT4 withdrawal and every 2 weeks until the end of the study
      • The randomization method was a computer-generated number sequence; the LT3 group was significantly older than the placebo group (mean age 64 compared to 46), suggesting imbalance in the randomization
      • Disease stage of participants was not reported
      • Approximately 15% of participants withdrew from this trial
    • Leboeuf et al. reported no significant differences between the two thyroid hormone withdrawal protocol groups for hypothyroid symptom scores at any time point in the trial in a protocol-based analysis
    • At the time of ablation or whole-body scanning, the mean TSH was not significantly different between groups
  • In summary, available evidence from recent RCTs suggests that either direct LT4 withdrawal or LT4 withdrawal with substitution of LT3 in initial weeks is associated with similar short-term quality of life and hypothyroidism symptom scores; moreover, the remnant abla- tion success rate appears comparable
• There is some conflicting observational evidence on whether any specific pre-RAI administration TSH level is associated with success of remnant ablation:
  • For example, in a secondary analysis of a RAI remnant ablation activity RCT, Fallahi et al:
    • Reported that a pre-RAI TSH of greater than 25 following (LT4 and LT3) thyroid hormone withdrawal was significantly associated with increased likelihood of successful remnant ablation (odds ratio 2.36, [95% CI 1.28–4.35], p=0.006), after adjustment for RAI activity, baseline serum Tg, on-LT4 TSH level, sex, age, histology, baseline RAI up-take, and extent of surgery
  • In two retrospective studies, each including several hundred DTC patients who underwent thyroid hormone withdrawal, no significant association was observed between pre-RAI TSH and rate of successful remnant ablation, in respective multivariable analyses adjusted for relevant variables such as disease extent, 131I activity, and gender:
    • However, results of these two studies may not necessarily be extrapolated to TSH levels below 30 mU/L, given that patients with such TSH thresholds were not generally considered eligible for RAI ablation in these studies
  • Pre–RAI ablation TSH was not a significant predictor of becoming disease free without further treatment in a secondary subgroup analysis of 50 patients who underwent thyroid hormone with- drawal, but the small number of patients in this subgroup may have limited the statistical power for a multivariate analysis
• In summary, there is some uncertainty on the optimal level pre–RAI treatment TSH following thyroid hormone withdrawal in considering long-term outcome effect

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