Withholding Radioactive Iodine for Lower-Risk Papillary Thyroid Cancers Is Safe, but Delays the Certainty of Treatment Response

• Clin Thyroidol 2021;33:117–120.
• Background
  • The past 10 to 15 years have seen two related paradigm shifts in the care of patients with papillary thyroid cancer:
    • Risk-stratification systems:
      • Have been developed and validated, which have allowed clinicians to recognize patients with an excellent prognosis
    • Treatment guidelines:
      • Have also undergone rapid change, particularly for patients with lower-risk cancers
    • These changes, which have led to a trend of less aggressive treatment of low-risk patients:
      • Have been controversial
  • One area of extreme controversy has been when to use postoperative radioactive iodine ablation
  • There are important reasons why the conser‐ vative use of radioactive iodine is ideal:
    • In the face of an excellent prognosis, salivary and lacrimal treatment-related adverse events, or even the potential of an increase in the rate of second cancers, become important:
  • However, proponents for the increased use of radioactive iodine point to:
    • Its usefulness in completing risk stratification
  • This study was a retrospective analysis of patient outcomes from a single Italian center (Sapienza University of Rome) before and after a policy change for the use of postoperative radioactive iodine
  • Prior to 2011 at this institution, most patients with papillary thyroid cancer had received radioactive iodine following total thyroidectomy as a standard procedure
  • In 2011, the default position changed for patients in whom the estimated risk of recur‐ rence was ≤ 8% and decision-making was deferred for approximately 12 months:
    • In this later group, delayed radioactive iodine ablation was recommended if:
      • The serum thyroglobulin concentration was ≥ 1 ng/mL
      • There is imaging evidence of persistent disease or
      • At the patients request
• Methods
  • Patients initially treated between 2005 and June 2011 were managed in the more aggressive radioactive iodine era (cohort 1; 116 patients)
  • Cohort 2 included 156 patients initially treated from July 2011 to December 2018
  • Follow-up was performed 3 months after surgery and then at least yearly, with analysis performed at 12 months, 3 years after surgery, and at last contact
  • Outcomes were classified according to dynamic risk-stratification criteria validated for patients undergoing total thyroidectomy followed by radioactive iodine, as stratified by:
    • Excellent response:
      • No clinical, biochemical, or structural evidence of disease with a very sensitive cutpoint for serum thyroglobulin of ≤ 0.2 ng/ml)
    • Indeterminate response:
      • Detectable but low serum thyroglobulin levels, positive thyroglobulin antibodies, or abnormal but nonspecific imaging findings
    • Biochemical incomplete response:
      • Abnormal serum thyroglobulin levels or rising thyroglobulin antibodies
    • Structural incomplete response:
      • Identifiable locoregional or distant metastatic disease
  • Analyses were performed by comparing numbers of patients with structural incomplete response with those with other outcomes, and “gray-zone” responses (indeterminate or biochemical incomplete response) with “black-or-white” responses (excellent or structural incomplete responses)
  • Modeling approaches attempted to account for potential confounding
• Results
  • In cohort 1, of the 116 patients, 90 (plus one additional patient during a median follow-up of 8 years) received postoperative radioactive iodine ablation
  • In cohort 2, of the 156 patients, 10 (plus three additional patients during a median follow-up of 4 years) received postoperative radioactive iodine
  • Apart from follow-up time, the only key tumor feature that differed between cohorts was a smaller median tumor size in the group from the later period (10 mm vs. 7 mm; range, 1–45 and 1–60 respectively)
  • Structurally incomplete responses were very rare in both cohorts and at all time points analyzed (1% to 3%, P=not significant)
  • Significantly higher proportion of gray-zone responses was apparent at 1 year of follow-up in cohort 2, driven mostly by the presence of more indeterminate responses due to serum thyroglobulin antibody positivity in that group (8.6% in cohort 1 vs. 18.6% in cohort 2)
  • While these statistically significant differences did not persist at final follow-up, gray-zone responses were very common and remained numerically higher in cohort 2 (30% in cohort 1 and 44% in cohort 2, from a combination of detectable serum thyroglobulin levels, persistent positive serum thyroglobulin antibodies, and non‐specific imaging findings
• Conclusions
  • In this longitudinal cohort study, structural incomplete responses were rare in lower-risk papillary thyroid cancer patients, whether or not they received radioactive iodine ablation:
    • However, less use of postoperative radioactive iodine does lead to a higher rate of “uncertain” disease response status, at least initially
• This study supports the success of modern risk-stratification systems in identifying patients with very low risk of structurally persistent or recurrent differentiated thyroid cancer:
  • Whether or not postoperative radioactive iodine ablation is given
• It builds on previous work showing low rates of recurrence in appropriately selected patients treated with surgery alone and should not surprise those familiar with the literature
• Clinicians can be reassured that withholding radioactive iodine in lower-risk patients rarely results in the development of clinically significant recurrent disease:
  • Acknowledging that most patients treated in this study had small, localized tumors and that follow-up was relatively short
• The other key message of the study is the trade-offs that occur between a more aggressive and a more conservative approach to radioactive iodine pre‐ scription:
  • At least in the short term, not administering postoperative radioactive iodine led to a lower chance of “certainty” in the success of the treatment response:
    • This gray-zone outcome was due to a combination of:
      • Detectable serum thyroglobulin (at extremely low levels), persistently positive serum thyroglobulin antibodies, and
      • Nonspecific imaging findings being more common in patients not receiving radioactive iodine
• Without a considered response, higher rates of gray-zone outcomes could lead to increased patient (and physician) anxiety and / or an increase in diagnostic procedures associated with hunting for low-volume structural recurrence
• Limiting these possibilities (and the side effects of overtreatment with radioactive iodine) requires attention to the biology of each patient’s thyroid cancer, a care team working together with consistent communication, careful discus‐ sion with patients about how common gray-zone responses are and relating that the majority do not represent recurrent disease, and assessment of the trends in each patient’s biochemical and imaging response over time
• Consultations take longer, and depending on a clinic’s imaging protocols, may result in an increase in ultrasound use to follow up on nonspecific imaging findings
• Flexibility is also required, particularly in recognizing that some patients’ anxiety can be reduced only by radioactive ablation and that the rare requirement for delayed radioactive iodine administration is not necessarily a treatment failure
• This study, therefore, adds a valuable contribution to the literature, in highlighting the issues of certainty trade-offs that occur with current trends toward less aggressive treatment of lower-risk differentiated thyroid cancers

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