Distinguishing remnant ablation from adjuvant treatment in differentiated thyroid cancer
Authors: R Michael Tuttle
Journal: The Lancet Diabetes & Endocrinology (2018)

Following thyroidectomy, radioactive iodine (131I) therapy can be given in an effort to destroy residual, presumably benign thyroid tissue in the thyroid bed (remnant ablation), suspected but not identified remaining disease (adjuvant treatment), or known residual or recurrent disease (treatment of known disease).1Haugen BR Alexander EK Bible KC 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: 1-133Crossref PubMed Scopus (7688) Google Scholar, 2Van Nostrand D Selected controversies of radioiodine imaging and therapy in differentiated thyroid cancer.Endocrinol Metab Clin North Am. 2017; 46: 783-793Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Unlike treatment of known disease, adjuvant 131I therapy is given for a risk and not for documented persistent disease. For remnant ablation, success is defined as having no biochemical, functional, or structural evidence of persistent thyroid cells 6–12 months after 131I ablation. Conversely, the success of adjuvant therapy is defined by improvements in disease-specific survival and structural disease recurrence rates, whereas destruction (and possibly stabilisation) of known disease would be considered an important measure of success for treatment of known disease. Results of two randomised non-inferiority trials, HiLo and ESTIMABL1, have shown that preparation with either thyroid hormone withdrawal or recombinant human thyroid-stimulating hormone (rhTSH), with administered activities of 1·1 GBq or 3·7 GBq, can achieve successful remnant ablation in 85–95% of patients.3Mallick U Harmer C Yap B et al.Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.N Engl J Med. 2012; 366: 1674-1685Crossref PubMed Scopus (402) Google Scholar, 4Schlumberger M Catargi B Borget I et al.Strategies of radioiodine ablation in patients with low-risk thyroid cancer.N Engl J Med. 2012; 366: 1663-1673Crossref PubMed Scopus (448) Google Scholar In The Lancet Diabetes & Endocrinology, Hakim-Moulay Dehbi and colleagues5Debhi H-M Mallick U Wadsley J Newbold K Harmer C Hackshaw A Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Nov 27. http://dx.doi.org/10.1016/S2213-8587(18)30306-1)Google Scholar now report long-term results of the HiLo trial. To assess the effect of the first administered activity of 131I for adjuvant treatment or treatment of known disease, they report the rates of persistent disease (biochemical or structural evidence of disease remaining after initial therapy) or recurrent disease (biochemical or structural disease subsequently identified in patients deemed to be disease free following initial therapy) detected over a median of 6·5 years of follow-up.5Debhi H-M Mallick U Wadsley J Newbold K Harmer C Hackshaw A Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Nov 27. http://dx.doi.org/10.1016/S2213-8587(18)30306-1)Google Scholar Recurrence rates based on a median follow-up of 5·4 years have recently also been reported for ESTIMABL1.6Schlumberger M Leboulleux S Catargi B et al.Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.Lancet Diabetes Endocrinol. 2018; 6: 618-626Summary Full Text Full Text PDF PubMed Scopus (80) Google Scholar Results of both trials confirm previous retrospective observations showing structural disease persistence and recurrence rates of less than 5% in patients with low to intermediate risk differentiated thyroid cancer.5Debhi H-M Mallick U Wadsley J Newbold K Harmer C Hackshaw A Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Nov 27. http://dx.doi.org/10.1016/S2213-8587(18)30306-1)Google Scholar, 6Schlumberger M Leboulleux S Catargi B et al.Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.Lancet Diabetes Endocrinol. 2018; 6: 618-626Summary Full Text Full Text PDF PubMed Scopus (80) Google Scholar They also show the importance of modifying risk estimates in response to initial therapy, as the rate of recurrent and persistent structural disease in patients who achieved successful remnant ablation dropped to less than 1%, whereas 15% of patients who did not achieve initial ablation were diagnosed with persistent or recurrent disease.5Debhi H-M Mallick U Wadsley J Newbold K Harmer C Hackshaw A Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Nov 27. http://dx.doi.org/10.1016/S2213-8587(18)30306-1)Google Scholar, 6Schlumberger M Leboulleux S Catargi B et al.Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.Lancet Diabetes Endocrinol. 2018; 6: 618-626Summary Full Text Full Text PDF PubMed Scopus (80) Google Scholar In the HiLo trial, recurrent or persistent structural disease was detected much earlier in patients who did not have successful ablation compared with patients who had successful ablation (data in appendix5Debhi H-M Mallick U Wadsley J Newbold K Harmer C Hackshaw A Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Nov 27. http://dx.doi.org/10.1016/S2213-8587(18)30306-1)Google Scholar). Thus, the success or failure of remnant ablation, assessed as early as 6–9 months after initial therapy, should be used to modify the frequency and intensity of follow-up that is planned on the basis of initial American Thyroid Association (ATA) risk stratification. However, it is important to remember that both of these trials were primarily designed and powered to assess the efficacy of remnant ablation in low to intermediate risk patients.3Mallick U Harmer C Yap B et al.Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.N Engl J Med. 2012; 366: 1674-1685Crossref PubMed Scopus (402) Google Scholar, 4Schlumberger M Catargi B Borget I et al.Strategies of radioiodine ablation in patients with low-risk thyroid cancer.N Engl J Med. 2012; 366: 1663-1673Crossref PubMed Scopus (448) Google Scholar As a result, these trials cannot provide definitive answers about the need for, or efficacy of, 131I therapy given primarily for adjuvant treatment. The low event rates (disease-specific mortality <1% and structural disease recurrence rates of <10%) anticipated in a properly designed adjuvant therapy trial of low to intermediate risk patients will require much larger samples sizes and longer follow-up periods.7Carling T Carty SE Ciarleglio MM et al.American Thyroid Association design and feasibility of a prospective randomized controlled trial of prophylactic central lymph node dissection for papillary thyroid carcinoma.Thyroid. 2012; 22: 237-244Crossref PubMed Scopus (158) Google Scholar Furthermore, since properly selected low to intermediate risk patients treated with thyroid surgery alone also have low structural disease recurrence rates, it is important to include a control group followed up without 131I adjuvant therapy in order to ascertain whether the excellent outcomes following initial therapy are a reflection of the effect of thyroid surgery coupled with the indolent nature of differentiated thyroid cancer or whether 131I therapy is having a meaningful impact on disease recurrence and overall survival. The authors of both the HiLo and ESTIMABL1 trials are to be commended on the design, implementation, and publication of these multicentre, randomised prospective trials that have provided reliable evidence about preparation methods and appropriate admin istered activities of 131I for remnant ablation. We look forward to the results of their currently accruing trials, the IoN trial (NCT01398085) and ESTIMABL2 (NCT01837745), examining the rates of persistent and recurrent disease in patients randomly assigned to either low-dose 131I or observation following total thyroidectomy.8Mallick U Harmer C Hackshaw A Moss L Iodine or Not (IoN) for low-risk differentiated thyroid cancer: the next UK National Cancer Research Network randomised trial following HiLo.Clin Oncol. 2012; 24: 159-161Summary Full Text Full Text PDF PubMed Scopus (53) Google Scholar These successful trials should provide the impetus for the thyroid cancer community to design and implement prospective, randomised clinical trials specifically designed to assess the efficacy and optimal administered activity of 131I when used as adjuvant treatment. To that end, selection of patients for adjuvant treatment trials should be based not only on initial risk stratification (eligibility based on estimates of the risk of recurrence or disease-specific mortality) but also on careful evaluation of disease status following appropriate initial surgery so that we can differentiate the potential role of 131I therapy for the treatment of known persistent disease from that of true adjuvant treatment. I declare no competing interests. Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trialThe recurrence rate among patients who had 1·1 GBq radioactive iodine ablation was not higher than that for 3·7 GBq, consistent with data from large, recent observational studies. These findings provide further evidence in favour of using low-dose radioactive iodine for treatment of patients with low-risk differentiated thyroid cancer. Our data also indicate that recurrence risk was not affected by use of rhTSH. Full-Text PDF Open Access