Abstract
The 2009 publication “Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer” (1), referred to here as “ATA Guidelines,” is followed by a great number of physicians all over the world. The subsection What is the role of postoperative radioiodine (RAI) remnant ablation starting on page 1181 discusses the indication of RAI ablation in differentiated thyroid carcinoma (DTC). Although we agree with most of the recommendations in this section, respectfully we would like to discuss those concerning microscopic multifocal papillary cancer.
On page 1182 of the 2009 ATA Guidelines (1), it is stated that “for microscopic multifocal papillary cancer, when all foci are <1 cm, recent data suggest that RAI is of no benefit in preventing recurrence.” Therefore, in table 5 (also page 1182), an “E” recommendation against RAI treatment in microscopic multifocal papillary cancer is stated (1), whereas in the previous 2006 ATA guidelines (2), on page 11, a “B” recommendation (R32) in favor of RAI treatment in stage I disease (including T1N0M0) with multifocal disease was listed.
To support this new recommendation on multifocal T1 tumors when all foci are <1 cm, two references (Refs. 216 and 217 of the 2009 ATA Guidelines) (3, 4) are provided. However, none of the cited references provides the “1 cm sum of all foci” threshold.
Reference 216 by Hay et al. (3) reported retrospective data (1945–2004) on 900 patients with micropapillary thyroid cancer (MPTC), defined as tumors smaller than 1 cm. In this cohort, multifocality was found in 23%, but interestingly without any mention of the sum of all foci. After a 20-year follow-up, local or distant recurrence was found in 5.7%, with a higher recurrence rate observed in patients with multifocal tumors (11%) versus unifocal tumors (4%) (p=0.002). Data concerning recurrence rates of unicentric versus multicentric tumors treated or not treated by RAI were in fact not given. Finally, as mentioned in the discussion, this study has major limitations: the very long period of this study (60 years) with consequently heterogeneous methods of recurrence detection, the fact that patients at higher risk of recurrence were more likely to be treated by RAI, introducing a major bias; and a quite low number of informative patients treated with RAI (103/900 patients).
In the second reference (Ref. 217), Ross et al. (4) studied the recurrence rate of MPTC, defined as a tumor smaller than 10 mm in maximal diameter. In this recent (1987) nonrandomized multicenter registry, 611 MPTC were prospectively analyzed: 38% had multifocal disease (again without any mention on the sum of all foci). During a very short follow-up (mean three years), 38 patients (6.2%) recurred: patients with multifocal disease had more recurrences than those with unifocal tumor (18% vs. 4%; p=0.009). Moreover, recurrence was more common without RAI between multifocal (7%) and unifocal disease (2%) (p=0.02). These data failed to show a benefit of RAI in patients with multifocal MPTC. But limitations must be noted. First, it's a registry analysis and not a randomized study, so the clinicians could be more aggressive depending on patients' characteristics. Second, the very short follow-up (only three years) could minimize the recurrence rate in these patients.
Whereas no RAI treatment on “very low-risk (LR)” tumors (i.e., unifocal ≤10 mm T1 N0Nx M0Mx tumors) is consensual, multifocality, a classical prognostic factor for recurrence of MPTC patients, has raised much interrogation. The prognostic value of multifocality in those tumors was again confirmed in two recent retrospective studies (5,6), but still not the 10 mm threshold of total foci size.
However, as no evidence of benefit of RAI treatment in decreasing rates of recurrence or death in patients with LR DTC was confirmed in a recent retrospective study (7), a process of treatment de-escalation has begun. The first step was to demonstrate that an equivalent rate of successful ablation was obtained either after a low activity (1.1 GBq) or a high activity (3.7 GBq) of RAI, after the use of recombinant human thyrotropin stimulation or thyroid hormone withdrawal (8,9). A new standard of care in LR DTC was thus validated.
The second step of treatment de-escalation is on the way, as prospective randomized trials involving a large number of patients with small thyroid cancers (pT1b N0Nx, and pT1m N0Nx with a “sum of all foci” between 1 and 2 cm) are ongoing to compare outcomes after 1.1 GBq RAI ablation following the use of recombinant human thyrotropin with no ablation at all (11). However, as persistent disease at ablation was found in 3.7% of the cohort of Schlumberger et al. (8), a proportion in agreement with another recent publication (10), we cannot totally exclude that RAI therapy (even after low dose) may optimize patients' follow-up and quality of life.
Finally, in the light of all these data, we ask two questions. First, should we define the utility of RAI therapy in multifocal T1 tumors based on the sum of all the foci? Second, how should we manage the follow-up of those patients, where a significant association between multifocality and recurrences was demonstrated?
In the subsection of the ATA Guidelines (1) ([B14] What is the role of postoperative radioiodine (RAI) remnant ablation, pp. 1181–1183), both the cited references either do not address or do not support the suggested opinions. Despite the very low mortality rates associated with MPTC and the relatively uncommon recurrences, we believe that multifocal disease, as well as nodal (and of course distant) metastases or more classical aggressive histology, may represent “selective indications” of adjunctive RAI treatment. We propose that this subsection should be rewritten considering our comments.