1. Walfish, Paul G. CM, OONT, MD, FRCP(C), FACP, FRSM(ENGL), FCAHS

Article Content

In the treatment of papillary thyroid cancer, radioiodine remnant ablation (RRA) is often used following thyroidectomy to destroy any occult microscopic carcinoma cells within the thyroid remnant, to facilitate radioactive iodine (RAI) scanning of recurrent metastatic disease, and to improve the value of serum thyroglobulin (Tg) as a tumor marker in follow-up (Endocr Pract 2001;7:202-220).

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Guidelines established by the American Thyroid Association indicate that use of remnant ablation involving administration of RAI can be considered, even among a select group of low-risk patients. However, patient selection criteria related to use of RRA are widely considered to include arbitrary and not reflective of objective biomarkers of residual disease risk. Widely used criteria, including age, primary tumor size, and pTNM staging, have not conclusively been shown to be accurate predictors of residual/recurrent well-differentiated thyroid carcinoma (Head & Neck 2009;31:782-788).


In addition to challenges based on patient selection criteria, the benefits of using RAI to reduce the risk of recurrence following thyroidectomy are not firmly established for all patients, especially among low-risk papillary thyroid cancer (PTC). In many cases these patients achieve a TSH-stimulated thyroglobulin (Stim-Tg) less than 1 [mu]g/L following total thyroidectomy, which makes remnant ablation unnecessary to reliably follow thyroglobulin level as a tumor marker (Laryngoscope 2003;113(1):77-81, Head Neck 2010;32(6):689-698, J Clin Endocrinol Metab 2005;90(3):1440-1445, Thyroid 2011;21(1):49-53, Clin Endocrinol 2007;66(1):58-64). There is also not clear evidence that use of RAI is decreasing the rates of recurrence or death in low-risk PTC (Endocrinol Metab Clin North Am 2008;37(2):457-480, J Clin Endocrinol Metab 2004;89(8):3668-3676, Thyroid 2010;20(11):1235-1245).


Despite questions about its usefulness, rates of RAI administration rose significantly from 1990 to 2008 (Clin Endocrinol 2014;81(Suppl 1):1-122). One factor at play is the fact that current ATA guidelines related to use of RAI remain vague and broad (JAMA 2011;306(7):721-728). Another factor is the lack of standardization in patient risk stratification. To address this challenge, in recent years researchers have worked to develop a personalized strategy for risk stratification and RAI administration with a special focus on low/intermediate-risk PTC. In these efforts, researchers have focused on clearly quantifiable factors including a patient's postoperative pathology, Stim-Tg and neck ultrasound Stim-Tg protocol (Head Neck 2010;32(6):689-698).


Stim-Tg & Neck Ultrasound in PTC

The utility of postoperative Stim-Tg in risk stratification to identify patients for RAI therapy is supported by several retrospective studies (Endocr Relat Cancer 2011;18(2):R29-R40, Thyroid 2012; doi:10.1089/thy.2012-0190) and two prospective studies (Head Neck 2010;32(6):689-698, Thyroid 2011;21(1):49-53). Results show Stim-Tg can effectively identify patients who may not need RAI, especially among those with a Stim-Tg less than 1 [mu]g/L.


In addition, two large systematic reviews confirm the high negative predictive value (NPV) of postoperative Tg for future disease-free status, measured during TSH-stimulation and during levothyroxine therapy using an ultrasensitive assay (J Clin Endocrinol Metab 2012;97(8):2754-2763, J Clin Endocrinol Metab 2014;99(2):440-447). While encouraging, long-term prospective experience on RAI selection criteria using Tg and neck ultrasound remains limited.


To address this need, our research team extended the follow-up of patients from a previous prospective study, to a mean of 6.2 years (Endocrine 2015; doi:10.1007/s12020-015-0575-0). Results of this research effort provide new levels of support for the use of a personalized risk stratification and RAI selection protocol (PRSP) based on serial postoperative Stim-Tg and neck ultrasound results in PTC patient (Endocrine 2015; doi:10.1007/s12020-015-0575-0).


Study Protocol

In this study, we followed low- and intermediate-risk PTC patients who were treated with total or subsequent completion thyroidectomy. Patients classified as low- and intermediate-risk had PTC nodules equal or greater than 1 cm (T1-T3) that were confined to the thyroid or central (level VI) lymph nodes (N0-N1a).


Patients excluded from the study included those with the following:


* tumors less than 1 cm given that their risk for PTC recurrence was defined as very low;


* detectable anti-thyroglobulin antibodies (TgAb) given their potential interference with the thyroglobulin (Tg) assay;


* lateral compartment lymph node involvement (N1b); and


* extrathyroidal extension (T4) or distant metastases (M1).



All patients were treated with postoperative Stim-Tg and neck ultrasound within approximately 3 months following thyroidectomy. Patients with a Stim-Tg greater than 5 [mu]g/L were determined to have an increased risk of residual/recurrent PTC and were advised to proceed with RAI therapy (Endocrine 2015; doi:10.1007/s12020-015-0575-0). Patients with Stim-Tg greater than 1 [mu]g/L but less than 5 [mu]g/L who also had a negative neck ultrasound were advised that they required active surveillance with a potential need for RAI in the future.


Patients were treated with thyroid hormone TSH-suppression therapy and underwent repeat neck ultrasound. They also received stimulated and basal thyroglobulin measurements every 6-12 months. Patients who received RAI underwent a posttreatment whole-body scan (WBS) 7 days after treatment. A total of 129 low/intermediate-risk PTC patients were followed prospectively for a mean duration of 6.2 years.


Study Findings

In the cohort of 129 low/intermediate-risk patients, 116 (90%) were not treated with RAI based on the use of the PRSP. These patients showed no risk of residual/recurrent disease at a mean follow-up of 6.2 years.


Based on use of PRSP, one patient who showed evidence of residual/recurrent disease was correctly identified to receive RAI. Overall, the risk for development of residual/recurrent PTC was determined to be less than 1 percent. A subsequent 2 year follow-up on this cohort showed no need for administration of RAI within this patient population.


Data presented by Orlov, et al, provide the first long-term prospective study cohort with a mean follow-up of over 8 years supporting use of serial postoperative stimulated thyroglobulin and neck ultrasound in PTC patient risk stratification (Endocrine 2015; doi:10.1007/s12020-015-0575-0). For clinicians, these results strongly indicate that postoperative Stim-Tg and neck ultrasound personalized criteria provide an accurate long-term assessment of risk that can help many patients avoid unnecessary treatment with RAI based on surgical pathology.


These observations further demonstrate that the risk factors that have previously been considered to support use of RAI are not always concordant with this personalized strategy and could support trends in overtreatment.


PAUL G. WALFISH, CM, OONT, MD, FRCP(C), FACP, FRSM(ENGL), FCAHS, is Professor Emeritus of Medicine, Pediatrics, Otolaryngology-Head & Neck Surgery, Pathology & Laboratory Medicine, University of Toronto; Senior Endocrine Consultant, Joseph and Mildred Sonshine Family Centre for Head & Neck Diseases; and Alex and Simona Shnaider Research Chair in Thyroid Oncology, Mount Sinai Hospital/Sinai Health Center, Toronto, Ontario Canada.

Paul G. Walfish, CM,... - Click to enlarge in new windowPaul G. Walfish, CM, OONT, MD, FRCP(C), FACP, FRSM(ENGL), FCAHS. Paul G. Walfish, CM, OONT, MD, FRCP(C), FACP, FRSM(ENGL), FCAHS