EDITORIALS AND COMMENTARYEDITORIAL

Clinical Relevance of Thyroglobulin Doubling Timein the Management of Patients with Differentiated

Thyroid Cancer

Furio Pacini,1 Mona M. Sabra,2 and R. Michael Tuttle2

The last several years have seen a renewed interest inrisk stratification in thyroid cancer with an increased

emphasis on how clinical data obtained during follow-up canbe used to modify our standard initial risk estimates of re-currence and disease-specific mortality (1). Using this ap-proach, recommendations regarding initial treatment,adjuvant therapy, and early follow-up are based on risk es-timates obtained using one of many clinico-pathology stagingsystems that integrate standard clinical–pathological features(age, primary tumor size, extrathyroidal extension, com-pleteness of resection, lymph node status, presence of distantmetastases) to predict either the risk of recurrence (AmericanThyroid Association [ATA] staging system) or risk of death(American Joint Committee on Cancer [AJCC], MACIS [dis-tant metastases, age, completeness of resection, local invasion,tumor size], etc.) (2). These initial risk estimates are thenactively modified (either increased or decreased) during fol-low-up as additional clinical information becomes available.For example, in two independent studies (3,4), our groupshave recently demonstrated that patients who achieve anexcellent response to therapy (clinical remission) as definedby stimulated thyroglobulin (Tg) values less than 1 ng/mLwith a negative neck ultrasound (US) should be reclassified aslow-risk patients, with appropriate reduction in the intensityof follow-up and degree of thyroid hormone suppression.Furthermore, patients failing to achieve an excellent responseto therapy (remission) had higher rates of recurrence/persis-tent disease than predicted by the initial static staging system,and therefore such patients should be followed more closelywith continued thyroid hormone–suppressive therapy andoften additional treatments.

In this issue of Thyroid, Miyauchi et al. (5) provide an im-portant quantitative tool to assist in dynamic risk assessmentby demonstrating that the doubling time of serum Tg mea-surements during follow-up of patients with persistent dis-ease is a more powerful predictor of overall survival, diseaserecurrence, and development of distant metastases than thestatic initial risk estimates obtained using standard clinico-pathologic factors. From a cohort of 1431 patients treated attheir center between 1998 and 2004, the authors identified 426

differentiated thyroid cancer patients who had at least fourserum Tg measurements obtained with a thyrotropin (TSH)<0.1 mIU/L in the absence of anti-Tg antibodies followingtotal thyroidectomy (167 also received radioactive iodine[RAI] remnant ablation). In most patients, serum Tg levelswere obtained 1 and 3 months postoperatively, then twice ayear for high-risk patients or once a year for low-risk patientsover a median follow-up period of 87 months.

Of the 426 eligible patients, 137 had four or more persis-tently detectable Tg levels obtained during follow-up, al-lowing for determination of the Tg doubling time. Anadditional 88 patients had three detectable Tg levels over timeand 201 had undetectable Tg values during follow-up. Duringfollow up, six patients died of thyroid cancer, 25 developednewly identified distant metastases, and 58 had loco-regionalrecurrence.

In a multivariate analysis that included the standard clinico-pathologic features, and tumor size, node metastases, distantmetastases (TNM) staging, only the Tg doubling time was anindependent predictor of disease-specific mortality, loco-regional recurrence, and development of newly identifieddistant metastases. For example, the 10-year cause-specificsurvival was only 50% in the 17 patients with a Tg doublingtime of less than 1 year; however, it was 95% when the dou-bling time was 1–3 years (21 patients), and 100% when thedoubling time was greater than 3 years (30 patients), the Tglevels declined over time (69 patients), or the Tg remainedundetectable on suppression during follow-up. Furthermore,these same Tg doubling time cut-offs (<1, 1–3, and >3 years)also effectively risk stratified patients with regard to both therisk of loco-regional recurrence and the risk of developingdistant metastases. Therefore, just as the authors have previ-ously demonstrated with regard to calcitonin doubling time inthe management of medullary thyroid cancer (6), the currentdata clearly support the clinical utility of Tg doubling times inthe dynamic risk assessment of patients with persistent thyr-oglobulinemia after total thyroidectomy.

In addition to using all Tg data points available over theentire course of follow-up, the authors also demonstrated thatthe Tg doubling time calculated using the first four Tg values

1Department of Internal Medicine, Endocrinology & Metabolism, and Biochemistry, Section of Endocrinology and Metabolism, Universityof Siena, Siena, Italy.

2Department of Endocrinology, Memorial Sloan Kettering Cancer Center, New York, New York.

THYROIDVolume 21, Number 7, 2011ª Mary Ann Liebert, Inc.DOI: 10.1089/thy.2011.2107.ed1

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obtained after thyroidectomy carried the same prognosticimportance. This important observation allows for an earlyrestratification of risk within the first 2 years of follow-up thatcan serve as a guide to frequency and intensity of follow-upby identifying both those patients with an excellent responseto therapy who are likely cured of their disease (in remission)and those with persistent disease most likely to developclinically significant outcomes (short Tg doubling times).

It is also important to point out that the Tg doubling timesappear to be an effective tool even if RAI remnant ablation isnot routinely performed. In this series, only 167 of 426 eligiblepatients had RAI ablation in addition to total thyroidectomy.While both persistent disease and normal thyroid remnantscan be associated with low-level persistent thyroglobulinemiafollowing total thyroidectomy, rising Tg values in the face ofongoing TSH suppression are far more likely to be an indi-cator of progressive disease than regrowth of normal thyroidtissue. Therefore, Tg doubling time may serve as a valuablepredictor of recurrent disease even in patients treated withtotal thyroidectomy without RAI remnant ablation.

As is the case with any risk stratification system that relies onserum Tg, the clinical utility is far less in patients with anti-Tgantibodies and is also dependent on the consistency of the assayused and the degree of TSH suppression. However, since theprimary finding of this study relates to the use of Tg doublingtime in patients with persistent hyperthyroglobulinemia, thedegree of TSH suppression is likely to be fairly consistentwithin an individual patient over several years of follow-up. Asthe authors point out, a simple web-based doubling time cal-culator is available on the ATA web site (http://www.thyroid.org/professionals/calculators/CDTC.php May 31, 2011).

The clinical implications of using Tg doubling times areparticularly important when one considers that only 34% ofour patients treated with total thyroidectomy and RAIachieved an undetectable suppressed Tg and stimulated Tgless than 1 ng/mL in the first 2 years of follow-up (4). In theabsence of structurally identifiable disease, the best course ofaction in patients with persistent low-level Tg values is usu-ally continued TSH suppression and observation over 1–2years to evaluate the trend in Tg values over time. Oftentimes,detectable serum Tg values in the absence of structurallyidentifiable disease slowly decline over time, sometimesreaching undetectable levels (7). Conversely, rising Tg valuesover time have been shown to be associated with an increasedrisk of disease recurrence. We can now add the specificcalculation of Tg doubling time to our ongoing assessmentto better predict which patients with persistent thyr-oglobulinemia are at risk of developing loco-regional recur-rence, distant metastases, and death.

While we do not currently recommend initiating systemicchemotherapy or a therapeutic drug trial on the basis of Tgdoubling time in the absence of structurally identifiable dis-ease, the Tg doubling time would guide the frequency, extent,and intensity of our evaluations since short doubling times areexpected to result in identification of structural disease pro-gression over months to years. Conversely, very long (ornonexistent) Tg doubling times are considered to be very re-assuring even in the setting of structurally identifiable diseaseand likely predict relatively slow disease progression in allbut the most poorly differentiated thyroid cancers. For ex-ample, a long Tg doubling time, particularly if associated witha negative 2-deoxy-2[18F]fluoro-d-glucose positron emission

tomography scan, would likely warrant cautious observationrather than systemic therapy in patients with structurallyidentifiable RAI refractory pulmonary metastases that are notcausing local compressive symptoms.

In conclusion, the Tg doubling time will serve as a usefultool that can identify those patients with persistent thyr-oglobulinemia after total thyroidectomy that are at highestrisk for developing loco-regional recurrence, distant metas-tases, and disease-specific mortality from differentiated thy-roid cancer. These data provide additional support to theconcept of dynamic risk assessment in which data obtainedduring routine clinical follow-up is used to modify our initialrisk estimates in order to tailor the intensity and frequency offollow-up, degree of TSH suppression, and need for addi-tional therapies to a realistic, personalized, and actively up-dated risk estimate.

References

1. Tuttle RM, Leboeuf R, Shaha A 2008 Medical management ofthyroid cancer: a risk adapted approach. J Surg Oncol 97:

712–716.2. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL,

Mandel SJ, Mazzaferri EL, McIver B, Pacini F, SchlumbergerM, Sherman SI, Steward DL, Tuttle RM 2009 Revised Amer-ican Thyroid Association management guidelines for patientswith thyroid nodules and differentiated thyroid cancer.Thyroid 19:1167–1214.

3. Castagna MG, Belardini V, Cipri C, Theodouropulus A,Pacini F 2010 The clinical impact of an ‘‘ongoing risk strati-fication’’ in patients with differentiated thyroid carcinoma.Abstract, International Thyroid Congress, Paris.

4. Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M,Brokhin M, Omry G, Fagin JA, Shaha A 2010 Estimating riskof recurrence in differentiated thyroid cancer after total thy-roidectomy and radioactive iodine remnant ablation: usingresponse to therapy variables to modify the initial risk esti-mates predicted by the new American Thyroid Associationstaging system. Thyroid 20:1341–1349.

5. Miyauchi A, Kudo T, Miya A, Kobayashi K, Ito Y, Shimoyamate-dori C, Takamura Y, Higashiyama T, Fukushima M, Kihara M,Tomoda C, Inoue H, Yabuta T, Masuoka H 2011 Prognosticimpact of serum thyroglobulin doubling-time under TSH sup-pression in patients with papillary thyroid carcinoma who un-derwent total thyroidectomy. Thyroid 21:707–716.

6. Miyauchi A, Onishi T, Morimoto S, Takai S, Matsuzuka F,Kuma K, Maeda M, Kumahara Y 1984 Relation of doublingtime of plasma calcitonin levels to prognosis and recurrenceof medullary thyroid carcinoma. Ann Surg 199:461–466.

7. Pacini F, Agate L, Elisei R, Capezzone M, Ceccarelli C, LippiF, Molinaro E, Pinchera A 2001 Outcome of differentiatedthyroid cancer with detectable serum Tg and negative diag-nostic (131)I whole body scan: comparison of patients treatedwith high (131)I activities versus untreated patients. J ClinEndocrinol Metab 86:4092–4097.

Address correspondence to:R. Michael Tuttle, M.D.

Department of EndocrinologyMemorial Sloan Kettering Cancer Center

1275 York Ave.New York, NY 10021

E-mail: tuttlem@mskcc.org

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