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Indications for radioiodine administration in follicular-derived thyroid cancer
Annales d’Endocrinologie 76 (2015) 1S2-1S7
Indications for radioiodine administration in follicular-derived thyroid cancer Les indications de l’irathérapie dans les cancers thyroïdiens de souche folliculaire C. Buffet, C. Ghander, E. le Marois, L. Leenhardt* Unité thyroïde-tumeurs endocrines, Institut d’endocrinologie E3M et Service de médecine nucléaire, Hôpital Pitié-Salpêtrière, Université Pierre-et-Marie-Curie/Institut Universitaire du Cancer, 83, boulevard de L’Hôpital, 75013 Paris, France
Abstract Indications for radioiodine administration after thyroid cancer surgery have shifted in recent years toward personalized management, adapted to the individual risk of tumor progression. The most recent guidelines and studies favor de-escalation in indications for administration, dosage and means of preparation with exogenous recombinant TSH stimulation as treatment of choice. Radioiodine administration has 3 possible objectives: • ablation of normal thyroid tissue remnants in patients with low risk of progression, using low radioiodine activity levels, with the advantage of completing disease staging on whole-body scintigraphy performed after administration of the radioiodine capsule, and of facilitating follow-up by thyroglobulin assay; • adjuvant treatment for suspected microscopic metastases in patients with intermediate or high risk of progression, using higher activity levels, with the theoretic aim of limiting recurrence and mortality; • curative treatment in high-risk patients with proven metastases, using exclusively high activity levels, with a view to improving specific survival. In future, indications for ablation and/or activity prescription may be governed by an algorithm incorporating individual baseline progression risk (essentially founded of pTNM staging) and postoperative data such as thyroglobulin level and neck ultrasound results. © 2015 Published by Elsevier Masson SAS. All rights reserved. Keywords: Risk-stratification; Remnant ablation; Radioiodine activity, rhTSH Résumé Les indications d’administration d’iode radioactif après une chirurgie pour cancer de la thyroïde se sont modifiées au cours de ces dernières années au profit d’une prise en charge personnalisée, adaptée au risque évolutif tumoral. Les dernières recommandations et les études les plus récentes vont dans le sens d’une désescalade des indications d’administration du radio-iode, des activités prescrites et des modalités de préparation à l’irathérapie au profit de la stimulation par TSH recombinante exogène. On distingue trois objectifs à l’irathérapie : • l’ablation de reliquats de tissus thyroïdiens normaux pour les patients à faible risque évolutif, obtenue avec de faibles activités ayant pour avantage de compléter le staging de la maladie grâce à la scintigraphie corps entier faite après prise de gélule d’iode et de faciliter le suivi du patient grâce au dosage de thyroglobuline ; • un traitement adjuvant d’une maladie métastatique microscopique suspectée chez des patients à risque évolutif intermédiaire ou élevé, obtenu avec de plus fortes activités, dans le but théorique de diminuer le nombre de récidive et de décès ; • un traitement curatif chez des patients à haut risque ayant une maladie métastatique prouvée, obtenu uniquement avec de fortes activités, dans le but d’améliorer la survie spécifique. À l’avenir, les indications d’ablation et/ou les activités prescrites pourraient dépendre d’un algorithme incluant le risque évolutif initial du patient (tenant compte essentiellement de la classification pTNM) et de données post-opératoires comme la valeur de thyroglobuline et le résultat de l’échographie cervicale. © 2015 Publié par Elsevier Masson SAS. Tous droits réservés. Mots-clés : Stratification du risque ; Ablation ; Activité ; TSH recombinante
* Corresponding author. E-mail Address: [email protected] (L. Leenhardt).
© 2015 Elsevier Masson SAS. All rights reserved.
C. Buffet et al. / Annales d’Endocrinologie 76 (2015) 1S2-1S7
1. Introduction Differentiated thyroid cancer (DTC) treatment usually consists of thyroidectomy, often followed by radioiodine administration. From the 1980s, radioiodine (RAI) was prescribed for virtually all DTC patients. The increase in the incidence of low recurrence-risk DTC patients brought the cost-benefitrisk rationale of this attitude into question. Over recent years, clinicians have, in the light of prospective or large retrospective studies, adopted a risk-adapted management approach. There is a current trend of de-escalation in indications for RAI, activities used and modality of preparation.
2. Initial risk stratification The most commonly used staging system to predict risk of death in patients with DTC is AJCC/UICC TNM staging (Table 1). Recurrence risk stratification systems have been developed and used in clinical practice for the management of DTC patients, and in particular for the decision to implement postoperative RAI. The most common classifications have been defined in the American [1] and European guidelines [2]. The results of postoperative thyroglobulin assay and post-treatment whole-body RAI scan are included in the assessment of recurrence risk in the American guidelines, which distinguish the following categories: • low-risk patients: pT1, pT2, intra-thyroidal pT3, N0 or M0 DTC, without aggressive histology and with normal posttreatment whole-body RAI scan if performed; • intermediate-risk patients: extra-thyroidal pT3 or N1 DTC, or aggressive histology or vascular invasion, or abnormal neck uptake on post-treatment whole-body RAI; • high-risk patients: pT4 or M1 DTC, or without complete tumor resection, or with thyroglobulin value suggestive of distant metastases. Risk stratification as defined by the European Thyroid Association (ETA) is as follows: • very low-risk patients: pT1a(s), N0, M0; • high-risk patients: N1 or M1 or pT3 or pT4, or without complete tumor resection; • low-risk patients: all other patients, including those with aggressive histology. Since the publication of these guidelines, recent data have supported the concept that not all N1 DTC patients are equal [3]. Specific characteristics of lymph-node metastases (pre- or per-operatively diagnosed, size, number, extra-capsular extension) could be used to stratify recurrence risk. Lymph-node metastases that are few in number (≤5) and small in size (<10 mm) and not diagnosed pre- or per-operatively are associated with limited recurrence risk (<5%). There is a need to reconsider the previous paradigm of equal risk magnitude for all N1 DTCs and to stratify management according to N1 characteristics.
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Whether all follicular thyroid cancers should be considered as at high risk of recurrence is controversial. Minimally invasive follicular tumor, especially in young patients (<45 years old) and without vascular invasion or distant metastasis, appears to have excellent prognosis [4,5]. It is noteworthy that at present none of the mortality or recurrence-risk assessment systems incorporate molecular testing results. Recent publications could lead to this attitude being revised, including molecular alterations such as BRAF or TERT (telomerase reverse transcriptase) promoter mutations in the stratification systems detailed above [6,7].
3. Goals of radioiodine administration Three situations should be distinguished regarding administration of RAI: • Remnant ablation, to eliminate the postsurgical normal thyroid remnant in order to achieve an undetectable serum thyroglobulin level. Remnant ablation facilitates followup and identification of recurrence by thyroglobulin assay. Systematic whole-body RAI scan, usually performed 3 to 5 days after RAI administration, allows completion of initial staging. Low RAI doses are sufficient for remnant ablation (30-50 mCi). • Adjuvant therapy, to destroy suspected neoplastic residual tumor in order to improve disease-free, overall and specific survival. • Treatment to destroy known metastatic locations at diagnosis or during follow-up. The goal of RAI therapy is to improve disease-free, overall and specific survival. Successful RAI administration in initial management of DTC is defined by an undetectable or very low basal thyroglobulin level (<0.15 ng/ml or 0.27 ng/ml) in the absence of interfering antibodies or low stimulated thyroglobulin level (<1 or 2 ng/ml) with normal neck ultrasound [8,9]. Diagnostic whole-body scan is not routinely performed and is mainly reserved for patients with thyroglobulin antibodies. The ultimate goal of RAI administration is to decrease recurrence and mortality rates without impairing quality of life.
4. When radioiodine should be performed and what activities should be used? There is general agreement that RAI administration improves overall and disease-specific mortality and diseasefree survival in high-risk DTC patients. In a systematic review of methodologically acceptable studies examining the effectiveness of postoperative RAI administration, disease-specific mortality was improved in 3 out of 12 eligible studies, including the largest (from Ohio State) and a Turkish study with a high proportion of high-risk individuals [10]. Another study, including about 2,900 patients with a median follow-up of 3 years, demonstrated improved disease-specific and disease-
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Table 1 AJCC 7th edition/TNM and staging Classification System for Differentiated Thyroid Carcinoma. TNM T T1a T1b T2 T3 T4a T4b N N0 N1a N1b
Definition Intrathyroidal tumor ≤1 cm Intrathyroidal tumor >1 cm but ≤2 cm in greatest dimension, Intrathyroidal tumor >2 cm but ≤4 cm in greatest dimension, Intrathyroidal tumor >4 cm in greatest dimension -orAny size tumor with minimal extrathyroid extension (e.g., extension into sternothyroid muscle or perithyroidal soft tissues). Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. Tumor of any size invading prevertebral fascia or encasing carotid artery or mediastinal vessels No metastatic nodes Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes). Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII)
M M0
No distant metastases
M1
Distant metastases
Staging
<45 yers-old
≥ 45 years-old
Stage I
Any T, any N, M0
pT1, N0, M0
Stage II
Any T, any N, M1
pT2, N0, M0
Stage III
–
pT1-3/N1a/M0, pT3/N0/M0,
Stage IV
–
pT1-4/N1b/M0, Any T, Any N, M1
free survival in stage III and IV patients, most of whom are at high risk (i.e., >45 years, pT4, N1b, pT3, N1a) [11]. RAI provides survival benefit in follicular thyroid carcinoma patients with distant metastasis and lymph-node involvement [12]. Current guidelines recommend routine RAI therapy with high activities (100-200 mCi) for high-risk patients, as it aims to destroy suspected or known tumoral foci [1,2]. For intermediate-risk DTC patients, there is controversy concerning the benefit of RAI administration. Disease-specific and disease-free survival were not improved after RAI administration in stage I DTC patients (any T, any N, M0 in patients <45 years, and pT1, N0, M0 in patients >45 years), although not all of these are intermediate-risk patients [11]. On the other hand, disease-specific and disease-free survival were improved in stage III DTC patients, corresponding to the ATA intermediate-risk category (>45 years pT3, N0, M0 and pT1-3, N1a, M0), and in stage IV DTC patients, which includes intermediate and high-risk patients (>45 years pT4a, N0 or N1a and pT1-pT4a, N1b, M0 and pT4b, and M1 patients) [11]. RAI administration also improved overall survival in papillary thyroid cancer (PTC) with aggressive histology (i.e., tall-cell or diffuse sclerosing variants) [13]. However, it did not significantly improve disease-specific mortality or tumor recurrence in the 1,917 PTC patients with
MACIS (distant metastasis, age, complete resection, local/ vascular invasion) scores <6, including patients with lymphnode metastasis [14]. Recurrence risk certainly varies within the category of intermediate-risk patients, especially in the sub-group of N1 patients [3]. RAI administration could be beneficial in intermediate-risk patients at the highest risk of recurrence: i.e., aggressive histology, massive lymph-node involvement and older patients. Regarding the optimal RAI activity to administer, there is little evidence to suggest that increasing RAI activity dose is associated with improved clinical outcome [1,15]. One option would be to select indications and/or RAI activities according to postoperative status assessed on serum thyroglobulin and neck ultrasonography. In a retrospective study of 638 N1 PTCs followed for a median 3.4 years, a combination of normal postoperative ultrasound and stimulated thyroglobulin <10 mg/L at the time of RAI ablation conferred a postoperatively reassessed risk of recurrence of less than 6% in all ATA risk-groups [16]. Early postoperative risk reassessment could help to individually tailor RAI treatment, leading to recommendations for low-dose RAI, as suggested by others [17]. For low-risk patients, publications failed to demonstrate improved overall or specific survival with RAI [11,18,19]. The risk of recurrence is by definition low in this group, and RAI ablation is unlikely to have a noticeable impact on the recurrence rate. In a retrospective cohort of 290 low-risk DTC patients (pT1-pT2, N0, M0), with a median follow-up of 5 years, only 1 patient had cervical lymphnode recurrence [20]. In a prospective study, 136 PTC patients, classified as low-risk patients (non-aggressive histology, pT1b-3N0M0) and undergoing total thyroidectomy with no signs of residual neoplastic foci (i.e., stimulated thyroglobulin ≤1 ng/ml, negative anti-Tg antibodies,
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and normal neck ultrasound) were followed for a median 3.5 years; only 1 patient (1.8 cm pT3(s), N0 PTC) had recurrence of cervical lymph-node metastasis detected by neck ultrasound [21]. However, the majority of reports are retrospective, incurring possible bias. Moreover, RAI remnant ablation in lowrisk patients presents the theoretical advantage of facilitating follow-up with thyroglobulin assay, especially in low-risk patients with elevated postoperative thyroglobulin, and of detecting occult disseminated disease that can rarely but sometimes be misdiagnosed based on cervical neck ultrasound and thyroglobulin testing alone. For such reasons, current guidelines advocate selective use of RAI with the minimum activity (30-100 mCi) necessary to achieve successful remnant ablation [1,2]. When RAI administration is implemented, one metaanalysis [22] and two prospective randomized trials [23,24] have demonstrated equivalent ablation rates for 30 and 100 mCi. In both reports (the “Essai stimulation ablation” trial with 752 patients [24] and the “High or Low” study with 438 patients [23]), most patients were at low risk of recurrence (pT1b, N0/Nx, pT2N0). These studies and other authors have also demonstrated the equivalence of rhTSH stimulation and levothyroxine withdrawal as methods of preparation prior to administration of low-dose radioiodine [25]. Since their publication, the use of rh-TSH and 30 mCi for remnant ablation in low-risk patients has been generalized. Others in France have proposed a medico-economically effective outpatient ablation strategy with 20 mCi for low-risk DTC patients (this activity threshold avoids hospital admission in France) [26]. Patients in these studies are currently being followed up to assess long-term recurrence risk and ensure that there is no increased recurrence risk in patients who received 30 mCi in comparison with those who received 100 mCi. Preliminary data on this issue have been mostly reassuring [19,27]. Notably, one recent publication questioned the relevance of low-dose administration for low-risk patients, especially for older subjects (>45 years), in whom disease-specific mortality increased after administration of low (<50 mCi) RAI doses [28]. Recent publications highlighted the fact that low-risk DTC patients can be cured without RAI ablation [20,21]. Moreover, thyroglobulin measurement, including the sensitive lastgeneration assay, can effectively be used in the follow-up of patients treated by total thyroidectomy without RAI ablation [29]. The next step is to determine whether low-activity RAI could be avoided in a selected population of low-risk DTC. Two ongoing prospective randomized clinical studies, a French trial (NCT01837745) and a British trial, will compare outcomes after either administration of 30 mCi following rhTSH preparation or no RAI administration in low-risk patients followed up for 5 years [30]. For very low-risk DTC patients, RAI administration is not recommended [1,2], as recurrence risk for such patients (pT1a uni- or multi-focal, N0/ Nx) is less than 3% [31,32].
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5. Which modality of preparation when RAI is used? Effective endogenous TSH stimulation can be achieved via two methods of preparation: • Thyroid hormone withdrawal for 4 weeks with possible T3 replacement stopped 2 weeks before RAI administration. This method is responsible for hypothyroidism symptoms and impaired quality of life. • Administration of rhTSH (Thyrogen, Genzyme Transgenics Corporation, Cambridge, MA) with the patient continuing L-thyroxine (LT4), with the advantage of avoiding hypothyroid-related symptoms and maintaining quality of life [23,24]. Both methods of preparation can achieve adequate stimulation: i.e., TSH >30 mUI/L in more than 90% of patients. The 2009 American guidelines recommended either thyroxine withdrawal or exogenous rhTSH stimulation. For low-risk DTC patients, the currently recommended modality of preparation has been detailed above. For high-risk patients, the 2006 European guidelines supported the use of thyroxin withdrawal. Since the publication of these guidelines, a few publications have focused on the modality of preparation for intermediate and high-risk DTC patients. Bartenstein et al., in a retrospective multicenter study, reported that remnant ablation, defined as no or only trace uptake in the thyroid bed on a diagnostic whole-body scan or stimulated thyroglobulin <2 ng/ml performed more than 6 months after RAI administration, was achieved equally either after thyroid hormone withdrawal or administration of rhTSH [33]. In a retrospective cohort of 586 DTC patients, 53% and 26% of whom were initially classified as being at respectively intermediate or high risk, prepared for RAI administration by either thyroid hormone withdrawal or rhTSH preparation, Hugo et al. analyzed response to initial therapy (based on thyroglobulin assay and neck ultrasound) and clinical status at final follow-up (median follow-up, 9 years). They concluded that rhTSH preparation for RAI administration can be effective in intermediate and high-risk patients without known distant metastases [34]. However, prospective controlled studies of long-term outcome are needed before rhTSH can be recommended for highrisk patients. For selected intermediate-risk DTC patients, preparation with rhTSH stimulation may be considered as an alternative to thyroid hormone withdrawal.
6. Conclusion Radioiodine indications depend on initial risk stratification which in turn mainly depends on the pTNM classification. For high-risk patients, high level RAI activities are certainly beneficial in terms of improvement of diseasespecific survival. RAI administration should be imple-
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mented in selected cases of intermediate-risk patients, especially those with the highest risk of recurrence (for example, extensive lymph node involvement). On the other hand, lower activities may be employed for selected intermediate-risk patients, in particular those with limited lymph-node involvement or considered to be in remission based on postoperative thyroglobulin assay and cervical ultrasound. Low-risk patients may benefit from low-dose RAI. Current studies are evaluating the risk-benefit ratio of simple follow-up for these patients. There is a need for prospective randomized trials to better delineate the indications and modalities of RAI administration per patient subgroup according to estimated recurrence risk. One challenge in the future will be to reduce variation in the management of DTC patients and to improve outcome and quality of life [35].
Conflicts of interest L. Leenhardt: Clinical trials: as main (head) clinical or laboratory investigator, or study coordinator (APHP). Occasional involvements: expert reports (Bayer, Sanofi Genzyme). Occasional involvements: advisory services (Bayer, Sanofi Genzyme, Roche). Conferences: attendance as contributor (SFE ECE ETA). Conferences: attendance as audience member (cost of travel and accommodation paid for by an organisation or company) (SFE ECE ETA). C. Buffet, C. Ghander, E. le Marois: authors declare no conflict of interest.
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[10] Sawka, A.M., et al., An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinol Metab Clin North Am 2008;37:457-80, x. [11] Jonklaas, J., et al., Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006;16:1229-42. [12] Podnos, Y.D., et al., The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer. Am Surg 2005;71:731-4. [13] Kazaure, H.S., S.A. Roman, and J.A. Sosa, Aggressive variants of papillary thyroid cancer: incidence, characteristics and predictors of survival among 43,738 patients. Ann Surg Oncol 2012;19:1874-80. [14] Hay, I.D., et al., Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26:879-85. [15] Castagna, M.G., et al., Post-surgical thyroid ablation with low or high radioiodine activities results in similar outcomes in intermediate risk differentiated thyroid cancer patients. Eur J Endocrinol 2013;169:23-9. [16] Lepoutre-Lussey, C., et al., Post-operative neck ultrasound and risk stratification in differentiated thyroid cancer patients with initial lymph node involvement. Eur J Endocrinol 2014;170:837-46. [17] Rosario, P.W. and M.R. Calsolari, Thyroid ablation with 1.1 GBq (30 mCi) iodine-131 in patients with papillary thyroid carcinoma at intermediate risk for recurrence. Thyroid 2014;24:826-31. [18] Jonklaas, J., et al., Radioiodine therapy in patients with stage I differentiated thyroid cancer. Thyroid 2010;20:1423-4. [19] Schvartz, C., et al., Impact on overall survival of radioactive iodine in low-risk differentiated thyroid cancer patients. J Clin Endocrinol Metab 2012;97:1526-35. [20] Durante, C., et al., Long-term surveillance of papillary thyroid cancer patients who do not undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement? J Clin Endocrinol Metab 2012;97:2748-53. [21] Rosario, P.W., et al., Postoperative Stimulated Thyroglobulin ≤ 1 ng/ml as a Criterion to Spare Low-Risk Patients with Papillary Thyroid Cancer from Radioiodine Ablation. Thyroid 2012. [22] Cheng, W., et al., Low- or high-dose radioiodine remnant ablation for differentiated thyroid carcinoma: a meta-analysis. J Clin Endocrinol Metab 2013;98:1353-60. [23] Mallick, U., et al., Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 2012;366:1674-85. [24] Schlumberger, M., et al., Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012;366:1663-73. [25] Molinaro, E., et al., Patients with differentiated thyroid cancer who underwent radioiodine thyroid remnant ablation with low-activity 131I after either recombinant human TSH or thyroid hormone therapy withdrawal showed the same outcome after a 10-year follow-up. J Clin Endocrinol Metab 2013;98:2693-700. [26] Clerc, J., et al., Outpatient thyroid remnant ablation using repeated low 131-iodine activities (740 MBq/20 mCix2) in patients with low-risk differentiated thyroid cancer. J Clin Endocrinol Metab 2012;97:871-80. [27] Maenpaa, H.O., et al., Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: a randomized study. PLoS One 2008;3:e1885. [28] Verburg, F.A., et al., Long-term survival in differentiated thyroid cancer is worse after low-activity initial post-surgical 131 I therapy in both high- and low-risk patients. J Clin Endocrinol Metab 2014;99:4487-96.
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[29] Nascimento, C., et al., Ultrasensitive serum thyroglobulin measurement is useful for the follow-up of patients treated with total thyroidectomy without radioactive iodine ablation. Eur J Endocrinol 2013;169:689-93. [30] Mallick, U., et al., Iodine or Not (IoN) for low-risk differentiated thyroid cancer: the next UK National Cancer Research Network randomised trial following HiLo. Clin Oncol (R Coll Radiol) 2012;24:159-61. [31] Buffet, C., et al., Scoring system for predicting recurrences in patients with papillary thyroid microcarcinoma. Eur J Endocrinol 2012. [32] Mehanna, H., et al., Differences in the recurrence and mortality outcomes rates of incidental and nonincidental papillary
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thyroid microcarcinoma: a systematic review and meta-analysis of 21 329 person-years of follow-up. J Clin Endocrinol Metab 2014;99:2834-43. [33] Bartenstein, P., et al., High-risk patients with differentiated thyroid cancer T4 primary tumors achieve remnant ablation equally well using rhTSH or thyroid hormone withdrawal. Thyroid 2014;24:p. 480-7. [34] Hugo, J., et al., Recombinant human thyroid stimulating hormone-assisted radioactive iodine remnant ablation in thyroid cancer patients at intermediate to high risk of recurrence. Thyroid 2012;22:1007-15. [35] Haymart, M.R., et al., Variation in the management of thyroid cancer. J Clin Endocrinol Metab 2013;98:2001-8.
Indications for radioiodine administration in follicular-derived thyroid cancer Les indications de l’irathérapie dans les cancers thyroïdiens de souche folliculaire C. Buffet, C. Ghander, E. le Marois, L. Leenhardt* Unité thyroïde-tumeurs endocrines, Institut d’endocrinologie E3M et Service de médecine nucléaire, Hôpital Pitié-Salpêtrière, Université Pierre-et-Marie-Curie/Institut Universitaire du Cancer, 83, boulevard de L’Hôpital, 75013 Paris, France
Abstract Indications for radioiodine administration after thyroid cancer surgery have shifted in recent years toward personalized management, adapted to the individual risk of tumor progression. The most recent guidelines and studies favor de-escalation in indications for administration, dosage and means of preparation with exogenous recombinant TSH stimulation as treatment of choice. Radioiodine administration has 3 possible objectives: • ablation of normal thyroid tissue remnants in patients with low risk of progression, using low radioiodine activity levels, with the advantage of completing disease staging on whole-body scintigraphy performed after administration of the radioiodine capsule, and of facilitating follow-up by thyroglobulin assay; • adjuvant treatment for suspected microscopic metastases in patients with intermediate or high risk of progression, using higher activity levels, with the theoretic aim of limiting recurrence and mortality; • curative treatment in high-risk patients with proven metastases, using exclusively high activity levels, with a view to improving specific survival. In future, indications for ablation and/or activity prescription may be governed by an algorithm incorporating individual baseline progression risk (essentially founded of pTNM staging) and postoperative data such as thyroglobulin level and neck ultrasound results. © 2015 Published by Elsevier Masson SAS. All rights reserved. Keywords: Risk-stratification; Remnant ablation; Radioiodine activity, rhTSH Résumé Les indications d’administration d’iode radioactif après une chirurgie pour cancer de la thyroïde se sont modifiées au cours de ces dernières années au profit d’une prise en charge personnalisée, adaptée au risque évolutif tumoral. Les dernières recommandations et les études les plus récentes vont dans le sens d’une désescalade des indications d’administration du radio-iode, des activités prescrites et des modalités de préparation à l’irathérapie au profit de la stimulation par TSH recombinante exogène. On distingue trois objectifs à l’irathérapie : • l’ablation de reliquats de tissus thyroïdiens normaux pour les patients à faible risque évolutif, obtenue avec de faibles activités ayant pour avantage de compléter le staging de la maladie grâce à la scintigraphie corps entier faite après prise de gélule d’iode et de faciliter le suivi du patient grâce au dosage de thyroglobuline ; • un traitement adjuvant d’une maladie métastatique microscopique suspectée chez des patients à risque évolutif intermédiaire ou élevé, obtenu avec de plus fortes activités, dans le but théorique de diminuer le nombre de récidive et de décès ; • un traitement curatif chez des patients à haut risque ayant une maladie métastatique prouvée, obtenu uniquement avec de fortes activités, dans le but d’améliorer la survie spécifique. À l’avenir, les indications d’ablation et/ou les activités prescrites pourraient dépendre d’un algorithme incluant le risque évolutif initial du patient (tenant compte essentiellement de la classification pTNM) et de données post-opératoires comme la valeur de thyroglobuline et le résultat de l’échographie cervicale. © 2015 Publié par Elsevier Masson SAS. Tous droits réservés. Mots-clés : Stratification du risque ; Ablation ; Activité ; TSH recombinante
* Corresponding author. E-mail Address: [email protected] (L. Leenhardt).
© 2015 Elsevier Masson SAS. All rights reserved.
C. Buffet et al. / Annales d’Endocrinologie 76 (2015) 1S2-1S7
1. Introduction Differentiated thyroid cancer (DTC) treatment usually consists of thyroidectomy, often followed by radioiodine administration. From the 1980s, radioiodine (RAI) was prescribed for virtually all DTC patients. The increase in the incidence of low recurrence-risk DTC patients brought the cost-benefitrisk rationale of this attitude into question. Over recent years, clinicians have, in the light of prospective or large retrospective studies, adopted a risk-adapted management approach. There is a current trend of de-escalation in indications for RAI, activities used and modality of preparation.
2. Initial risk stratification The most commonly used staging system to predict risk of death in patients with DTC is AJCC/UICC TNM staging (Table 1). Recurrence risk stratification systems have been developed and used in clinical practice for the management of DTC patients, and in particular for the decision to implement postoperative RAI. The most common classifications have been defined in the American [1] and European guidelines [2]. The results of postoperative thyroglobulin assay and post-treatment whole-body RAI scan are included in the assessment of recurrence risk in the American guidelines, which distinguish the following categories: • low-risk patients: pT1, pT2, intra-thyroidal pT3, N0 or M0 DTC, without aggressive histology and with normal posttreatment whole-body RAI scan if performed; • intermediate-risk patients: extra-thyroidal pT3 or N1 DTC, or aggressive histology or vascular invasion, or abnormal neck uptake on post-treatment whole-body RAI; • high-risk patients: pT4 or M1 DTC, or without complete tumor resection, or with thyroglobulin value suggestive of distant metastases. Risk stratification as defined by the European Thyroid Association (ETA) is as follows: • very low-risk patients: pT1a(s), N0, M0; • high-risk patients: N1 or M1 or pT3 or pT4, or without complete tumor resection; • low-risk patients: all other patients, including those with aggressive histology. Since the publication of these guidelines, recent data have supported the concept that not all N1 DTC patients are equal [3]. Specific characteristics of lymph-node metastases (pre- or per-operatively diagnosed, size, number, extra-capsular extension) could be used to stratify recurrence risk. Lymph-node metastases that are few in number (≤5) and small in size (<10 mm) and not diagnosed pre- or per-operatively are associated with limited recurrence risk (<5%). There is a need to reconsider the previous paradigm of equal risk magnitude for all N1 DTCs and to stratify management according to N1 characteristics.
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Whether all follicular thyroid cancers should be considered as at high risk of recurrence is controversial. Minimally invasive follicular tumor, especially in young patients (<45 years old) and without vascular invasion or distant metastasis, appears to have excellent prognosis [4,5]. It is noteworthy that at present none of the mortality or recurrence-risk assessment systems incorporate molecular testing results. Recent publications could lead to this attitude being revised, including molecular alterations such as BRAF or TERT (telomerase reverse transcriptase) promoter mutations in the stratification systems detailed above [6,7].
3. Goals of radioiodine administration Three situations should be distinguished regarding administration of RAI: • Remnant ablation, to eliminate the postsurgical normal thyroid remnant in order to achieve an undetectable serum thyroglobulin level. Remnant ablation facilitates followup and identification of recurrence by thyroglobulin assay. Systematic whole-body RAI scan, usually performed 3 to 5 days after RAI administration, allows completion of initial staging. Low RAI doses are sufficient for remnant ablation (30-50 mCi). • Adjuvant therapy, to destroy suspected neoplastic residual tumor in order to improve disease-free, overall and specific survival. • Treatment to destroy known metastatic locations at diagnosis or during follow-up. The goal of RAI therapy is to improve disease-free, overall and specific survival. Successful RAI administration in initial management of DTC is defined by an undetectable or very low basal thyroglobulin level (<0.15 ng/ml or 0.27 ng/ml) in the absence of interfering antibodies or low stimulated thyroglobulin level (<1 or 2 ng/ml) with normal neck ultrasound [8,9]. Diagnostic whole-body scan is not routinely performed and is mainly reserved for patients with thyroglobulin antibodies. The ultimate goal of RAI administration is to decrease recurrence and mortality rates without impairing quality of life.
4. When radioiodine should be performed and what activities should be used? There is general agreement that RAI administration improves overall and disease-specific mortality and diseasefree survival in high-risk DTC patients. In a systematic review of methodologically acceptable studies examining the effectiveness of postoperative RAI administration, disease-specific mortality was improved in 3 out of 12 eligible studies, including the largest (from Ohio State) and a Turkish study with a high proportion of high-risk individuals [10]. Another study, including about 2,900 patients with a median follow-up of 3 years, demonstrated improved disease-specific and disease-
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Table 1 AJCC 7th edition/TNM and staging Classification System for Differentiated Thyroid Carcinoma. TNM T T1a T1b T2 T3 T4a T4b N N0 N1a N1b
Definition Intrathyroidal tumor ≤1 cm Intrathyroidal tumor >1 cm but ≤2 cm in greatest dimension, Intrathyroidal tumor >2 cm but ≤4 cm in greatest dimension, Intrathyroidal tumor >4 cm in greatest dimension -orAny size tumor with minimal extrathyroid extension (e.g., extension into sternothyroid muscle or perithyroidal soft tissues). Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. Tumor of any size invading prevertebral fascia or encasing carotid artery or mediastinal vessels No metastatic nodes Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes). Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII)
M M0
No distant metastases
M1
Distant metastases
Staging
<45 yers-old
≥ 45 years-old
Stage I
Any T, any N, M0
pT1, N0, M0
Stage II
Any T, any N, M1
pT2, N0, M0
Stage III
–
pT1-3/N1a/M0, pT3/N0/M0,
Stage IV
–
pT1-4/N1b/M0, Any T, Any N, M1
free survival in stage III and IV patients, most of whom are at high risk (i.e., >45 years, pT4, N1b, pT3, N1a) [11]. RAI provides survival benefit in follicular thyroid carcinoma patients with distant metastasis and lymph-node involvement [12]. Current guidelines recommend routine RAI therapy with high activities (100-200 mCi) for high-risk patients, as it aims to destroy suspected or known tumoral foci [1,2]. For intermediate-risk DTC patients, there is controversy concerning the benefit of RAI administration. Disease-specific and disease-free survival were not improved after RAI administration in stage I DTC patients (any T, any N, M0 in patients <45 years, and pT1, N0, M0 in patients >45 years), although not all of these are intermediate-risk patients [11]. On the other hand, disease-specific and disease-free survival were improved in stage III DTC patients, corresponding to the ATA intermediate-risk category (>45 years pT3, N0, M0 and pT1-3, N1a, M0), and in stage IV DTC patients, which includes intermediate and high-risk patients (>45 years pT4a, N0 or N1a and pT1-pT4a, N1b, M0 and pT4b, and M1 patients) [11]. RAI administration also improved overall survival in papillary thyroid cancer (PTC) with aggressive histology (i.e., tall-cell or diffuse sclerosing variants) [13]. However, it did not significantly improve disease-specific mortality or tumor recurrence in the 1,917 PTC patients with
MACIS (distant metastasis, age, complete resection, local/ vascular invasion) scores <6, including patients with lymphnode metastasis [14]. Recurrence risk certainly varies within the category of intermediate-risk patients, especially in the sub-group of N1 patients [3]. RAI administration could be beneficial in intermediate-risk patients at the highest risk of recurrence: i.e., aggressive histology, massive lymph-node involvement and older patients. Regarding the optimal RAI activity to administer, there is little evidence to suggest that increasing RAI activity dose is associated with improved clinical outcome [1,15]. One option would be to select indications and/or RAI activities according to postoperative status assessed on serum thyroglobulin and neck ultrasonography. In a retrospective study of 638 N1 PTCs followed for a median 3.4 years, a combination of normal postoperative ultrasound and stimulated thyroglobulin <10 mg/L at the time of RAI ablation conferred a postoperatively reassessed risk of recurrence of less than 6% in all ATA risk-groups [16]. Early postoperative risk reassessment could help to individually tailor RAI treatment, leading to recommendations for low-dose RAI, as suggested by others [17]. For low-risk patients, publications failed to demonstrate improved overall or specific survival with RAI [11,18,19]. The risk of recurrence is by definition low in this group, and RAI ablation is unlikely to have a noticeable impact on the recurrence rate. In a retrospective cohort of 290 low-risk DTC patients (pT1-pT2, N0, M0), with a median follow-up of 5 years, only 1 patient had cervical lymphnode recurrence [20]. In a prospective study, 136 PTC patients, classified as low-risk patients (non-aggressive histology, pT1b-3N0M0) and undergoing total thyroidectomy with no signs of residual neoplastic foci (i.e., stimulated thyroglobulin ≤1 ng/ml, negative anti-Tg antibodies,
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and normal neck ultrasound) were followed for a median 3.5 years; only 1 patient (1.8 cm pT3(s), N0 PTC) had recurrence of cervical lymph-node metastasis detected by neck ultrasound [21]. However, the majority of reports are retrospective, incurring possible bias. Moreover, RAI remnant ablation in lowrisk patients presents the theoretical advantage of facilitating follow-up with thyroglobulin assay, especially in low-risk patients with elevated postoperative thyroglobulin, and of detecting occult disseminated disease that can rarely but sometimes be misdiagnosed based on cervical neck ultrasound and thyroglobulin testing alone. For such reasons, current guidelines advocate selective use of RAI with the minimum activity (30-100 mCi) necessary to achieve successful remnant ablation [1,2]. When RAI administration is implemented, one metaanalysis [22] and two prospective randomized trials [23,24] have demonstrated equivalent ablation rates for 30 and 100 mCi. In both reports (the “Essai stimulation ablation” trial with 752 patients [24] and the “High or Low” study with 438 patients [23]), most patients were at low risk of recurrence (pT1b, N0/Nx, pT2N0). These studies and other authors have also demonstrated the equivalence of rhTSH stimulation and levothyroxine withdrawal as methods of preparation prior to administration of low-dose radioiodine [25]. Since their publication, the use of rh-TSH and 30 mCi for remnant ablation in low-risk patients has been generalized. Others in France have proposed a medico-economically effective outpatient ablation strategy with 20 mCi for low-risk DTC patients (this activity threshold avoids hospital admission in France) [26]. Patients in these studies are currently being followed up to assess long-term recurrence risk and ensure that there is no increased recurrence risk in patients who received 30 mCi in comparison with those who received 100 mCi. Preliminary data on this issue have been mostly reassuring [19,27]. Notably, one recent publication questioned the relevance of low-dose administration for low-risk patients, especially for older subjects (>45 years), in whom disease-specific mortality increased after administration of low (<50 mCi) RAI doses [28]. Recent publications highlighted the fact that low-risk DTC patients can be cured without RAI ablation [20,21]. Moreover, thyroglobulin measurement, including the sensitive lastgeneration assay, can effectively be used in the follow-up of patients treated by total thyroidectomy without RAI ablation [29]. The next step is to determine whether low-activity RAI could be avoided in a selected population of low-risk DTC. Two ongoing prospective randomized clinical studies, a French trial (NCT01837745) and a British trial, will compare outcomes after either administration of 30 mCi following rhTSH preparation or no RAI administration in low-risk patients followed up for 5 years [30]. For very low-risk DTC patients, RAI administration is not recommended [1,2], as recurrence risk for such patients (pT1a uni- or multi-focal, N0/ Nx) is less than 3% [31,32].
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5. Which modality of preparation when RAI is used? Effective endogenous TSH stimulation can be achieved via two methods of preparation: • Thyroid hormone withdrawal for 4 weeks with possible T3 replacement stopped 2 weeks before RAI administration. This method is responsible for hypothyroidism symptoms and impaired quality of life. • Administration of rhTSH (Thyrogen, Genzyme Transgenics Corporation, Cambridge, MA) with the patient continuing L-thyroxine (LT4), with the advantage of avoiding hypothyroid-related symptoms and maintaining quality of life [23,24]. Both methods of preparation can achieve adequate stimulation: i.e., TSH >30 mUI/L in more than 90% of patients. The 2009 American guidelines recommended either thyroxine withdrawal or exogenous rhTSH stimulation. For low-risk DTC patients, the currently recommended modality of preparation has been detailed above. For high-risk patients, the 2006 European guidelines supported the use of thyroxin withdrawal. Since the publication of these guidelines, a few publications have focused on the modality of preparation for intermediate and high-risk DTC patients. Bartenstein et al., in a retrospective multicenter study, reported that remnant ablation, defined as no or only trace uptake in the thyroid bed on a diagnostic whole-body scan or stimulated thyroglobulin <2 ng/ml performed more than 6 months after RAI administration, was achieved equally either after thyroid hormone withdrawal or administration of rhTSH [33]. In a retrospective cohort of 586 DTC patients, 53% and 26% of whom were initially classified as being at respectively intermediate or high risk, prepared for RAI administration by either thyroid hormone withdrawal or rhTSH preparation, Hugo et al. analyzed response to initial therapy (based on thyroglobulin assay and neck ultrasound) and clinical status at final follow-up (median follow-up, 9 years). They concluded that rhTSH preparation for RAI administration can be effective in intermediate and high-risk patients without known distant metastases [34]. However, prospective controlled studies of long-term outcome are needed before rhTSH can be recommended for highrisk patients. For selected intermediate-risk DTC patients, preparation with rhTSH stimulation may be considered as an alternative to thyroid hormone withdrawal.
6. Conclusion Radioiodine indications depend on initial risk stratification which in turn mainly depends on the pTNM classification. For high-risk patients, high level RAI activities are certainly beneficial in terms of improvement of diseasespecific survival. RAI administration should be imple-
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mented in selected cases of intermediate-risk patients, especially those with the highest risk of recurrence (for example, extensive lymph node involvement). On the other hand, lower activities may be employed for selected intermediate-risk patients, in particular those with limited lymph-node involvement or considered to be in remission based on postoperative thyroglobulin assay and cervical ultrasound. Low-risk patients may benefit from low-dose RAI. Current studies are evaluating the risk-benefit ratio of simple follow-up for these patients. There is a need for prospective randomized trials to better delineate the indications and modalities of RAI administration per patient subgroup according to estimated recurrence risk. One challenge in the future will be to reduce variation in the management of DTC patients and to improve outcome and quality of life [35].
Conflicts of interest L. Leenhardt: Clinical trials: as main (head) clinical or laboratory investigator, or study coordinator (APHP). Occasional involvements: expert reports (Bayer, Sanofi Genzyme). Occasional involvements: advisory services (Bayer, Sanofi Genzyme, Roche). Conferences: attendance as contributor (SFE ECE ETA). Conferences: attendance as audience member (cost of travel and accommodation paid for by an organisation or company) (SFE ECE ETA). C. Buffet, C. Ghander, E. le Marois: authors declare no conflict of interest.
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