New advances in the management of differentiated thyroid cancer

ACHAIKI IATRIKI | 2021; 40(1):22–24

Editorial

Georgios K. Markantes, Marina A. Michalaki


Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

Received: 05 May 2020; Accepted: 29 Jun 2020

Corresponding author: Marina A. Michalaki, Endocrinology, Department of Internal Medicine, University of Patras School of Health Sciences, Patras, PC 26500, Greece, Tel: +30 2610 999427, E-mail: mixmar@upatras.gr

Key words: Thyroid cancer,differentiated thyroid cancer, management, RAI, tyrosine kinase inhibitors

 


Thyroid cancer (TC) accounts for 88% of all endocrine carcinomas [1], is the fifth commonest new cancer diagnosis in women and the eighth most common new cancer diagnosis overall in the US [2]. Differentiated thyroid carcinoma (DTC), namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), constitutes 85-95% of all TC cases [3,4]. PTC represents 90-95% of DTC [3] and is considered an indolent tumor with 10- and 30-year disease-specific mortality rates less than 5% [5] and 10% [6], respectively. Rare and more aggressive subtypes of TC also exist, such as poorly differentiated thyroid cancers (6% of TC), anaplastic carcinoma (<1% of TC) and the C-cell origin medullary carcinoma-MTC (4% of TC) [3]. Over the last two decades, a rising incidence of TC is observed worldwide that can be attributed almost entirely to PTC [7-9]. The observed universal rise in PTC incidence rates is probably due to the increased sensitivity of modern diagnostic methods, since only the incidence of small (T1) PTC increases, while mortality rates remain stable or even decrease [10]. The widespread use of thyroid ultrasonography has led to an increased incidental diagnosis of TC in asymptomatic individuals [8,11].

For many years, the standard of care for all DTC patients included total thyroidectomy with or without cervical lymph node dissection, routine post-operative radioactive I131 (RAI) therapy and thyroid hormone suppressive therapy. After initial treatment, DTC patients were closely followed for life, since recurrences or death could occur even thirty years after the initial diagnosis [6]. However, several clinical trials have shown that such an approach is unnecessarily aggressive for the majority of DTC patients. Therefore, the recently developed guidelines from the American Thyroid Association (ATA) [12] propose a less aggressive initial approach and a less intensive follow up for selected DTC patients.

In particular, they suggest that lobectomy could replace total thyroidectomy in intrathyroidal DTC tumors measuring less than 4cm. Suppressive therapy with levothyroxine which causes iatrogenic subclinical hyperthyroidism with well recognized deleterious health consequences especially in the elderly and in postmenopausal women, is reserved only for patients with metastatic disease or at high risk for recurrence. Furthermore, they propose a more conservative use of postoperative RAI therapy with limited indications, lower activities (as low as 30mCi) and without thyroid hormone withdrawal but with the newly developed human recombinant thyrotropin (rhTSH). Depending on the primary goal of postoperative RAI administration, ATA classifies RAI therapy as: “RAI ablation therapy”, intended to destroy benign thyroid remnants and facilitate follow up; “RAI adjuvant therapy”, aiming to destroy suspected but unproven residual disease and decrease recurrences; and “RAI treatment”, designated to destroy residual or metastatic disease and improve survival [12]. In this guideline, it is also acknowledged that DTC has a distinct biological behavior and though death is rare, recurrences or persistent disease could be more frequent. Therefore, besides the classical AJCC/UICC/ΤΝΜ staging system which predicts mortality, the ATA designed another staging system to evaluate the risk of recurrence and/or persistent disease in DTC patients. The 2015 ATA risk stratification system stratifies patients into three risk groups (low, intermediate, and high) for recurrent/persistent disease, depending on their clinicopathological characteristics after thyroidectomy [12]. The usefulness of this system lies in its availability to aid clinicians in determining the need for RAI therapy after thyroidectomy, the degree of TSH suppression and the intensity of follow-up. Accordingly, RAI ablation therapy after thyroidectomy is not routinely recommended for unifocal or multifocal papillary tumors <1cm, neither for other ATA low-risk DTC patients in the absence of any other adverse feature. Moreover, RAI adjuvant therapy is not recommended but considered in patients at intermediate risk for recurrence or persistent disease [12].

However, other scientific societies have questioned many recommendations of the 2015 ATA guidance. More specifically, the European Thyroid Association (ETA) disagreed with the proposed extent of surgery (lobectomy) for low-risk DTC tumors >2 and <4cm.  They stated three reasons. Firstly, in many European countries with current or recent longstanding iodine deficiency, multinodular disease and bilateral involvement are frequent; secondly, a significant number of patients undergoing lobectomy (30-43%) will need completion total thyroidectomy due to the discovery of high-risk features in pathology reports; finally, lobectomy precludes the subsequent use of RAI therapy [13]. Besides, the ETA, the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) had many concerns regarding the optimal selection of patients for RAI therapy postoperatively as well as the recommended I131 activities for adjuvant therapy [13-15]. European experts favor retaining the longstanding, widely applied practice of RAI postoperative therapy in low- and intermediate-risk patients, since data from prospective, controlled, randomized trials are currently lacking [13]. Notably, two ongoing prospective, multicenter, RCTs -IoN from the United Kingdom and ESTIMABL 2 from France (clinicaltrials.gov identifiers NCT01398085 and NCT01837745, respectively)- are comparing I131 in a dose of 1.11 GBq (30mCi) versus no I131 in low-risk and, in the case of IoN, also in intermediate-risk patients.

Finally, during the last decade, much progress has been made in understanding the molecular landscape of thyroid cancer. Activating mutations of genes encoding effectors of the mitogen-activated protein kinase (MAPK) and PI3/AKT/mTOR pathways have been implicated in the pathogenesis of DTC [3]. These two classical downstream pathways are coupled with receptors with tyrosine kinase activity. BRAFV600E is the most common driver mutation occurring in approximately 50-60% of PTC and rather predisposing to aggressive tumor behavior, while RAS mutations account for 15% of FTCs [3]. Chromosomal rearrangements of several receptors with tyrosine kinase activity, such as RET, NTRK, and ALK have also been described in DTC [3]. Advances in understanding the molecular profile of these tumors lead to improvements in the diagnosis and treatment of DTC patients. Although DTC is considered a tumor with excellent prognosis, approximately 30% of patients with distant metastatic disease do not respond to RAI therapy [16]. “RAI refractory” patients have an unfavorable prognosis with overall survival of <50% at 3 years [5]. Sorafenib and lenvatinib are inhibitors of receptors with tyrosine kinase activity (TKI) and recently they have been used for the treatment of DTC patients with advanced, progressing and RAI refractory disease. However, despite increasing the progression-free survival, they do not increase overall survival, and have numerous adverse effects that severely impair patients’ quality of life [3]. RAI therapy in DTC is based on the ability of thyrocytes to accumulate RAI via the Na+/I- symporter (NIS). RAI-refractory disease develops because NIS expression is suppressed or even absent in a subgroup of malignant thyroid tumors. Novel TKIs (such as selumetinib) that can restore NIS expression and consequently RAI uptake with satisfactory clinical outcomes have recently been developed. All these drugs are currently being tested in clinical trials [16].

In conclusion, the current approach of DTC patients is more sophisticated, less aggressive, and more cost-effective than in the recent past. However, it is surprising that throughout the last century, the mortality and morbidity rates of DTC have practically remained unaltered [17]. The development of novel, targeted therapies based on molecular data will mark the beginning of a new, very promising era in the management of DTC.

Conflict of interest disclosure: None to declare.

Declaration of funding sources: None to declare.

References
  1. Van der Zwan JM, Mallone S, Van Dijk B, Bielska-Lasota M, Otter R, Foschi R, et al. Carcinoma of endocrine organs: results of the RARECARE project. Eur J Cancer. 2012;48:1923-31.
  2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. Jan-Feb 2014;64(1):9-29.
  3. Fagin JA, Wells SA Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med. 2016;375(23):1054-67.
  4. Sherman SI. Thyroid carcinoma. Lancet. 2003;361(9356):501–11.
  5. Riesco-Eizaguirre G, Santisteban P. ENDOCRINE TUMOURS: Advances in the Molecular Pathogenesis of Thyroid Cancer: Lessons From the Cancer Genome. Eur J Endocrinol. 2016;175(5):R203-17.
  6. Dong W, Horiuchi K, Tokumitsu H, Sakamoto A, Noguchi E, Ueda Y, et al. Time-Varying Pattern of Mortality and Recurrence From Papillary Thyroid Cancer: Lessons From a Long-Term Follow-Up. Thyroid. 2019;29(6):802-8.
  7. Wiltshire J, Drake T, Uttley L, Balasubramanian B. Systematic Review of Trends in the Incidence Rates of Thyroid Cancer. Thyroid. 2016;26(11):1541-52.
  8. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295(18):2164-67.
  9. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013; 2013:965212.
  10. Li M, Brito JP, Vaccarella S. Long-Term Declines of Thyroid Cancer Mortality: An International Age–Period–Cohort Analysis. Thyroid. 2020;30(6):838-846.
  11. Russ G, Leboulleux S, Leenhardt L, Hegedüs L. Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. Eur Thyroid J. 2014;3(3):154-63.
  12. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, 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):1-133.
  13. Luster M, Aktolun C, Amendoeira I, Barczyński M, Bible KC, Duntas LH, et al. European perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Proceedings of an interactive international symposium. Thyroid. 2019;29(1):7-26.
  14. Verburg FA, Aktolun C, Chiti A, Frangos S, Giovanella L, Hoffmann M, et al. Why the European Association of Nuclear Medicine has declined to endorse the 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2016;43(6):1001–05.
  15. Tuttle RM, Ahuja S, Avram AM, Bernet VJ, Bourguet P, Daniels GH, et al. Controversies, Consensus, and Collaboration in the Use of 131 I Therapy in Differentiated Thyroid Cancer: A Joint Statement From the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid. 2019;29(4):461-70.
  16. Jhiang SM, Konda B, Sipos JA, Nabhan FA. Prospects for Redifferentiating Agents in the Use of Radioactive Iodine Therapy for Thyroid Cancer. Thyroid. 2020;30(4):471-73.
  17. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary Thyroid Cancer Treated at the Mayo Clinic, 1946 Through 1970: Initial Manifestations, Pathologic Findings, Therapy, and Outcome. Mayo Clin Proc. 1986;61(12):978-96.