Clinical and Translational Oncology (2020) 22:223–235 https://doi.org/10.1007/s12094-019-02284-8 CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline thyroid cancer (2019) E. Gallardo1 · J. Medina2 · J. C. Sánchez3 · A. Viúdez4 · E. Grande5 · I. Porras6 · T. Ramón y Cajal7 · J. Trigo8 · L. Iglesias9 · J. Capdevila10 Received: 27 December 2019 / Accepted: 27 December 2019 / Published online: 31 January 2020 © The Author(s) 2020 Abstract Thyroid carcinoma is the most frequent endocrine malignancy and accounts for around 3% of global cancer incidence. Differ- ent histologies and clinical scenarios make necessary a multidisciplinary approach that includes new diagnostic methods and surgical, radiopharmaceutical and systemic therapies. This guideline updates several aspects of management of thyroid cancer. Keywords Thyroid cancer · Multidisciplinary · Systemic therapy Methodology Health Service Grading System (Table 1). The final text was reviewed and approved by all the authors. The goal of this SEOM guidelines have been developed with the consen- document consists of providing clear practical recommenda- sus of ten members from the Spanish Society of Medical tions about the management of thyroid cancer. Oncology (SEOM). In order to assess the level and quality of evidence and to establish a grade of recommendation of the different statements in this guideline, we based ourselves on The Infectious Diseases Society of America-US Public * E. Gallardo Universitat Autònoma de Barcelona, 08208 Barcelona, egallardo@tauli.cat Sabadell, Spain 2 J. Medina Oncology Department, Hospital Virgen de la Salud, Toledo, boladiez39@yahoo.es Spain 3 J. C. Sánchez Oncology Department, Hospital Universitario Puerta de juancristobal.sg@gmail.com Hierro, Majadahonda, Madrid, Spain 4 A. Viúdez Oncology Department, Complejo Hospitalario de Navarra, aviudez@outlook.es Pamplona, Spain 5 E. Grande Oncology Department, MD Anderson Cancer Center, egrande@mdanderson.es Madrid, Spain 6 I. Porras Oncology Department, Hospital Universitario Reina Sofía, iporras@wanadoo.es Córdoba, Spain 7 T. Ramón y Cajal Oncology Department, Hospital de la Santa Creu i Sant Pau, tramon@santpau.cat Barcelona, Spain 8 J. Trigo Oncology Department, Hospital Universitario Regional jmtrigo@seom.org Virgen de la Victoria, Málaga, Spain 9 L. Iglesias Oncology Department, Hospital Universitario 12 de Octubre, laraiglesias@hotmail.com Madrid, Spain 10 J. Capdevila Oncology Department, Hospital Universitari Vall d’Hebron, jacapdevila@vhebron.net Vall d’Hebron Institut d’Oncologia (VHIO), Barcelona, Spain 1 Oncology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, 13 Vol.:(0123456789) 224 Clinical and Translational Oncology (2020) 22:223–235 Table 1  Infectious diseases Category, grade Definition society of America-US Public Health Service Grading System Strength of recommendation A Good evidence to support a recommendation for use B Moderate evidence to support a recommendation for use C Poor evidence to support a recommendation D Moderate evidence to support a recommendation against use E Good evidence to support a recommendation against use Quality of evidence I Evidence from ≥ 1 properly randomized, controlled trial II Evidence from ≥ 1 well-designed clinical trial, without rand- omization; from cohort or case-controlled analytic studies (preferably from > 1 center); from multiple time series; or from dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees Note: From [43] Introduction variant, columnar cell variant, and diffuse sclerosing vari- ant, have a worse prognosis, as do more highly invasive Thyroid cancer is the most common endocrine malignancy variants of follicular cancer. Medullary thyroid carcinoma, and accounts for 3.1% of global cancer incidence. In 2018, thyroid C-cell derived tumor, accounts for 4% of thyroid 567,000 new cases were estimated worldwide, with dif- cancer. Poorly differentiated, 6%, and anaplastic thyroid ferences by geographical area, age and sex. The global carcinomas, 1%, are associated with aggressive disease age-adjusted incidence rate in women is three times higher [5]. than in men: 10.2 and 3.1 per 100,000, respectively [1]. Although most cases are sporadic, 3–9% of DTC are famil- The estimated incidence of thyroid cancer in Spain in 2018 ial, mainly component of cancer syndromes: Cowden’s dis- was 13.7 per 100,000 in women and 3.8 per 100,000 in ease, familial adenomatous polyposis, and Werner’s syndrome, men [2]. A higher incidence is found in developed coun- are caused by germline loss-of function mutations in PTEN, tries, compared to developing ones [1] and race-ethnic APC, and WRN5, respectively. 20% of medullary thyroid car- differences could be found [3]. However, despite the inci- cinoma are related to hereditary multiple endocrine neoplasia dence differences, mortality rates are quite similar between (MEN) type 2 syndromes, caused by autosomal dominant countries, gender and approximately the same in all ethnic gain-of-function mutations in the RET proto-oncogene. There groups [3]. are three subtypes: MEN2A, MEN2B and familial medul- Incidence has increased progressively worldwide in lary thyroid cancer (FMTC). 98% of MEN2A, 99–100% of recent decades, mostly secondary to small papillary car- MEN2B, and 85% of FMTC cases, present mutations in RET. cinomas as the main consequence of a better diagnostic 6% of patients with clinically sporadic medullary thyroid can- accuracy and overdiagnosis of indolent disease [4]. The cer carry a germline mutation in RET [5]. only well established risk factor for thyroid cancer is ion- The majority of patients have an excellent prognosis, izing radiation, particularly when exposure is in childhood, with a 5-year relative overall survival of 98.2% for all stages although there is evidence that other factors (obesity, (99.9% localized; 98.2% regional; 56.2% distant disease) [3] smoking, hormonal exposures, and certain environmental and, despite increasing incidence, mortality rates from the pollutants) may play a role [1]. disease remain stable and low, with age-adjusted rates of 0.4 Based on the pathology, thyroid cancer can be classified and 0.5 per 100,000 men and women [1]. into subtypes: differentiated, medullary, poorly differenti- ated and anaplastic carcinoma. Differentiated thyroid can- cer (DTC), which arises from follicular thyroid cells, is the Diagnosis, pathology and molecular most common type and is subdivided into papillary thyroid classification carcinoma, 85% of thyroid cancer, follicular thyroid car- cinoma, 2–5%, and Hürthle-cell carcinomas accounting A radiological study by ultrasound (US) must be carried for 2% [5]. Certain subtypes of papillary cancer: tall cell out in any patient with a thyroid gland alteration detected at physical examination, or with an anomalous/incidental 13 Clinical and Translational Oncology (2020) 22:223–235 225 nodular image observed by any imaging test [6, 7]. Although Differentiated thyroid cancer around half of the population may have thyroid nodules, TC (thyroid cancer) diagnosis is rare (about 5% of all thyroid Surgical treatment nodules). Some US characteristics may increase the specific- ity for diagnosis beyond 90% (microcalcifications, hypoeco- Most guidelines recommend total thyroidectomy in genicity, higher shape taller that longer, irregular margins, patients with nodules > 4 cm and who tolerate surgical solid appearance, absence of halo, intranodular blood flow) treatment, since it is associated with greater disease-free [8]. In this sense, the American Thyroid Association (ATA) survival, covers the possibility of multicentricity of pap- has stratified the US findings in five risk groups (from highly illary carcinoma (30–40% of patients), it allows the use suspicious to clearly benign) to justify the performance of of radioactive iodine as a diagnostic and therapeutic tool fine-needle-aspiration (FNA) [9]. Regardless of risk stratifi- and facilitates the monitoring of Tg (always together with cation, a FNA is recommended in any thyroid nodule > 1 cm autoantibodies against Tg, TgAb) as a marker of persis- or in those smaller but with clinical suspicion (previous head tence or disease recurrence. It also reduces the need for and neck irradiation, family history of TC, suspicion features second surgeries. For patients with thyroid cancer > 1 cm at palpation and/or presence of cervical node). However, and < 4 cm without extrathyroidal extension, and without in case of low-risk echographic pattern, such as in cystic clinical evidence of any lymph node metastases (cN0), or spongiform nodules or isoechoic without halo or hyper- the initial surgical procedure can be either a bilateral pro- echoic nodules, FNA is recommended when size is > 2 cm. cedure (near total or total thyroidectomy) or a unilateral Due to early nodal dissemination (> 90% of cases present procedure (lobectomy). Thyroid lobectomy alone may be at least microscopic nodal involvement in histopathological sufficient treatment for small (< 1 cm), low-risk, unifo- analysis), US may detect nodal involvement in more than cal, intrathyroidal papillary carcinomas in the absence of 20% of cases [10]. Based on FNA findings, the 2017-ver- prior head and neck irradiation or radiologically or clini- sion of Bethesda classification includes six scenarios (from cally involved cervical nodal metastases [9]. Thyroidec- non-diagnostic/unsatisfactory-Bethesda I to diagnosis tomy without prophylactic central neck dissection may be of malignancy-Bethesda VI) with their respective risk of appropriate for small thyroid papillary carcinomas (T1- malignancy based on the inclusion or not of neoplasm with T2), non-invasive, with negative nodes (cN0) and for most papillary-like nuclear features [11]. This updated classifica- follicular carcinomas. tion also assesses the performance of molecular tests as well Node dissections must be performed per compartments. as their hypothetical role to further refine the estimation of Central therapeutic dissection (level VI) must be associated malignancy of undetermined thyroid nodules. In this way, with total thyroidectomy when there are clinically affected several molecular tests based on transcriptomic analysis, nodes. Prophylactic central dissection (ipsilateral or bilat- mutational panels (most of them focused on BRAF, HRAS, eral) should be considered in patients with papillary thyroid KRAS, PIK3CA and fusion genes such as PTC1, PTC3, carcinoma with clinically unaffected lymph nodes in the cen- PAX8/PPARγ, RET, NTRK, ALK, etc.) and microRNA clas- tral compartment (cN0), with advanced primary tumors (T3 sification are currently being developed, in spite of their real or T4; > 4 cm or with invasion of neighboring structures) or chance for routine clinical implementation should still over- affected lateral nodes (cN1b). Therapeutic lateral dissection come multiple methodological, availability and/or clinical of the cervical lateral compartment should be performed in effectiveness issues [12]. Routine preoperative thyroglobulin patients with metastatic lymph nodes. Prophylactic lateral (Tg) is not recommended although measurement of serum dissection is not indicated [9]. calcitonin can be useful for medullary thyroid cancer (MTC) In the case of locally advanced thyroid cancer, the sur- even with higher sensitivity than FNA in this context [8]. gical treatment will be specific according to the affected anatomical structure, seeking control of the entire macro- scopic disease with function preservation. For unresect- Recommendations able or high-risk R1/R2 resections, neoadjuvant therapy with targeted agents may be considered; even the level of Patients with suspicion of thyroid alteration during the evidence is low (case reports). physical examination, or in which an anomalous/inciden- tal nodular image is observed by any imaging test should undergo neck ultrasonography (level of evidence: I, grade Recommendations of recommendation: A). It should be complemented with a FNA in any thyroid nodule with clinical suspicion. Routine Total thyroidectomy is recommended in indicated cases preoperative serum biomarkers may be useful in MTC sce- of DTC, mainly in size > 4 cm (level of evidence: I, grade nario (level of evidence: III, grade of recommendation: B). 13 226 Clinical and Translational Oncology (2020) 22:223–235 of recommendation: A). All patients should have a pre- Table 3  Differentiated thyroid carcinoma TNM staging AJCC UICC operative ultrasound evaluation of the central and lateral 8th edition neck lymph nodes to plan the surgical procedure (level of When age And T is… And N is… And M is… Then the evidence: III, grade of recommendation: B). at diagnosis stage group is… is… Staging and risk classification < 55 years Any T Any N M0 I Any T Any N M1 II AJCC/TNM 8th edition staging is used for predicting dis- ≥ 55 years T1 N0/NX M0 I ease specific survival. Clinical staging is based on inspec- T1 N1 M0 II tion/palpation and imaging (ultrasound, CT, PET-CT, etc.) T2 N0/NX M0 I of thyroid gland and regional lymph nodes. Pathologic stag- T2 N1 M0 II ing (pTNM) is based on all information used for clinical T3a/T3b Any N M0 II staging plus histologic examination plus surgeon’s descrip- T4a Any N M0 III tion of gross unresected tumor [13]. Tables 2 and 3 show T4b Any N M0 IVA TNM staging classification. Other factors involving risk of Any T Any N M1 IVB persistent or recurrent disease are included in the ATA clas- sification (Table 4). Table 2  Differentiated thyroid carcinoma TNM-staging AJCC UICC 8th edition T Category T Criteria Definition of primary tumor (T) for papillary and follicular thyroid carcinomas TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor ≤ 2 cm in greatest dimension limited to the thyroid T1a Tumor ≤ 1 cm in greatest dimension limited to the thyroid T1b Tumor > 1 cm but ≤ 2 cm in greatest dimension, limited to the thyroid T2 Tumor > 2 cm but ≤ 4 cm in greatest dimension limited to the thyroid T3* Tumor > 4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles T3a* Tumor > 4 cm limited to the thyroid T3b* Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size T4 Includes gross extrathyroidal extension into major neck structures T4a Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size T4b Gross extrathyroidal extension invading prevertebral fascia or encasing carotid artery or mediastinal vessels from a tumor of any size N Category N Criteria Definition of regional lymph node (N) NX Regional lymph nodes cannot be assessed N0 No evidence of regional lymph nodes metastasis N0a* One or more cytological or histologically confirmed benign lymph node N0b* No radiologic or clinical evidence of locoregional lymph node metastasis N1* Metastasis to regional nodes N1a* Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease N1b* Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (Levels I, II, III, IV, or V) or retropharyngeal lymph nodes M Category M Criteria Definition of distant metastasis (M) M0 No distant metastasis M1 Distant metastasis 13 Clinical and Translational Oncology (2020) 22:223–235 227 Table 4  ATA risk stratification system to estimate risk of persistent/recurrent disease Low risk Papillary thyroid cancer with all of the following present: No local or distant metastases All macroscopic tumor has been resected No invasion of locoregional tissues Tumor does not have aggressive histology (aggressive histologies include tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, follicular thyroid cancer, hobnail variant) No vascular invasion No 131I uptake outside the thyroid bed on the post-treatment scan, if done Clinical N0 or ≤ 5 pathologic N1 micrometastases (< 0.2 cm in largest dimension)* Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer* Intrathyroidal, well-differentiated follicular thyroid cancer with capsular invasion and no or minimal (< 4 foci) vascular invasion* Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAF V600E mutated (if known)* Intermediate risk Any of the following present: Microscopic invasion into the perithyroidal soft tissues Cervical lymph node metastases or 131I avid metastatic foci in the neck on the post-treatment scan done after thyroid remnant ablation Tumor with aggressive histology or vascular invasion (aggressive histologies include tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, follicular thyroid cancer, hobnail variant) Clinical N1 or > 5 pathologic N1 with all involved lymph nodes < 3 cm in largest dimension* Multifocal papillary thyroid microcarcinoma with extrathyroidal extension and BRAF V600E mutated (if known)* High risk Any of the following present: Macroscopic tumor invasion Incomplete tumor resection with gross residual disease Distant metastases Postoperative serum thyroglobulin suggestive of distant metastases Pathologic N1 with any metastatic lymph node ≥ 3 cm in largest dimension* Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion)* Adapted from reference 9. *Proposed modifications, not present in the original 2009 initial risk stratification system. Although not yet proven, it seems reasonable to consider either more careful follow-up or potentially more aggressive therapies for tumors with the highest risk mutational profiles (particularly those with mutational combinations associated with the poorest clinical outcomes). Xing M. Genetic-guided risk assess- ment and management of thyroid cancer. Endocrinol Metab Clin North Am. 2019;48(1):109–124 Postoperative adjuvant therapy and follow up should be given after TSH stimulation by withdrawing LT4 for 4–5 weeks or by administering recombinant human TSH Risk for local and distant recurrence after radical surgery (rhTSH) to increase isotope uptake [15]. depends mostly on pathological assessment and age and dic- Clinical decisions for an adjuvant treatment with RAI tates the need for adjuvant treatment and frequency and type should be based on multidisciplinary discussions case by of follow up [8]. Thyroid ablation with radioactive iodine case in centers with sufficient experience and adequate 131 facilities. As a general rule, there is a consensus to offer I (RAI) aims to completely eliminate residual remnant thyroid tissue and presumed neoplastic cells thereby reduc- RAI adjuvant therapy (≥ 100 mCi, 3.7 GBq; rhTSH admin- ing the risk of recurrence and probably the mortality rate. In istration or levothyroxine withdrawal) in those patients with addition, thyroid ablation allows for an earlier detection of high risk of recurrence and should be considered in inter- recurrence based on serum Tg measurement and eventually mediate-risk patients and low-risk patients, based on TNM on 131I whole-body scan (WBS) during follow up [9]. Thy- stadification, presenting with clinical risk factors. Low doses roid-stimulating hormone (TSH) suppressive therapy (serum of radioiodine (30 mCi, 1.1 GBq) following thyroidectomy TSH < 0.1 mU/l) with levothyroxine (LT4) is mandatory in seem to be better tolerated than standard doses achieving patients with evidence of persistent disease and is given to similar remnant ablation rate [16]. In general, it is not rec- regulate the postsurgical hypothyroidism and to inhibit the ommended the administration of ablative RAI in patients TSH-dependent growth of residual cancer cells [14]. RAI with DTC smaller than 4 cm and no evidence of locoregional 13 228 Clinical and Translational Oncology (2020) 22:223–235 metastasis, but it could be contemplated in some specific leading to RAI-refractory metastatic disease, defined as: no scenarios like tumors with aggressive histology or vascular uptake of RAI at the initial diagnosis of distant metastases or invasion [17]. Patients pT1b-pT2-pT3a, N0 or N1a, may be locoregional recurrence; progressive loosing of RAI uptake considered for low dose RAI ablation (30 mCi, 1.11 GBq). after several sessions of RAI therapy; evidence of different Follow up schedule and test to be performed after surgery foci of distant metastases, some of them with uptake and and consolidation treatment may vary depending on risk for some others without RAI uptake in the body scan; tumor recurrence or persistent disease, histology, and response to progression after an adequate RAI treatment even with pre- RAI. Serum Tg assays and neck US are the cornerstones of vious substantial RAI uptake. Other additional criteria that DTC follow-up [18]. play a role in the definition of RAI-refractory disease are In patients treated with total thyroidectomy plus RAI significant uptake in 18FDG-PET, total cumulative doses of remnant ablation, stimulated serum Tg levels < 1 ng/mL are RAI over 600 mCi, unresectable primary tumors or aggres- highly predictive of an excellent response to therapy. When sive DTC histologies, such as poorly differentiated, insu- detectable Tg levels emerge in a patient with negative imag- lar or Hürtle Cell carcinomas [20]. The final decision on ing findings, the response to therapy is classified as inde- the RAI-refractoriness must be taken by multidisciplinary terminate or biochemical incomplete. Uptake on 131I WBS committees and reassessed during the treatment evolution. is highly specific (91–100%) for the presence of thyroid When a patient with DTC is classified as refractory to RAI, tissue. Fluorodeoxyglucose-positron emission tomography there is no indication for further RAI treatment. No clear (FDG-PET) is useful for assessing the extent of disease and recommendation regarding TSH suppression is available in defining the prognosis especially for aggressive histologies RAI-refractory DTC. Intravenous bisphosphonate (eg, zole- and serum Tg levels above 10 ng/dL. Patients with DTC dronic acid) or denosumab therapy may be considered for should be evaluated 6–12 months after primary treatment bone metastases. and follow-up schedule will be adapted on the initial risk of For clinically progressive or symptomatic RAI-refractory persistent/recurrent disease and responses to therapy [19], metastatic DTC, not otherwise amenable to local therapies, as shown in Fig. 1. multikinase inhibitor (MKI) therapy should be considered (Fig. 2). Two randomized, placebo-controlled, phase III tri- Recommendations als (DECISION and SELECT) have demonstrated the effi- cacy of sorafenib [21] and lenvatinib [22], respectively, in Decision for adjuvant therapy should be made after risk these patients. Both drugs were each associated with sta- assessment in a multidisciplinary fashion (level of evidence: tistically significant improvement in progression-free sur- III, grade of recommendation: B). Ablative RAI should be vival (PFS) relative to those patients treated with placebo offered to high-risk patients and considered in intermediate- and were approved by regulatory authorities worldwide for risk patients (level of evidence: III, grade of recommenda- RAI-refractory metastatic disease. Although sorafenib and tion: A). lenvatinib showed an increase in the response rate and PFS versus placebo, they failed to show significant differences in Treatment of tumor relapse/metastatic DTC overall survival due to crossover at progression. Currently, there are no clinical or molecular biomarkers that help us to Locoregional recurrence occurs in up to 20% of patients, and predict the response to these drugs. The differences between distant metastases in approximately 10% at 10 years. Surgery these drugs must be taken into account when deciding which is the preferred therapy for locoregional recurrent disease or is the best treatment option for each patient considering both low-volume distant metastatic disease. efficacy and toxicity profile of these drugs. At progression RAI is currently the first-line treatment for distant metas- disease, there is no current evidence of efficacy of sequential tases that are RAI-avid. Doses of RAI therapy are, at pre- treatment with MKIs and patients should be considered for sent, controversial, ranging from 100 to 200 mCi. Active clinical trials. surveillance may be considered for patients with low-volume There are several molecular biomarkers, such as muta- disease with no apparent tumor progression and distant from tions in BRAF or fusions in RET/PTC that may predict the critical structures. response to specific BRAF or RET inhibitors in advanced External beam radiotherapy (EBRT) may be indicated RAI-refractory DTC. However, current data is available for symptomatic bone metastases and central nervous sys- only from phase I/II clinical trials, with no data on the best tem spread. Evidence of efficacy of EBRT for unresectable treatment sequence and no formal approval in this setting. locoregional relapses is low and may be considered together Recently, the European Medicine Agency (EMA) approved with other locoregional treatments such as local ablations. the first tumor agnostic therapy for solid tumors directed to Up to two-thirds of patients with metastatic or unresect- NTRK fusions, larotrectinib. Thyroid cancer is the second able locoregional disease lose the ability for iodine uptake most frequent tumor with NTRK fusions with an incidence 13 Clinical and Translational Oncology (2020) 22:223–235 229 Fig. 1  Post-operative manage- ment and follow up adapted on the initial risk of persistent/ recurrent disease and responses Esmate to therapy Intermedi risk of High Risk Low Risk ate Risk recurrenc e RAI (> or RAI (30 to Recomme = 100 mCi 100 mCi + No RAI* nded + rhTSH rhTSH or *discuss if aggressive adjuvant or LT4 LT4 histologies or vascular invasion treatmen withdraw withdraw t al) al) Inc Inc Ex Ex o o cel cel Response m m len len to RAI ple ple t t te te TSH 0.1- TSH 0.1-0.5 0.5 mU/L TSH 0.5- mU/L TSH 0.5- Serum Tg 2 mU/L Serum Tg 2 mU/L TSH 0.5-2 and TgAb Serum and TgAb Serum mU/L and Neck Tg and and Neck Tg and Serum Tg Recomme US TgAb US TgAb and TgAb and and and Neck nded every 3 to every 6 to US follow up 6 months Neck US 12months Neck US or FDG PET every 6 or FDG PET every every 12 if Tg rising to 12 if Tg rising 12 to 24 months ar TgAbs months ar TgAbs months trend trend that ranges from 5 to 25%. Larotrectinib demonstrated high Recommendations durable response rate (including complete responses) in NTRK fusion tumors (79% of overall response rate in thyroid RAI is the first choice for RAI-avid advanced or relapsed cancer) and should be considered in the treatment strategy of DTC (level of evidence: III, grade of recommendation: B). patients with NTRK altered advanced DTC [23]. Addition- Lenvatinib or sorafenib should be offered in most patients ally, due to higher target selectivity, toxicity profile is more with RAI-refractory metastatic DTC (level of evidence: I; favorable compared with classical MKIs. grade of recommendation: A). 13 230 Clinical and Translational Oncology (2020) 22:223–235 Fig. 2  Treatment algorithm for Advanced RAI-refractory DTC advanced RAI-refractory DTC Locoregional progressión or isolated metastasesMacro/mulples metastases Surgery Clinically progressive or symtomac disease EBRT Local therapies Yes No Poor performance status Acve surveillance Yes No Best supporve care Sorafenib Lenvanib Larotrecnib* Clinical trials Progression Lenvanib** Larotrecnib* Clinical trials *Larotrecnib: EMA approved (not AEMPS approved yet). Efficacy showed in first-line and aer progression to prior MKIs **Lenvanib efficacy showed in first and second lines. No data of sorafenib efficacy aer lenvanib Medullary thyroid carcinoma contrast-enhanced CT of chest, MRI/ 3-phase CT of liver, axial MRI and bone scintigraphy. Total thyroidectomy and Initial management and follow up bilateral central neck dissection (level VI) and involved lat- eral neck compartments (levels II–V) are recommended for MTC accounts for 2–8% of primary thyroid tumors. A neck confined ≥ 1 cm or bilateral thyroid disease. For unilat- thyroid tumor with any suspicious feature of MTC should eral and < 1 cm tumors, total thyroidectomy should be com- include immunohistochemistry analysis of calcitonin, chro- pleted and contralateral neck dissection be considered based mogranin, carcinoembryonic antigen (CEA) and the absence on calcitonin levels. Residual lymph node metastases after of Tg. All patients should be offered genetic counseling and thyroidectomy, based on calcitonin level, imaging studies be tested for germline RET mutations to rule out the diagno- or inadequate surgery could benefit from re-operation [24]. sis of a MEN2 in the family. Preoperative workup includes Postoperative follow-up includes measurements of cal- thyroid and neck ultrasound and basal calcitonin, CEA, cal- citonin and CEA levels. Calcitonin < 150 pg/mL should be cium, plasma or 24-h urine collection of metanephrines and evaluated together with physical examination, serum mark- normetanephrines. Either calcitonin > 500 pg/mL or signs/ ers and neck ultrasound every 6 months to determine the symptoms of regional/distant disease should be studied with doubling time of serial measurements and concentrations of 13 Clinical and Translational Oncology (2020) 22:223–235 231 calcitonin > 150 pg/mL, should be completed with chest CT, Multidisciplinary approach, experience in dealing with MRI or liver three-phase contrast-enhanced CT, bone scin- advanced MTC and skills in the management of MKIs are tigraphy, pelvis/axial MRI or FDG-PET. Abnormal serum mandatory for the correct management of advanced MTC markers in asymptomatic patients with repeated negative patients in the daily clinical practice. imaging can be followed every 6 months or consider reop- eration, after excluding liver occult metastasis. Recommendations Recommendations Vandetanib and cabozantinib should be offered as the first- Total thyroidectomy, bilateral central neck dissection and line systemic treatment for progressive locally advanced/ involved lateral neck compartments are recommended for metastatic MTC (level of evidence: I, grade of recommen- neck confined ≥ 1 cm or bilateral thyroid disease for MTC, dation: B). based on preoperative serum calcitonin levels and neck imaging (level of evidence: III, grade of recommendation: B). Poorly differentiated thyroid carcinoma Treatment of tumor relapse/metastatic MTC Poorly differentiated carcinoma is an aggressive thyroid Locoregional recurrence should be approached with com- tumor characterized by a partial loss of the features of partmental dissection of image-positive or biopsy- posi- thyroid differentiation that occupies morphologically and tive disease in the central (level VI) or lateral (levels II–V) behaviorally an intermediate position between well-differen- neck compartments. Postoperative radiotherapy could be tiated papillary and follicular carcinomas and fully dediffer- considered in case of residual MTC, extrathyroidal exten- entiated anaplastic carcinoma. They account for up to 10% of sion, or extensive lymph node metastases and risk of airway all thyroid cancers with a 10-year survival close to 50% [27]. obstruction, after weighing the benefits against the poten- Diagnostic criteria for poorly differentiated carcinoma tial toxicity. Management goals of MTC distant disease are are based on the consensus Turin proposal and include the loco-regional disease control, survival increase and the pal- following three features: (i) solid/trabecular/insular micro- liation of symptoms. Spinal cord compression and painful scopic growth pattern, (ii) lack of well-developed nuclear bone metastasis require consideration of surgery, EBRT and features of papillary carcinoma, and (iii) convoluted nuclei bisphosphonates. Resection, ablation and liver embolization (evidence for partial loss of differentiation in papillary may be considered in patients with solitary lung and liver cancer), tumor necrosis, or three or more mitoses per 10 metastases. high-power fields [28]. In terms of patient follow-up carci- Somatic RET mutations (30–50% of sporadic and almost noma serum Tg and TgAb levels should be assessed every all hereditary MTC), RAS mutations along with overexpres- 6–12 months and FDG–PET combined with CT is more sion of vascular endothelial growth factor receptor (VEGF) sensitive than post-therapeutic body scan for detecting per- 1 and 2, fibroblast growth factor (FGF) and the platelet- sistent disease in these patients [29]. derived growth factor (PDGF) are common molecular fea- There is no standardized treatment for poorly differenti- tures in MTC. Based on phase III randomized clinical trials ated thyroid carcinoma to date. However, it is accepted that vandetanib and cabozantinib are recommended as systemic a more aggressive approach is needed to treat these tumors. therapy in patients with symptomatic or progressive unre- If possible, a total thyroidectomy including lymph node dis- sectable locally advanced or metastatic MTC. Both vande- section should be performed. RAI treatment is only success- tanib and cabozantinib demonstrated PFS benefit in front ful in a subset of patients, nevertheless, given the potential of placebo and a response rate ranging from 28 to 45% [25, therapeutic benefit, high-dose of RAI treatment is currently 26]. Treatment decision between both drugs should be based recommended for all these patients. EBRT for large tumors on the different safety profile, baseline patients’ character- of > 4 cm with stage T3 and T4 and for patients with regional istics and clinical experience. Beyond the progression on lymph node metastases should be assessed individually for vandetanib or cabozantinib, no other MKI therapy has dem- patients as the data are based on extrapolation from stud- onstrated efficacy and treatment on clinical trials should be ies of DTC. The basis of systemic treatment in the RAI- offered to patients. Based on promising results of clinical refractory setting is MKIs as well as DTC, as this histology research with selective RET inhibitors, patients with RET subtype was included in registrational phase III studies. mutations should be offered to participate in clinical trials Chemotherapy is currently not standard of care, although with RET inhibitors both in first-line and in refractory set- positive effects have rarely been observed in some patients ting after progression to MKIs. with platinum- and anthracycline-based schemes [30]. 13 232 Clinical and Translational Oncology (2020) 22:223–235 Undifferentiated/anaplastic thyroid palliative resection (R2) or ‘debulking’, which is not gener- carcinoma (ATC) ally recommended [33]. Tracheostomy may be needed to alleviate symptoms in patients with moderately progressive Initial management and follow up disease, but the impact of tracheostomy on quality of life (QoL) should be considered. Undifferentiated/anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer that is associated with a Radiotherapy very poor prognosis. Although ATC accounts for < 2% of all thyroid malignancies, it comprises > 50% of thyroid cancer- Optimal outcomes in terms of survival and local disease related mortalities. Overall survival after initial diagnosis control in ATC require complete or near-complete [no resid- is usually less than 6 months with 1-year survival rates of ual tumor (R0) or microscopic residual tumor (R1) resec- approximately 20% [31]. The morbidity and poor prognosis tion followed by high-dose radiotherapy, with or without of ATC is due either to locoregional disease because of the concomitant chemotherapy [34]. However, this multimodal numerous critical structures located near the thyroid or the approach can strongly impact QoL and should be reserved high incidence of metastatic disease, with nearly one-half of for carefully selected patients to ensure clinical benefit. all patients with ATC presenting with metastatic disease at Timely discussion within a multidisciplinary team setting the time of initial diagnosis. The most common metastatic is strongly recommended. sites include lungs, bones and brain. A meta-analysis of 17 retrospective studies including ATC is morphologically heterogeneous and must be dis- 1147 patients looked at the impact of postoperative EBRT tinguished from other neck tumors, including squamous after radical ATC resection and found that it significantly carcinoma of the larynx, sarcomas and lymphomas. Preop- reduced the risk of death as compared with radical resec- erative biopsy assessment includes diagnostic immunomark- tion alone (HR 0.556, 95% CI 0.419–0.737, P < 0.001) [35]. ers that can differentiate ATC from large cell lymphoma, Exploratory analyses demonstrated that EBRT might also pleomorphic sarcoma and poorly differentiated DTC. A thor- confer a survival benefit in patients with stage IVA or IVB ough imaging work-up should be carried out soon after the disease but not for stage IVC. For best outcomes, EBRT diagnosis. The FDG-PET scan is the most sensitive tool for should be delivered as soon as possible after surgery. documenting the extent of disease. Scans should be repeated Because of the improved dose distribution and the ability at all stages of treatment [32]. to reduce toxicity, intensity-modulated radiotherapy (IMRT) is the recommended approach [36]. There is some evidence of a dose–response relation. An analysis of the United States Recommendations National Cancer Database showed maximal benefits with doses > 60 Gy [37]. Histological and immunohistochemical accurate study of For stage IVA or IVB disease, concomitant chemotherapy tumor samples is required to exclude other forms of thyroid (usually with doxorubicin, platinum agents or taxanes, alone cancer. Preoperative radiological studies include ultrasound, or in combination) has been used. Most of the data reported CT or MRI, and FDG-PET scan to rule out distant metasta- on this approach came from single-institution series and the ses at initial diagnosis (level of evidence: III, grade of rec- clinical benefits reported are variable. In patients with unre- ommendation: C). sectable disease, palliative EBRT has a role in symptom control. The aim is usually to reduce the rate of growth of the neck mass and thereby the pressure symptoms. Treatment of local/locoregional disease Recommendation Total thyroidectomy with lateral and Surgery central node dissection should be performed in resectable non-metastatic ATC. Adjuvant EBRT with or without con- ATC is rarely amenable to complete resection. Total thyroid- comitant chemotherapy should be offered to ATC patients ectomy with bilateral central neck dissection may be carried with adequate performance status. Timely discussion by a out in those very rare cases of localized resectable ATC. multidisciplinary team is strongly recommended (level of Extensive resection with total laryngectomy, esophagec- evidence: III, grade of recommendation: B). tomy and/or resection of the great vessels has been reported in highly selected cases in specialized centers, but postop- Treatment of advanced/metastatic disease erative mortality and morbidity are high and there is no high-level evidence to indicate that this approach improves The priority in ATC patients with distant metastases should survival. The prognosis is also unaffected by incomplete be proper control of symptoms, as no randomized study has 13 Clinical and Translational Oncology (2020) 22:223–235 233 demonstrated benefit in survival or QoL. Novel systemic chances (dabrafenib-trametinib for BRAFV600E mutated and therapies are urgently needed to improve the generally poor larotrectinib for NTRK fusion ATCs). Clinical trial enrol- outcomes associated with ATC. Clinical trial enrolment ment should be encouraged (level of evidence: II, grade of should, therefore, be encouraged for patients with good recommendation: C). clinical PS. For patients ineligible for systemic treatments or clinical trials, best supportive care should be discussed. Acknowledgments The guideline was reviewed by Dr. Ismael Capel (Endocrinology Department, Parc Taulí Hospital Universitari. Institut To date, cytotoxic chemotherapy has been the primary d’Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de treatment for metastatic disease, but it is associated with Barcelona. Sabadell, Spain), Dr. Carles Zafon (Endocrinology Depart- very low response rates and significant toxicities. Recom- ment, Hospital Universitari Vall d’Hebron, Barcelona, Spain) and Dr. mended regimens consist of single-agent therapy with pacli- Joan Castell (Nuclear Medicine Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain). We thank them for their support and taxel or doxorubicin or combined treatments (e.g., carbopl- valuable contributions. atin/paclitaxel, docetaxel/doxorubicin) administered weekly or every 3–4 weeks [38, 39]. Compliance with ethical standards No evidence of efficacy of MKIs is currently available in western countries for advanced ATC. An international, Conflict of interest Dr. Gallardo reports personal fees and non-fi- multicenter, phase II trial with lenvatinib was stopped early nancial support from Eisai, personal fees and non-financial support due to futility (NCT02657369). from Bayer, during the conduct of the study; grants, personal fees and non-financial support from Astellas, grants, personal fees and non- Molecular profiling studies have begun to elucidate the financial support from Janssen, grants, personal fees and non-financial molecular drivers in ATC [40]. BRAF mutations have been support from Sanofi, grants, personal fees and non-financial support reported up to 40% of ATC cases. In a phase II, open-label from Bayer, grants, personal fees and non-financial support from Ip- basket trial, patients with BRAFV600E-positive malignancies sen, personal fees and non-financial support from Roche, grants from Ferrer, grants from GSK, personal fees from Novartis, personal fees (including 16 with ATC) were treated with the BRAF inhibi- and non-financial support from Pfizer, personal fees and non-financial tor dabrafenib (150 mg twice daily) plus the MEK inhibitor support from BMS, personal fees from EUSA Pharma, personal fees trametinib (2 mg once daily). The overall response rate was and non-financial support from Rovi, personal fees and non-financial 69% (11/16) and the treatment was well tolerated [41]. In support from Daiichi Sankyo, personal fees and non-financial support from Leo Pharma, personal fees from Techdow, personal fees and non- May 2018, this combination received FDA approval for the financial support from Menarini, personal fees and non-financial sup- treatment of locally advanced or metastatic ATC with the port from AstraZeneca, personal fees from Boehringer, personal fees BRAFV600E mutation. Despite of there were only 16 patients from Merck, personal fees from MSD, outside the submitted work. with ATC treated with this combination; the promising Dr. Medina reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from results may position this treatment as the first-line therapy Novartis, grants, personal fees and non-financial support from BMS, for advanced BRAFV600E ATC patients. Other rare muta- personal fees and non-financial support from Pierre Fabre, personal tions and genetic aberrations may also prove to be drugga- fees and non-financial support from MSD, outside the submitted work. ble, such as ALK and NTRK translocations. As mentioned Dr. Sánchez reports personal fees (meeting and travel support) from Pierre Fabre and Boehringer Ingelheim; personal fees from Roche; before, larotrectinib has the first tumor agnostic approval personal fees (advisory board, consultancy, speaker honoraria or travel in Europe for the treatment of NTRK altered cancers. The support) from Eisai, Sanofi, Bristol-Myers Squibb, MSD, Merck Se- initial cohort of thyroid cancer patients treated with larotrec- rono and Kyowa Kirin, outside the submitted work. Dr. Viúdez has tinib also included ATC, with objective responses. Extended nothing to disclose. Dr. Grande reports grants from Roche, grants from Pfizer, grants from BMS, grants from IPSEN, grants from EUSA molecular profiling of ATCs should be strongly encouraged Pharma, grants from MSD, grants from Sanofi, grants from Adacap, upfront as it may reveal promising possibilities for targeted grants from Pierre Fabre, grants from Lexicon, grants from MTEM/ therapies. THreshold, grants from Astra Zeneca, during the conduct of the study. Immunotherapy has reported initial promising activity Dr. Porras reports non-financial support from BMS, personal fees and non-financial support from Pfizer, non-financial support from Astra- in patients with advanced ATC regardless BRAF mutations Zeneca, personal fees and non-financial support from Merck, during [42]. Additional research is still needed to define the role of the conduct of the study. Dr. Ramón y Cajal has nothing to disclose. immunotherapy in ATC. Dr. Trigo reports personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees from Bayer, non-financial support from MSD, personal fees from Recommendation Takeda, personal fees from Eisai, personal fees from Merck, during the conduct of the study. Dr. Iglesias reports personal fees from Bayer, Systemic chemotherapy based on taxanes and/or anthracy- personal fees from Eisai, during the conduct of the study; personal fees clines may be offered in patients with good performance sta- from BMS, personal fees from Merck, personal fees from MSD, per- sonal fees from Roche, personal fees from Sanofi, outside the submit- tus. New clinical trials may offer an opportunity to improve ted work. Dr. Capdevila reports grants and personal fees from Bayer, the outcome in advanced ATC patients. Extended molecular grants and personal fees from Eisai, grants from Astrazeneca, grants profiling of ATCs should be strongly encouraged upfront and personal fees from Advanced Accelerator Applications, grants and could offer new targeted therapy with higher response and personal fees from Ipsen, personal fees from Novartis, personal 13 234 Clinical and Translational Oncology (2020) 22:223–235 fees from Pfizer, personal fees from Merck, personal fees from Sanofi, differentiated thyroid cancer: the American Thyroid Association personal fees from Amgen, personal fees from Exelixis, outside the Guidelines Task Force on Thyroid Nodules and Differentiated submitted work. Thyroid Cancer. Thyroid. 2016;26(1):1–133. 10. O’Connell K, Yen TW, Quiroz F, Evans DB, Wang TS. 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