Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for persistent/recurrent and metastatic differentiated thyroid cancer 2018 (English version)

Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for persistent/recurrent and metastatic differentiated thyroid cancer working group

Contents

1. Diagnosis and dynamic assessment of persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC)

1.1 Basic principles of diagnosis

1.2 Diagnostic methods

1.3 Ongoing assessment of response to therapy

2. Multidisciplinary treatment of prmDTC

2.1 Basic principles of treatment

2.2 Surgical management

2.2.1 Preoperative clinical assessment

2.2.2 Principles of surgical treatment for prmDTC

2.3131I therapy

2.3.1 Clinical assessment before131I therapy

2.3.2 Management of131I therapy for prmDTC

2.4 TSH suppression therapy

2.4.1 Strategy for TSH suppression therapy

2.4.2 Management of adverse effects of TSH suppression therapy

2.5 External beam radiation therapy

2.6 Systemic therapy

1. Diagnosis and dynamic assessment of persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC)

Differentiated thyroid cancer (DTC), including papillary,follicular and Hürthle cell types, accounts for nearly 95%of all thyroid carcinomas. The concept of DTC recurrence or persistence after surgery is still difficult to define due to its indolent nature. The recurrent or persistent tumors in this guideline refer to new lesions or residual tumors found during the follow-up after initial treatments.

1.1 Basic principles of diagnosis

The role of multidisciplinary team (MDT) should be emphasized during the diagnosis of prmDTC. A task force of specialists with complementary expertise (endocrinology,surgery, nuclear medicine, radiology, pathology, oncology,molecular diagnostics, and epidemiology) should be included in the MDT management of prmDTC. The diagnosis or further managements of prmDTC which may include surgical managment, radioiodine-131 (131I) therapy,thyroid stimulating hormone (TSH) suppressive therapy, as well as molecular targeted therapy (or being enrolled in certain clinical trial) or radiation therapy, etc., should be tailored according to comprehensive consideration of MDT.

1.2 Diagnostic methods

Laboratory tests, imaging studies and pathological examinations are recommended in the diagnosis of prmDTC (Table 1).

1.3 Ongoing assessment of response to therapy (Table 2)

As the risk of recurrence and cancer-related death in prmDTC may change over time, life long follow-up and periodical surveillance including laboratory and imaging evaluation are needed. Ongoing assessment of response to therapy should be used to guide the long-term surveillance and therapeutic management decision. In this guideline, we adopted the system of response to therapy which was put forward by 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer.

Multiple factors including clinical, biochemical, imaging(structural and functional) and cytopathology findings were taken into comprehensive consideration in this response system to assess the individual response to therapy during follow-up. It has been verified as an objective ongoing evaluation system to reflect the clinical outcomes fromboth the risk of recurrence and mortality (1). Four categories including excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR)and structural incomplete response (SIR) are used to describe clinical outcomes at any time after initial treatment (1).

Table 1 Diagnostic methods of prmDTC

Figure 1 Sonographic features of persistent/recurrent and metastatic differentiated thyroid cancers (prmDTCs). (A, B) Local recurrence of thyroid bed (among cursors and arrows); (C-E) Suspicious metastatic lymph nodes; (F, G) Recurrence in soft tissue (among cursors); (H)Venous tumor thrombus; (I) Tracheal invasion (arrow point). M, mass; IJV, internal jugular vein; CCA, common carotid artery.

Table 2 Stratification of ongoing assessment of response to therapy

Tg, thyroglobulin; TgAb, thyroglobulin antibody; TSH, thyroid stimulating hormone; FDG, fluorodeoxyglucose.a, The risk of recurrence ranged from 1% to 4% over 5-10 years among ER patients.
b, 15%-20% of IDR patients are reclassified as persistent/recurrent disease over approximately 10 years.
c, 8%-17% of BIR patients developing structurally identifiable disease over 5-10 years.
d, Death from disease was seen in 11% of patients with a loco-SIR and in 57% of patients with distant SIR.

Indeterminate responsebNon-stimulated Tg detectable,Non-specific findings onContinuing observation with(IDR)but less than 1 ng/mL.imaging studies. Or faintappropriate serial imaging of the Stimulated Tg detectable, butuptake in thyroid bed on RAInonspecific lesions and serum Tg less than 10 ng/mL. Or Tgscanningmonitoring. Nonspecific findings antibodies stable or declining inthat become suspicious over time the absence of structural orcan be further evaluated with functional diseaseadditional imaging or biopsy (1A)Structural incompleteSerum Tg or TgAb at any level Structural or functionalAdditional treatments or ongoing responsed(SIR)evidence of diseaseobservation depending on multiple clinicopathologic factors including the size, location, rate of growth, RAI avidity,18FDG avidity, and specific pathology of the structural lesions (1A)

11.Gao L, Jiang Y, Liang Z, et al. Cervical soft tissue recurrence of differentiated thyroid carcinoma after thyroidectomy indicates a poor prognosis. Int J Surg 2017;48:254-9.

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18.Qiu ZL, Xue YL, Song HJ, et al. Comparison of the diagnostic and prognostic values of 99mTc-MDP-planar bone scintigraphy,131I-SPECT/CT and18F-FDG-PET/CT for the detection of bone metastases from differentiated thyroid cancer.Nucl Med Commun 2012, 33:1232-42.

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2. Multidisciplinary treatment of prmDTC

2.1 Basic principles of treatment

Treatment options for prmDTCs usually include surgical resection,131I therapy of lesions that can uptake131I,external beam radiation therapy, active follow-up under LT4 suppression therapy and other options (e.g., targeted medicines, radiofrequency or ethanol ablation). Among them, surgery should be the first choice for resectable lesions with surgical indications.

2.2 Surgical management

PrmDTCs are commonly seen in clinical practice,approximately 95% of which occur in the neck (1). Since the difficulty and risk of reoperation increase significantly,the risks and benefits of surgery must always be balanced when selecting reoperation. Surgery should be performed by experienced specialists, and frequently even under multidisciplinary collaboration.

2.2.1 Preoperative clinical assessment

Preoperative clinical assessment includes the review of previous treatments, current status of the disease and vital organ function, which are the basis for the decision regarding intervention and extent of revision surgery.Structural lesions are required as a target for a surgical revision approach, therefore, imaging evaluation is of the utmost importance to surgeons to identify and localize the structural lesions (Table 3).

2.2.2 Principles of surgical treatment for prmDTC

The timing and extent of surgery are the most important issues which should be considered when the surgical management of prmDTC is decided. In general, the goal of revision surgery should be to try to cure or control the disease, improve survival, and preserve the function of the vital organs as far as possible (Table 4).

Table 3 Recommendations of preoperative clinical assessment

PTH, parathyroid hormone; CT, computed tomography; MRI, magnetic resonance imaging; WBS, whole body scan; SPECT, single photon emission computed tomography; FDG, fluorodeoxyglucose.
a, Thyroglobulin (Tg), Tg antibody (TgAb) and imaging examinations can be used to evaluate the current state of disease. Neck ultrasonography is the most important technique to detect structural lesions (2,3).

EvaluationLevel ILevel IILevel III contentarecommendationrecommendationrecommendationLaboratory tests Serum Tg, TgAb, see 1.2 Diagnostic methods (2A)— —Parathyroid function evaluation: serum calcium and PTH levels

Table 4 Recommendations of surgical treatment principles

Cervical lesions with invasion to surrounding vital structurescRecurrent laryngeal nerve involvementdShave the tumor off as much as possible and preserve the nerve in patient without vocal cord paralysis (2A)Remove lesions and the affected nerve in patient with preoperative vocal cord paralysis or intraoperative finding of complete tumor encapsulation of the nerve(2A)Nerve reinnervation simultaneously at surgery after resection or injury of the nerve, if feasible (2A)Second-look operation with nerve repair for postoperative identification of recurrent laryngeal nerve injury (2A)—Airway/digestive tract (larynx trachea/esophagus)involvemente—Consider shaving tumor in patient with no intraluminal tumor invasion (2A)Resection of the lesion and involved organs in patient with intraluminal tumor invasion; If feasible,simultaneous airway/digestive tract repair and reconstruction, otherwise, tracheostomy (2A)Palliative surgery, such as tracheostomy or gastrostomy, in patients having asphyxiation or hemoptysis symptoms with unresectable lesions(2A)—

Table4 (continued)

a, The most important and difficult decision for these patients is the timing of the operation. At present, it is commonly accepted that the patient can be closely followed up when the lesion is less than 8 mm in the central compartment and ＜10 mm in the lateral compartment, otherwise, reoperation should be considered (1-10). Preoperative fine needle aspiration (FNA) diagnosis is an important step in preoperative evaluation to avoid unnecessary reoperations. The threshold of 8 mm (central) and 10 mm (lateral) in the smallest dimension signifies disease sufficiently macroscopic to be potentially dangerous if it were to grow, and amenable to FNA as well as surgical localization if it were to be targeted for excision(1-4,9,10). In the decision-making of surgery, the following factors should also be considered (1,2,8,9): location of the lesion (whether it is adjacent to the important structures), doubling time of Tg (11), whether a positive result is shown on18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging, the extent of previous operation, complications, and whether the primary lesion is a highly malignant subtype. For revision surgery, it may be a standardized lymph node dissection (1-5,9,10) or a limited operation (2,12,13).
b, The incidence of temporary and permanent recurrent laryngeal nerve injury during reoperation is 1.5%-22.2% and 0.3%-6.4%,respectively (14-16), and the incidence of temporary and permanent hypoparathyroidism during reoperation is 6.5%-46.3% and 9.5%, respectively (15-17). The recurrent laryngeal nerve monitoring in such operations plays an important role in reducing nerve injury and improving the safety of the operation (18-21). The time of nerve repair may be different between patients (21-23).Parathyroid glands should be carefully identified, rescued and preserved in situ or auto-transplanted into other locations, such as the sternocleidomastoid (1-5).
c, The extent of surgical resection for such lesions has been controversial, but the removal of visible tumors is very important to control local recurrence of tumor and prolong the survival of patients (24).
d, 33%-61% of thyroid cancers that invade the surrounding vital structures have recurrent laryngeal nerve invasion (24-27). Studies have shown that recurrent laryngeal nerve involvement is not an independent risk factor for survival (25), residual trace lesions do not increase the local recurrence rate and reduce the survival rate (26,27). Therefore, the nerve should be preserved as far as possible (1,4,28), and if not, the affected nerve should be removed and reconstructed (1,4,28,29). Of course, when determining the surgical approach, the contralateral recurrent laryngeal nerve function and distant metastases status should also be considered in order to balance the risks and benefits of surgery.
e, Airway/digestive tract (laryngeal trachea/esophageal) involvement is more serious situation, and over half of disease-specific deaths are related to airway obstruction and bleeding (28). For such patients, there are different options in surgery (1,2,28,30), when partial esophageal/tracheal/laryngectomy can be carried out, it can not only ensure adequate resection margins, but also avoid serious complications caused by more extensive resection, however, postoperative adjuvant therapies such as RAI treatment and radiotherapy are generally needed (1,28).
f, Reconstruction may be required in the treatment of cervical vascular involvement (28), although severe invasions to the major blood vessels of the neck by differentiated thyroid cancers (DTCs) are rare (31). The involvement of internal jugular veins by metastatic lesions is the most common (32). Obstruction of bilateral internal jugular veins can cause at least 2% of patients to die (33)g, Common distant metastatic sites of DTC include lung, bone, and brain. In general, surgery is feasible for solitary lesion and lesions that cause complications (34,35). Intracranial metastases may be preferred for surgical treatment, which can not only remove metastatic lesions, but also relieve life-threatening intracranial complications (36).

Lesions Level I recommendation Level III recommendation Cervical vascular involvementfLevel II recommendation—Sacrifice of the unilateral internal jugular vein without reconstruction if it is significantly involved(2A)Reconstruction of at least one side with autologous vein graft after resection of the bilateral involved internal jugular veins (2A)Reconstruction of the common carotid artery after resection for its local involvement (2A)—

2.31
31I therapy

131I therapy is one of the important adjuvant postoperative treatment modalities for prmDTC patients. It can reduce the risks of tumor recurrence, metastasis and death in high risk population (1,2), and significantly improve the 5- and 10-year survival for high-risk DTC patients with iodineavid lesions (3-9).

131I therapy is recommended in patients with iodine-avid prmDTC lesions, and should be repeated at an interval of 6-12 months as long as the lesions continue to concentrate radioiodine and respond clinically. In addition, cumulative radioiodine activities, balance between benefits and risks,and patient preferences, are relevant to131I therapy decisionmaking. Patients with TSH stimulation and iodine preparation, whose lesions no longer concentrate131I or respond to131I therapy, are identified as radioactive iodine refractory DTC (RAIR-DTC) in four basic ways: 1) the malignant metastatic lesion does not ever concentrate RAI(no uptake outside the thyroid bed at the first therapeutic WBS); 2) the tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease (in the absence of stable iodine contamination); 3) RAI is concentrated in some lesions but not in others; and 4) disease progresses despite significant concentration of RAI (10).

2.3.1 Clinical assessment before131I therapy

Clinical information, as well as the status exactly before131I therapy should be considered for tailoring the management of prmDTC (Table 5). Further surgical consultation should be advised if a patient has lesions which might be amenable to surgery. While in terms of the clinical information,evaluation of the response to previous therapeutics is critical for subsequent131I therapy of prmDTC, for instance, a previous131I unresponsive patient would be unlikely to benefit from another repeated131I therapy.

Table 5 Recommendations of pretherapeutic evaluation for initial/further131I therapy in prmDTC patients

prmDTC, persistent/recurrent and metastatic differentiated thyroid cancer; WBS, whole body scan; CT, computed tomography;MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography.
a, Serum TSH should be ＞30 mIU/L through L-T4withdrawl before131I therapy (11,12). Currently, thyrogen is not approved by CFDA.
b, Diagnostic WBS (Dx-WBS) can be used for identifying radioiodine-avid lesions, tailoring dosage of131I, and predicting the efficacy of131I therapy (1).
c, BRAFV600Emutation is the most common oncogenic mutation and related to aggressive disease, recurrence and mortality.BRAFV600Emutation in isolation or in combination with TERT mutation appears to be associated with more aggressive tumor behavior, and more likely to be refractory to131I therapy (1,13,14).

Evaluation content Level I recommendation Level II recommendation Level III recommendationine —Laboratory Imaging examination Diagnostic131I WBSb(2A)Cervical ultrasonography (2A) CT (2A)Bone scan (2A)MRI (2A)18F-FDG PET/CT (2A)—

Table 6 Recommendations for131I administration in prmDTC patients

?

Table6 (continued)

a, It has been demonstrated that131I therapy on iodine-avid local recurrent or metastatic tumor is of value (1,2), and131I adjuvant therapy after lymphadenectomy for DTC relapse is associated with better progression-free survival (PFS) in patients with Tg-on≥1 ng/mL (3).
b, Most radioiodine-avid pulmonary metastases from DTC can obtain partial or complete remission after131I therapy (1,4). For patients with responsive radioiodine-avid metastases,131I therapy should be repeated every 6-12 months, and complete remission can commonly be achieved in patients with micrometastases (5-8). Radioiodine-avid macronodular metastases may be treated with131I and131I may be repeated if benefits of structural or serum Tg/TgAb reduction have been observed, whereas complete remission is uncommon and the survival remains poor (2). It's unclear whether the benefits of131I therapy could be gained in patients with non-iodine-avid pulmonary metastases (9,10).
c, Although131I therapy is rarely curative, it can be recommended for patients with radioiodine-avid bone metastases, as some benefits may be obtained, such as stable disease, tumor reduction, and survival improvement (1,2,6,11). Other local therapies also should be considered for those unresectable bone metastases, including external beam radiotherapy, endovascular embolization,bisphosphonate therapy, and vertebroplasty.
d, Surgical resection and external beam radiotherapy are the main therapeutic methods for brain metastases. For the radioiodine-avid brain metastases,131I therapy can be considered. And if131I therapy is employed, concomitant glucocorticoid therapy would be recommended to minimize the radioiodine-induced inflammatory response.
e, Tg(+)131I (-) refers to the status in the absence of imaging evidence of structural lesions [anatomic imaging and131I-whole body scan(WBS)], with significantly elevated serum Tg levels or rapidly rising serum Tg (2). So far, no survival advantages had been documented under the empiric131I therapy in such cases.
f, There are insufficient data to support the utilization of recombinant human thyroid stimulating hormone (rhTSH) in prmDTC patients. It may be considered as an alternative to thyroid hormone withdrawal in elder patients who could not withstand hypothyroidism,or mount an adequate endogenous TSH response (1,2,12).
g, Avoiding iodine exposure, a low-iodine diet (＜50 μg/d) before131I administration is recommended (1,2,12).
h, There are three approaches to determining the therapeutic doses of131I: empiric fixed dosage, dosage determined by the upper limit of blood and body dosimetry, and quantitative lesional dosimetry. Currently, empiric dosimetric method is the most commonly used method (1,2,12,13).
i, Dosimetric methods are often reserved for patients with unusual situations, such as children, the elderly or renal insufficiency(1,2,12,13). Empirically administered131I activities exceeding 150 mCi should be avoided in patients over age 70 years.131I is a relatively safe treatment method. Currently, there is no recommendation for the upper limit of single or cumulative131I doses based on prospective clinical studies. However, according to previous studies, the risk of radiation-related adverse events may be associated with the increasing cumulative131I dose and the treatment times (13).
j, There are few data to support the efficacy of131I therapy for brain metastases, so no appropriate dosage could be recommended(1,2,14).
k, Empiric (100-200 mCi)131I therapy may be considered in patients with significantly elevated serum Tg levels (≥10 ng/mL), and undetectable structural disease which is unrevealed by anatomic imaging,131I-WBS and/or18FDG-PET/CT. Besides, the131I therapy should be stopped when there is no benefit showed after the empiric therapy (2).
l, For individualized TSH suppression, please refer to 2.4.

Items Recommendation Level I Level II Level III Dose for131I therapy Local lesions 100-150 mCih,i(1A)— —Cervical lymph node metastases 100-200 mC ih,i(1A)——Lung metastases 150-200 mC ih,i(1A)——Bone metastases 150-200 mC ih,i(1A)——Brain metastases —NAj(2A)—Tg(+)131I(-)—100-200 mC ik(2B)—M anag e m e n t of prmDTC after131I thera py Post-the r a p y131I-WBS Perform post-therapy131I-WBS 2-10 days after131I therapy——TSH sup p r ession therapy Continue TSH suppression therapy within 3 days after131I administrationl——

2.4 TSH suppression therapy

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13.Molenaar RJ, Sidana S, Radivoyevitch T, et al. Risk of hematologic malignancies after radioiodine treatment of welldifferentiated thyroid cancer. J Clin Oncol 2018;36:1831-9.

14.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines?): Thyroid Carcinoma Version 2. 2017.

2.4.1 Strategy for TSH suppression therapy

For prmDTC that expresses TSH receptor, TSH suppression therapy is important in postoperative management of differentiated thyroid cancer. It has been realized the optimal degree of TSH suppression varies. An individually tailored approach to deciding TSH targets in prmDTC patients considering risk of side effects has been raised (Table 7).

Table 7 Strategy for TSH suppression therapy

ER, excellent response; IDR, indeterminate response; BIR, biochemical incomplete response; SIR, structural incomplete response.
a, If the tumor is poorly differentiated and no longer expresses thyroid stimulating hormone (TSH) receptor, only thyroid hormone replacement is needed (1,2).
b, The initial treatment period refers to within one year after the persistent/recurrent and metastatic differentiated thyroid cancer(prmDTC) being treated with surgery and/or radioactive iodine (3,4).
c, The long-term follow-up period refers to one year after the prmDTC being treated with surgery and/or radioactive iodine (3,4). TSH suppression goals may not be uniform and should be adjusted according to results of surveillance (5-8).

Whole-courseaApplicable patients: prmDTC expresses TSH recept(category 1A)or First-line medication: oral L-T4 agents (category 1A)Starting L-T4 dose: based on patient's age and coexisting diseases Final L-T4 dose: titrated according to patient's TSH goal and results of monitoring (category 1A)Check TSH every 4-6 weeks during the L-T4 dose adjustment (category 1A)—Extend intervals of TSH monitor to 3-6 months once TSH reaches the goal(category 2A)Initial periodbTSH target based on risks of TSH suppression therapy —(category 1A)-Low risk: ＜0.1 mU/L (category 2A)-High risk: If tolerated, ＜0.1 mU/L to lower normal limit(category 2A)

Table 8 Management of adverse effects of TSH suppression therapy

All AEaSet individualized TSH targets, monitor AEs and adjust L-T4 doses in a timely manner (1A)—Cardiovascular AEbBaseline cardiovascular assessment (2A), β blockers (2A) —Skeletal system AEcBaseline skeletal assessment (2A), primary prevention of osteoporosis (OP);anti-OP treatment (2A)—a,When thyroid stimulating hormone (TSH) has to be suppressed below the normal range (i.e. subclinical thyrotoxicosis) for a long period, especially below 0.1 mU/L, it may cause AE, mainly involving cardiovascular system, as well as skeletal system in postmenopausal women (1-5).b, Patients with underlying heart diseases or high risk of cardiovascular events should be given appropriate treatments by specialists,and their TSH targets should be adjusted accordingly (6-9).c, Particular attention is warranted for female patients after menopause (10).

2.5 External beam radiation therapy

External beam radiation therapy (EBRT) is an effictive and safe local therapy with benefit to local control and palliative care for prmDTC. EBRT, stereotactic radiation therapy(SBRT) and other local therapies can be used for symptomatic, weight-bearing, key site metastasis, and oligo-metastasis (Table 9).

2.6 Systemic therapy

Close follow-up is recommended in patients identified as RAIR-DTC. The degree of disease progression should be factored into treatment decisions. Systemic therapy,including chemotherapy and molecular targeted therapy,should be considered in RAIR-DTC patients with rapidly progressive and/or symptomatic disease. Potential benefits and risks of systemic therapy should be thoroughly balanced in the candidates (Table 10, 11).

Table 9 Recommendation of external beam radiation therapy for prmDTC

a, External beam radiation therapy (EBRT) and stereotactic radiation therapy (SBRT) can be considered for persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC), such as local recurrence and distant metastasis, especially for non-iodine-avid disease or RAI-rafractory throid cancer (1,2).
b, The optimal target volume and dose for EBRT are still controversial (3,4). Conventional fractionation radiotherapy dose is: 1) Gross target volume (GTV, mainly including recurrent or residual tumor regions, metastase): 60-70 Gy; and 2) Clinical target volume (CTV,mainly including subclinical area): 50-60 Gy (5). Precise radiotherapy technologies, such as intensity-modulated radiotherapy (IMRT)and image guided radiotherapy (IGRT), are safe, effective, and less morbid (6,7).
c, In the case of DTC lung metastases, EBRT or SBRT mainly applies to: 1) Single or oligo-metastasis (the definition of oligo-metastasis is not uniformly standardized, and it is generally considered that the number of metastases is ≤3-4); and 2) Lung metastases that do not intake iodine (8).
d, EBRT or SBRT can be mainly considered for symptomatic skeletal metastases or those that are asymptomatic in weight-bearing sites. The main role is to relieve the pain symptoms, reduce the risk of pathological bone events, and improve the quality of life(9,10).
e, EBRT or SBRT is one of the main treatments for brain metastases regardless of the number and size of lesions, or the iodine intake status. Once brain metastases are diagnosed, disease-specific mortality is very high (67%), with median survival of 12.4 months. Survival can be significantly improved by neurosurgical resection. With the development of radiotherapy techniques, SBRT can achieve similar results to neurosurgery (11-13).

Local recurrent lesions—EBRT (unresectable local recurrent lesions)a,b(2A)—Metastatic lesions— — —Lung metastases —EBRT/SBRT (single or oligo-metastasis)c(2A)EBRT/SBRT (selective for multiple metastases) (2B)Bone metastases —EBRT/SBRT (symptomatic or weight bearing bones)d(2A)—Brain metastases EBRT/SBRT (single or oligo-metastasis)e(2A)EBRT/SBRT (multiple metastases) (2B) —Other metastases —EBRT/SBRT (non-iodine-avid disease,palliative relief of local symptoms) (2B)—

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7.Pacini F, Castagna MG, Brilli L, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol 2012 Suppl 7;23:110-9.

8.Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet 2014;384:319-28.

9.Chen L, Shen Y, Luo Q, et al. Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma. Thyroid 2011;21:119-24.

10.Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008;26:4714-9.

11.Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675-84.

12.Hoftijzer H, Heemstra KA, Morreau H, et al. Beneficial effectsof sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol 2009;161:923-31.

Table 10 Stratified recommendations for potential systemic therapy in RAI-refractory prmDTC patients

a, Patients with very indolent disease who are asymptomatic may not be appropriate for systemic therapy, and the follow-up strategy of every 3-6 months is recommended. Whereas patients with more rapidly progressive disease may benefit from systemic therapy (1,2).
b, The following points should be taken into consideration when patients are tentatively regarded as candidates for molecular targeted therapy (3-7): 1) The benefit of molecular targeted therapy may primarily yield the prolongation of progression-free survival(PFS) rather than overall survival (OS); 2) Molecular targeted drugs may induce adverse effects and result in low quality of life (QoL);and 3) Despite radioactive iodine refractory (RAIR), the disease may remain stable for several months to several years.
c, Sorafenib is the first targeted drug applied in a completed randomized, double-blind, phase 3 trial for the treatment of locally advanced or metastatic RAIR-DTC (8). It was approved by China Food and Drug Administration (CFDA) in March 2017 for the treatment of progressive RAIR-DTC (9). Considering the balance of efficacy and side effects, 400 mg b.i.d. has been commonly utilized in most clinical trials (10-13); but the applications of low-dose sorafenib (200 mg b.i.d.) for treatment of RAIR-DTC could also achieve well efficacy with slight side effects, which may improve the compliance of patients and reduce medical costs (9,14).
d, The indications of clinical trials in this entity may include: 1) Locally advanced or metastatic RAIR-DTC patients with disease progression determined by Response Evaluation Criteria In Solid Tumors (RECIST); and 2) Patients with BRAF, PPARγ or other tumor-related gene mutations which could be targeted by molecular drugs.
e, Chemotherapy is only a palliative or experimental method for persistent/recurrent and metastatic differentiated thyroid cancer(prmDTC) with no response to other treatment. Adriamycin is the only chemotherapeutic drug approved by the US FDA (15,16).
f, Molecular targeted therapy-induced adverse effects are common, and may lead to dose reduction and drug discontinuation.Common adverse effects reported include skin toxicity, hypertension, gastrointestinal toxicity, proteinuria, fatigue, thyroidstimulating hormone inhibitory disorders, and impaired thyroid function. Before treatment, comprehensive assessment of certain risk factors that may increase the risk of adverse effects and necessary intervention to control concomitant diseases are recommended.For adverse effects during treatment, multidisciplinary consultation should be considered to protect important organs, improve the quality of life, and maximize the effects of targeted drugs. If the degree of adverse reactions is low and the function of important organs is well, the sustained targeted therapy is recommended to obtain the maximum curative effect and survival benefit from targeted drugs; if grade 3-4 adverse effects or the damage of important organs occur, the dose reduction or drug discontinuation should be promptly adopted until the weakening or disappearance of adverse effects, and then the therapy should restart from a lower dose.

?

13.Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab 2010;95:2588-95.

14.Shen Y, Ruan M, Luo Q, et al. Brain metastasis from follicular thyroid carcinoma: treatment with sorafenib. Thyroid 2012;22:856-60.

15.Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30.

16.Lin Y, Wang C, Gao W, et al. Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer. Oncotarget 2017;8:42252-61.

17.Shimaoka K, Schoenfeld DA, DeWys WD, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985;56:2155-60.

18.Droz JP, Schlumberger M, Rougier P, et al. Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. Tumori 1990;76:480-3.

Table 11 Efficacy of molecular targeted drugs for thyroid cancer therapeutics

ORR, objective response rate; PFS, proression-free survival; RAIR-DTC, radioactive iodine refractory differentiated thyroid cancer;MTC, medullary thyroid carcinoma; RCT, randomized controlled clinical trial; PLC, placebo; SOR, sorafenib; LEN, lenvatinib; VAN,vandetanib; NR, not reported; NE, not evaluated.
a, The SELEC study showed that lenvatinib significantly prolonged PFS in RAIR-DTC compared with placebo (17). Lenvatinib mesylate has been approved by the European Commission for the treatment of invasive, locally advanced or metastatic DTCs.
b, A single-arm prospective clinical trial had been conducted to evaluate the efficacy and safety of apatinib in the treatment of advanced RAIR-DTC, suggesting well tolerance with rapid-onset efficacy and high-rate of objective response in the first 8-week therapy (18).

Medicines PathologicalExperimentalNumber of cases ORR Median PFSReferences typedesign (month)LenvatinibaRAIR-DTC Phase III261 LEN, 131 PLC 64.8% vs. 1.5% 18.3 vs. 3.6 New England journal of medicine RCT vs. PLC2015;372: 621-30.Pazopanib RAIR-DTC Phase II 37 49% 11.7 The Lancet Oncology 2010;11:962-72.Axitinib RAIR-Phase II 45 RAIR-DTC, 11 MTC 30% 16.1 Cancer 2014;120:2694-703.DTC/MTC RAIR-Phase II 45 RAIR-DTC, 6 MTC 35% 15 Cancer Chemotherapy and DTC/MTCPharmacology 2014;74:1261-70.

Working group members

Chair:Yansong Lin

Associate chair:Huiqiang Huang, Ye Guo, Libo Chen

Task force member (listed alphabetically by last name)(＊, writing member)

Jiandong Bao Jiangsu Institute of Nuclear Medicine, Jiangsu Jiangyuan

Hospital, Wuxi Institute of Thyroid Diseases

Ge Chen Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Libo Chen＊Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Yali Cui Affiliated Tumor Hospital, Harbin Medical University

Yong Ding＊Beijing People's Liberation Army 307 Hospital

Haixia Guan＊The First Hospital of China Medical University

Ye Guo＊Shanghai East Hospital, Tongji University

Zairong Gao＊Union Hospital, Tongji Medical College, Huazhong

University of Science and Technology

Huiqiang Huang Affiliated Tumor Hospital, Sun Yat-sen University

Rui Huang＊West China Hospital, Sichuan University

Tao Huang Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Xiaorong Hou＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xiayun He＊Cancer Hospital, Fudan University

Mei Li＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Shaohua Li Nanjing First Hospital

Xiaoyi Li＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xuena Li The First Hospital of China Medical University

Yujun Li Affiliated Hospital of Qingdao University, Qingdao University

Zhiyong Liang＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Yukun Luo Chinese People's Liberation Army General Hospital

Yansong Lin＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jing Lyu Affiliated Hospital of Qingdao University, Qingdao University

Qingjie Ma China-Japan Union Hospital, Jilin University

Lijuan Niu＊Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Wenhai Sun Affiliated Hospital of Qingdao University, Qingdao University

Feng Wang Nanjing First Hospital

Renfei Wang＊Tianjin Medical University General Hospital, Tianjin Medical University

Feng Wei First Affiliated Hospital, Baotou Medical College, Inner Mongolia University of Science and Technology

Yu Xia Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Aiming Yang The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University

Bin Zhang＊Peking University Cancer Hospital & Institute

Bo Zhang＊Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Guang Zhang＊China-Japan Union Hospital, Jilin University

Hong Zhang Sun Yat-sen Memorial Hospital, Sun Yat-Sen University

Li Zhang Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xiangqian Zheng＊Tianjin Medical University Cancer Institute &Hospital, Tianjin Medical University

Review expert committee (listed alphabetically by last name)

Rui An Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Jugao Fang Beijing Tongren Hospital, Capital Medical University

Youben Fan Shanghai Sixth People's Hospital, Shanghai Jiao Tong

University

Ming Gao Tianjin Medical University Cancer Institute & Hospital,

Tianjin Medical University

Zhuming Guo Sun Yat-sen University Cancer Center, Sun Yat-sen

University

Gang Huang Shanghai University of Medicine & Health Sciences

Qinghai Ji Fudan University Shanghai Cancer Certer, Fudan University

Ningyi Jiang Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

Yuxin Jiang Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Anren Kuang West China Hospital, Sichuan University

Fang Li Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Sijin Li First Hospital of Shanxi Medical University, Shanxi Medical University

Yaming Li The First Hospital of China Medical University

Shaoyan Liu Cancer Hospital Chinese Academy of Medical

Sciences, Chinese Academy of Medical Sciences

Hui Sun China-Japan Union Hospital, Jilin University

Zhongyan Shan The First Hospital of China Medical University

Jian Tan Tianjin Medical University General Hospital, Tianjin Medical University

Wen Tian Chinese People's Liberation Army General Hospital

Jing Wang Xijing Hospital, Fourth Military Medical University

Tie Wang Beijing Chaoyang Hospital, Capital Medical University

Xiaoping Xing Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Zhengang Xu Cancer Hospital, Chinese Academy of Medical

Sciences and Peking Union Medical College

Fuquan Zhang Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jiajun Zhao Shandong Provincial Hospital

Yupei Zhao Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jingqiang Zhu West China Hospital, Sichuan University

Secretary (listed alphabetically by last name)

Hui Li Peking Union Medical College Hospital, Peking Union Medical College, Academy of Medical Science

Jiao Li Affiliated Hospital of Qingdao University, Qingdao University

Li Li Peking University International Hospital

Yingjie Zhang Shandong Cancer Hospital & Institute

Teng Zhao Beijing Chaoyang Hospital, Capital Medical University