Radioiodine refractory differentiated thyroid cancer - Critical Reviews ...

Critical Reviews in Oncology / Hematology 125 (2018) 111–120

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Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc

Radioiodine refractory differentiated thyroid cancer a

b

a

a

Yuchen Jin , Douglas Van Nostrand , Lingxiao Cheng , Min Liu , Libo Chen a b

a,⁎

T

Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, People’s Republic of China MedStar Health Research Institute and Washington Hospital Center, Washington, DC, 20010, United States

A R T I C LE I N FO

A B S T R A C T

Keywords: Radioactive iodine refractory differentiated thyroid cancer Molecular imaging Targeted chemotherapy Gene therapy Immunotherapy

Differentiated thyroid cancer (DTC) is usually curable with surgery, radioactive iodine (RAI), and thyroid-stimulating hormone (TSH) suppression. However, local recurrence and/or distant metastases occur in approximately 15% of cases during follow-up, and nearly two-thirds of these patients will become RAI-refractory (RRDTC) with a poor prognosis. This review focuses on the most challenging and rapidly evolving aspects of RRDTC, and we discuss the considerable improvement in more accurately defining RR-DTC, more effective therapeutic strategies, and describe the diagnosis, pathogenesis, and future prospects of RR-DTC. Along with the detection of serum thyroglobulin and anatomic imaging modalities, such as ultrasound and computer tomography, radionuclide molecular imaging plays a vital role in the evaluation of RR-DTC. In addition, continual progress has been made in the management of RR-DTC, including watchful waiting under appropriate TSH suppression, local treatment approaches, and systemic therapies (molecular targeted therapy, redifferentiation therapy, gene therapy, and cancer immunotherapy). These all hold promise to change the natural history of RRDTC.

1. Introduction The occurrence of thyroid cancer has been steeply increasing over the last several decades (Lim et al., 2017). Surveillance and Epidemiology and End Results (SEER) data revealed that there might be approximately 56,870 new reports of thyroid cancer in patients and about 2010 deaths due to the disease in 2017 (Thyroid Cancer Stat Facts, 2018). Further, by 2030, thyroid cancer is predicted to be the second-leading cancer that is diagnosed in women and the ninthleading in men (Rahib et al., 2014). The most prevalent kinds of thyroid cancer originate from follicular cells, accounting for 90–95% of the cases, and they are distinguished as differentiated thyroid cancers (DTCs) (Lim et al., 2017). Notwithstanding the variations in their biological activities, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are together referred to as DTCs, and the conditions receive comparable treatments. Surgery, radioactive iodine (RAI) remnant ablation or therapy, and thyroid stimulating hormone (TSH) suppression therapy have resulted in a favorable prognosis as reflected by 10-year survival rates of about 90% (Durante et al., 2006). However, local recurrence and distant metastases can occur in up to approximately 20% and 10% of cases, respectively, in the 10 years after the initial operation; for these cases, there are multiple therapeutic

options, such as RAI therapy, metastasectomy, and external beam radiotherapy (Haugen et al., 2016). Despite these therapies, a complete response can only be achieved in one-third of patients; the remaining two-thirds of patients will become RAI-refractory (RR-DTC), and they have a poor overall prognosis, which is an inevitable challenge in the current medical management of the disease (Durante et al., 2006; Schlumberger et al., 2014). Over the past decade, given the controversies in some areas, continual progress has been made in the diagnosis and therapy of RR-DTC. A systematic search was conducted using Excerpta Medica Database for primary references available prior to January 17, 2018 to update the comprehensive review of the field to clinicians, scholars and students for better knowledge and clinical practice. In this review, the definitions, pathogenesis, diagnosis and management choices including watchful waiting, local therapies and systemic therapies (targeted chemotherapy, redifferentiation therapy, immunotherapy, gene therapy, and vascular endothelial growth factor trap therapy) for RR-DTC have been addressed. 2. Definitions The definition of RR-DTC needs further refinement because classifying radioiodine refractory disease is critical in helping to determine

⁎ Corresponding author at: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Yishan Rd. 600, Shanghai 200233, People’s Republic of China. E-mail addresses: [email protected] (Y. Jin), [email protected] (D. Van Nostrand), [email protected] (L. Cheng), [email protected] (M. Liu), [email protected] (L. Chen).

https://doi.org/10.1016/j.critrevonc.2018.03.012 Received 2 July 2017; Received in revised form 22 January 2018; Accepted 21 March 2018 1040-8428/ © 2018 Elsevier B.V. All rights reserved.


Y. Jin et al.

Fig. 1. Disease progression of radioactive iodine-avid metastatic differentiated thyroid cancer in less than one year after 131I therapy. Whole body scintigraphy 3 days post administration of 131I (200 mCi) showed several 131Iavid foci in the lungs of a 46-year-old woman who had undergone total thyroidectomy for poorly differentiated follicular thyroid carcinoma (A, anterior; B, posterior; arrow, the largest targeted lesion). Simultaneous 131I SPECT/CT fusion imaging (C), diagnostic CT imaging (D), and 18F-FDG PET/CT scan (E) revealed nodules accumulating both 131I and 18 F-FDG (arrow, the largest targeted lesion; Size: 25 × 22 mm; SUVmax: 6.7), indicating iodine- and glucose-avid metastases from follicular thyroid carcinoma. At 5 months post 131I therapy, diagnostic CT (F) showed an enlarged nodule (54 × 34 mm) accompanied by rising serum thyroglobulin (2136 ng/mL) when hemoptysis occurred, demonstrating disease progression. At 6 months after the initiation of sorafenib therapy (200 mg, bid), serum thyroglobulin decreased to 449.4 ng/mL, and CT imaging (G) showed moderate tumor shrinkage (42 × 35 mm), indicating a stable disease response.

3. Pathogenesis

which patients should be considered for treatments other than RAI, and misclassification will eliminate the patient’s chance of receiving additional RAI therapy from which the patient may benefit. RR-DTC is traditionally defined more by the natural behavior of thyroid follicular cells than by a specific histopathology. According to the 2015 guidelines of the American Thyroid Association (ATA), RRDTC is defined in patients with the following conditions (Haugen et al., 2016; Schlumberger et al., 2014): (i) the foci never concentrate RAI; (ii) despite previous evidence of RAI concentration, the foci lose the ability to be RAI-avid; (iii) despite the significant concentration of RAI, concentration is presented in some foci but not in others; or (iv) metastasis progress within one year after RAI therapy (Fig. 1). For RR-DTCs, the probability of being cured by further RAI therapies is very low, and adverse effects, including leukemia, secondary tumors, and lung toxicity, may be increased (Brown et al., 2008; Rubino et al., 2003). Additionally, patients may be considered RAI-refractory after receiving an RAI dose of more than 600 mCi based on the benefits (longer progression-free survival and overall survival) and risks (higher incidence of adverse effects) (Schlumberger et al., 2014). Moreover, patients with local advanced or end-stage disease who are not amenable to surgery should also be managed as RR-DTC since RAI is ineffective when a thyroid gland is still present. Although few studies have been performed, patients with elevated levels of serum thyroglobulin (Tg), especially those having a short doubling time (< 1 year) of Tg, do not seem to have a good prognosis, and they may also be considered as RAIrefractory (Matthews et al., 2016; Shinohara et al., 2015).

RR-DTC is associated with the abnormal function of sodium iodide symporter (NIS), the decreased expression of other iodine handling genes, including Tg, thyroperoxidase (TPO), and thyroid-stimulating hormone receptor (TSHR) (Cheng et al., 2017). Further, the iodine concentrating ability of DTC cells may be impaired by reduced NIS expression (Ruan et al., 2015). On the contrary, patients with positive NIS immunostaining showed a better response to RAI therapy (Lazar et al., 1999). In fact, a lack of NIS function is not restricted to a decreased or absent expression, but it can also be the result of insufficient retention of NIS and damaged targeting on the plasma membrane. Overexpression and simultaneous intracellular localization could be seen in about 70% of thyroid cancer samples (Durante et al., 2007). In addition to the changes in NIS protein, the mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in the development, dedifferentiation, and progression of DTC. The most potent activators of the MAPK pathway are BRAF mutations, which decrease the ability to take up RAI (Phay and Ringel, 2013). The phosphatidyl-inositiol-3-kinase (PI3K) pathway has also been found to have a crucial role in differentiation of thyroid cancer (Hou et al., 2010). In TSH-stimulated thyroid cells, the activation of the PI3K pathway could reduce NIS expression at the transcriptional level (De Souza et al., 2010; Kogai et al., 2008). Serine–threonine protein kinase mammalian target of rapamycin (mTOR) causes the inhibition of thyroid iodide uptake through the activation of the PI3K/Akt pathway, which leads to a 112


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in these patients. Despite the slow progression of the metastatic lesions, careful follow-up should take place every 3–6 months for RR-DTC patients, with an assessment of potential symptoms, imaging studies, and serum tests. The 2015 ATA guidelines recommend that TSH suppression should be considered below 0.1 mIU/L in RR-DTC patients with an incomplete structural response to therapy indefinitely, and 0.1–0.5 mIU/L in RRDTC patients with an incomplete biochemical response given no contraindication (Haugen et al., 2016).

decrease in NIS expression in thyroid cancer cells (Kogai et al., 2008). In addition, thyroid cancers harboring the BRAFV600E mutation have been reported to be positively correlated with NADPH oxidase NOX4, which is a critical mediator of the downregulation of NIS and inversely correlated to thyroid differentiation. NOX4-dependent reactive oxygen species (ROS) generation, regulated by TGF-β1, could be involved in the BRAFV600E-induced repression of NIS, which may be silenced by the activation of NOX4-derived ROS (Azouzi et al., 2017). 4. Diagnosis

5.2. Local therapy

Serum Tg tests combined with RAI whole body scan (WBS) are standard protocol for detecting recurrent and metastatic DTC after total/near total thyroidectomy and RAI therapy. It is important to note that metastases may be too small to see, and diagnostic scans have a lower sensitivity than therapeutic scans (Kist et al., 2016; Pacini et al., 2001). In a comparison of the results of diagnostic scans to post-therapy scans, 6–13% of patients have newly identified foci on post-therapy WBS that were not found on diagnostic WBS (Avram et al., 2013; Sherman et al., 1994). This can be as high as 20–64% on empirical 131Itherapy scans in patients who had a previously positive post-therapy scan, but are now negative on a diagnostic scan. Khorjekar et al. have shown that even in patients with a negative 124I-PET/CT scan, positive foci was presented in 83% patients on the 131I post-therapy scan (Khorjekar et al., 2014). Radionuclide molecular imaging modalities other than RAI scans are still needed to identify RR-DTC foci. 18F-FDG PET/CT (fluoro-18deoxy-glucose positron emission tomography) has been accepted for investigating DTC with high stimulated Tg levels (> 10 ng/mL) and negative RAI-WBS as a standard of care for RR-DTC. The higher the Tg level, the higher the sensitivity of the 18F-FDG PET/CT scan (Nascimento et al., 2015). Other nuclear medicine methods for the detection of focal lesions include somatostatin receptor scintigraphy and choline imaging, which remain experimental at present (Jois et al., 2014; Ocak et al., 2013); combined with the findings of 18F-FDG PET/ CT, they can improve sensitivity (Sager et al., 2013). In addition, although neck ultrasound (US) shows a higher accuracy compared to 18F-FDG PET/CT in cervical lesions, US is not always feasible in detecting distant metastasis, and the high spatial resolution capacity of neck US is only useful for detecting metastatic lymph nodes that are larger than 2 mm in diameter (Choi et al., 2010). In PTC, lymph node recurrence is accurately diagnosed by US-guided fine-needle aspiration biopsy, which helps in making therapeutic decisions (Tomoda et al., 2016).

Local therapy indicated in RR-DTC is determined by the location (aerodigestive tract, lung, extra cervical lymph nodes, brain, and bones), number of lesions, tumor burden, and technical feasibility (Table 1). Main local therapies include surgery, external beam radiation (EBRT), radiofrequency ablation (RFA), ethanol ablation, and laser ablation. Surgery is the first choice in the case of locoregional disease, and central/lateral neck dissection is recommended if there is limited involvement of vital structures. However, in the case of intractable, distant metastases, locoregional disease therapy does not display significant benefits with the exceptions of decreasing the risk of potential lethal bleeding, alleviating symptoms, and removing the aerodigestive obstruction (Haugen et al., 2016). In special cases, since the situation of a stable lymphnode with high tumor burden which is not feasible for local therapy is rare, the management strategy remains undetermined, and evidence of recommendations for RR-DTC patients with stable and symptomatic lymph node is lacking. In patients with pulmonary metastases, local therapies, such as laser ablation, metastasectomy, or EBRT, are recommended to palliate intrathoracic symptoms of hydrothorax or hydropericardium (Capdevila et al., 2017). Although some of the patients with multiple lesions could be “cured” by surgery, this notion has not been confirmed by long-term outcomes to the best of our knowledge. On the contrary, disease progression (recurrence and new metastases) usually occur after resection of metastatic lesions (Liu et al., 2014). In patients with bone metastases, particularly with isolated progressive and/or symptomatic metastases, complete resection should be taken into consideration to improve survival, especially in young patients with a slow progressive disease (Haugen et al., 2016; “NCCN Guideline,” 2017). Meanwhile, in the presence of an impending compression fracture (especially vertebral compression fracture), RFA combined with cement augmentation may be performed to achieve bone structural stabilization. Antiresorptive therapy with either a bisphosphonate or denosumab has been also endorsed by ATA guidelines to delay time to occurrence of subsequent skeletal-related adverse events, including fracture, pain, and neurological complications, and to improve symptoms, and these agents may provide benefits for patients with diffuse bone metastases (Haugen et al., 2016; Kushchayeva et al., 2014). Ethanol ablation was the first minimally invasive technique for the non-surgical treatment of metastatic cervical lymph nodes in DTC patients. The treatment reduces lymph node volume but possesses limitations, such as difficulty in inducing a necrotic area, and it needs multiple doses for complete ablation (Kim et al., 2008). Percutaneous laser ablation possesses advantages in dealing with cervical lesions. The deployed thermal energy is precise, and better outcomes are expected if it is used on smaller lesions (< 15 mm) (Mauri et al., 2016). RFA and ethanol ablation can be used to ablate larger nodes. The largest nodes reported were 40 mm by RFA (Monchik et al., 2006) and 29 mm by ethanol ablation (Lim et al., 2007), but RFA may cause permanent peripheral tissue injuries (Monchik et al., 2006) and ethanol ablation may require repeated injections (Kim et al., 2008).

5. Management The 2015 ATA management guidelines specified four basic principles for managing RR-DTC patients: careful monitoring with active TSH suppression therapy; directed therapy, such as surgery, radiotherapy, or thermal ablation for specific threatening or symptomatic lesions; systemic therapy, preferably with approved targeted chemotherapies and entry into clinical trials (Haugen et al., 2016). Other emerging therapeutic modalities, such as redifferentiation therapy, immunotherapy, gene therapy, and vascular endothelial growth factor trap (VT) therapy, which may improve the prognosis of RR-DTC, are worthy of further investigation. 5.1. Watchful waiting under TSH suppression RR-DTC could be asymptomatic for a long time. Watchful waiting should be taken into consideration for patients with an indolent disease; unresectable metastatic cancer; asymptomatic, stable, or low tumor burden; low likelihood of developing the rapidly progressive disease, and no adverse impact from disease burden (Table 1). No further therapy except for TSH suppression and active surveillance are required 113

114

× ×

× ×

×

× × × ×

× ×

× × ×

HIgh

Low

Progressive

Stable and asymptomatic

Stable and symptomatic

Tumor burden

Disease status

×

×

×

×

×

×

Feasibile

×

×

×

×

×

×

Not feasibile

Local therapy

Watchful waiting Watchful waiting Local therapy Lack evidence Local therapy Systemic therapy Local therapy Systemic therapy Local therapy Watchful waiting Local therapy Systemic therapy Local therapy Systemic therapy

Decision

Brose et al. (2014), Haugen et al. (2016), Kushchayeva et al. (2014), NCCN Guideline (2017)

Haugen et al., (2016), NCCN Guideline (2017)

Haugen et al. (2016), NCCN Guideline (2017), Schlumberger et al. (2014) Haugen et al., 2016, NCCN Guideline (2017), Schlumberger et al. (2014), Tomoda et al. (2016)

Reference

Local therapy: surgery, external beam radiotherapy/stereotactic body radiotherapy, embolization, etc.; Watchful waiting: follow-up every 3–12 mos; CNS, central nervous system; Systemic therapy: targeted chemotherapy, rediffrentiation therapy, immunotherapy, gene therapy, etc. * Bisphosphonates or denosumab can be recommended in all situations of bone metastasis without contraindication.

Peripheral nerve, trachea, blood vessel, CNS Bone* and other soft tissues (lung, etc.)

Lymph node

Negative imaging

Location

Table 1 Imaging-aided treatment decision of radioiodine refractory differentiated thyroid cancer.

Y. Jin et al.



Y. Jin et al.

downgrade the patients’ quality of life and increase the risk of death in RR-DTC patients as in most cases these therapies require long-term administration. It should be emphasized that such targeted chemotherapy should be better considered in RR-DTC patients with disease progression and/or prominent symptoms that are not amenable to local therapies (Table 1). Targeted chemotherapies seem to induce similar adverse effects, but there is a more common prevalence of hypertension in the use of lenvatinib and hand and foot syndrome in the use of sorafenib (Table 2). Therefore, the use of lenvatinib and sorafenib in starting targeted chemotherapy should be individualized with the considerations of the general health conditions of the patient, the presence of other relevant diseases, and the use of other drugs. Additionally, the timing of the initial targeted chemotherapy in RRDTC patients is that single large tumor burdens (> 3 cm) or multiple tumor burdens (> 1–2 cm) are rapidly progressing (Brose et al., 2017a, b; Schlumberger et al., 2014). However, as RR-DTC can follow an indolent course, physicians may adopt a watchful waiting approach before initiating targeted chemotherapy (Dadu and Cabanillas, 2012).

5.3. Systemic therapy For patients with RR-DTC that progresses despite TSH suppression and local therapy, therapeutic options have been historically limited. Presently, targeted chemotherapy holds promise in the therapy of RRDTC. Sorafenib and lenvatinib are the only two multitargeted kinase inhibitors that have been approved by the US Food and Drug Administration (FDA) for use in patients with progressive RR-DTC, while most of the other agents remain investigational. Additional new approaches, including redifferentiation therapy, immunotherapy, gene therapy and VT therapy have emerged as effective alternatives for progressive diseases, which has not been approved by the FDA. 5.3.1. Targeted chemotherapy Targeted chemotherapies for RR-DTC mainly act by two mechanisms, either by inhibiting angiogenesis or by inhibiting cell proliferation and survival. Thyroid tumors are well vascularized, and the tumor growth depends on the provision of nutrients through vascularization. Vascular endothelial growth factor (VEGF) drives tumor vascularization, and it is related to a larger tumor size and poor prognosis in DTCs. Platelet-derived growth factor (PDGF) complements VEGF in vessel formation. Multikinase inhibitors can inhibit VEGF or PDGF, and thus inhibit angiogenesis by depriving the tumor of a vascular supply. Signaling pathways, such as the MAPK/ERK and PI3K/AKT pathways, regulate cell proliferation, and targeted therapies interfere with these pathways (Wei et al., 2017; Worden, 2014). Table 2 shows the critical data of targeted chemotherapies for RR-DTC. In addition, several drugs that are listed in the ClinicalTrials.gov database are being evaluated in ongoing trials, including cediranib, dabrafenib, cabozantinib, everolimus, trametinib, pazopanib, lenvatinib, sunitinib, selumetinib, temsirolimus, vemurafenib, and vandetanib. Significant improvement in progression-free survival (PFS) was achieved in patients with progressive RReDTC using sorafenib (Brose et al., 2014) or lenvatinib (Schlumberger et al., 2015), which were compared with placebo. Lenvatinib, an oral multikinase inhibitor, is the most recent drug approved by the FDA for the treatment of RR-DTC (Nair et al., 2015). In a randomized, multicenter, double-blind, placebocontrolled trial (RCT), the median PFS reached 18.3 months using lenvatinib compared with 3.6 months using the placebo (Schlumberger et al., 2015). Of note, in most recent subgroup analyses of young and old patients with lenvatinib treatment, benefits in younger patients showed higher objective response rate (ORR), longer PFS and lower rate of grade 3 adverse events. Meanwhile, improved PFS and OS with lenvatinib treatment was observed in the older group, suggesting that lenvatinib could be considered for RR-DTC patients of any age (Brose et al., 2017a, b; Elisei et al., 2015). By comparing the PFS of placebo groups (3.6 vs. 5.8 mo), the degree of the improvement of PFS (14.7 vs. 5 mo) and ORR (64.7% vs. 12.2%) of the two studies, patients may be "sicker" at baseline in the lenvatinib trial and it seems that lenvatinib got a better efficacy. However, it must be pointed out that the baseline characteristics of the subjects and the design of the two RCTs were different. A head-to-head study comparing both efficacy and safety of lenvatinib and sorafenib has not been conducted as of now. Pazopanib (Bible et al., 2010), axitinib (Cohen et al., 2008), selumetinib (Hayes et al., 2012), everolimus (Lim et al., 2013), gefitinib (Pennell et al., 2008), and motesanib (Sherman et al., 2008) exhibited promising activity in the initial phases of the clinical trials. Recently, based on FDG-PET/CT, an overwhelming rapid metabolic and structural response (60.8%) was observed after the initiation of apatinib in metastatic RR-DTC by Lin et al. (Lin et al., 2017), and in local recurrence by our team (Fig. 2). Such non-concordance of therapeutic response among a variety of targeted chemotherapeutic agents may be related to the different profiles of molecular targets and their IC50, which possibly lead to the optimization of targeted chemotherapy and a new adjuvant therapy of advanced DTC. Drug-induced adverse effects are commonly observed; they

5.3.2. Redifferentiation therapy Redifferentiation therapy remains an ongoing research area in RRDTC since the development of de-differentiated DTC is related to the loss or absence of RAI uptake ability, and redifferentiation therapeutic strategies could potentially reactivate the RAI uptake ability of thyroid carcinoma (Spitzweg et al., 2014). Recently, phase Ⅱ clinical trials of BRAF and MEK inhibitors, including dabrafenib and selumetinib, showed significant enhancement of RAI incorporation and notable efficacy in a subset of patients with PTC. A pilot trial of the MEK inhibitor selumetinib in 20 patients with RR-DTC showed the RAI restoration in metastatic foci in 14 patients. In 8 of the 14 patients, the uptake was sufficient to enable RAI therapy with remarkable clinical responses (Ho et al., 2013). Similar findings have been shown with the BRAF inhibitor dabrafenib (Rothenberg et al., 2015). A phase Ⅲ, placebo-controlled, double-blind, randomized trial (ClinicalTrials.gov number, NCT01843062) evaluating the ability of selumetinib to enhance the response to adjuvant radioiodine therapy in high-risk patients is ongoing. In addition, the multikinase inhibitor sorafenib or cabozantinib-induced restoration of RAI uptake in thyroid cancer cells has been demonstrated by our group in vitro (Ruan et al., 2015). Histone deacetylase inhibitors (HDIs), such as panobinostat, depsipeptide, and valproic acid (VA), may play positive roles in the redifferentiation process. Histone deacetylation by histone deacetylase (HDAC) at the promoter region of NIS is a mechanism in its aberrant silencing, and the suppression of HDAC could robustly enhance thyroid gene expression and RAI uptake in basic research (Zhang et al., 2014) (Fig. 3A). Panobinostat showed a stable disease (SD) in half of the RRDTCs in a phase Ⅱ trial (Traynor et al., 2013). Depsipeptide restored RAI avidity in only 10% of the RR-DTC patients, while SD was achieved in only half of all of the enrolled patients in a phase Ⅱ study (Sherman et al., 2009). VA has been reported to upregulate the expression of NIS and increased RAI uptake in preclinical studies. However, in a phase Ⅱ clinical study, VA did not increase RAI uptake in RR-DTC patients (Nilubol et al., 2016). Moreover, the BRAFV600E-activated MAPK pathway could cause histone deacetylation at the NIS promoter, and HDIs also synergized the stimulatory effects of the BRAFV600E inhibitor in thyroid cancer. Suppression of BRAFV600E by vemurafenib could increase histone acetylation at the promoter of NIS. The effects of the BRAFV600E inhibitor on thyroid gene expression and RAI uptake were more profound in the BRAFV600E mutation thyroid cancer cells, particularly those cotreated with TSH. Dual therapy with vemurafenib and vorinostat on thyroid gene expression and RAI uptake were more pronounced, even in cells harboring the wild-type BRAF (Cheng et al., 2016).

115

VEGFR, PDGFR, c-Kit, RET

VEGFR, PDGFR, c-Kit, RET, RAF

VEGFR, RET, PDGFR, c-Kit VEGFR, PDGFR, c-Kit

Axitinib

Sorafenib

Motesanib

116

mTOR

VEGFR, FGFR, c-Kit, RET, PDGFR

FLT3, c-Kit, FGFR, VEGFR EGFR

Selumetinib Vandetanib

Everolimus

Lenvatinib

Dovitinib

NR 23–37.5 (NA) NE NE NE

30 56 (52) 417 (207) 34 93

40 27

Single, Ⅱ Pennell et al. (2008)

NE

58

27.4 (10.5-NE)

NE

LEN: NE

NR

NE 56.5 (16.8–63.3) NR NR

382 (261)

40

35 (33) 23 39 (32) 145 (72)

Single, Ⅱ Carr et al. (2010) Single, Ⅱ Bikas et al.,(2016) Single, Ⅱ Hayes et al. (2012) RCT, Ⅱ Leboulleux et al. (2012) Single-arm, phase Ⅱ Lim et al. (2013) RCT, Ⅲ Schlumberger et al. (2015) Single, Ⅱ Cabanillas et al. (2015) Single, Ⅱ Lim et al. (2015)

NE

34.5 (19–50)

31

39 (37)

NE (20.8-NE) NE (21.6-NE) 27.4 (14.7–40.3) NR

60 (45) 60 52 32 (31)

Single, Ⅱ Cohen et al. (2008) Single, Ⅱ Cohen et al. (2014) Single, Ⅱ Locati et al. (2014) Single, Ⅱ Hoftijzer et al. (2009) Single, Ⅱ Schneider et al. (2012) Single, Ⅱ Gupta-Abramson et al. (2008) Multi, Ⅱ Shah et al. (2009) RCT, phase Ⅲ. Brose et al. (2014) Single, Ⅱ Ahmed et al. (2011) Single, Ⅱ Sherman et al. (2008) Single, Ⅱ Bible et al. (2010)

OS, mo (95% CI)

Enrolled n (evaluable)

Arm, phase (Reference)

3.9 (2.8–6.8)

5.4 (2.0–8.8)

12.6 (9.9–16.1)

18.3 (15.1-NE)

11.8 (3.7–19.7)

NR 8 (3.8–17.3) 7.4 (1.9–-12.9) 11.1 (7.7–14.0)

11.7 (NR)

NE 9.2 (7.4–11.5)

4.5–16 (NA) 10.8

19.7(NR)

18 (7–29)

18.1 (12.1-NE) 15 (10–20) 16.2 (14,8–21.6) 58 (47–68)

Median PFS, mo (95% CI)

0

0

0

1.5

0

1 0 0 NR

0

0 0

NR NR

0

0

0 0 NR 0

CR

12

20.5

50

63.2

5

28 26 3 1

49

NR 14

0–15 12.2

23

31

40 33–60 35 25

PR

NR

48.7

28

23

76

46 57 54 54

NR

65 67

57–82 41.8

53

12

51 27–33 35 34

SD

RECIST response (%)

38

10.3

5

6.9

18

17 4 28 44

NR

NR 8

9–12 NR

3

58

9 7–8 NR 22

PD

Anorexia (11%), diarrhea (4%), rash (7%)

Neutropenia (12.8%)

Mucositis (15%), diarrhea (10%), neutropenia (5%), hypertriglyceridemia (5%) Hypertension (10–41.8%), diarrhea (8–10%), fatigue or asthenia (9.2%), decreased weight (9.6–12%), Proteinuria (10%)

Hypertension (25%), diarrhea (13%), weight loss (5%), abdominal pain (5%) Raised ALT concentration (10.8%) Lower-gastrointestinal haemorrhage (8.1%) Neutropenia (34%), leukopenia (13-31%), diarrhea (17%), HFSR (17%), hypertension (13%), fatigue (11%) Rash (18%), fatigue (8%), diarrhea (5%), peripheral edema (5%) Diarrhea (10%), asthenia (7%), fatigue (5%).

HFSR (16–44.1%), weight loss (8.4%-11.5%), hypertension (9.7–15.5%), rash (16.1%), hypertension (16.1%)

Fatigue (5–12%), hypertension (6–13%), dyspnea (12%), lymphopenia (10%) proteinuria (8%)

Main adverse events (Grade ≥ 3)

Chemo, chemotherapy; CI, confidence interval; CR, complete response; NE, not estimable; NR, not reported; NA, not applicable, OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; PTC, papillary thyroid cancer; RCT, randomized controlled trial; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; FGFR, fibroblast growth factor receptor; FLT3, Fms-like tyrosine kinase 3; MEK1, MAPK/ERK kinase 1; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; RAF, rapidly accelerated fibrosarcoma; RET, glial cell line-derived neurotrophic factor receptor; VEGFR, vascular endothelial growth factor receptor; c-kit, stem cell factor receptor; EGFR, epidermal growth factor receptor; HFSR, hand-foot-skin reaction.

Gefitinib

VEGFR, PDGFR, c-Kit, RET, FLT3 MEK1 VEGFR, EGFR, RET

Sunitinib

Pazopanib

Targets

Drug

Table 2 Update of clinical trials of targeted chemotherapies for radioiodine refractory differentiated thyroid cancer.

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Fig. 2. Rapid shrinkage of local recurrent radioactive radioiodine refractory differentiated thyroid cancer and metastatic disease after targeted chemotherapy. A 54year-old female with papillary thyroid cancer underwent total thyroidectomy and regional lymph node dissection. Six years later, a neck mass, recurrent papillary thyroid cancer, which was confirmed by repeated examination of fine needle aspiration cytology, gradually grew to 63 × 40 mm (A, photograph; and B, CT imaging) when pulmonary metastases-induced hemoptysis occurred (C, CT imaging). Since resection was not amenable and the efficacy of 131I therapy could not be anticipated, apatinib (500 mg, q.d.) was given. Three months after the beginning of apatinib treatment, significant shrinkage of the tumor was noticed in the neck (D, photograph; and E, CT imaging) and lungs (F, CT imaging), indicating a partial response. Two weeks after the withdraw of apatinib, resection of the neck mass was successfully performed.

Fig. 3. Mechanisms of new emerging therapeutic strategies. Histone deacetylase inhibitors (HDIs) block the action of deacetylation and result in hyperacetylation of histones, thereby enhancing iodine-handling gene expression (A). Inhibitors (anti-PD-L1 and anti-PD-1 antibodies) block the interaction of PD-L1 with the PD-1 receptor, which can prevent the thyroid cancer cells from evading the immune system responses (B). After viral vector internalized into endothelial cells, PPE-1-3x promoter causes Fas-TNFR-1 to be expressed on the endothelial cell surface, trapping tumor necrosis factors and subsequently causes cell apoptosis (C). VEGF Trap inhibits the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as placental growth factor (PGF), preventing the interaction with its receptors and activation of downstream signaling pathways to inhibit the growth of new blood vessels in the tumor (D).

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5.3.3. Immunotherapy Pembrolizumab, an anti-PD-1 antibody inhibiting the interaction between PD-1, PD-L1, and PD-L2 (Bastman et al., 2016) (Fig. 3B), showed promising results in the RR-DTC patients in a phaseⅠ study (Mehnert et al., 2016). The SD rate was about 54.5% with a 6-month OS rate of 100% and a 6-month PFS rate of 58.7%. Most patients showed therapy-related adverse events of diarrhea and fatigue. PD-1 blockade could benefit patients with less severe forms of DTC who suffered from multiple recurrences in the regional lymph nodes. In these patients, the antibody to PD-1 could be delivered directly under guided ultrasound to the tumor-involved lymph nodes to provide durable tumor regression theoretically; however, this localized approach has yet to be tested.

and may thereby yield heightened opportunities to incite antitumor immunological responses. With continuously enriched knowledge of immune responses in thyroid cancer, together with the development of a broad repertoire of actionable immune targets, we propose an expansion of the investigation into these novel approaches for RR-DTC. Rationally designed clinical trials that incorporate combination strategies targeting immune cells, thyroid cancer, or endothelial cells could provide the greatest benefits for the advanced thyroid cancer population. Future research may also focus on better molecular characterization, the redifferentiation process, and innovation in systemic therapy.

5.3.4. Gene therapy VB-111, an engineered non-replicating, E1-deleted adenovirus 5 (Ad-5), has been reported to be administered systemically to infect a variety of cells in vitro, including endothelial cells within the vascularity (Triozzi and Borden, 2011; Varda-Bloom et al., 2001). The virus consists of a modified murine pre-proendothelin (PPE) promoter and a Faschimera (Fas-c) transgene. Smooth muscle cell mitogen can endogenously recognize the PPE-1 promoter, and afterward, PPE-1, the precursor protein for endothelin-1, can be synthesized by the endothelial cells that act as potent vasoconstrictors (Harats et al., 1995). The Fas-c pro-apoptotic transgene, under the control of the PPE-1 promoter, can specifically express Fas-c in angiogenetic endothelial cells. The intramembranal domains of Fas and the extracellular domains of the human TNF receptor 1 (TNFR-1/p55) compose the chimera (Boldin et al., 1995). TNF-α in the tumor microenvironment binds to the TNFR1 component of the chimeric receptor, which activates the Fas component, leading to targeted apoptosis of these vessels (Fig. 3C) (Boldin et al., 1995; Triozzi and Borden, 2011). In a phase Ⅱ dose-escalating trial that enrolled 29 patients with advanced progressive RRDTC, 35% of the patients (6/17) who received a dose of 1013 viral particles every 2 months showed a PFS of 6 months (Jasim et al., 2015).

The authors declare they do not have any conflicts of interest.

Conflicts of interest

Acknowledgments This study was sponsored by the National Natural Science Foundation of China (grant numbers 81671711, 81701731) and Shanghai key discipline of medical imaging (grant number 2017ZZ02005). References Ahmed, M., Barbachano, Y., Riddell, A., Hickey, J., Newbold, K.L., Viros, A., Harrington, K.J., Marais, R., Nutting, C.M., 2011. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur. J. Endocrinol. 165, 315–322. http://dx.doi.org/10.1530/EJE-11-0129. Avram, A.M., Fig, L.M., Frey, K.A., Gross, M.D., Wong, K.K., 2013. Preablation 131-I scans with SPECT/CT in postoperative thyroid cancer patients: what is the impact on staging? J. Clin. Endocrinol. Metab. 98, 1163–1171. http://dx.doi.org/10.1210/jc. 2012-3630. Azouzi, N., Cailloux, J., Cazarin, J.M., Knauf, J.A., Cracchiolo, J., Al Ghuzlan, A., Hartl, D., Polak, M., Carré, A., El Mzibri, M., Filali-Maltouf, A., Al Bouzidi, A., Schlumberger, M., Fagin, J.A., Ameziane-El-Hassani, R., Dupuy, C., 2017. NADPH oxidase NOX4 Is a critical mediator of BRAF(V600E)-induced downregulation of the sodium/iodide symporter in papillary thyroid carcinomas. Antioxid. Redox Signal. 26, 864–877. http://dx.doi.org/10.1089/ars.2015.6616. Bastman, J.J., Serracino, H.S., Zhu, Y., Koenig, M.R., Mateescu, V., Sams, S.B., Davies, K.D., Raeburn, C.D., McIntyre, R.C., Haugen, B.R., French, J.D., 2016. Tumor-infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 101, 2863–2873. http://dx.doi. org/10.1210/jc.2015-4227. Bible, K.C., Suman, V.J., Molina, J.R., Smallridge, R.C., Maples, W.J., Menefee, M.E., Rubin, J., Sideras, K., Morris, J.C., McIver, B., Burton, J.K., Webster, K.P., Bieber, C., Traynor, A.M., Flynn, P.J., Goh, B.C., Tang, H., Ivy, S.P., Erlichman, C., 2010. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 11, 962–972. http://dx.doi.org/10.1016/S1470-2045(10)70203-5. Bikas, A., Kundra, P., Desale, S., Mete, M., O’Keefe, K., Clark, B.G., Wray, L., Gandhi, R., Barett, C., Jelinek, J.S., Wexler, J.A., Wartofsky, L., Burman, K.D., 2016. Phase 2 clinical trial of sunitinib as adjunctive treatment in patients with advanced differentiated thyroid cancer. Eur. J. Endocrinol. 174, 373–380. http://dx.doi.org/10. 1530/EJE-15-0930. Boldin, M.P., Mett, I.L., Varfolomeev, E.E., Chumakov, I., Shemer-Avni, Y., Camonis, J.H., Wallach, D., 1995. Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J. Biol. Chem. 270, 387–391. http://dx.doi.org/10.1074/jbc.270.1.387. Brose, M.S., Nutting, C.M., Jarzab, B., Elisei, R., Siena, S., Bastholt, L., de la Fouchardiere, C., Pacini, F., Paschke, R., Shong, Y.K., Sherman, S.I., Smit, J.W.A., Chung, J., Kappeler, C., Peña, C., Molnár, I., Schlumberger, M.J., 2014. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384, 319–328. http://dx.doi.org/10. 1016/S0140-6736(14)60421-9. Brose, M.S., Smit, J., Lin, C.C., Pitoia, F., Fellous, M., De Sanctis, Y., Schlumberger, M., Tori, M., Sugitani, I., 2017a. Timing of multikinase inhibitor initiation in differentiated thyroid cancer. Endocr. Relat. Cancer 24, 237–242. http://dx.doi.org/10. 1530/ERC-17-0016. Brose, M.S., Worden, F.P., Newbold, K.L., Guo, M., Hurria, A., 2017b. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial. J Clin. Oncol. 35. http://dx.doi.org/10.1200/ JCO.2016.71.6472. Brown, A.P., Chen, J., Hitchcock, Y.J., Szabo, A., Shrieve, D.C., Tward, J.D., 2008. The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 93, 504–515. http://dx.doi. org/10.1210/jc.2007-1154. Cabanillas, M.E., Schlumberger, M., Jarzab, B., Martins, R.G., Pacini, F., Robinson, B., McCaffrey, J.C., Shah, M.H., Bodenner, D.L., Topliss, D., Andresen, C., O’Brien, J.P.,

5.3.5. VEGF trap therapy Historically, systemic therapy for RR-DTC has been understudied, but activity has recently been seen with kinase inhibitors that partly act as angiogenesis inhibitors. Targeted chemotherapy has activity in RRDTC, at least, the anti-tumor effect may be partly attributed to the inhibition of tumor angiogenesis. VT incorporates the binding domains of VEGFR-1 and VEGFR-2 by fusing these protein sequences to the Fc segment of a human IgG backbone (Holash et al., 2002). VT can bind the VEGF-A family, VEGF-B, and placental growth factor (Fig. 3D) (Fricke et al., 2007). VT has a well-defined rationale for study in RRDTCs and allows for a more precise therapy strategy of angiogenesis inhibition in these tumors. The most common adverse effects include proteinuria, thrombotic microangiopathy, pain, ischemia, cerebrovascular confusion/posterior reversible encephalopathy syndrome, duodenal hemorrhage, fatigue, and myocardial infarction (Sherman et al., 2011). 6. Future perspectives Recent discoveries in molecular medicine, coupled with advances in biotechnology and medicinal chemistry, have led to enormous progress in the diagnosis and treatment of patients with RR-DTC. We have no doubt that this progress will continue with the development of more effective therapies that are based on new compounds that have greater specificity for oncogenic targets and combinatorial regimens that overcome resistance to RAI. Although prolonged PFS has been reported in the clinical trials of systemic therapies, improved OS compared to placebo remains unreported. Moreover, drug-related toxicity and resistance have been recognized as problems that could be addressed by the optimization of targeted therapies. In addition, thyroid tissues are among the most highly immunogenic of all of the tissues in the body 118


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Ho, A.L., Grewal, R.K., Leboeuf, R., Sherman, E.J., Pfister, D.G., Deandreis, D., Pentlow, K.S., Zanzonico, P.B., Haque, S., Gavane, S., Ghossein, R.A., Ricarte-Filho, J.C., Domínguez, J.M., Shen, R., Tuttle, R.M., Larson, S.M., Fagin, J.A., 2013. Selumetinibenhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623–632. http://dx.doi.org/10.1056/NEJMoa1209288. Hoftijzer, H., Heemstra, K.A., Morreau, H., Stokkel, M.P., Corssmit, E.P., Gelderblom, H., Weijers, K., Pereira, A.M., Huijberts, M., Kapiteijn, E., Romijn, J.A., Smit, J.W., 2009. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur. J. Endocrinol. 161, 923–931. http://dx.doi.org/10.1530/EJE-09-0702. Holash, J., Davis, S., Papadopoulos, N., Croll, S.D., Ho, L., Russell, M., Boland, P., Leidich, R., Hylton, D., Burova, E., Ioffe, E., Huang, T., Radziejewski, C., Bailey, K., Fandl, J.P., Daly, T., Wiegand, S.J., Yancopoulos, G.D., Rudge, J.S., 2002. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. 99, 11393–11398. http://dx.doi.org/10.1073/pnas.172398299. Hou, P., Bojdani, E., Xing, M., 2010. Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. J. Clin. Endocrinol. Metab. 95, 820–828. http://dx.doi.org/10.1210/jc.2009-1888. Jasim, S., Menefee, M.E., Smallridge, R.C., Burton, J., Bieber, C., Cohen, Y., Harats, D., Bible, K.C., 2015. 15Th international thyroid congress program and meeting abstracts. Thyroid 25http://dx.doi.org/10.1089/thy.2015.29004.abstracts. P-1-A-337. Jois, B., Asopa, R., Basu, S., 2014. Somatostatin receptor imaging in non–131i-avid metastatic differentiated thyroid carcinoma for determining the feasibility of peptide receptor radionuclide therapy with 177Lu-DOTATATE. Clin. Nucl. Med. 36, 505–510. http://dx.doi.org/10.1097/RLU.0000000000000429. Khorjekar, G.R., Van Nostrand, D., Garcia, C., O’Neil, J., Moreau, S., Atkins, F.B., Mete, M., Orquiza, M.H., Burman, K., Wartofsky, L., 2014. Do negative 124 I pretherapy positron emission tomography scans in patients with elevated serum thyroglobulin levels predict negative 131 I posttherapy scans? Thyroid 24, 1394–1399. http://dx. doi.org/10.1089/thy.2013.0713. Kim, B.M., Kim, M.J., Kim, E.K., Park II, S., Park, C.S., Chung, W.Y., 2008. Controlling recurrent papillary thyroid carcinoma in the neck by ultrasonography-guided percutaneous ethanol injection. Eur. Radiol. 18, 835–842. http://dx.doi.org/10.1007/ s00330-007-0809-5. Kist, J.W., de Keizer, B., Vogel, W.V., 2016. Letter to the editor regarding the article “124I PET/CT in patients with differentiated thyroid cancer: clinical and quantitativei analysis”. Thyroid 26, 1141–1142. http://dx.doi.org/10.1089/thy.2016.0180. Kogai, T., Sajid-Crockett, S., Newmarch, L.S., Liu, Y.Y., Brent, G.A., 2008. Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells. J. Endocrinol. 199, 243–252. http://dx.doi.org/10.1677/JOE-08-0333. Kushchayeva, Y.S., Kushchayev, S.V., Wexler, J.A., Carroll, N.M., Preul, M.C., Teytelboym, O.M., Sonntag, V.K.H., Van Nostrand, D., Burman, K.D., Boyle, L.M., 2014. Current treatment modalities for spinal metastases secondary to thyroid carcinoma. Thyroid 24, 1443–1455. http://dx.doi.org/10.1089/thy.2013.0634. Lazar, V., Bidart, J.M., Caillou, B., Mahé, C., Lacroix, L., Filetti, S., Schlumberger, M., 1999. Expression of the na+/I- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J. Clin. Endocrinol. Metab. 84, 3228–3234. http://dx.doi.org/10.1210/jcem.84.9.5996. Leboulleux, S., Bastholt, L., Krause, T., de la Fouchardiere, C., Tennvall, J., Awada, A., Gómez, J.M., Bonichon, F., Leenhardt, L., Soufflet, C., Licour, M., Schlumberger, M.J., 2012. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 13, 897–905. http://dx.doi. org/10.1016/S1470-2045(12)70335-2. Lim, C.Y., Yun, J.-S., Lee, J., Nam, K.-H., Chung, W.Y., Park, C.S., 2007. Percutaneous ethanol injection therapy for locally recurrent papillary thyroid carcinoma. Thyroid 17, 347–350. http://dx.doi.org/10.1089/thy.2006.0251. Lim, H., Devesa, S.S., Sosa, J.A., Check, D., Kitahara, C.M., 2017. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 317, 1338–1348. http://dx.doi.org/10.1001/jama.2017.2719. Lim, S.M., Chang, H., Yoon, M.J., Hong, Y.K., Kim, H., Chung, W.Y., Park, C.S., Nam, K.H., Kang, S.W., Kim, M.K., Kim, B.S., Lee, S.H., Kim, H.G., Na, I.I., Kim, Y.S., Choi, M.Y., Kim, J.G., Park, K.U., Yun, H.J., Kim, J.H., Cho, B.C., 2013. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann. Oncol. 24, 3089–3093. http://dx.doi.org/10.1093/annonc/ mdt379. Lim, S.M., Chung, W.Y., Nam, K.-H., Kang, S.-W., Lim, J.Y., Kim, H.-G., Shin, S.H., Sun, J.M., Kim, S.-G., Kim, J.-H., Kang, C.W., Kim, H.R., Cho, B.C., 2015. An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer. Eur. J. Cancer 51, 1588–1595. http://dx.doi.org/10.1016/j.ejca.2015.05.020. Lin, Y., Wang, C., Gao, W., Cui, R., Liang, J., 2017. Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer. Oncotarget 8, 42252–42261. http://dx.doi.org/10.18632/oncotarget.15036. Liu, M., Shen, Y., Ruan, M., Li, M., Chen, L., 2014. Notable decrease of malignant pleural effusion after treatment with sorafenib in radioiodine-refractory follicular thyroid carcinoma. Thyroid 24, 1179–1183. http://dx.doi.org/10.1089/thy.2013.0703. Locati, L.D., Licitra, L., Agate, L., Ou, S.H.I., Boucher, A., Jarzab, B., Qin, S., Kane, M.A., Wirth, L.J., Chen, C., Kim, S., Ingrosso, A., Pithavala, Y.K., Bycott, P., Cohen, E.E.W., 2014. Treatment of advanced thyroid cancer with axitinib: pPhase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments. Cancer 120, 2694–2703. http://dx.doi.org/10.1002/cncr.28766. Matthews, T.J., Chua, E., Gargya, A., Clark, J., Gao, K., Elliott, M., 2016. Elevated serum thyroglobulin levels at the time of ablative radioactive iodine therapy indicate a worse prognosis in thyroid cancer: an Australian retrospective cohort study. J. Laryngol. Otol. 130, S50–S53. http://dx.doi.org/10.1017/S0022215116008331. Mauri, G., Cova, L., Ierace, T., Baroli, A., Di Mauro, E., Pacella, C.M., Goldberg, S.N.,

Ren, M., Funahashi, Y., Allison, R., Elisei, R., Newbold, K., Licitra, L.F., Sherman, S.I., Ball, D.W., 2015. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: a clinical outcomes and biomarker assessment. Cancer 121, 2749–2756. http://dx.doi.org/10.1002/cncr.29395. Capdevila, J., Galofré, J.C., Grande, E., Zafón Llopis, C., Ramón, Y., Cajal Asensio, T., Navarro González, E., Jiménez-Fonseca, P., Santamaría Sandi, J., Gómez Sáez, J.M., Riesco Eizaguirre, G., 2017. Consensus on the management of advanced radioactive iodine-refractory differentiated thyroid cancer on behalf of the Spanish society of endocrinology thyroid cancer working group (GTSEEN) and Spanish rare cancer working group (GETHI). Clin. Transl. Oncol. 19, 279–287. http://dx.doi.org/10. 1007/s12094-016-1554-5. Carr, L.L., Mankoff, D.A., Goulart, B.H., Eaton, K.D., Capell, P.T., Kell, E.M., Bauman, J.E., Martins, R.G., 2010. Phase II study of daily sunitinib in FDG-PET-positive, iodinerefractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin. Cancer Res. 16, 5260–5268. http:// dx.doi.org/10.1158/1078-0432.CCR-10-0994. Cheng, L., Jin, Y., Liu, M., Ruan, M., Chen, L., 2017. HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E. Oncotarget 8, 19843–19854. http://dx.doi.org/10.18632/oncotarget. 15773. Cheng, W., Liu, R., Zhu, G., Wang, H., Xing, M., 2016. Robust thyroid gene expression and radioiodine uptake induced by simultaneous suppression of BRAF V600E and histone deacetylase in thyroid cancer cells. J. Clin. Endocrinol. Metab. 101, 962–971. http:// dx.doi.org/10.1210/jc.2015-3433. Choi, J.W., Lee, J.H., Baek, J.H., Choi, B.S., Jeong, K.S., Ryu, J.-S., Kim, T.Y., Kim, W.B., Shong, Y.K., 2010. Diagnostic accuracy of ultrasound and 18-F-FDG PET or PET/CT for patients with suspected recurrent papillary thyroid carcinoma. Ultrasound Med. Biol. 36, 1608–1615. http://dx.doi.org/10.1016/j.ultrasmedbio.2010.07.013. Cohen, E.E.W., Rosen, L.S., Vokes, E.E., Kies, M.S., Forastiere, A.A., Worden, F.P., Kane, M.A., Sherman, E., Kim, S., Bycott, P., Tortorici, M., Shalinsky, D.R., Liau, K.F., Cohen, R.B., 2008. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J. Clin. Oncol. 26, 4708–4713. http://dx.doi.org/10.1200/JCO.2007.15.9566. Cohen, E.E.W., Tortorici, M., Kim, S., Ingrosso, A., Pithavala, Y.K., Bycott, P., 2014. A phase ii trial of axitinib in patients with various histologic subtypes of advanced thyroid cancer: long-term outcomes and pharmacokinetic/pharmacodynamic analyses. Cancer Chemother. Pharmacol. 74, 1261–1270. http://dx.doi.org/10.1007/ s00280-014-2604-8. Dadu, R., Cabanillas, M.E., 2012. Optimizing therapy for radioactive iodine-refractory differentiated thyroid cancer: current state of the art and future directions. Minerva Endocrinol. 37, 335–356. http://dx.doi.org/10.1016/j.biotechadv.2011.08.021. Secreted. De Souza, E.C.L., Padrón, Á.S., Braga, W.M.O., De Andrade, B.M., Vaisman, M., Nasciutti, L.E., Ferreira, A.C.F., De Carvalho, D.P., 2010. MTOR downregulates iodide uptake in thyrocytes. J. Endocrinol. 206, 113–120. http://dx.doi.org/10.1677/JOE-09-0436. Durante, C., Haddy, N., Baudin, E., Leboulleux, S., Hartl, D., Travagli, J.P., Caillou, B., Ricard, M., Lumbroso, J.D., De Vathaire, F., Schlumberger, M., 2006. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J. Clin. Endocrinol. Metab. 91, 2892–2899. http://dx.doi.org/10.1210/jc.2005-2838. Durante, C., Puxeddu, E., Ferretti, E., Morisi, R., Moretti, S., Bruno, R., Barbi, F., Avenia, N., Scipioni, A., Verrienti, A., Tosi, E., Cavaliere, A., Gulino, A., Filetti, S., Russo, D., 2007. Brief report: BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92, 2840–2843. http://dx. doi.org/10.1210/jc.2006-2707. Elisei, R., Schlumberger, M., Tahara, M., Robinson, B., Brose, M., Dutcus, C., Zhu, J., Newbold, K., Kiyota, N., Kim, S.-B., Sherman, S., Wirth, L., 2015. Subgroup analysis according to differentiated thyroid cancer histology in phase 3 (SELECT) trial of lenvatinib. Oncol. Res. Treat. 38, 1–288. http://dx.doi.org/10.1159/000439070. Fricke, I., Mirza, N., Dupont, J., Lockhart, C., Jackson, A., Lee, J.H., Sosman, J.A., Gabrilovich, D.I., 2007. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin. Cancer Res. 13, 4840–4848. http://dx.doi.org/10.1158/1078-0432. CCR-07-0409. Gupta-Abramson, V., Troxel, A.B., Nellore, A., Puttaswamy, K., Redlinger, M., Ransone, K., Mandel, S.J., Flaherty, K.T., Loevner, L.A., O’Dwyer, P.J., Brose, M.S., 2008. Phase II trial of sorafenib in advanced thyroid cancer. J. Clin. Oncol. 26, 4714–4719. http:// dx.doi.org/10.1200/JCO.2008.16.3279. Harats, D., Kurihara, H., Belloni, P., Oakley, H., Ziober, A., Ackley, D., Cain, G., Kurihara, Y., Lawn, R., Sigal, E., 1995. Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter. J. Clin. Invest. 95, 1335–1344. http://dx.doi.org/10.1172/JCI117784. Haugen, B.R., Alexander, E.K., Bible, K.C., Doherty, G.M., Mandel, S.J., Nikiforov, Y.E., Pacini, F., Randolph, G.W., Sawka, A.M., Schlumberger, M., Schuff, K.G., Sherman, S.I., Sosa, J.A., Steward, D.L., Tuttle, R.M., Wartofsky, L., 2016. 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 26, 1–133. http://dx.doi.org/10.1089/thy.2015.0020. Hayes, D.N., Lucas, A.S., Tanvetyanon, T., Krzyzanowska, M.K., Chung, C.H., Murphy, B.A., Gilbert, J., Mehra, R., Moore, D.T., Sheikh, A., Hoskins, J., Hayward, M.C., Zhao, N., O’Connor, W., Weck, K.E., Cohen, R.B., Cohen, E.E.W., 2012. Phase II efficacy and pharmacogenomic study of selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin. Cancer Res. 18, 2056–2065. http://dx.doi.org/10.1158/1078-0432.CCR-110563.

119


Y. Jin et al.

S2213-8587(13)70215-8. Schlumberger, M., Tahara, M., Wirth, L.J., Robinson, B., Brose, M.S., Elisei, R., Habra, M.A., Newbold, K., Shah, M.H., Hoff, A.O., Gianoukakis, A.G., Kiyota, N., Taylor, M.H., Kim, S.-B., Krzyzanowska, M.K., Dutcus, C.E., de las Heras, B., Zhu, J., Sherman, S.I., 2015. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 372, 621–630. http://dx.doi.org/10.1056/NEJMoa1406470. Schneider, T.C., Abdulrahman, R.M., Corssmit, E.P., Morreau, H., Smit, J.W.A., Kapiteijn, E., 2012. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur. J. Endocrinol. 167, 643–650. http://dx.doi.org/10.1530/EJE-12-0405. Shah, M.H., Kloos, R.T., Ringel, M.D., Knopp, M.V., Hall, N.C., King, M., Stevens, R., Liang, J., Wakely, P.E., Vasko, V.V., Saji, M., Rittenberry, J., Wei, L., Arbogast, D., Collamore, M., Wright, J.J., Grever, M., 2009. Phase II trial of sorafenib in metastatic thyroid cancer. J. Clin. Oncol. 27, 1675–1684. http://dx.doi.org/10.1200/JCO.2008. 18.2717. Sherman, E.J., Fury, M.G., Tuttle, R.M., Ghossein, R., Stambuk, H., Baum, M., Lisa, D., Su, Y.B., Shaha, A., Pfister, D.G., 2009. Phase II study of depsipeptide (DEP) in radioiodine (RAI)-refractory metastatic nonmedullary thyroid carcinoma. J. Clin. Oncol. 27, e6059. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6059. Sherman, E.J., Ho, A.L., Haque, S., Tuttle, R.M., Ghossein, R.A., Schöder, H., Baum, M.S., Kelly, K., Chen, A.P., Shaha, A.R., Pfister, D.G., 2011. A phase II study of VEGF trap in patients with radioactive iodine (RAI) refractory thyroid carcinoma. J. Clin. Oncol. 29, e5566. http://dx.doi.org/10.1200/jco.2011.29.15_suppl.5566. Sherman, S.I., Tielens, E.T., Sostre, S., Wharam, M.D., Ladenson, P.W., 1994. Clinical utility of posttreatment radioiodine scans in the management of patients with thyroid carcinoma. J. Clin. Endocrinol. Metab. 78, 629–634. http://dx.doi.org/10.1210/ jcem.78.3.8126134. Sherman, S.I., Wirth, L.J., Droz, J.-P., Hofmann, M., Bastholt, L., Martins, R.G., Licitra, L., Eschenberg, M.J., Sun, Y.-N., Juan, T., Stepan, D.E., Schlumberger, M.J., 2008. Motesanib diphosphate in progressive differentiated thyroid cancer. N. Engl. J. Med. 359, 31–42. http://dx.doi.org/10.1056/NEJMoa075853. Shinohara, S., Kikuchi, M., Suehiro, A., Kishimoto, I., Harada, H., Hino, M., Ishihara, T., 2015. Characteristics and prognosis of patients with thyroglobulin-positive and radioactive iodine whole-body scan-negative differentiated thyroid carcinoma. Jpn. J. Clin. Oncol. 45, 427–432. http://dx.doi.org/10.1093/jjco/hyv021. Spitzweg, C., Bible, K.C., Hofbauer, L.C., Morris, J.C., 2014. Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets. Lancet Diabetes Endocrinol. 2, 830–842. http://dx.doi. org/10.1016/S2213-8587(14)70051-8. Thyroid Cancer Stat Facts, 2018. WWW Document]. (Accessed 17 January 18). https:// seer.cancer.gov/statfacts/html/thyro.html. Tomoda, C., Sugino, K., Matsuzu, K., Uruno, T., Ohkuwa, K., Kitagawa, W., Nagahama, M., Ito, K., 2016. Cervical lymph node metastases after thyroidectomy for papillary thyroid carcinoma usually remain stable for years. Thyroid 26, 1706–1711. http:// dx.doi.org/10.1089/thy.2016.0225. Traynor, A.M., Leverson, G.E., Elson, D.F., Hernan, H.R., Larson, M.M., Blank, J.H., Fareau, G.G., Wisinski, K.B., Mattison, R.J., Chen, H., Sippel, R.S., 2013. Panobinostat, a novel histone deacetylase inhibitor, in advanced medullary and iodine-refractory differentiated thyroid cancer: a Wisconsin oncology network trial. J. Clin. Oncol. 31, e17025. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e17025. Triozzi, P.L., Borden, E.C., 2011. VB-111 for cancer. Expert Opin. Biol. Ther. 11, 1669–1676. http://dx.doi.org/10.1517/14712598.2011.618122. Varda-Bloom, N., Shaish, A., Gonen, A., Levanon, K., Greenbereger, S., Ferber, S., Levkovitz, H., Castel, D., Goldberg, I., Afek, A., Kopolovitc, Y., Harats, D., 2001. Tissue-specific gene therapy directed to tumor angiogenesis. Gene Ther. 8, 819–827. http://dx.doi.org/10.1038/sj.gt.3301472. Wei, W.-J., Sun, Z.-K., Shen, C.-T., Song, H.-J., Zhang, X.-Y., Qiu, Z.-L., Luo, Q.-Y., 2017. Obatoclax and LY3009120 efficiently overcome vemurafenib resistance in differentiated thyroid cancer. Theranostics 7, 987–1001. http://dx.doi.org/10.7150/thno. 17322. Worden, F., 2014. Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Ther. Adv. Med. Oncol. 6, 267–279. http://dx.doi.org/10.1177/ 1758834014548188. Zhang, Z., Liu, D., Murugan, A.K., Liu, Z., Xing, M., 2014. Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer. Endocr. Relat. Cancer 21, 161–173. http://dx.doi.org/10.1530/ERC-13-0399.

Solbiati, L., 2016. Treatment of metastatic lymph nodes in the neck from papillary thyroid carcinoma with percutaneous laser ablation. Cardiovasc. Intervent. Radiol. 39, 1023–1030. http://dx.doi.org/10.1007/s00270-016-1313-6. Mehnert, J.M., Varga, A., Brose, M., Aggarwal, R.R., Lin, C.-C., Prawira, A., De Braud, F., Tamura, K., Doi, T., Piha-Paul, S.A., Gilbert, J., Saraf, S., Thanigaimani, P., Cheng, J.D., Keam, B., 2016. Pembrolizumab for advanced papillary or follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 study. J. Clin. Oncol. 34, e6091. http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.6091. Monchik, J.M., Donatini, G., Iannuccilli, J., Dupuy, D.E., 2006. Radiofrequency ablation and percutaneous ethanol injection treatment for recurrent local and distant welldifferentiated thyroid carcinoma. Ann. Surg. 244, 296–304. http://dx.doi.org/10. 1097/01.sla.0000217685.85467.2d. Nair, A., Lemery, S.J., Yang, J., Marathe, A., Zhao, L., Zhao, H., Jiang, X., He, K., Ladouceur, G., Mitra, A.K., Zhou, L., Fox, E., Aungst, S., Helms, W., Keegan, P., Pazdur, R., 2015. FDA approval summary: lenvatinib for progressive, radio-iodinerefractory differentiated thyroid cancer. Clin. Cancer Res. 21, 5205–5208. http://dx. doi.org/10.1158/1078-0432.CCR-15-1377. Nascimento, C., Borget, I., Al Ghuzlan, A., Deandreis, D., Hartl, D., Lumbroso, J., Berdelou, A., Lepoutre-Lussey, C., Mirghani, H., Baudin, E., Schlumberger, M., Leboulleux, S., 2015. Postoperative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography: an important imaging modality in patients with aggressive histology of differentiated thyroid cancer. Thyroid 25, 437–444. http://dx.doi.org/10.1089/thy.2014.0320. NCCN Guideline, 2017. WWW Document]. https://www.nccn.org/professionals/ physician_gls/pdf/thyroid_blocks.pdf. Nilubol, N., Merkel, R., Yang, L., Patel, D., Reynolds, J.C., Sadowski, S.M., Neychev, V., Kebebew, E., 2016. A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin. Clin. Endocrinol. (Oxf.). 86, 128–133. http://dx.doi.org/10.1111/cen.13154. Ocak, M., Demirci, E., Kabasakal, L., Aygun, A., Tutar, R.O., Araman, A., Kanmaz, B., 2013. Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/ CT imaging in well-differentiated thyroid cancer. Nucl. Med. Commun. 34, 1084–1089. http://dx.doi.org/10.1097/MNM.0b013e328364eaab. Pacini, F., Agate, L., Elisei, R., Capezzone, M., Ceccarelli, C., Lippi, F., Molinaro, E., Pinchera, a, 2001. Outcome of differentiated thyroid cancer with detectable serum Tg and negative diagnostic 131 I whole body scan : comparison of patients treated with high. J. Clin. Endocrinol. Metab. 86, 4092–4097. http://dx.doi.org/10.1210/jcem. 86.9.7831. Pennell, N.A., Daniels, G.H., Haddad, R.I., Ross, D.S., Evans, T., Wirth, L.J., Fidias, P.H., Temel, J.S., Gurubhagavatula, S., Heist, R.S., Clark, J.R., Lynch, T.J., 2008. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid 18, 317–323. http://dx.doi.org/10.1089/thy.2007.0120. Phay, J.E., Ringel, M.D., 2013. Metastatic mechanisms in follicular cell-derived thyroid cancer. Endocr. Relat. Cancer 20, R307–19. http://dx.doi.org/10.1530/ERC-130187. Rahib, L., Smith, B.D., Aizenberg, R., Rosenzweig, A.B., Fleshman, J.M., Matrisian, L.M., 2014. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921. http://dx.doi.org/10.1158/0008-5472.CAN-14-0155. Rothenberg, S.M., McFadden, D.G., Palmer, E.L., Daniels, G.H., Wirth, L.J., 2015. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin. Cancer Res. 21, 1028–1035. http://dx.doi.org/ 10.1158/1078-0432.CCR-14-2915. Ruan, M., Liu, M., Dong, Q., Chen, L., 2015. Iodide- and glucose-handling gene expression regulated by sorafenib or cabozantinib in papillary thyroid cancer. J. Clin. Endocrinol. Metab. 100, 1771–1779. http://dx.doi.org/10.1210/jc.2014-3023. Rubino, C., de Vathaire, F., Dottorini, M.E., Hall, P., Schvartz, C., Couette, J.E., Dondon, M.G., Abbas, M.T., Langlois, C., Schlumberger, M., 2003. Second primary malignancies in thyroid cancer patients. Br. J. Cancer 89, 1638–1644. http://dx.doi.org/ 10.1038/sj.bjc.6601319. Sager, S., Kabasakal, L., Halac, M., Maecke, H., Uslu, L., Onsel, C., Kanmaz, B., 2013. Comparison of 99mTc-HYNIC-TOC and HYNIC-TATE octreotide scintigraphy with FDG PET and 99mTc-MIBI in local recurrent or distant metastatic thyroid cancers. Clin. Nucl. Med. 38, 321–325. http://dx.doi.org/10.1097/RLU.0b013e3182868062. Schlumberger, M., Brose, M., Elisei, R., Leboulleux, S., Luster, M., Pitoia, F., Pacini, F., 2014. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2, 356–358. http://dx.doi.org/10.1016/

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