Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions

Abstract

Approximately 90% of thyroid cancers are differentiated (DTCs) and have papillary, follicular or Hürthle cell morphology. Although treatment with surgery and radioactive iodine (I-131; RAI), as appropriate, is associated with significant cure rates and survival benefits, clonal disease progression with development of refractoriness to RAI poses a major therapeutic challenge in about 15% of patients. Traditional chemotherapeutic agents are relatively ineffective and are associated with significant toxicities. Molecular studies have demonstrated that the development and progression of DTC are associated with a series of consistent abnormalities in pathways such as MAPK/ERK and PI3/Akt, which govern cellular growth, proliferation, apoptosis and angiogenesis. Small molecular inhibitors that target these pathogenic pathways, without many of the impairments associated with cytotoxic chemotherapy, have demonstrated efficacy in a variety of malignancies, including renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer and chronic myelogenous leukemia. Several targeted therapeutic agents are in development for the treatment of RAI-refractory DTC. Sorafenib and lenvatinib are being studied in placebo-controlled Phase III trials based on encouraging efficacy results observed in single-arm Phase II studies.

Keywords::

• kinase inhibitors
• MAPK/ERK
• PI3/Akt
• RAF
• RAS
• RET
• thyroid cancer

Figure 1. Growth factor receptors and the MAPK/ERK pathway.

EGFR: EGF receptor; VEGFR: VEGF receptor.Adapted with permission from [95].

Globally, the age-standardized incidence of thyroid cancer in the general population is 16.4/100,000, with a mortality rate of 1.7/100,000 [1]. Its prevalence is approximately threefold higher in developed than in the less-developed countries. In the USA, for example, approximately 45,000 patients were newly diagnosed with thyroid cancer in 2010 [2].

Cancers of the follicular epithelium of the thyroid are generally categorized as papillary (80%), follicular (11%), Hürthle cell (3%) and anaplastic (2%) [3]. The first three types are categorized as differentiated thyroid cancers (DTCs) [201]. Anaplastic thyroid cancer generally arises from DTC, with approximately half of these patients having a previous or coexisting DTC at the time of diagnosis [4,5]. Medullary thyroid carcinoma (MTC) is derived from parafollicular C cells rather than the follicular epithelium and is observed in approximately 4% of patients. Although these histologic types have different disease manifestations and tumor markers, as well as differences in expression of oncogenes and tumor suppressor genes, patients with DTC are often treated similarly.

As the epithelium of DTC generally retains the ability of the parent tissue to take up iodine from the blood, radioactive iodine (I-131) is often used to locate and ablate residual tissue, reduce recurrence and treat metastatic disease. The authors review the treatment of DTC with I-131, its limitations and the management of patients with I-131 refractory disease. They also examine the molecular pathways implicated in the development of DTC and describe the principle of targeted therapy and the investigational agents that may be used in future treatment.

Current treatments of DTC & their limitations

DTCs are clinicopathologically staged to evaluate prognosis and make treatment decisions. Staging schemes can vary among institutions and geographic regions. Although these staging schemes can adequately predict DTC-specific mortality, they generally cannot predict recurrence for individual patients. Examples of staging systems include the International Union Against Cancer/American Joint Committee on Cancer tumor node metastasis system, the European Organization for Research on Treatment of Cancer, the National Comprehensive Cancer Network, the National Thyroid Cancer Treatment Cooperative Study, the American Thyroid Association, and the two scoring systems. Intra-operative age, metastases, extent, size; and metastasis, age, completeness of resection, invasion and size [6–11,202]. Factors common to these staging systems include age at diagnosis, the size of the primary tumor, histology, evidence of vascular tumor invasion, extent of spread and presence of distant metastases.

Although treatment guidelines for DTC differ regarding the extent of surgery and I-131 dosing, care is similar between countries [9,12–15; Brose MS et al., rationale and design of decision: a double-blind, randomized, placebo-controlled phase iii trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (rai)-refractory, differentiated thyroid cancer (2011), Submitted]. Surgery is the primary treatment for any DTC, except for low-risk papillary microcarcinomas [16,17], and total thyroidectomy is the treatment of choice, followed by I-131 ablation. The risk of recurrent disease and death are lower in patients who undergo total or near-total thyroidectomy than in those who undergo lobectomy [18–21]. Lymph node dissection may be prophylactic or therapeutic. If there is clinical or ultrasonic evidence of lymph node involvement, therapeutic dissection should be performed. The indications for prophylactic dissection remain unclear, but it should be considered in patients with DTCs showing high-risk features such as papillary carcinomas >4 cm and/or extension outside the capsule [9] or in a particular population at risk; such as those affected by the Chernobyl nuclear reactor accident [22]. Limitations of surgery include residual or metastatic disease and risks of hypoparathyroidism and injury to the recurrent laryngeal nerve or other neurovascular structures of the neck [23,24], but reoperation after recurrence to the central compartment is more difficult and can induce these complications more frequently than central node dissection at initial surgery.

Since over 90% of patients show I-131 uptake in the thyroid bed after thyroidectomy [25], I-131 is used to ablate residual thyroid tissue and act as adjuvant treatment for DTC [9]. Retrospective studies and meta-analyses have demonstrated that I-131 ablation of the thyroid can decrease the 10-year risk of recurrence up to 50%, lower the risk of metastatic disease by 3% and reduce mortality [19,26–28]. Although the optimal I-131 dosage required to successfully ablate all residual thyroid tissue remains unclear [29], recent evidence suggests that low activities are as effective as high activities, even in patients with extrathyroidal disease, whether performed after thyroid hormone withdrawal or after treatment with recombinant human thyroid-stimulating hormone (rhTSH) [30,31].

Although I-131 is generally effective in treating subclinical micrometastatic disease, as well as residual and metastatic tumors, its potential for success is lower in patients with bulky disease [32]. Optimal preparation for I-131 therapy is traditionally based on thyroid hormone withdrawal, although preparation with rhTSH was recently shown to be equally effective [9,22,33–35].

I-131 refractory DTC

I-131 refractory DTC can be defined as an inability of malignant/metastatic tissue to take up I-131 from the start of treatment or loss of ability to take up I-131 after previous evidence of uptake. It is detected by a combination of imaging modalities, including an I-131 whole body scan showing at least one lesion that does not take up I-131, or clinical evidence that I-131 is no longer providing benefit to the patient, for example, at cumulative I-131 > 600 mCi (222,000 MBq [36]).

A registry in the USA reported that 2204 out of 2936 patients (75%) were considered disease-free after near-total thyroidectomy, I-131 ablation and aggressive thyroid hormone suppression [37]. Of patients considered disease-free after primary therapy, 10% had recurrent disease after a median of 1.5 years; of the latter, 71% had local or regional tumor recurrence and 18% had distant metastases, whereas, in the other 11%, the site of tumor recurrence was not reported. Although the prognosis of patients with DTC is usually favorable, treatment of recurrent or metastatic disease is problematic, especially when these foci have become refractory to I-131, with most of these patients dying within 3 years [38].

To optimize care, it is important to reach a common definition of I-131 refractory disease, both for clinical trials and in community practice. At a minimum, I-131 refractory disease should be defined as the presence of a lesion detected at imaging that does not take up I-131 or clinical evidence that I-131 is no longer beneficial despite visible uptake [36]. In the latter, tumor progression should also be confirmed by imaging 6–14 months later according to Response Evaluation Criteria in Solid Tumors [39]. As tumor markers such as thyroglobulin reflect risk, not tumor burden, increasing concentrations of these markers should be considered suspicious but not diagnostic of progressive disease, as should the results of F-18 fluorodeoxyglucose (FDG) PET/computerized tomography. To date, it remains unclear whether empiric I-131 therapy reduces morbidity or mortality in patients with increased serum thyroglobulin concentration, but negative on diagnostic I-131 whole body scan [202]. Although not confirmed in randomized trials, patients with a mixed response to I-131 may have resistant clones requiring a different therapeutic intervention.

External beam radiation therapy

External beam radiation therapy (EBRT) has been used successfully in patients with thyroid tumors, including DTC, as the first-line treatment in patients with unresectable tumors, as adjuvant therapy in patients considered at high risk for recurrence following resection and as treatment of I-131-negative recurrences and metastases. Potential risk factors for recurrent disease include older age, grossly visible extrathyroidal tumor extension at the time of surgery, a high likelihood of microscopic residual disease and/or gross residual tumor considered unresectable or resistant to I-131 [9].

A retrospective study in 113 patients with DTC showed that megavoltage EBRT was effective, but that benefits were related to tumor burden [40]. The 5-year survival rates of patients with residual microscopic disease and gross residual disease were 85 and 27%, respectively, and the 4-year relapse-free, disease-specific and overall survival (OS) rates following EBRT in patients with DTC were each at least 73% [41]. Treatment-related morbidities included esophageal stricture, chronic dysphagia requiring a feeding tube and laryngeal stenosis or edema, although these adverse events (AEs) can be minimized by intensity-modulated radiotherapy.

Cytotoxic chemotherapy

Although chemotherapy has significantly benefited patients with hematologic neoplasms, lymphomas, small-cell-lung cancer and other solid tumors, it is much less effective in patients with I-131 refractory DTC, with response rates to bleomycin, methotrexate, melphalan, mitoxantrone and etoposide each being ≤25% [42]. Patients with I-131 refractory DTC have shown low partial response (PR) rates to doxorubicin monotherapy, with these responses being short-lasting and associated with high toxicity rates [43–46]. Response rates were highest in patients with a high performance status and those with lung metastases. Complications include cytopenia, nausea, vomiting, hair loss and potential cardiac toxicity. Although some patients have shown durable responses, no survival benefit has been reported. Owing to the low response rates to doxorubicin monotherapy, this agent has been combined with other chemotherapeutic agents, including cisplatin, carboplatin and epirubicin, but complete or PR rates were similar to or worse than those with doxorubicin monotherapy [47–49].

Taxane-based regimens have also been evaluated, based on their systemic activity against anaplastic carcinomas of the thyroid. Twice-weekly docetaxel was reported to produce disease stabilization for 14–18 months, but no objective responses, in three patients with I-131 refractory DTC [50], whereas nine patients treated with paclitaxel plus gemcitabine showed no response [51].

Alternative treatment modalities have included the combination of external radiotherapy and chemotherapy, but the results have been only marginally superior to those of each one alone, excluding some patients with anaplastic carcinoma. In selected cases, liver and bone metastases have been treated with local therapies such as arterial embolizaion or chemoembolization. Although some lesions may show significant tumor reduction, these procedures are never curative and have no impact on final survival.

Signaling pathways implicated in the development of DTC

Owing to the poor results with the above-mentioned treatment modalities, the molecular pathways involved in the pathogenesis and progression of DTC have been assessed to identify elements of receptor-signaling pathways that may serve as targets for innovative treatments.

The genotype of specific cancers determines their behavior and may determine their response to treatment [52]. Some mutations may also provide significant prognostic information on these patients. A key molecular element in the biology of DTC is the tyrosine kinase RAS/RAF/MEK MAPK/ERK pathway. Normally, activation of a tyrosine kinase leads to a cascade of sequential phosphorylation of RAS, BRAF, MEK and then MAPK (Figure 1) [53]. Physiologically, signaling through these pathways leads to the activation of transcription factors involved in cell cycle regulation and cellular differentiation [54]. Constitutive activation of this and other pathways has been observed in patients with DTC.

The PI3/Akt pathway is also involved in the pathogenesis of DTC and other thyroid cancers [55]. When activated and free of the inhibitory effects of the tumor-suppressor gene product, PTEN, Akt phosphorylates elements of the mTOR pathway; a key element in cell growth, proliferation, and survival, and a pathway crucial in cell growth, proliferation and angiogenesis. In addition to its upregulation of MAPK/ERK, Ras can upregulate the PI3/Akt pathway. Moreover, poorly differentiated and anaplastic thyroid cancers are characterized by an additional genetic event, the loss of the tumor suppressor gene, p53 [52].

Papillary carcinoma

RET and NTRK1 are involved in the pathogenesis of papillary thyroid carcinoma (PTC). Both genes code for nerve growth factor receptors with tyrosine kinase activity [56,57]. Approximately 20–40% of PTCs have rearrangements of one of these genes with other genes, forming chimeric oncogenes, including RET/PTC in tumors with RET rearrangements, with RET alterations being approximately threefold more common than NTRK1 rearrangements [58,59].

The RAS family of proto-oncogenes includes KrasA, KrasB and Nras, all of which are membrane-bound GTP/GDP-binding (G) molecules [60]. These proteins transfer signals from activated tyrosine receptors in the cell membrane to pathways that lead to the synthesis of key proteins involved in cell growth, proliferation and survival. Although Ras mutations have been observed in 10–15% of PTCs, they are more commonly associated with follicular carcinoma and the follicular variant of papillary cancer [52,61]. ARaf, BRaf and CRaf are isoforms of the mammalian Raf serine–threonine kinase that participate in the RAF/MEK/MAPK pathway. BRAF mutations, observed in nearly 40% of PTCs [62], have been associated with a more aggressive course of disease [63,64], although a study from Japan, involving over 600 patients, reported a negative relationship between BRAF mutation and patient prognosis [65]. The presence of RET/PTC and BRAF mutations in microcarcinomas of the thyroid suggests that these mutations are early events in thyroid carcinogenesis and contribute significantly to the initiation and progression of PTCs [66–68]. Moreover, the presence of BRAF and RET mutations in the same tumor, although extremely rare, is associated with an increased risk of recurrence [69].

Among the other genetic anomalies identified in patients with PTC are single-nucleotide polymorphisms in genes that regulate transcription, upregulation of microRNAs that modify gene expression and increased methylation of tumor suppressor genes [70–73]. In addition, familial PTC has been associated with abnormalities in the short arm of chromosome 19 and the long arms of chromosomes 1, 2 and 8 [74–76], as well as with short telomeres in the germline [77].

Follicular carcinoma

A translocation involving the PAX8 promotor gene on the long arm of chromosome 2 and the PPAR-γ-1 gene on the short arm of chromosome 3 [t(2;3)(q13;p25)] has been observed in follicular carcinoma cells, resulting in the fusion of their DNA-binding domains. PAX8 is a critical regulator of the development and differentiation of follicular epithelium [78], whereas PPAR-γ is a nuclear hormone receptor, not normally expressed at high concentrations in thyroid, which is involved in carbohydrate and lipid metabolism and inflammation [79]. The exact mechanism by which this fusion protein exerts its effects is unknown. In one study, this cytogenetic abnormality was observed in five out of eight follicular carcinomas but in zero out of 20 follicular adenomas [80], suggesting that it may be a marker of follicular carcinoma in fine-needle aspirates, distinguishing between well-differentiated follicular carcinomas without microscopic vascular tumor invasion and follicular adenomas in surgical specimens.

Mutations of Nras, Hras and Kras have been observed in both benign and malignant thyroid follicular lesions [81–83]. Similar to the overexpression of c-myc and c-fos in these lesions, these RAS mutations probably promote tumor growth rather than transformation. The PIK3/Akt pathway is also upregulated in DTCs, most often in follicular carcinomas [52], possibly by amplification of the PIK3CA gene [84,85]. Although hypermethylation of the tumor suppressor gene, RASSF1A, has been observed in 75% of follicular carcinomas, it has also been detected in PTCs and follicular adenomas [86].

Hürthle cell carcinoma

Hürthle cells are characterized on light and electron microscopy by their oncocytic and mitochondria-rich cytoplasm, respectively [52]. These tumors have abnormalities in both mitochondrial and nuclear genes, which may disrupt oxidative phosphorylation. Specific molecular pathways that may be involved in Hürthle cell carcinomas are currently being investigated.

Overview of a targeted approach to I-131 refractory DTC

Historically, treatment options have been limited in patients with I-131 refractory DTC. Molecular abnormalities common to DTCs may provide the opportunity to target specific pathways involved in tumor cell growth, metastasis and cancer-induced angiogenesis without the collateral damage to the hematopoietic, gastrointestinal and other organ systems resulting from standard chemotherapy.

Kinase receptors and elements of the MAPK/ERK pathway are centrally involved in the growth and progression of DTC [87]. RET mutations can activate its encoded tyrosine kinase independent of ligand, upregulate the MAPK/ERK pathway, inhibit apoptosis and protect cells from the cytotoxic actions of doxorubicin [88,89]. RAS and RAF mutations (e.g., in BRAF) can result in the constitutive activation of MAPK/ERK. BRAF mutations are associated with resistance to I-131 [90]. VEGF stimulates endothelial cell growth and migration and promotes the formation of collateral blood vessels. VEGF and other growth factors signal through the PI3/Akt pathway. Serum VEGF concentrations are elevated in patients with metastatic DTC and may represent an important potential target [91]. Owing to the fact that most thyroid cancers have multiple mutations that modulate different pathways, agents targeting one or more of these pathways may improve outcomes in patients with I-131 refractory DTC [92].

A number of small molecular weight inhibitors of these signaling kinase pathways have been developed. The proof-of-concept of targeted therapy for cancer has become well established. Receptor kinase pathway inhibitors have been successfully used to treat patients with a variety of different tumor types, including gastrointestinal stromal tumors, non-small-cell lung cancer, renal cell carcinoma, hepatocellular carcinoma and melanoma [93]. Since activation of these signaling pathways is associated with the pathogenesis, growth, invasion, metastasis, survival and angiogenesis of DTC, inhibiting these pathways may represent a significant therapeutic approach to patients with thyroid cancer [36,87,94,95]. Response rates to these inhibitors have suggested that they may be successful in treating patients with I-131 refractory DTC, and thus targeted therapies have been included in recent guidelines. Although these compounds are generally well tolerated, dose-limiting toxicities have been observed [87]. The efficacy of these agents may depend on the site of disease, suggesting that combinations of inhibitors that target different pathways may be more beneficial than monotherapy [96].

Trial design issues for studies in I-131 refractory DTC

Patient selection and trial end points should be the prime considerations in designing trials of patients with I-131 refractory DTC. As noted earlier, I-131 refractory DTC can be defined as an inability to take up I-131, either upon initial exposure or upon loss of prior evidence of uptake. Such determinations should be made under conditions of low-iodine diet and adequate endogenous TSH elevation or rhTSH stimulation. However, the threshold of iodine uptake, the definition of progressive disease and the cumulative amount of I-131 received should be defined in advance. Moreover, the heterogeneity in disease progression within this patient population suggests the importance of enrolling patients with comparable rates of disease progression. Up to now, most of the patients enrolled in clinical trials had measurable node or distant metastases (according to RECIST criteria), while local infiltration in the neck cannot be clearly assessed and thus is excluded from the studies. This is an important issue that should be addressed in the future.

Most of the drugs being developed for the treatment of I-131 refractory DTC are agents targeted to molecular pathways thought to be critical for tumor growth. Whereas traditional chemotherapeutic agents were generally approved based on tumor shrinkage, targeted agents are more commonly approved based on improvements in progression-free survival (PFS) or time to tumor progression. This is due in part to the recognition that anti-angiogenic activity is important for the clinical efficacy of many of these targeted agents, such that stable disease (SD) rather than tumor shrinkage may be the principal outcome. In 2007, the US FDA issued guidelines stating that PFS prolongation may be a surrogate end point for clinical benefits [97]. Although OS remains the preferred end point for oncology trials, the reality of patient crossover and the availability and subsequent use of alternative therapies upon progression tends to confound OS end points. For this reason, the approval of sorafenib, sunitinib, pazopanib, everolimus and bevacizumab in the treatment of patients with advanced refractory DTC was based on studies showing improvements in PFS. In addition, the recent approval of vandetanib to treat MTC was based on a Phase III trial whose primary end point was an improvement in PFS [98].

Targeted agents in Phase III development for treatment of DTC

Two targeted agents, sorafenib and lenvatinib, are currently in Phase III trials in patients with I-131 refractory DTC (Table 1).

Sorafenib

Sorafenib is a multiple kinase inhibitor, targeting CRAF, BRAF, VEGF receptor (VEGFR)-1, -2, -3, PDGF receptor (PDGFR)-β, RET, c-kit and Flt-3 [99]. As a multifunctional inhibitor, sorafenib inhibits tumor growth, progression, metastasis and angiogenesis, as well as downregulating mechanisms that protect tumors from apoptosis. These findings have suggested that sorafenib may significantly improve outcomes in patients with DTC.

Several Phase II trials have assessed the effects of sorafenib monotherapy in over 200 patients with thyroid cancer, most with DTC, with other patients having medullary and anaplastic carcinomas (Table 1) [100–104]. The median PFS ranged from 58 to 96 weeks, with PR rates as high as 38% and disease control rates (defined as SD plus PR) of 59–100%. Median OS was reported to be as long as 141 weeks. Approximately 62% of patients required dose reductions due to adverse events (AEs) that were mostly grade 1 or 2. The most common AEs have been hand–foot skin reactions and other skin toxicities, fatigue, weight loss, diarrhea and musculoskeletal pain/arthralgias.

In addition, a recently reported retrospective trial reported the results of sorafenib treatment in 34 patients with metastatic thyroid cancer, including 16 with DTC [105]. Of the 34 patients, 11 (32%) achieved PR, including three out of 16 (19%) with DTC, and 14 (41%) achieved SD for >6 months, including 8 (50%) with DTC. At a median follow-up of 11.5 months, the median PFS was 10.5 months (95% CI: 6.13–14.87 months) in all patients and 13.3 months (95% CI: 6.28–20.45 months) in patients with DTC; and the median OS was 23.6 months for all patients and for those with DTC.

These encouraging results and the need for improvement in the treatment of I-131 refractory DTC have led to the designing of a double-blind, multicenter, multinational, randomized Phase III trial of sorafenib in 380 patients with locally advanced or metastatic I-131 refractory DTC (DECISION) [106]. Briefly, patients should have evidence of progressive disease based on RECIST criteria within the previous 14 months. I-131 refractoriness in this trial is defined as a lack of I-131 uptake by a qualified target lesion in patients with low-iodine diets and adequate endogenous TSH elevation or rhTSH stimulation. In addition, patients with some iodine uptake (i.e., those who received I-131 within the last 16 months and whose target lesions had progressed, and those who received multiple I-131 treatments and whose target lesions had progressed after each of two I-131 treatments within 16 months), as well as patients who had received cumulative I-131 ≥ 22.2 GBq (600 mCi), are eligible for inclusion. The primary efficacy end point is PFS and treatment groups will be compared using a one-sided log-rank test with an overall one-sided a of 0.01 stratified by age (< 60 years vs ≥ 60 years) and geographic region. Secondary outcome measures will include OS, time to tumor progression, duration of response, disease control rates, complete response, PR and SD defined by RECIST criteria. Patient-reported quality-of-life outcomes will be measured using the FACT-G and EQ-5D questionnaires. No interim analysis for efficacy or futility is planned. Sorafenib 400 mg or matching placebo will be administered orally twice daily until radiologically documented progression of disease or unacceptable toxicity. At the investigators’ discretion, patients who develop progressive disease while on placebo will be allowed to cross over to sorafenib. This trial has completed enrollment, and results are expected to be reported in 2012. Sorafenib is also being evaluated in combination with the mTOR inhibitor temsirolimus (rapamycin) and its derivative, everolimus, in patients with DTC. Other combination regimens being investigated include sorafenib/everolimus/pasireotide and sorafenib/cediranib/lenalidomide.

Lenvatinib

Lenvatinib, previously known as E7080, inhibits RET, VEGFR 1, -2, -3, PDGFR, c-kit and FGF receptor 1, 2, 3 and 4 [107]. A Phase II trial of this multikinase inhibitor in 58 patients with I-131 refractory DTC and disease progression over the previous 12 months by RECIST criteria showed that 50% of patients achieved a PR, with a median PFS of 12.6 months [108]. Most AEs were grade 1–2, with only 8.6% of patients experiencing a grade 4 event. AEs included hypertension, fatigue, diarrhea, weight loss, anorexia and proteinuria.

In 2011, a multicenter, randomized, double-blind, placebo-controlled, Phase III study of lenvatinib (24 mg once daily) was initiated in patients with I-131 refractory DTC and radiographic evidence of disease progression within the prior 12 months; prior targeted therapy is not an exclusion criterion [203]. The primary end point of the trial is PFS and the secondary end point is OS.

Other targeted agents for the treatment of DTC

Clinical trials have been conducted with several other targeted agents and some are in various stages of clinical development in the treatment of patients with DTC (Table 2).

Sunitinib

Sunitinib is a selective, orally administered tyrosine kinase receptor inhibitor that targets all three VEGF receptors, RET and RET/PTC [109]. A Phase I trial in two patients with metastatic, progressive PTC or follicular carcinoma resulted in clinical responses sustained for 4 years [110]. Preliminary results from two Phase II trials of patients with I-131 refractory DTC support additional studies of sunitinib. In an open-label, Phase II trial of 43 subjects, (37 with DTC), sunitinib produced PRs in 13% and SD in 68% [111]. AEs included fatigue, diarrhea, palmar–plantar erythrodysesthesia, neutropenia and hypertension. Interim results from a second Phase II trial showed that sunitinib induced PR or SD for more than 12 weeks in two out of 12 patients with DTC [112]. Continuous dosing of sunitinib in patients with F-18 FDG/PET-avid advanced thyroid cancer, 26 with DTC and seven with medullary carcinoma, showed complete response, PR and SD rates of 7, 25, and 48%, respectively [113]. FDG/PET responses were reported in 36% of these patients, 88% of whom had disease control by RECIST criteria.

Pazopanib

Pazopanib is an orally bioavailable tyrosine kinase receptor inhibitor with activity at low nanomolar concentrations against VEGFR, PDGFR and c-kit [114]. It inhibits the growth of a wide range of human tumor xenografts in a murine model. In a Phase II study, 39 patients with I-131 refractory DTC were treated with 800 mg/day of pazopanib in 4-week cycles, with a median 12 cycles received by patients [115]. Nineteen patients (49%) had a confirmed PR, and Kaplan–Meier analysis showed a 1-year response rate of 66%.

Vemurafenib

Vemurafenib (PLX4032, RG7204 or RO5185426) is a selective inhibitor of the V600E mutant BRAF and was recently approved by the FDA for treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation [116]. Preclinical studies have shown that thyroid cancer cells are sensitive to this agent [117]. An ongoing Phase II trial is testing vemurafenib in patients with papillary thyroid cancer who are positive for BRAF V600E mutations and resistant to I-131 (NCT01286753) (Table 2).

Gefitinib

Gefitinib is an orally active inhibitor of epidermal growth factor signaling that blocks EGF receptor (EGFR) autophosphorylation in several EGFR-expressing human tumor cell lines [118]. It is currently licensed for the treatment of patients with non-small cell lung cancer after they become refractory to platinum-based compounds and taxanes. A Phase II study of gefitinib in patients with advanced thyroid cancer, 67% of whom had DTC, showed no objective responses, but 32% of patients had small reductions in tumor volume, and five patients with SD showed reductions in serum thyroglobulin concentrations to <90% of normal [119].

Axitinib

Axitinib is an oral inhibitor of VEGF but not RET. A multicenter, open-label, Phase II trial in 60 patients with I-131 resistant thyroid cancer of various histologic types showed an overall PR rate of 30% (including 31% of the patients with DTC), with a median PFS of 18 months [120].

Vandetanib

Vandetanib is a VEGFR, EGFR and RET tyrosine kinase inhibitor (TKIs) and has been approved for treatment of MTC [98]. It is currently being studied in patients with papillary or follicular thyroid cancer (NCT00537095) (Table 2).

Everolimus

The mTOR is a serine–threonine protein kinase that regulates cellular metabolism, growth and proliferation and may play a role in thyroid carcinogenesis. Everolimus is a mTOR inhibitor and is currently being studied in a Phase II trial in patients with locally advanced or metastatic thyroid cancer (medullary, differentiated or anaplastic; NCT00936858) (Table 2).

Others

A number of other agents are in various stages of development as potential treatment for patients with thyroid cancer: motesanib, axitinib, XL281, panobinostat, pasireotide and cabozantinib.

Motesanib is an oral tyrosine kinase receptor inhibitor that targets VEGF-1, -2 and -3. In a Phase II open-label trial that included 93 patients with DTC, 13 patients (14%) achieved a PR and 33 (35%) had SD [121].

XL281 is an inhibitor of wild-type and mutant RAF kinase that has shown activity in a Phase I trial of patients with multiple tumor types, including PTC [122].

Panobinostat (LBH589) is an inhibitor of histone deacetylase [123]. Patients with DTC and medullary carcinoma of the thyroid are currently being recruited for a Phase II trial of panobinostat.

Pasireotide (SOM230) is a novel, multireceptor-targeted somatostatin analog with high-binding affinity for somatostatin receptors 1, 2, 3 and 5, suggesting it has antisecretory and potential antitumor properties [123]. It is currently being studied as monotherapy and in combination with everolimus in patients with I-131 refractory DTC and in those with medullary carcinoma.

Cabozantinib (XL184) is a potent inhibitor of the tyrosine kinases MET and VEGFR-2. Preliminary results of a Phase III trial of cabozantinib in patients with medullary thyroid cancer reported that this drug met its primary outcome, improved PFS [124,125], suggesting that testing of this agent may be warranted in patients with I-131 refractory DTC.

Management of AEs

TKIs are generally quite well tolerated and associated with much less toxicity than chemotherapy. AEs are evaluated, by convention, using the National Cancer Institute’s Common Terminology Criteria for Adverse Event, in which severity of each event can be classified in various grades and, according to these, the study drug is temporary or permanently withdrawn or the dosage is reduced. The most common AEs are represented by constitutional symptoms such fatigue, weight loss, diarrhea and nausea, although only rarely do they reach grade 3 or 4 severity, for which temporary discontinuation or dosage reduction is required. Hypertension is a common effect of all VEGF inhibitors; total incidence varies from 17 to 56% with grade ≥3 between 2 and 25%. Common to almost all TKIs is the occurrence of a series of cutaneous AEs including hand–foot skin reaction, mucositis, papulopustolar rash, alopecia and xerosis. Skin reaction may be attenuated or prevented using the application of cream or other topical agents.

Another common side effect with some TKIs is the increase of serum TSH that often requires an adjustment of l-tyroxine therapy. The intimate mechanism of this alteration is still unknown but an interference in thyroid hormone metabolism or a decrease in l-tyroxine absorption has been postulated.

Future directions

The paucity of current treatment options for patients with I-131 refractory DTC, together with the number of investigational targeted therapies, make study design and definitions keys to optimizing treatment with these agents. It is important to clearly define patient inclusion and exclusion criteria and to select appropriate outcome measures. Significant issues include the definitions of I-131 refractory disease, differentiation between indolent and progressive disease, and primary and secondary outcome variables (Table 3). In addition, among patients with progressive disease, it is important to distinguish those who may benefit from a TKI from those for whom watchful waiting may be the best approach. Most studies of I-131 refractory patients use RECIST criteria to assess targeted and other antineoplastic strategies, although limitations associated with this morphologic assessment should be considered (e.g., necrosis and edema) [39].

At present, there is sufficient evidence for the efficacy of sorafenib and lenvatinib to support Phase III trials. Future studies of these and other novel agents will include different dosing regimens and combinations with other kinase inhibitors involved in cell growth, proliferation and metastasis, such as mTOR inhibitors, somatostatin analogs and thalidomide derivatives.

Conclusion

The global incidence of thyroid cancer is increasing. Although most patients with DTC can be successfully treated by surgery and adjuvant I-131, some thyroid cancers develop resistance to I-131. In these patients, therapeutic options have been limited, are relatively ineffective and associated with significant and treatment-limiting toxicities and impaired quality of life. Therefore, patients with I-131 refractory DTC are candidates for clinical trials of various interventions, which may improve outcomes.

Advances in molecular biology have been accompanied by significant improvements in understanding the cellular alterations associated with transformation and progression of thyroid cancers. Knowledge of signaling pathways in DTC has led to the development of small molecular weight inhibitors of those pathways. Kinase inhibitors have significantly improved outcomes in patients with non-small-cell lung cancer, chronic myelogenous leukemia, hepatocellular carcinoma and renal cell carcinoma. Phase I and II trials have suggested that kinase inhibitors, either as monotherapy or in combination with other agents, may improve outcomes in patients with I-131-resistant DTC. Targeted therapies also have a narrower spectrum of toxicities than cytotoxic chemotherapy, thus improving the patients’ quality of life.

Expert commentary

The involvement of signaling pathways in the development of DTC has suggested that agents targeting these pathways may be effective in treating patients with I-131 refractory DTC. Several TKIs targeting these signal pathways have shown efficacy in the treatment of these patients. Two targeted agents, sorafenib and lenvatinib, are currently in Phase III trials in patients with I-131 refractory DTC, and several other agents are currently being tested in Phase II trials. Expansion of the therapeutic armamentarium in the treatment of I-131 refractory DTC may enhance survival of these patients.

Five-year view

Evidence to date supports Phase III trials of sorafenib and lenvatinib in patients with I-131 refractory DTC, and several other TKIs now being tested may also be shown to be effective. Future developments are directed toward the definition of the most appropriate dosage in the intent of reducing AEs and side effects, which are currently the main limitation. In addition, the problem of resistance to the drug after a period of favorable response is one of the key issues that needs to be addressed in the years to come.

Table 1. Phase II trials of sorafenib in differentiated thyroid cancers.

Trial design	Patients (n)	Treatment	Efficacy results in DTC cohort	Grade ≥3 AEs in ≥5% of patients	NCT ID	Ref.
Two-stage single-arm trial; DTC, PD, medullary and anaplastic patients (first stage)	Total = 30; DTC = 27	Median duration of treatment = 27 weeks. Dose reduction (due to AEs) required in 47% of patients.	mPFS = 84 weeks	Hypertension, hand–foot syndrome, rash, weight loss, diarrhea, elevated LFTs^†	NCT00654238	[100]
Two-stage single-arm trial; DTC, PD, medullary and anaplastic patients (first and second stages)	Total = 55; DTC/PD = 50	Patients with progressing advanced, iodine-refractory differentiated or PD thyroid cancer	mPFS = 96 weeks; mOS 140.9 weeks; PR = 38%; SD = 57% and CBR = 95%	Rash, weight loss, hand–foot syndrome, diarrhea, hypertension	NCT00654238	[101]
Two-stage two-arm trial; Arm A – chemotherapy naive papillary TC with biopsy; Arm B – papillary vs non-papillary. Primary end point; ORR	Total = 56; DTC = 41 (arms A and B)	Dose reduction (due to AEs) required in 52% of patients	ORR = 15%; mPFS = 16 month; mOS = 23 month SD = 57% and DCR = 72%	Fatigue, hand–foot skin reaction, weight loss, skin rash, hypertension, diarrhea, stomatitis, tongue/tooth pain, abdominal/rectal pain, proximal myopathy, back pain, general pain, hand/foot pain, arthralgia, colon perforation	NCT00095683	[102]
Single-arm trial; primary end point: radiologic RR at 6 months	Total = 34; DTC = 19	Median duration = 16.5 months; dose reduction (due to AEs) required in 79% of patients	RR (6 month) = 16%; RR (12 month) = 18%;mPFS and mOS not reached at 19 months; 1-year OS = 79% and 1-year PFS = 68%	Hand–foot syndrome, other skin toxicities, diarrhea, alopecia	N/A	[103]
Single-arm two-stage design trial; primary end point: percentage of patients with reuptake of radioiodine at 26 weeks	Total = 32; DTC = 32	22 patients completed the 26-week therapy (21 evaluable for RaI uptake); dose reduction (due to AEs) was required in 56% of patients	Reinduction of RaI uptake not observed. mPFS = 58 weeks; SD = 34%; PR = 25% and DCR = 59%	Hand–foot skin reaction, hypertension, weight loss	NCT00887107	[104]

^†One patient developed grade 3/4 LFT abnormalities at 8 weeks and died of liver failure 12 weeks later.

AE: Adverse event; CBR: Clinical benefit rate; DCR: Disease control rate; DTC: Differentiated thyroid cancer; LFT: Liver function test; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Overall response rate; PD: Poorly differentiated; PR: Partial response; RR: Radiologic response rate; SD: Stable disease.

Table 2. Targeted therapeutic agents in late-stage clinical trials for differentiated thyroid cancer.

Agent	Patients (n)	Molecular targets	Description of study	NCT ID	Trial phase	Estimated completion date
Monotherapy
Sunitinib	66	VEGFRs, PDGFRs, kit	Nonrandomized, open-label trial of sunitinib in locally advanced or metastatic anaplastic, differentiated or medullary thyroid cancer	NCT00510640	II	Febuary 2011
Gefitinib	38	EGFR	Nonrandomized, open-label trial of gefitinib in advanced thyroid cancer	NCT00095836	II	March 2011
Motesanib	184	VEGFRs, PDGFR, kit	Nonrandomized, open-label trial of motesanib in locally advanced or metastatic thyroid cancer	NCT00121628	II	August 2011
Lenvatinib	104	VEGFRs, FGFRs, RET, kit, PDGFb	Multicenter, open-label, single-arm trial of oral lenvatinib in medullary and RAI-refractory, unresectable DTCs	NCT00784303	II	October 2011
Sorafenib	419	VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf	Double-blind, randomized trial of sorafenib in locally advanced/metastatic RAI-refractory DTC	NCT00984282	III	November 2011
Panobinostat	33	HDAC inhibitor	Nonrandomized, open-label trial of panobinostat in metastatic medullary thyroid cancer and RAI-resistant DTC	NCT01013597	II	January 2012
Pazopanib	188	VEGFRs, PDGFRs, kit	Open-label trial of pazopanib in advanced thyroid cancer	NCT00625846	II	May 2012
Everolimus	42	mTOR inhibitor	Open-label trial of everolimus in unresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinomas	NCT01118065	II	May 2012
Everolimus	33	mTOR inhibitor	Nonrandomized, open-label trial of everolimus in RAI-refractory thyroid cancer	NCT00936858	II	June 2012
Vandetanib^†	145	VEGFR-2, EGFR, RET	Multicenter, randomized, double-blind, placebo-controlled trial of vandetanib in locally advanced or metastatic papillary or follicular thyroid carcinoma	NCT00537095	II	December 2012
Sorafenib	419	VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf	Double-blind, randomized trial of sorafenib in locally advanced/metastatic RAI-refractory DTC	NCT00984282	III	March 2013
Cabozantinib	315	MET, VEGFR-2	International, randomized, double-blind trial of cabozantinib in unresectable, locally advanced or metastatic medullary thyroid cancer	NCT00704730	III	March 2013
Everolimus	32	mTOR inhibitor	Multicenter, open-label trial of everolimus in advanced thyroid cancer	NCT01164176	II	March 2013
Lenvatinib	360	VEGFRs, FGFRs, RET, kit, PDGFb	Multicenter, randomized, double-blind, placebo-controlled trial in RAI-refractory DTC	NCT01321554	III	July 2013
Axitinib	52	VEGFRs	Nonrandomized, open-label trial of axitinib in RAI-refractory thyroid cancer	NCT00389441	II	August 2013
Sunitinib	46	VEGFRs, PDGFRs, kit	Nonrandomized, open-label trial of sunitinib in DTC	NCT00668811	II	December 2013
Everolimus	30	mTOR inhibitor	Randomized, open-label trial of pasireotide and everolimus in RAI-refractory DTCs and medullary thyroid cancers	NCT01270321	II	June 2014
Vemurafenib	40	(V600E) BRAF inhibitor	Nonrandomized, open-label, multicenter trial of vemurafenib in metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to RAI	NCT01286753	II	June 2014
Valproic acid	25	HDAC inhibitor	Nonrandomized, open-label trial of valproic acid in advanced thyroid cancers of follicular origin	NCT01182285	II	September 2014
Axitinib	100	VEGFRs	Nonrandomized, open-label trial of axitinib in patients previously receiving axitinib in clinical trials	NCT00828919	II	December 2015
Combination therapy
Sorafenib plus everolimus	38	Sorafenib: VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf Everolimus: mTOR inhibitor	Nonrandomized, open-label of the combination of everolimus and sorafenib in RAI-refractory thyroid cancer	NCT01141309	II	June 2012
Sorafenib plus temsirolimus	40	Sorafenib: VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf Temsirolimus: mTOR inhibitor	Open-label of the combination of temsirolimus and sorafenib in RAI-refractory thyroid cancer	NCT01025453	II	December 2012
Cediranib plus lenalidomide	30	Cediranib: VEGFRsLenalidomide: immunomodulator	Randomized, open-label of cediranib with or without lenalideomide in thyroid cancer	NCT01208051	II	September 2013
Everolimus plus pasireotide	30	Everolimus: mTOR inhibitor Pasireotide: somatostatin analogue	Randomized, open-label of pasireotide and everolimus in RAI-refractory differentiated and medullary thyroid cancer	NCT01270321	II	October 2013

Phase II trials for agents in Phase III are not listed.

^†Approved by the US FDA for medullary cancer.

DTC: Differentiated thyroid cancer; EGFR: EGFR receptor; FGFR: FGF receptor; PDGFR: PDGF receptor; RAI: Radioactive iodine; VEGFR: VEGF receptor.

Data taken from [203].

Table 3. Key terms and outcome measures for clinical trials of targeted therapies in patients with differentiated thyroid cancer.

Term	Definition/criteria
Target lesion	To assess the burden of disease and identify objective tumor responses, it is important to be able to estimate the overall tumor burden at baselineTarget lesions are those with the longest diameters that lend themselves to reproducible repeated measurementsTarget lesions should be selected to be representative of all involved organs and should include all lesions up to a maximum of five
Stable disease	Neither sufficient increase nor decrease in the size of target lesions considered to be meaningful
Progressive disease	A 20% or greater increase in the sum of diameters of the target lesions
Partial response	At least a 30% decrease in the sum of diameters of target lesions
Complete response	Disappearance of all target lesions. Any pathologic lymph nodes must have a reduction in their short axis to <10 mm

Adapted with permission from [39].

Financial & competing interests disclosure

The authors were supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc. F Pitoia is a consultant to and member of the speaker’s bureau of Genzyme Corp. B Robinson is a consultant or advisor with Eisai Corporation. L Wirth is a consultant or advisor with AstraZeneca and Boehringer Ingelheim Corporations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors thank BelMed Professional Resources, NY, USA for editorial support, with funding provided by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.