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A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma.
Abstract
5514
Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple targets, including RAF, VEGFR1, and VEGFR2. Published response rates with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. Temsirolimus is an intravenous inhibitor of mTOR; mutations in the PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be associated with aggressive disease. Methods: The study was a single institution, phase II design. Primary objective was response rate. Eligible patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 38 patients were enrolled; 37 were eligible and 36 patients started treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. Fourteen pts are still actively on study. Results: Of the 37 eligible pts, demographics: female-46%; median age-64 years (30-81); histology-papillary (23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic (2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): grade 4 – colonic perforation (1 pt). Evaluation of best response: partial (PR) (8, including 3 with anaplastic/poorly differentiated); stable disease (SD) (21); progression (1); inevaluable (7). The partial response rate was 38% in the cohort that previously did not receive any systemic treatment. There was no correlation of response to either BRAF (10) or RAS (5) mutational status. Median time on treatment is 203 days (range 14-638 days) at the cutoff date. For the 21 pts with SD, the maximum percentage shrinkage by RECIST criteria ranged from -2% to -35% (one patient with unconfirmed PR) with a median time on treatment of 203 days (range 39-503 days). Conclusions: The combination of sorafenib and temsirolimus shows promising results in a heavily pretreated population. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc.
... The systematic review uncovered four relevant sorafenib trials that evaluated its use in RAI-R DTC patients in combination with another targeted agent (see Table 3) such as tipifarnib (Hong et al, 14 Cabanillas et al 15 ), temsirolimus (Sherman et al 29 ), and everolimus (Sherman et al 30 ). Tipifarnib is a farnesyl transferase inhibitor, while temsirolimus is an intravenous inhibitor of mTOR and everolimus is an mTOR inhibitor given by mouth. ...
... 14,15 mPFS was 18 months in the Hong et al 2011 study, but the analysis included MTC participants. 14 29 There was no correlation of response to either BRAF or RAS mutational status. 29 Sherman et al then reported a sorafenib/everolimus combination two-stage prospective Phase II study in 2013 with 28 RAI-R DTC of various histological subtypes and found PR rates between 50% and 67% and SD rates between ...
... 14 29 There was no correlation of response to either BRAF or RAS mutational status. 29 Sherman et al then reported a sorafenib/everolimus combination two-stage prospective Phase II study in 2013 with 28 RAI-R DTC of various histological subtypes and found PR rates between 50% and 67% and SD rates between ...
Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials.
... One sample from the PTC nodal metastasis in 2010 was snap frozen for WES and RNA sequencing. In 2011, lung metastases were treated with sorafenib and temsirolimus (30), with tumor experiencing partial response (31). Treatment was continued for 13 months until disease progression. ...
Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K–AKT–mTOR, MAPK, and JAK–STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation.
Implications
The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further.
... This result is consistent with other phase II data regarding sorafenib [33]. See Table 4 for a summary of studies describing targeted therapy in DTC [15][16][17][18][19][20][21][22][23][24][25][26]. ...
Objectives . Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy. Methods . We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Results . These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC. Additionally, the SELECT trial shows that the targeted therapy lenvatinib is effective in the treatment of DTC and could be useful as neoadjuvant therapy for this disease due to its short time to response. Pazopanib has also demonstrated promise in phase II data. Conclusions . Thus, chemotherapy in the neoadjuvant setting could possibly be useful for managing advanced DTC. Additionally, some of the new tyrosine kinase inhibitors (TKIs) hold promise for use in the neoadjuvant setting in DTC.
... Среди 19 пациентов с ДРЩЖ в этом исследовании частичный ответ наблюдался у 11 больных (58%) и стабилизация процесса в 7 случаях (37%) [34]. Еще один ингибитор m-TOR -темсиролимус был оценен во II фазе (N = 37) исследования [35] у пациентов с прогрессирующим рецидивирующим /метастатическим немедуллярным РЩЖ. В этом исследовании частичный ответ наблюдался у 8 больных (22%) и стабилизация процесса у 21 (57%) из 37 пациентов. ...
Thyroid cancer is one of the most widespreaded malignant endocrine tumors. Morbidity is constantly increasing in the world and in Russian Federation during last decade [1, 2]. So, in the United States marked annual increase of diagnosed cases of thyroid cancer by 6.4% with increasing of mortality by 0.9% [3]. In Russian Federation marked annual increase of diagnosed cases by 5.4% in 2003–2013. In 2013 in Russian Federation diagnosed 9624 new cases of thyroid cancer with morbidity 93.2 on 100 000 citizens [1]. Differentiated thyroid cancer is more than 90% of all cases of thyroid cancer [4].
... identifier: NCT01025453] in patients with progressive recurrent/metastatic nonmedullary thyroid cancer. In this study, PRs were seen in 8 (22%) (including three with anaplastic/poorly differentiated thyroid cancer) and SD in 21 (57%) of 37 patients[Sherman et al. 2012]. Finally, the University of Chicago Phase II Consortium is exploring the combination of lenalidomide with cediranib in patients with metastatic RAI-refractory DTC [ClinicalTrials.gov ...
Until recently, no truly effective treatment options have existed for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), a serious disease with poor prognosis. In November 2013, the targeted multikinase inhibitor, sorafenib, was approved for use in these patients based on substantially improved progression-free survival compared with placebo. A number of other targeted agents, including lenvatinib, are being investigated in phase II and phase III trials. With the advent of these new treatment options, practitioners are faced with making important decisions in determining which patients are candidates for systemic treatment and the optimal timing for treatment initiation. Since patients may remain asymptomatic for a protracted period of time, tumor size and growth rate are the primary considerations for making these choices. Proactive management of side effects is also critical in optimizing the effectiveness of treatment. Here we review targeted systemic agents that are either in use or are under investigation for RAI-refractory DTC and provide recommendations on the rationale for initiating systemic treatment and on managing adverse events. Four illustrative case studies are provided.
... Sherman et al. reported phase II study on use of combination of sorafenib and temsirolimus in 37 patients radioiodine refractory thyroid carcinoma. 21.6% patients had partial response and 56.7% had stable after median time on treatment of 206 days [41]. ...
Although the majority of papillary thyroid carcinoma could be successfully managed by complete surgical resection alone or resection followed by radioiodine ablation, a small proportion of patients may develop radioiodine-refractory progressive disease which is not amenable to surgery, local ablative treatment or other treatment modalities. The use of FDG-PET/CT scan for persistent/recurrent disease has improved the accuracy of restaging as well as cancer prognostication. Given that patients with RAI-refractory disease tend to do significantly worse than those with radioiodine-avid or non-progressive disease, an increasing number of phase I and II studies have been conducted to evaluate the efficacy of new molecular targeted drugs such as the tyrosine kinase inhibitors and redifferentiation drugs. The overall response rate of these drugs ranged between 0-53%, depending on whether the patients had been previously treated with these drugs, performance status and extent of disease. However, drug toxicity remains a major concern in administration of target therapies. Nevertheless, there are also ongoing phase III studies evaluating the efficacy of these new drugs. The aim of the review was to summarize and discuss the results of these targeted drugs and redifferentiation agents for patients with progressive, radioiodine-refractory papillary thyroid carcinoma.
... The preliminary results of a phase II study of the combination of sorafenib and temsirolimus shows promising results in patients with RAI-refractory thyroid carcinoma 80 . The data were presented at the 2012 ASCO Annual Meeting. ...
The majority of patients with differentiated thyroid cancer are cured with standard primary treatments including surgery, radioactive iodine and TSH suppression. A small proportion of patients who develop radioactive iodine-refractory metastatic disease have few treatment options. Recent discovery of the molecular mechanisms that contribute to thyroid cancer tumorigenesis and its progression have revealed key targets that are currently being evaluated in clinical trials. In the last decade several novel targeted therapies have shown encouraging results and have brought hope to patients with advanced disease. However, identifying the subpopulation of patients who may benefit from systemic therapies remains a challenge as the use of these therapeutic modalities is associated with high toxicity rates and most patients have a long indolent phase where the tumor is stable or slowly progressive and asymptomatic. The objective of this review is to summarize the management of patients with metastatic, radioactive iodine refractory differentiated thyroid cancer.
The incidence of differentiated thyroid cancer (DTC) has increased over the last few decades, though it remains to be a rare disease. The prognosis of DTC is excellent; its treatment includes surgery (near-/total thyroidectomy), which is usually followed by remnant thyroid bed ablation using radio-iodine, as well as a risk-stratified follow-ups, including hormone replacement. Treatment of patients who are non-responsive to radioactive iodine (RAI) remains a challenge. Targeted therapies for RAI refractory DTC act primarily through inhibition of cell proliferation, survival and angiogenesis. Tyrosine kinase inhibitors (TKI) have achieved prolonged responses and improved progression-free survival, thereby representing a shift in the treatment of advanced thyroid cancer. There will be number of targeted treatment options for this patient population in the near future. Evidence regarding which drug should be used first and whether there is crossover drug resistance between these drugs is still lacking. Clinicians should be able to choose precisely which patients should be treated with novel targeted therapies after taking into account the following facts: i) TKIs have still not demonstrated a survival benefit. ii) The adverse effects of long-lasting treatment with TKIs could worsen quality of life, which is mostly excellent in these patients before starting treatment with these agents.
Background
Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC).
Objectives
We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima ® ; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar ® ; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC.
Data sources
EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined.
Review methods
We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC.
Results
Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained.
Limitations
We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib.
Conclusions
Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway.
Study registration
This study is registered as PROSPERO CRD42017055516.
Funding
The National Institute for Health Research Health Technology Assessment programme.
Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15-20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients' overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor's ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.
Opinion statement:
Radioiodine refractory differentiated thyroid cancer (RAI-R DTC) is a challenging malignancy with limited prognosis and treatment options. Recently, clinical trials with targeted therapies have advanced the outlook of these patients, and inhibition of the vascular endothelial growth factor (VEGF) axis has led to the approval of small-molecule tyrosine kinase inhibitors (TKIs) for first-line treatment of radioiodine refractory disease. In addition to approved therapies (sorafenib and lenvatinib), other multi-targeted tyrosine kinase inhibitors that are commercially available have been recognized as viable treatment options for RAI-R DTC. Our preference is to initially use lenvatinib, given the dramatic progression-free survival (PFS) improvement versus placebo, with the caveat that 24 mg daily is not often tolerated and lower doses often used. In patients with BRAF V600E mutation, BRAF inhibitors are now considered for treatment, especially if patients are at high risk from antiangiogenic therapy. Research is continuing to evolve in identifying mechanisms related to radioiodine refractoriness, and trials are evaluating therapeutic molecules to overcome this resistance. Clinical care of patients with RAI-R DTC requires careful consideration of both patient and disease characteristics. Many patients with asymptomatic and indolent disease can be followed for years without treatment while others with high volume or rapidly progressive disease merit early intervention.
Targeted therapies are emerging rapidly and are challenging the traditional roles of nonsurgical therapy for the treatment of thyroid cancers. Molecular pathways hold the key for designing rationally based drugs such as the already FDA-approved tyrosine kinase inhibitors: sorafenib, vandetanib, and cabozantinib. Many more targeted therapies are under investigation. For instance, selumetinib is a MEK inhibitor that has been shown to restore radioiodine avidity to radioiodine refractory thyroid cancers. This chapter reviews standard nonsurgical treatments including the historical use of cytotoxic chemotherapy, the molecular science behind newly approved and experimental targeted agents, and their supporting clinical trial data. Lastly, the chapter presents four common scenarios in thyroid cancer management where an increased role is forthcoming for nonsurgical modalities such as tyrosine kinase inhibitors. These cases contrast the cutting edge use of pharmacology, as monotherapy or in combination, with the current held standard of care. Nonsurgical modalities for thyroid cancer care are rapidly advancing, and the best use of these modalities has yet to be established as highlighted in the cases.
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials. This led to the Phase III trial (DECISION) which showed that there was an improvement in progression-free survival of 5 months for patients on sorafenib when compared to those on placebo. Adverse events with this drug are common but usually manageable. The development of resistance after 1 or 2 years is almost a rule in most patients who showed partial response or stabilization of the disease while on sorafenib, which makes it necessary to think of a plan for subsequent therapies. These may include the use of another MKI, such as lenvatinib, the second approved MKI for advanced differentiated thyroid cancer, or include patients in clinical trials or the off-label use of other MKIs. Given sorafenib’s earlier approval, most centers now have access to its prescription. The goal of this review was to improve the care of these patients by describing key aspects that all prescribers will need to master in order to optimize outcomes.
Papillary (PTC) and follicular (FTC) thyroid cancer (TC) belong to
differentiated thyroid cancer (DTC). The initial treatment of DTC is surgery
followed by radioiodine remnant ablation. Although the prognosis of
DTC is generally good, approximately 10-15% of DTC patients will devolp
advanced disease and their disease will become radioiodine refractory. Even
in radioiodine refractory patients the natural history of disease can be slowly progressive or indolent.The expanded knowledge of the the biological basis of DTC has opened new opportunities in therapy – targeted therapy, aimed at inhibiting specific molecular targets and pathways in tumor proliferation, survival and progression. We rewieved different tageted therapies in DTC. Sorafenib was the first and only targeted drug approved by FDA for progressive and radiodine-refractory DTC. Also, lenvatinib had promising efficacy results in phase III trial, probably even better than sorafenib, but with more treatment-related deaths. The timing of targeted therapy for DTC is of decisive importance. The potential benefit should be balanced with potential toxicity of targeted
therapies.
Introduction:
While the vast majority of patients with thyroid cancer have an excellent prognosis, those with more aggressive courses experience significant morbidity and mortality. Advanced forms of thyroid cancer are typically refractory to standard therapy. Numerous agents with potential usefulness in the treatment of advanced thyroid cancer have recently come under study.
Areas covered:
This article reviews agents identified through a systematic review of the scientific literature as being under investigation for treatment of advanced thyroid cancer. A search of both PubMed and the NCI Clinical Trials website was performed to identify such agents having reached Phase II or III testing. Improved understanding of cancer cell signaling pathways has led to the identification of > 500 kinases as potential therapeutic targets. Additional agents of interest include those that inhibit neoangiogenesis, alter epigenetic factors or stimulate antitumor immune reactions. While presently available agents have shown promise in improving progression-free survival (PFS), complete responses are not seen and significant adverse side effects are encountered.
Expert opinion:
The development of numerous new anticancer agents holds the promise of treatment regimens that will extend PFS and ultimately overall survival in patients with advanced thyroid cancer. Anticipated future developments include individualized, multimodal treatment regimens based on specific tumor cell biology and driver mutations.
Objective:
To discuss the approach to care of patients with advanced differentiated thyroid cancer (DTC), in particular those with radioactive iodine (RAI)-refractory disease, and the transition to systemic treatment.
Methods:
A PubMed search was conducted using the search terms "radioactive iodine-refractory, differentiated thyroid cancer and treatment" restricted to a 2000-2012 timeframe, English language, and humans. Relevant articles were identified from the bibliographies of selected references. Four patient cases are presented to illustrate the clinical course of RAI-refractory DTC.
Results:
The current standard of care for early stage DTC could include surgery, RAI in some cases, and thyroid hormone suppression. For advanced RAI-refractory DTC, clinical practice guidelines established by the National Comprehensive Cancer Network and the American Thyroid Association recommend, as one option, the use of systemic therapy, including kinase inhibitors. Numerous trials are underway to evaluate the clinical benefit of these targeted therapies.
Conclusion:
Preliminary results are encouraging with respect to the clinical benefit of targeted systemic therapies. However, at present there is no consensus on the criteria that define RAI-refractory disease and the optimal timing for transition to systemic therapy. There remains a need to establish common criteria to enhance patient care and enable better comparison across clinical studies.
Substantial developments have occurred in the past 5-10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAF(V600E) mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine.
Advanced differentiated thyroid cancer (DTC), defined by clinical characteristics including gross extrathyroidal invasion, distant metastases, radioiodine (RAI) resistance, and avidity for 18-fluorodeoxyglucose (positron emission tomography-positive), is found in approximately 10-20% of patients with DTC. Standard therapy (surgery, RAI, TSH suppression with levothyroxine) is ineffective for many of these patients, as is standard chemotherapy. Our understanding of the molecular mechanisms leading to DTC and the transformation to advanced DTC has rapidly evolved over the past 15-20 years. Newer targeted therapy, specifically inhibitors of intracellular kinase signaling pathways, and cooperative multicenter clinical trials have dramatically changed the therapeutic landscape for patients with advanced DTC. In this review focusing on morbidities, molecules, and medicinals, we present a patient with advanced DTC, explore the genetics and molecular biology of advanced DTC, and review evolving therapies for these patients including multikinase inhibitors, selective kinase inhibitors, and combination therapies.
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