Managing anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid cancer is one of the most lethal malignancies, with dismal prognosis, resistance to multimodal treatments and a median survival of only 5–6 months. Advances in the discovery of genetic pathway aberrations involved in this aggressive disease have been made, and multiple novel therapies targeting these pathways are undergoing clinical trials. So far, there is no single effective treatment for this disease; however, multimodal therapies with a combination of surgery, radiation and chemotherapy hold some promise. We conducted a PubMed search using the words thyroid neoplasm, anaplastic thyroid carcinoma, anaplastic thyroid cancer and anaplastic thyroid neoplasm, revealing 1673 publications. We review the pathophysiology, current treatments and advances made in identifying the alterations in genetic pathways, as well as novel therapies targeting these pathways.

Keywords::

• anaplastic thyroid carcinoma
• multimodal treatments
• novel therapy
• pathogenesis
• signaling pathways
• staging
• targeted therapy

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Release date: 19 October 2011; Expiration date: 19 October 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe the clinical characteristics and prognostic factors in anaplastic thyroid cancer

• • Describe management of patients with anaplastic thyroid carcinoma when surgery is feasible

• • Describe management of patients with anaplastic thyroid carcinoma who are not operative candidates

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC.

Disclosure:Laurie Barclay has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Ejigayehu G Abate, MD

Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida, USA.

Disclosure:Ejigayehu G Abate has disclosed no relevant financial relationships.

Robert C Smallridge, MD

Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida, USA.

Disclosure:Robert C Smallridge is the principal investigator in a Phase I clinical trial for anaplastic thyroid cancer sponsored by Daiichi-Sankyo. This work was supported in part by Mayo Clinic, NIH grant R01CA136665 (RCS), the Bankhead-Coley Cancer Research Program, Florida Department of Health (RCS) and a generous gift from Alfred D and Audrey M Petersen.

Figure 1. Anaplastic transformation is a multistep carcinogenetic process generated by three pathways.

These three pathways are as follows: (1) A normal thyroid cell is transformed into PTC by BRAF or RAS mutation or RET/PTC rearrangement. Thyrocytes with BRAF mutation further de-differentiate into ATC. (2) PTC cells with p53 inactivation, PI3KA activation and β-catenin mutation have the ability to transform into PDTC. PDTC with a BRAF mutation can develop into ATC. (3) Normal thyrocytes with PAX8/PPARγ fusion or RAS mutation transform into FTC. Development of FTC from FA has been reported [6,18]. Mutations of β-catenin, p53 inactivation and PI3KCA activation are seen in ATC.

ATC: Anaplastic thyroid cancer; FA: Follicular adenoma; FTC: Follicular thyroid carcinoma; PDTC: Poorly differentiated thyroid cancer; PTC: Papillary thyroid cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies [1], with a median survival of 5–6 months from time of diagnosis [2,3]. Thyroid carcinomas are divided into medullary, differentiated (papillary, follicular and Hürthle cell variant of follicular carcinoma), poorly differentiated and undifferentiated (anaplastic) thyroid carcinomas. ATC originates from follicular thyroid cells and accounts for 1–2% of thyroid cancer cases. Approximately 20% of ATC cases arise from a prior differentiated thyroid cancer [4], 20–30% may coexist with differentiated thyroid carcinomas [5], and some may originate de novo.

Presentation

Anaplastic thyroid cancer presents in the sixth to seventh decades of life [3,6], with fewer than 5% of cases seen in patients less than 40 years of age [6]. The incidence of ATC has decreased after the introduction of higher iodination of salt [7–9], suggesting that a low iodine diet may contribute to the higher incidence of ATC.

Presentation is typically advanced at diagnosis, and frequently surgically unresectable with local invasion of the neck soft tissues, airway compromise and distant metastasis [10,11]. A total of 30–40% of patients with ATC at the time of presentation have evidence of lymph node involvement [2,12]. The most common presenting symptom is a rapidly enlarging neck mass [13], resulting in invasion and compression of surrounding structures; therefore, patients may present with dyspnea, stridor, dysphagia, neck pain and hoarseness [2]. Tumor size has been reported to range from 3 to 20 cm, with a mean of 8 cm [14,15].

Risk factors for a worse outcome include older age, acute symptoms, extracapsular extension, distant metastasis and tumor size >7 cm [16], whereas age under 60 years and intrathyroidal ATC are independent factors for low all-cause mortality [10,14]. Lymph node and distant metastasis predict poor outcome [16].

Pathology

Cytologic morphology is variable in ATC. Three distinct morphological patterns are observed: spindle cell pattern (sarcoma-like with hyperchromatic and mitotic nuclei with some atypia), giant cell pattern (pleomorphic giant cells with multiple hyperchromatic and mitotic nuclei, abundant acidophilic cytoplasm, oval, plump round shape, inflammatory neutrophils present) and squamoid (appearance similar to keratinized squamous cell carcinoma with irregular tumor nests and islands configuration, pleomorphism and absent giant cells) [4,11].

Staging

All ATCs are considered stage IV. The American Joint Committee on Cancer/Union for International Cancer Control classification is stage IVA = T4a, any N, M0 (T4a-intrathyroidal ATC); stage IVB = T4b (ATC with gross extrathyroidal extension), any N, M0; and stage IVC = any T, any N, M1 [11,17].

Molecular genetics

In contrast to differentiated thyroid carcinomas that generally have a single mutation, ATC results from a complex genotype with chromosomal aberrations in 85–100% of cases [1,18]. The major research focus has been characterizing the molecular genetic changes of ATC and signaling pathways as potential novel targets for future therapies. The most frequent genetic aberrations in ATC are listed in Table 1. The BRAF^V600E mutation is detected in between 26 [1] and 24% [19] of anaplastic carcinomas, whereas a RAS mutation is detected in 6–50% of ATC [1], suggesting that ATC may arise from RAS-mutated follicular thyroid carcinoma (FTC) [18]. In addition, the function of the tumor suppressor gene p53, a known gatekeeper preventing progression to aggressive thyroid carcinoma, is altered in ATC (mutation 20–83%) [1],and overexpression of abnormal p53 protein with aberrant function was also shown by an increased immunohistochemical staining of p53 in ATC compared to DTC [20,21]. The PI3KCA gene that encodes a catalytic subunit of PI3K is mutated in 12–23% of ATCs, and copy gains occur in 38–61%, leading to Akt activation [1,22,23]. PTEN, a tumor suppressor gene important in downregulation of the PI3K/Akt pathway, is mutated in 12% of ATCs, resulting in unregulated Akt activation [1,22]. Axin 1, a tumor suppressor protein that is a negative regulator of the wnt signaling pathway, is mutated in 82% of ATC [24]. Alteration of the wnt signaling pathway has been associated with carcinogenesis in ATC [24]. In addition, late mutations, such as in β-catenin (cadherin associated protein, β1 gene involved in wnt signaling and cell–cell adhesion), result in the aggressive behavior of ATC [1,24,25].

Anaplastic thyroid cancer can be derived from multistep chromosomal abnormalities from well-differentiated thyroid carcinomas such as papillary thyroid cancer (PTC) or FTC, and from poorly differentiated thyroid carcinoma (PDTC) as depicted in Figure 1.

In vitro and in vivo studies examining gene transcription, mitosis, signaling pathways, proliferation, apoptosis, migration, protein degradation and epigenetics (acetylation; methylation) are reviewed in detail by Smallridge et al.[1,3]. Table 2 updates these observations, with additional studies of previously identified genes/proteins, as well as new potential targets [4,25–37]. The understanding of these deregulated genes and proteins involved in this lethal disease continues to increase, and will lead to the development of high-quality clinical trials.

Current management of ATC

Combination of surgery with other treatment modalities

Currently, there is no established evidence-based treatment guideline for the management of anaplastic thyroid carcinoma due to the rarity of this disease. Local treatments with surgery and radiation are useful in controlling neck disease and relieving obstruction [3,38]. The majority of series in the literature support primary surgical resection (when possible) followed by postoperative radiotherapy (RT) and/or chemotherapy for palliation and to improve survival [12,39]. However, such an operative strategy can only be adopted for a selected subset of patients with resectable tumors in the absence of gross metastatic disease. A literature review on the efficacy of multimodal therapy appears in Table 3[16,40–45].

Complete tumor resection is the preferred surgical option in local control of ATC and avoids the need for tracheostomy [12]. In addition, it has been shown to confer substantial benefit in multiple retrospective studies [6,8,41,42]. R0 surgery (complete removal of all tumor with microscopically negative margins) or R1 (microscopically positive margins) significantly improved median survival to 43 months compared with only 3 months with palliative surgery in 33 patients [42]. R0 resection was associated with improved survival including in stage T4a and T4b ATC disease in 120 patients [8]. Swaak-Kragten et al. reported 75 patients with stage IVA, IVB and IVC disease [41]. Of the 36 patients who underwent surgery, 53% were capable of achieving negative or microscopically positive margins (R0, R1). Those patients who underwent surgery and adjuvant chemoradiation (low-dose doxorubicin) had the best results. Although surgical debulking is associated with survival benefit, extensive surgery including segmental resection of larynx, trachea and esophagus negatively affect quality of life [8]. Patients with stage IVA ATC have the best chance of survival with curative surgery and multimodal treatment [6]. Those with stages IVB and C have similar prognosis, and complete resection of the disease is not possible; therefore, these patients should not routinely be offered surgical debulking [6]. However, Ito et al. recently reported that a subset of patients with stage IVB ATC may benefit from surgery [45]. In a retrospective review, 40 consecutive patients with stage IVB and C disease were treated with one or more modalities consisting of surgery, radiation and chemotherapy (single or combination therapy with cisplatin and one or two agents [epirubicin, adriamycin, VP16 or 5-fluourouracil]). Median survival time of stage IVB and C were 6 months and 4.2 months, respectively. Stage IVB tumors were divided into IVB-a (tumor extending beyond the thyroid capsule, into soft tissue, larynx, trachea, esophagus, recurrent laryngeal nerve) and IVB-b (tumor invading prevertebral fascia, encasing the carotid artery or mediastinal vessels). All stage IVB-a patients underwent mostly total thyroidectomy with some subtotal thyroidectomy, and one patient had palliative resection. Few patients (two out of 13 in stage IV-b and five out of 15 patients with stage IVC) underwent palliative resection. Median survival time for patients treated with curative surgery followed by external-beam radiation and chemotherapy was 13.7 months, for radiation and chemotherapy was 7.8 months and for radiation alone was 3.1 months for all patients. A subset of patients classified as stage IVB-a had a median survival time of 9.6 months, IVB-b had a median survival time of 4.0 months, and stage IVC = 4.2 months. There was no significant survival difference between stage IVB-b tumors and those with distant metastasis (IVC). Therefore, a subgroup of patients with extrathyroidal neck disease (stage IVB-a) may benefit from curative surgery, chemotherapy and radiation, similarly to stage IVA disease [45].

Others have reported a better survival of 11.6 versus 3.2 months survival time when curative surgery is performed versus palliative surgery; the highest survival is in those treated with radical surgery followed by chemoradiotherapy (11.6 months when limited to the neck) [16]. Therefore, curative surgery should be offered to those with stage IVA and a subset of IVB patients (classified as IVB-a by Ito et al.[45]) as they have a similar prognosis. Those with stage IVB-b and IVC have a poor prognosis. It is important to consider a selection bias as a confounding factor when analyzing the effect of surgery on the outcome of patients who undergo curative surgery, as they often have less extensive disease [46]. A study from Foote et al. reported that in ten patients with stage IVA and B disease treated with surgery (R0 = four patients, R1 = three patients, R2 [macroscopic residual tumor] = three patients) along with adjuvant chemotherapy with multiagent (doxorubicin, paclitaxel or docetaxel, cisplatin or carboplatin) chemotherapy and intensity-modulated radiation therapy (IMRT; twice-daily accelerated IMRT in three out of ten, once-daily slightly accelerated simultaneous integrated boost IMRT in four out of ten, and once-daily conventional IMRT in three out of ten in conjunction with chemotherapy with doxorubicin), greater than 2.5-year disease-free survival was seen in 50% of patients, confirming that aggressive combination chemotherapy with IMRT may produce long-term survival [40]. Patients with stage IVC disease have a dismal prognosis and there are no promising studies to date showing prolongation of life expectancy or disease control. In part, these patients are difficult to study as they typically succumb to this fatal disease quickly and treatment options currently available, including systemic chemotherapy, are not effective. Novel therapies incorporated into an aggressive multimodal approach may provide the best options for stage IVC patients.

Radiation therapy

Radiation therapy alone has not been shown to alter disease outcome in ATC, but in combination with surgery and chemotherapy, it shows some improvement in survival [47]. IMRT is the most promising form of RT that can deliver higher doses of radiation directly into the tumor while intensity of radiation can be changed during treatment, sparing more adjoining normal tissue [47]. Thus, an increased dose of radiation can be delivered to the tumor using IMRT by hyperfractionation technique over a short time with less toxicity [48,49]. A retrospective review of 47 patients treated with once-a-day conventional therapy compared with twice-a-day fractionated external RT showed a median survival of 13.6 months in the fractionated group compared with 10.3 months in the conventional once-a-day treated group, although the difference was not significant [50]. A study of 55 consecutive patients with stage IVA and C disease treated with doxorubicin, hyperfractionated accelerated RT and surgery when feasible showed a 60% local control rate, but a 2-year survival of only 9%. No response was noted in distant metastasis [51]. High doses of RT covering a large area volume from mastoid to the carina showed a median survival of 70 days with unacceptable toxicity [52]. Therefore, fractionated RT appears to be an effective treatment option. Radiosensitizing agents such as taxanes may be more effective chemotherapeutic agents, as discussed later.

Chemotherapy

Traditional cytotoxic chemotherapies have been highly toxic and largely ineffective at prolonging survival in this challenging group of patients, and the efficacy of a single chemotherapeutic agent in the treatment of ATC is unlikely [53]. ATC cell lines in vitro have been shown to overexpress multidrug resistance-associated protein, multiple drug resistance (mdr1) mRNA and P-glycoproteins [54,55], rendering ATC resistant to chemotherapy [47]. Doxorubicin is the most commonly used chemotherapy shown to have efficacy against ATC as a radiosensitizing agent [16,41–43], but failed to show any significant improvement compared with monotherapy in in vitro studies [46,56]. In patient studies, external-beam radiation therapy alone or in conjunction with doxorubicin radiosensitization did not show any improvement in overall survival [13].

Taxanes (paclitaxel and docetaxel) are another group of chemotherapeutic agents used in ATC; they affect microtubules, blocking cell division and damaging tumor cell DNA. In vivo data with paclitaxel (2.5 mg/kg/day for 7 days) and single dose γ-irradiation IR (5 Gy) decreased tumor volume to 0–0.3% of the controls; therefore, RT augmented the apoptotic effect of paclitaxel on tumor cells [53].

In a Phase II trial with paclitaxel, 20 patients with aggressive or metastatic disease despite previous treatment with surgery and/or radiation therapy were treated with a continuous infusion of paclitaxel (seven patients with 120 mg/m² per 96 h and the rest 140mg/m² per 96 h), resulting in a short-term 53% total response rate, (1 = complete response, 9 = partial response, 8 = progressive disease) [57]. The data suggest that although paclitaxel is a valuable therapy that has significant systemic activity clinically against ATC, its efficacy does not greatly alter the disease [57].

Docetaxel is another taxane that has a reported clinical efficacy against ATC. Docetaxel with standard external-beam radiation treatment of six patients with ATC showed that five out of six patients treated were alive at a median follow-up of 12.5 months (2–40 months) [38]. This is a promising therapy when compared with the current reported median survival time of 5–6 months without treatment. In a prospective feasibility study, docetaxel given to seven ATC patients with no prior chemotherapy exposure resulted in a complete response in one patient, stable disease in two and progressive disease in four [58]. Kurukahvecioglu et al. reported on one patient treated with a combination of surgery, docetaxel and RT without evidence of recurrence after 36 months follow-up [59].

It is reasonable to advocate that all cases initially seen with localized disease should be treated with an attempt at complete resection (if possible), total thyroidectomy and neck dissection. Surgery can also be used for palliative measures, particularly to avoid upper airway obstruction. In addition, we advocate the use of multimodal treatment (chemotherapy – taxanes in particular appear to have the most promising efficacy, or hyperfractionated RT) as adjuvant therapy for better success and outcome in this lethal disease.

Potential treatment targets & novel therapies

Receptor tyrosine kinases

Despite multimodal therapy (surgery, chemotherapy and RT), the outcome of ATC is poor; therefore, the need for targeted therapies is high. Current molecular strategies are directed at interrupting intracellular signal transduction pathways known to be altered, including mutation of BRAF, activation of the RAS–RAF–MAPK pathway, p53 mutation, increased tyrosine kinase receptor expression (EGF, VEGF and PGF receptors) [30,37,60,61], as well as apoptosis. Novel therapies targeting cell surface and intracellular signaling pathways are underway [30,35,60]. These receptors are discussed later.

EGF receptor

The EGF receptor (EGFR) is a tyrosine kinase cell surface receptor protein, highly expressed in malignant thyroid tissue [6,39]. EGFR on the cell surface binds to ligands, resulting in activation of downstream proteins, particularly PI3K, AKT, mammalian target of rapamycin (mTOR), and full activation of ERK1/2 in FRO cells [62]. Overexpression of the EGFR was reported in vivo, in vitro and in human tissue arrays of ATC cells [63], with a frequency of 19/41 (46.3%) ATC cell lines documented by Liu et al.[64], 84% in 32 ATC cases using tissue microarray documented by Wiseman et al.[21], and in 18 of 31 (58%) ATC cases [65]. Receptor genomic copy number gains were seen in these studies and receptor mutation was not present in several studies [64,65], but was reported in case reports [66,67]. EGFR expression has also been linked to advanced tumor staging, metastatic potential and overall poor clinical outcomes [39].

C-Met

C-Met, a high-affinity receptor for hepatocyte growth factor, is a proto-oncogene and is worth mentioning as it is regulated by EGFR [61]. Its reported expression in ATC is variable. Overexpression of c-Met was reported in some studies [68,69], whereas weak or absent expression was reported in others [70–72]. Activation of c-Met regulates downstream cell migration, differentiation and angiogenesis [70]. C-Met is regulated by EGFR, and upregulated by RAS and RET genes [61]. C-Met may have a potential role in future ATC treatment.

VEGF receptor

The VEGF receptor (VEGFR) is important for tumor neovascularization. VEGF was implicated in angiogenesis and metastasis after it was shown to be highly expressed in cancer versus normal thyroid cell lines, and the tumors with high VEGF content were shown to have a higher rate of cell proliferation [73]. Tumor cells are able to provide their own blood supply by increasing VEGF and PDGF. These tyrosine kinase membrane-bound receptors, when bound to VEGF, are able to exert downstream signaling and release of angiogenic factors, resulting in new blood vessel formation [61].

PDGF receptor

Platelet derived growth factor receptor (PDGFR) is overexpressed in ATC [74,75]. Ha et al. have reported unpublished data from their institution that PDGFR-β relative expression was 10–30-fold higher in an ATC microarray study than in normal thyroid cells, PTC and multinodular hyperplasia [76].

Tyrosine kinase receptor inhibitors – erlotinib, gefitinib, vandetanib, sorafenib, imatinib and monoclonal antibodies (cetuximab and bevacizumab) – have emerged recently in vivo and in vitro as potential therapies against EGFR and/or VEGF [77]. Tyrosine kinase receptor inhibitors are small-molecule agents that have shown promising results in preclinical studies and in clinical Phase II/III trials, and as US FDA-approved drugs. Most have effects on multiple tyrosine kinases or tyrosine kinase receptors, and combination therapy with chemotherapy or other monoclonal antibodies appears to be promising, as discussed later.

Tyrosine kinase inhibitors

Preclinical studies

Cetuximab, a monoclonal antibody EGFR inhibitor, has demonstrated efficacy in ATC cell lines [78,79]. Cetuximab alone or in combination with bevacizumab (monoclonal antibody against VEGF) inhibited tumor growth and angiogenesis in a murine orthotopic model of ATC [78]. The combination of cetuximab and irinotecan (a topoisomerase inhibitor) showed a superior benefit in ATC xenografts, inhibiting growth and progression of ATC [79]. Cetuximab alone also decreased VEGF action in HTh 74 and C643 ATC cell lines, showing regulation of VEGF secretion by EGF through the EGFR [77].

AEE788, a dual-kinase inhibitor of EGF and VEGF receptors, has shown the ability to reduce both kinase receptors in vitro in a dose-dependent manner in thyroid cancer cell lines [77].

The small-molecule tyrosine kinase inhibitor vandetanib, in multiple ATC cell lines, inhibited p-EGFR and p-VEGFR2, reduced microvessels and increased apoptosis. The drug also inhibited tumor growth and vascular permeability and volume in mouse xenografts of ATC tumors [80]. This drug targets both the EGFR and VEGFR2, and appears promising for potential therapy.

Erlotinib is another small-molecule anti-EGFR tyrosine kinase inhibitor that is a potential novel therapy. FRO cells showed dose-dependent inhibition of cell proliferation after exposure to erlotinib [62]. The combination of erlotinib with chemotherapy agents (doxorubicin or paclitaxel) showed erlotinib, followed by paclitaxel, had maximal synergism compared with doxorubicin [62].

Gefitinib, an EGFR tyrosine kinase inhibitor, showed a dose-dependent inhibition of EGF stimulated cell growth and inhibition of p-ERK1/2 and p-Akt in xenograft mice [81]. Gefitinib was also shown to block EGFR stimulation by EGF, inhibiting ATC cellular proliferation, and it induced apoptosis in vitro[63]. In vivo, it was also reported to have anti-tumor activity in an ATC subcutaneous nude mouse model [63].

Clinical studies

Erlotinib was shown to result in 6 months of disease stability in a 65-year-old Japanese woman with ATC metastatic to the lungs and carrying an EGFR somatic mutation, L858R [66]. Hogan et al. reported one patient with recurrent previously treated ATC. Daily oral erlotinib resulted in radiographic evidence of improvement, significant symptom improvement and control of disease in 6 weeks [67].

In a clinical trial gefitinib resulted in a 32% tumor volume reduction without any objective responses in 27 patients, of whom five had ATC [82]. Disease was stable over 12 months in one patient with ATC [82].

Sorafenib is another small-molecule tyrosine kinase inhibitor of Raf-1 protein kinase receptor, VEGFR2 and PDGFR-β that holds some promise for therapy. In a Phase II trial of oral sorafenib in 16 patients with progressive ATC, despite chemotherapy with or without radiation given at a dose of 400 mg twice daily on 28-day cycles, two out of 15 patients had partial response, and four out of 15 had stable disease [83]. Sorafenib alone and in combination with bevacizumab is undergoing a clinical trial [201].

Combretastatin (CA4P), also known as fosbretabulin, is a tubulin-binding agent that disrupts vascular flow of existing blood vessels, therefore depriving tumor cells of nutrients and oxygen [84,85]. In a Phase I trial that included a single ATC patient, treatment with CA4P showed the greatest effect in tumors with increased vascularity, with complete response of greater than 9 months. In a Phase II trial, 26 patients with ATC were treated with 45 mg/m² CA4P as a 10-min infusion on days 1, 8 and 15 of a 28-day cycle. No objective responses were seen, but overall median survival was 4.7 months; 34% were alive at 6 months and 23% alive at 12 months [85]. One patient had event-free survival of 20 months [85]. QT prolongation was reported with use of combretastatin [85,86].

Imatinib (Gleevec^®) is a protein-tyrosine kinase inhibitor that targets Bcr-Abl and c-kit/ PDGFR tyrosine kinases [87,88]. A preclinical study of imatinib showed efficacy in inhibiting growth of ATC cell lines [88]. Although the molecular target of imatinib is not clearly defined [87,88], the proposed mechanisms include inhibition of PDGF, KIT and c-ABL. A single-institution study of imatinib (400 mg twice daily orally) in 11 patients with ATC showed, among eight evaluable patients, that two had a partial response, four had stable disease and two had progressive disease. 6-month progression-free survival was 27%; 6-month survival was 46% [76]. Frequent toxicities included lymphopenia, edema, anemia and hyponatremia. Because of poor accrual related to the rarity of ATC, the trial was prematurely terminated.

Novel signaling pathway/gene targets

RAS/RAF/MAPK

The RAS family regulates the RAS–RAF–MEK–ERK and the PI3K/AKT1 pathways in thyroid cancer [1]. Ras mutations are seen in benign and malignant thyroid tumors, including ATCs, with reported frequencies ranging from 6 to 50% of cases [1,3].

Growth factors that activate genes in this pathway cause growth, differentiation and survival of the cell. Many proteins including MAPK are involved in phosphorylation, acting as an on and off switch of nearby proteins. Activation of the MAPK pathway by mutation, overexpression or amplification of its components, including mitogen-activated protein kinase kinase, Raf, and ERK1/2 led to growth, inhibition of differentiation and apoptosis [89]. Inhibition of these components has been shown to prevent growth of ATC cell lines, and thus can serve as potential therapy targets [89].

BRAF, a member of the RAF family, is an important regulator of thyroid-specific protein expression and proliferation and is the most common genetic alteration seen in PTC as well as in the progression of differentiated thyroid carcinoma to ATC [19,90]. BRAF mutations have been observed in 26% of patients with ATC [1]. Mutation of BRAF results in radioiodine resistance in thyroid cancer due to changes in the sodium–iodide symporter in these mutated cells, which limits their sensitivity to radioactive iodine [30]. There is a significant association of BRAF^V600E with recurrent and persistent disease, increased risk of lymph node metastasis and a higher staging of differentiated tumors [91]. In addition, a recent genome-wide expression profiling approach (Gene Set Enrichment Analysis [GSEA]) and in vitro and in vivo functional studies revealed that BRAF^V600E may promote thyroid cancer expression, migration and invasion through gene signaling pathways such as phospho-MEK1/2 and phospho-ERK1/2 [91].

Preclinical studies

The kinase inhibitors, AAL881 and AZD6244, have been shown to inhibit the RAF–MEK–ERK pathway in ATC [30]. Other novel therapies with the potential to affect this pathway include BRAF inhibitors (e.g., sorafenib [92], PLX4032 [35,93])and inhibitors selective for mitogen-activated protein kinase 1/2 (CI-1040, U0126) [89]. They are seen to decrease tumor growth and angiogenesis in xenograft ATC tumors in mice in the studies described earlier.

Preclinical data with PLX4720 reduced cell proliferation, migration and invasiveness, and upregulated the thyroid differentiation markers thyroid transcription factor 1 and paired box gene 8 (PAX8) [35]. In addition, adjuvant therapy with PLX4720 in combination with neck surgery was very effective in BRAF^V600E mutated mice in treating orthotopic ATC implanted tumors without distant metastasis [93].

The multikinase inhibitor, sorafenib, targets BRAF kinase in addition to its angiogenic (PDGFR and VEGF) targets [30]. Sorafenib has shown efficacy in inhibiting cell proliferation in ATC cell lines while reducing tumor growth and angiogenesis in orthotopic ATC xenografts [92]. Furthermore, sorafenib improved survival of the tested animals [92].

Aurora kinases (A, B and C) are serine/threonine kinases, with Aurora A and B being associated with the MAPK/ERK pathway and regulating mitosis, chromosome segregation and cytokinesis [94]. They are upregulated in tumor cells. The inhibition of Aurora kinases interferes with chromosome segregation and cytokinesis, resulting in G2/M accumulation and cell death [95]. Wunderlich et al. reported MLN8054, an inhibitor of the Aurora serine/threonine kinases, resulted in an increase of apoptotic cells, decreased histone H3 phosphorylation and induced cell cycle arrest in nine xenograft models and reduced tumor blood flow and growth [94]. AZD1152, another Aurora B inhibitor, alone or in combination with oncolytic virus dl922–947, showed a synergistic effect by decreasing or abolishing phosphorylation of histone H33 (ser 10), the main Aurora B substrate, inhibiting its function in a preclinical model [95].

Raf1 kinase inhibitory protein (RKIP) is a tumor suppressor protein that is important in regulation of the RAS activated pathway. It suppresses mitogen-activated protein kinase (MEK) signaling by binding to RAF1 and inhibiting interaction of RAF1 with MEK. In addition, it inhibits NF-κB and PI3K. Tumors increase their metastatic potential by downregulating this particular protein. Immunostaining of RKIP expression was analyzed in 104 thyroid cancers, of which 13 were ATC. Uniform RKIP expression was seen in normal thyroid tissues, and all cases of differentiated thyroid carcinoma and medullary carcinoma; however, RKIP expression was completely absent in all ATC [36]. Therefore, an agent targeting RKIP would be a potential target for therapy.

PI3K/AKT mammalian target of rapamycin pathway

The PI3K/AKT signaling pathway is an important regulator of cell apoptosis, proliferation and motility. Mutation of PIK3CA has been reported in 12–23% of ATC cases [1]. This mutation results in aberrant activation of cell-cycle regulatory genes and cell survival [30]. It is seen in tumor cells as a result of several genetic alterations including epigenetic silencing of PTEN (negative regulator of Pl3K/Akt pathway) and activating mutations and gene amplification of the gene coding for the catalytic subunit of PI3K in ATC [23,61]. In addition, it is activated by IL-4 and IL-10, cytokines that trigger phosphorylation of STAT6 and STAT3 following JAK1 activation [96]. The activation of this pathway leads to refractoriness of these cancer cells to death [96].

Mammalian target of rapamycin is a serine-threonine kinase involved in cell regulation, exerting its effect downstream of PIK3. Immunohistochemical stains of tumor tissues of two patients with ATC showed immunoreactivities of p-mTOR, p-Akt, p-70S6K and PLD1 [97].

Mammalian target of rapamycin consists of multiprotein complexes, mTORC1 and mTORC2. mTORC1 can be directly inhibited by rapamycin (sirolimus) and its derivatives, whereas mTORC2 is resistant to these agents [30,98]. Everolimus showed dose-dependent inhibition of ATC cell growth [98].

In vitro studies showed dual inhibition of mTORC1 and MEK by the MEK inhibitor, AZD6244, and the mTOR inhibitor, rapamycin. Combined treatment resulted in a greater cell death than MEK and mTORC1 inhibitors individually, suggesting a potential for a dual treatment role using MEK/mTORC inhibitors as targets for therapy [99].

Anaplastic lymphoma kinase

Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor subfamily of receptor tyrosine kinases, and gain of function mutations of C3592T and G3602A were reported in exon 23 of the ALK gene in 11.1% of ATC cases. However, this mutation was not found in well-differentiated thyroid cancers [29]. This mutation results in ALK tyrosine kinase activating both the PI3K/Akt pathway and RAS–RAF–MEK–ERK pathways [29]. ALK gene gain-of-function mutations have been reported to increase phosphorylation of AKT and ERK signaling pathways in ATC tumor tissues, thus promoting the aggressive nature of the disease by promoting cell focus formation, anchorage-independent growth and cell invasion [29]. This oncogene has a potential to be a therapeutic target in ATC, and ALK inhibitors are in clinical trials for other cancers.

Src-FAK

Src and focal adhesion kinase (FAK) are both overexpressed and/or activated in many types of cancer. Recently, the Src inhibitor AZD0530 (saracatinib) has entered human clinical trials. Schweppe et al. reported that FAK and Src are phosphorylated in several thyroid cancer cell lines [100], and that treatment of PTC and ATC cells with saracatinib selectively inhibited the growth and invasion of cells expressing elevated levels of phospho-FAK. This study provided the first evidence that FAK is activated in PTC and ATC, and that the FAK–Src complex represents a viable therapeutic target for a subset of patients with advanced thyroid cancer.

Cell apoptosis

Tumor cells develop the ability to overcome cell apoptosis. Defects in apoptotic pathway genes (NF-κB, p53 and Bcl-2) have been reported in ATC, increasing its metastatic potential.

NF-κB – transcription factor

Multiple studies show the role of NF-κB in thyroid cancer [101]. NF-κB l is inactive when complexed with the inhibitory protein IκB-α in the cytoplasm. A variety of extracellular signals, through the intermediacy of integral membrane receptors, can activate the enzyme IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα protein, which results in ubiquitination and dissociation of IκBα from NF-κB, and eventual degradation of IκBα by the proteosome. The activated NF-κB is then translocated into the nucleus where it binds to specific sequences of DNA and DNA/NF-κB complex. This complex then recruits other proteins such as coactivators and RNA polymerase that transcribe DNA into mRNA which, in turn, is translated into protein, resulting in changes of cell function [101,102].

Preclinical data demonstrated that dehydroxymethylepoxy quinomicin blocked NF-κB nuclear translocation, and was able to induce apoptosis in nude mice xenografted with FRO cells [103].

One pharmacologic inhibitor of NF-κB is bortezomib, a ubiquitin-proteasome inhibitor currently approved for treatment of multiple myeloma. This drug interferes with cell proliferation and death of neoplastic cells via the apoptotic pathway and it has been shown to have anti-tumor activity in preclinical studies [104,105]. Bortezomib activates intrinsic cell death by release of proapoptotic mediators, cytochrome C and SMAC/Diablo [106], and inhibits NF-κB, increasing p53, p21 and Jun expression, inducing caspase-dependent apoptosis [61]. It also interacts with family members such as TNF-related apoptosis-induced ligand (TRAIL) and activates caspases for cellular protein substrate cleavage. Investigation into its use against ATC is underway in Phase II and III clinical trials [201].

NF-κB also has a physiologic role in inflammation, immunity and cellular homeostasis, and therefore drugs targeting NF-κB need to be selective to the oncogenic apoptotic pathway without interfering with its physiologic role in immune function [101].

TRAIL

TNF-related apoptosis inducing ligand (TRAIL) is a protein involved in apoptosis of tumor by binding to death receptors (TNF receptors). The downstream effect is unclear, although nitric oxide-mediated S-nitrosylation of GAPDH leading to nuclear translocation of GAPDH might be the mechanism of its effect [30]. However, it also selectively induces tumor cell apoptosis [106]. Combination treatment of TRAIL with the proteasome inhibitor, bortezomib, in preclinical studies showed anti-tumor effect in an ATC cell line isolated from a patient with ATC [105,106].

Bcl-2 pathway – apoptotic regulator

Cvejic et al. reviewed 34 ATC cases by immunohistochemical staining of two proapoptotic genes, Bcl-2 and Bax. The average Bcl-2 staining score was significantly lower, and Bax expression was higher in ATC cells. Proliferation-related markers increased significantly, indicating a disturbance in the balance between proliferation and apoptosis in progression of ATC [107].

Statins

Statins such as lovastatin are 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, and have been of research interest in anticancer therapy as they have shown some cytotoxic effect in ATC via apoptosis. However, combination treatment with paclitaxel and the HMG reductase inhibitor lovastatin in ATC cell lines did not enhance the treatment in ATC, but rather was antagonistic [108]. The statins’ cytotoxic effect is thought to be through inhibition of Rho geranylgeranylation and RhoA/Rock signaling [109].

Transcription factors

P53

Decreased activity of this tumor suppressor gene (whose function is to increase the cyclin kinase inhibitor, p21) on chromosome 17p is present in 55% of ATCs [1], which leads to cell cycle arrest at G1/S, thus inhibiting suppression of gene synthesis. Loss in function of p53 plays a role in transformation of well-differentiated thyroid cancer to ATC [110]. Re-expression of p53 in some studies resulted in inhibition of cellular proliferation and restoration of responsiveness to thyroid-stimulating hormone [111] and re-expression of thyroid peroxidase [112]. In addition, an increase in chemosensitivity was noted in ATC cell lines that re-express p53 [113]. The level of p53 is regulated through ubiquitination-mediated degradation [114]. Thus, proteasome inhibitors that selectively induce p53 can lead to selective apoptosis of tumor cells. Bortezomib, currently approved for multiple myeloma therapy, appears to have a promising role in its effect in p53 regulation [114,115].

Peroxisome proliferator activated receptor γ

Peroxisome proliferator activated receptor (PPAR)γ is a member of the PPAR nuclear receptor family that regulates adipocyte differentiation. Activation of PPARγ protein results in antineoplastic and anti-inflammatory effects [30]. PPAR agonists (thiazolidinediones) are well-known therapy options for diabetes and reducing insulin resistance. PPARγ also has oncocytic effects. Its expression was higher in ATC than differentiated thyroid carcinoma [116], and in combination with paclitaxel it was effective in apoptotic synergy [117].

In a Phase I multicenter study, CS-7017, a drug that inhibits ATC proliferation via activation of PPARγ, when used in combination with paclitaxel, showed a partial response lasting 175 days in one out of 15 patients, and eight out of 15 patients had stable disease. Median time to progression of seven out of 15 patients at the higher dose of CS-7017 (0.3 mg twice a day) was 140 days [118].

Epigenetic alterations

Epigenetics refers to variations in gene expression not involving changes in the base sequence of DNA. DNA methylation and histone modification have crucial roles in the control of gene activity and nuclear architecture. Histone modification results from changes in chromatin configuration resulting from a variety of post-translational modifications, such as acetylation of lysine, methylation of lysines and arginines, phosphorylation of serines and threonines, as well as ADP ribosylation [119]. One of the mechanisms by which cells can block the expression of certain genes is by enzymes that methylate these genes or deacetylate the histones that envelop a particular gene. Medications that can inhibit methylation and reverse histone deacetylation may lead to the re-expression of genes that are silenced in cancer.

DNA methylation

Human cancer cells undergo loss of DNA methylation, but also acquire specific patterns of hypermethylation of certain promoters to inactivate tumor suppressor genes resulting in loss of function in cancer cells. On the other hand, hypomethylation of tumor cell DNA (compared with normal cells) allows nuclear transcription in tumor cells. The degree of hypomethylation increases as a tumor progresses from the benign to invasive stages.

Histone acetylation

Histone deacetylase (HDAC) inhibitors such as valproic acid have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The exact mechanisms by which the compounds may work are unclear, but they have been used as adjunct treatment. In cultured ATC KAT-18 cell lines, valproic acid in combination with doxorubicin or a proteasome inhibitor (lactacystin) was effective in facilitating cell death or apoptosis of ATC cells [120].

Panobinostat (LBH589) is a deacetylase inhibitor with an antitumor effect against ATC. In a study of three ATC cell lines (BHT-101, CAL-62 and 8305C), it increased expression of p21 and decreased cyclin D, resulting in tumor proliferation inhibition, cell cycle arrest and apoptosis activation. The result was a 2.5-fold reduction in tumor size [119].

Rap1 GAP is a member of the Ras superfamily of small GTPases that act as tumor suppressors. Rap1 GAP is downregulated in ATC, resulting in tumor progression and metastasis. Agents that increase Rap1 GAP expression (sodium butyrate, trichostatin A and 5-aza-deoxycytidine) were shown to restore its function in one ATC cell line, and the demethylating agent 5-aza-deoxycytidine enhanced the effects of HDAC inhibitors in a second anaplastic cell line [33]. Marlow et al. also demonstrated that the HDAC inhibitor, romidepsin, inhibited cell proliferation in ATC cell lines and upregulated RhoB. RhoB protein has anti-tumor activity against ATC [121,122].

MicroRNAs (miRs) are small noncoding RNAs that act as either tumor suppressors or oncogenes at the post-transcriptional level of protein formation [3]. Several microRNAs have been reported to be increased or decreased in ATC [1,123,124]. These changes in microRNAs affect the expression of genes such as HMGA1, hTERT, RB and PTEN[3], resulting in molecular derangements that lead to thyroid carcinoma development. In particular, two miRNAs, miR200 and 30, were identified to be downregulated in ATC as compared with PTC and FTC, while TGF-β receptor 1 (TGFBR1) was upregulated in ATC [32]. miR200 is thought to play a role in epithelial to mesenchymal transition and be regulated by TGFBR1; therefore, transdifferentiation and invasion of ATC is mediated, at least in part, through TGFBR1 downregulation of miR200 and 30 [32]. Inhibiting overexpression of miRNAs, as well as restoration of downregulation seen in ATC, can be potential targets for future therapy [123]. In addition, inhibition of TGFBR1 could be a potential treatment strategy for ATC [32]. miR-1 is a tumor suppressor recently reported to be downregulated in thyroid cancer (PTC, FTC and ATC), benign thyroid disease (follicular adenoma) and hyperproliferative benign states, such as goiter, compared with normal thyroid cells [125]. miR-1 is able to downregulate multiple genes including the CCND2 gene coding for cyclin D2, CXCR4 chemokine and SDF-1/CXCL12 promoting cell proliferation, invasion and migration [125]. Restoring miR-1 expression in FRO cells inhibited growth, invasion, migration and motility of these cancer cells. Therefore, agents that can upregulate miR-1 may be potential therapeutics.

Stem cell therapy/epithelial–mesenchymal transition in ATC

Epithelial–mesenchymal transition (EMT) is thought to play a role in dedifferentiation of cancer cells to ATC [126,127]. EMT is a biological process that allows epithelial cells to assume a mesenchymal cell phenotype that includes enhanced migratory capacity and invasiveness, and it plays a role in cancer progression [126]. Mesenchymal cells can migrate away from the original cell across the endothelium to target tissues at sites of injury or ischemia and in tumor microenvironments [127]. E-cadherin and nestin are well-known EMT-associated markers. E-cadherin is required for cell-to-cell adhesion, which is lost in ATC, and nestin is an intermediate filament protein useful as a stem cell and neovascularization marker [126]. Immunohistochemical staining of archived thyroid tissues from two patients with ATC and contiguous well-differentiated thyroid cancer (PTC and FTC) showed absent E-cadherin and strong nestin expression in ATC, whereas nestin was absent and E-cadherin was present in PTC and FTC [126]. One reason for chemoresistance in ATC may be that doxorubicin promotes survival of cancer stem cells and upregulates multidrug resistance genes [56].

Several strategies involving cancer stem cells could potentially be exploited for therapy in ATC. First, the Notch and Hedgehog pathways are being explored as an approach to targeting cancer stem cells, and there are several inhibitors in clinical development [128,129]. Second, there is interest in using genetically modified mesenchymal stem cells as a vector for transporting effective therapy to isolated tumors and metastatic disease, given their innate migratory properties [127].

Clinical trials

Understanding the target genes and proteins involved in pathogenesis of ATC has led to the development of Phase II/III clinical trials of novel anticancer drugs. At the time of manuscript submission, the following trials for ATC were listed on www.clinicaltrials.gov [201]: in the USA, active and recruiting trials included sorafenib and crolibulin + cisplatin; active, not recruiting trials included gefitinib, pazopanib, combretastatin + paclitaxel, CS-7017 + paclitaxel; and suspended trials included IMRT + paclitaxel (+/- pazopanib). Other trials included everolimus (The Netherlands and Korea), bevacizumab + doxorubicin (Sweden) and pemetrexed + paclitaxel (Germany).

Expert commentary

Anaplastic thyroid carcinoma is one of the most aggressive cancers characterized by almost complete refractoriness to multimodal treatments. Over the last decade, advances have been made in identifying target oncogenes, proteins, miRNAs and signaling pathways that play a role in the development of ATC. The discovery of these targets, mostly through retrospective studies, has led to a better understanding of ATC that involves chromosomal alterations at multiple genetic levels. In the last 5 years, we have begun to see clinical trials; however, there is no effective therapy to date and the life expectancy of this disease remains the same for stage IVC disease.

Proposed treatment algorithm

Surgery (when feasible), in particular an R0 or R1 resection, results in a better outcome than R2, and should incorporate hyperfractionated RT and chemotherapy (taxanes and cisplatin) for stage IVA and some IVB disease (operable cases).

Patients with inoperable cases and IVC disease who desire aggressive therapy should be treated with RT and cytotoxic chemotherapy (taxane, doxorubicin or cisplatin) and consideration of a combination with one of the novel drug therapies under clinical trial, such as pazopanib, combretastatin or an EGFR inhibitor. Other potential targets based on preclinical results could include the Aurora kinases, polo-like kinase 1 or ALK, but there are currently no human studies to suggest one approach over another. The role of novel therapies in ATC confined to the neck (stages IVA and B) should be considered as part of multimodal therapy, since the outcome of all stage IV disease is dismal. The sequence of treatment remains unknown. In a patient with airway compromise and stage IVA and B disease, surgery should be offered for cure or tumor debulking. The use of only a single mode of therapy (either surgery, RT, chemotherapy or novel targeted agents) should not be undertaken as it will not be effective in this rapidly dividing and growing cancer.

Five-year view

There is no effective therapy for ATC at this time, and the median survival of patients with ATC has not changed over the last several decades. The unraveling of the molecular pathways has played a pivotal role in the development of targeted therapies for thyroid cancer. Tyrosine receptor kinase inhibitors and antiangiogenic agents such as bevacizumab, sorafanib and others, in combination with other treatment modalities such as surgery, radiation and/or chemotherapy, will hopefully be more effective. Alternative approaches, including immunotherapy and gene therapy, should be explored. Currently, several new drugs are under clinical trials. Surgery (when feasible), chemotherapy with doxorubicin and/or a taxane, along with hyperfractionated radiation therapy, will probably remain as a first-line treatment option. A more comprehensive genomic analysis of patients’ individual tumors, followed by rapid bioinformatic analysis and identification of critical pathway targets, is most likely to effectively identify optimal drug combinations to inhibit such an aggressive tumor as ATC. The optimal sequence of treatments remains unknown, but for a disease which almost always becomes systemic, an aggressive multimodal approach offers the most promise. Multicenter international clinical trials would expedite identifying effective treatments for this rare cancer.

Table 1. The prevalence of genetic or molecular aberrations in anaplastic thyroid cancer and downstream effect.

Genetic/molecular aberration	Incidence (%)	Mechanism	Results
RAS	6–50	RAS mutation	FTC to ATC de-differentiation
PIK3CA	12–23	Copy gain	Activation of PI3K/Akt pathway resulting in tumor cell growth and survival
P53	40–70	Mutation	Tumor suppression inactivated, ↑ aggressiveness
β-catenin	60	Mutation, abnormal nuclear localization	↑ Invasiveness, metastatic potential
BRAF	26	Mutation, transversion T1799A leading to a Glu substitution for Val at codon 600 {V600E}	Cell proliferation, disease aggressiveness
PTEN	12	Mutation	Lack of inhibition of PI3K/Akt pathway
Axin	82	Mutation	↓ Tumor suppression

ATC: Anaplastic thyroid cancer; FTC: Follicular thyroid carcinoma.

Table 2. Genes/proteins that have been further studied or newly identified in anaplastic thyroid cancer since prior reviews.

Genes/proteins	Expression pattern	Activity in ATC	Ref.
Transcription
PAX8	Absent^†	Lack of differentiation	[4]
TTF1	Absent	Lack of differentiation	[4]
TTF2 (FOXE)	Absent	Lack of differentiation	[4]
Twist 1	Upregulated	Chemotherapy resistance	[26]
Enhancer of Zeste Homolog 2 (EZH2)	Overexpressed	Results in transcriptional silencing of PAX8 gene and ATC differentiation	[27]
Signaling pathway
mTOR kinase	Increased	Cell growth, ↑ PI3K/AKT	[97]
ALK gene	Increased	Gain of tumor aggressiveness function, ↑ PI3K/AKT activation	[29]
Mitosis
Ki-67	Increased	Cell proliferation	[97]
Skp2	Increased	Cell cycle regulator	[97]
Cyclin D1	Increased	Cell cycle regulator	[97]
P27	Decreased	Cell cycle regulator	[97]
PLK1	Increased	G2/M transition, cell proliferation, survival, anchorage	[31]
Proliferation
De-/trans-differentiation/invasiveness
miR-200	Decreased	Increased invasiveness	[32]
miR-30	Decreased	Increased invasiveness	[32]
TGFBR1	Increased	Increased invasiveness	[32]
miR-1	Downregulated	Increase proliferation, cell invasion, metastasis, lack of tumor suppression	[125]
Apoptosis
Rap1GAP	Downregulated	Tumor progression, metastasis	[33]
TP53, MIB-1, Topoisomerase II	Upregulated	Upregulated in transformation from DTC to ATC	[34]
Thyroglobulin, E-cadherin	Downregulated	Downregulated in transformation from DTC to ATC	[34]
Migration/metastasis
BRAF^V600E	Mutation	Gene mutation; cell migration, metastasis	[35]
IQGIP1	Copy gain	Upregulate E-cadherin, increase invasiveness	[28]
RKIP	Reduced	Increased RAS activation	[36]

^†Recently, Nonaka et al. reported a 79% expression of PAX8, 18% expression of TTF1 and 9% expression of TTF2 using immunohistochemistry [37].

AKT: Protein kinase B; ATC: Anaplastic thyroid cancer; DTC: Differentiated thyroid carcinoma.

Table 3. Multimodality treatment of anaplastic thyroid cancer: review of retrospective studies.

Author	Patients (n)	Stages	Treatment modalities	Results	Ref.
Siironen et al.^†	44		S + Ch + RT	Patients who underwent radical neck surgery had median survival of 11.6 months, compared with those with palliative surgery, for whom median survival was 3.2 months (p = 0.012). The best median survival of 11.6 months (p = 0.001) was seen in patients treated with surgery followed by Ch and RT.	[16]
Foote et al.^‡	10	IVA + B	IMRT + S + Ch	Treatment with IMRT, surgery and Ch resulted in a 1-year, 2-year and >2.5-year disease-free survival of 70, 60 and 50%, respectively	[40]
Swaak-Kragten et al.^§	75	IVA, B, C	S + Ch + HRT	The best result was in those who underwent R0/R1 resection and chemoradiation (complete remission 89%). Doxorubicin and radiation treatment resulted in a median survival of 3 months	[41]
Haigh et al.	33	IVA, B, C	S + Ch + HRT	Potentially curative resection resulted in median survival of 43 months. The median survival was 3 months with palliative surgery. Only Ch and radiation and palliative surgery had similar survival times of 3.3 months (p = 0.63)	[42]
Pudney et al.^¶	5	IVB	RT + Ch^††	Treatment with RT and Ch resulted in a median survival of 13 months	[43]
Higashiyama^#	9	IVB, C	Ch ± S	The total 1-year median survival was 44% in IVB-treated groups vs 5.9% in controls. No improvement in overall survival in stage IVC was seen	[44]
Ito et al.^††	40	IVA, IVB, IVC IVB-a, b	S + Ch + RT	Best median survival was seen in surgery followed by Ch and RT of 13.7 months in IVA, 6 months in IVB group and 4.2 months in the IVC group. IVB-a median survival was 9.6 months and IVB-b median survival was 4.0 months	[45]

^†Surgery classified as radical vs palliative. Ch = either doxorubicin or paclitaxel.

^‡IMRT.

^§HRT, Ch = doxorubicin.

^¶Doxorubicin or docetaxel/doxorubicin + cyclophosphamide.

^#Ch = induction paclitaxel in comparison with control groups. 1-year survival was 44% in the IVB-treated group versus 5.9% in control. No improvement in overall survival in stage IVC.

^††See text.

Ch: Chemotherapy; HRT: Hyperfractionated radiation therapy; IMRT: Individualized intensity modulated radiation therapy; RT: Radiation therapy; S: Surgery.

Key issues

• • Anaplastic thyroid cancer remains a very aggressive malignancy with very few effective treatments.

• • Multimodal therapy with surgery, radiation therapy and chemotherapy offers the best result for therapy at this time.

• • Owing to its rarity and rapidly fatal outcome, it has been difficult to conduct clinical trials to evaluate anaplastic thyroid cancer therapies.

• • Advancement in the studies of genetics, molecular targeting and signaling pathway derangements occurring in this disease will likely open the door for novel molecular-targeted therapies.

• • The need for targeted therapies is high, and multicenter clinical trials incorporating multimodal with novel therapeutic targets, perhaps including stem cells, might provide more information on this devastating disease.

Acknowledgements

The authors wish to thank Ms Kathleen Norton for assistance with manuscript preparation.

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Managing anaplastic thyroid carcinoma

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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1. Your patient is a 65-year-old man with anaplastic thyroid cancer (ATC) who presents with hoarseness and a rapidly enlarging neck mass, 6 cm in diameter, when first evaluated. On the basis of the review by authors Abate and Smallridge, which of the following statements about his clinical course and prognosis is most likely correct?

• □ A He is likely to respond well to a single form of therapy

• □ B Median survival is 2–3 years

• □ C About 10% of patients with ATC have evidence of lymph node involvement at the time of presentation

• □ D Risk factors for a worse outcome include older age, acute symptoms, extracapsular extension, distant metastasis, and tumor size >7 cm

2. The patient described above has stage IVA disease and is scheduled for surgery. On the basis of the above review by Drs. Abate and Smallridge, which of the following statements about treatment options is most likely correct?

• □ A Surgery alone offers the best prognosis

• □ B Chemotherapy is not indicated

• □ C R0 surgery is preferred to palliative surgery

• □ D Many clinical trials have proven which regimen and sequence of treatment is optimal in ATC

3. On the basis of the review by Drs. Abate and Smallridge, which of the following statements about aggressive management of patients with ATC who are not operative candidates is most likely correct?

• □ A Human studies have proven that targeting the Aurora kinases is effective

• □ B Pazopanib, combretastatin, or an EGFR inhibitor should be considered

• □ C Radiotherapy alone is recommended

• □ D Doxorubicin is contraindicated