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Anaplastic thyroid cancer

Ranganath, Rohita,b; Shah, Manish A.a; Shah, Ashok R.a

Current Opinion in Endocrinology, Diabetes and Obesity: October 2015 - Volume 22 - Issue 5 - p 387–391
doi: 10.1097/MED.0000000000000189
THYROID: Edited by Angela M. Leung and Lewis E. Braverman
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Purpose of review Anaplastic thyroid cancer (ATC) is a rare malignancy of the thyroid with a high mortality rate. Conventional therapy has not been effective. Several biological agents are being investigated. The purpose of the review is to highlight the current standards for treatment and review new targets for treating ATC.

Recent findings Retrospective studies have led to formulation of guidelines for management, including those by the American Thyroid Association. An expansion in the understanding of the genetic mutations has led to several newer biological agents being tested to treat ATC. Aurora kinase inhibitors, PPAR γ agonists, and vascular targeting agents are some of the latest therapeutic agents that have shown promise and could become standard of therapy with further supporting research.

Summary Further well coordinated preclinical and clinical research is needed to support the emerging treatments for ATC.

aMemorial Sloan Kettering Cancer Center, New York

bMercy Catholic Medical Center, Philadelphia, USA

Correspondence to Ashok R. Shaha, MD, FACS, Head and Neck Surgery, Memorial Sloan Kettering Cancer Center 1275 York Ave, New York, NY 10065. Tel: +1 212 639 7649; fax: +1 212 717 3302; e-mail: shahaa@mskcc.org

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INTRODUCTION

Anaplastic thyroid cancer (ATC) is a rare form of undifferentiated cancer and accounts for 1.7% of all thyroid cancers. However, the mortality attributed to this cancer is 33–50%, which is disproportionately high. The median survival is 5 months, with less than 20% surviving at 1 year [1,2]. Recognizing this fact, the American Joint Committee on Cancer has designated all ATC as Stage IV on diagnosis, with Stage IVA being intrathyroid tumors, Stage IVB denoting primary tumor with gross extra thyroidal extension, and Stage IVC signifying the presence of distant metastasis.

Box 1

Box 1

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CLINICAL COURSE OF THE DISEASE

ATC has a sudden onset and rapid progression, with only 10% of patients presenting with the tumor confined to the thyroid. Forty percent of patients have extra thyroidal extension and lymph node metastasis, and the remainder present with distant metastasis. The common metastatic sites are lung (25%), mediastinum (25%), liver (10%), bone (6%), kidney/adrenals (5%), heart (5%), and brain 3%. Mortality is due to the effects of distant metastases, including the frequent presentation of airway compromise. This requires a complete airway and fiberoptic laryngoscopy and vocal cord assessment, as patients frequently have recurrent laryngeal nerve palsy. In patients with symptoms suggestive of tracheal and esophageal involvement, panendoscopy and bronchoscopy are warranted. A complete blood count is recommended to assess hemoglobin and for the presence of leukocytosis, which suggests a proinflammatory state. Serum calcium and electrolyte concentrations, liver function tests, and renal function are also indicated. As thyrotoxicosis may be associated with ATC, serum thyroid function tests should be assessed. Finally, asssessment of nutritional status is important, as patients may require enteral or parenteral nutrition.

Usually, ATC presents with a rapidly growing thyroid mass over a period of weeks, thus making a timely and definitive diagnosis with fine needle aspiration and core biopsy extremely critical. Appropriate immunohistochemistry should be undertaken to confirm the diagnosis. Lymphoma, which is readily treatable with good results, should be ruled out. Appropriate imaging of the neck by computed tomography (CT) scan and/or MRI with contrast enhancement will delineate the extent of locoregional disease. The presence of distant metastasis is best evaluated with modalities such as CT chest or PET-CT [3]. In spite of distant disease, consideration should be given to treat locoregional disease for best control in the central compartment.

This review aims to highlight the current standards of therapy and recent research regarding ATC.

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THE CURRENT STANDARDS OF MULTIMODAL THERAPY

Complete surgical/R0 resection, rather than debulking, is the single intervention that improves survival in appropriate cases [4]. However, as alluded to earlier, the clinical presentation of ATC limits surgical treatment in the majority of patients with ATC. The aim of surgical therapy is control of the central compartment, and, thus, the guidelines recommend that surgery should be considered, even in the presence of distant disease, if it improves palliation [3].

Postoperative radiation therapy is shown to reduce morbidity and mortality due to locoregional complications and improve survival when a dose of greater than 45 Gy is delivered [5]. Intensity-Modulated Radiation Therapy has shown better results with reduced toxicity [6]. Chemoradiation has been shown to be superior to radiation alone [7,8]. The recommended chemotherapeutic agents are doxorubicine alone or a combination of drugs in patients with good performance status who desire aggressive therapy. The commonly used combinations are taxanes (paclitaxel or docetaxel) and/or anthracylicine (doxorubicin) and/or platins (cisplatin or carboplatin), in combination with radiotherapy.

A recent retrospective review of 95 patients at a tertiary cancer center highlights the prognostic factors and outcomes associated with ATC [8]. More than 65% of the patients were over the age of 65 years, with 50% of patients having concurrent or previous history of differentiated thyroid cancer. The data suggest that patients with aggressive histology are at a greater risk of ATC. Seventy one percent of patients were treated with surgery and radiotherapy with or without chemotherapy, and 12% received surgery alone. The 1-year disease-specific survival was 33%. Multivariate analyses showed that the absence of gross extrathyroidal extension (ETE), gross total resection (R0/R1), and multimodality therapy were the only significant predictors of improved outcome. The presence of acute symptoms, tumor size more than 5 cm, distant metastasis, and WBC more than 10 000 per microliter were indicators for worse survival in a multimodal analysis. The authors proposed that this index would help in patient selection for multimodal therapy [9]. In another study of 100 patients with ATC, multivariate analyses showed that older age, an elevated WBC, ETE, distant metastasis at presentation, incomplete resection, and radiation therapy in a dose of less than 40 Gy were risk factors for decreased survival [4]. However, in contrast to above mentioned reports, the presence of distant metastasis was not a statistically significant predictor of outcome.

Indicators of improved survival are younger age at presentation, completeness of resection, and high-dose radiotherapy. The literature [8,10–12] has led to the recommendation that multimodal therapy achieves the best survival outcome.

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ROLE OF TRACHEOSTOMY

Elective tracheostomy is often the first step in the management of ATC at many centers. However, the American Thyroid Association (ATA) recommends against elective tracheostomy, with the procedure performed by only an experienced surgeon if required. The patient without a tracheostomy should be closely monitored throughout radiation therapy. Tracheostomy is used only when a patient is experiencing severe airway issues. It should be noted that the tumor may grow through the tracheostomy wound or around the tracheostomy, thus, leading to further airway issues.

The management of ATC, especially rapidly growing tumors, raises several ethical issues regarding its management and the role of hospice care. Hence, the ATA guidelines have specifically included ethical issues in their discussion of ATC as not every patient is a suitable candidate for aggressive multimodality therapy.

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TUMOR BIOLOGY AND TARGETED THERAPY

In order to improve the potential outcomes of ATC, an understanding of the tumor biology and identification of new targets is warranted. Thyroid cancer is classified based on the cell of origin into follicular/epithelial and medullary, which are those arising from C-cells that produce calcitonin [13]. In decreasing order of frequency, the epithelial cancers include papillary, follicular, Hurthle, and anaplastic thyroid cancers [14]. On the basis of the degree of differentiation, they are also divided into well differentiated thyroid cancers (WDTC), poorly-differentiated thyroid cancers (PDTC), and undifferentiated or ATC. ATC has no features to suggest thyroid differentiation, but has multinucleated cells with large nuclei and atypical mitotic figures. A recent study suggested that ATCs with a hobnail pattern on pathology indicate increased aggressiveness [15], and cells of monocyte/histiocytic lineage and T-cell progenitors are frequently seen, suggesting a background of inflammation, which is protumorigenic. Driving these progenitors to maturity is being investigated as a therapeutic approach [16].

The tumorigenesis of ATC is a matter of ongoing study and has various potential hypotheses. It is thought to arise de novo as giant and spindle-cell tumor or from WDTC to PDTC and subsequently to ATC, which represents postmalignant dedifferentiation [17,18]. It is also more frequently seen to arise in individuals with a longstanding goiter [19]. Deregulation of microRNA is now increasingly being proposed as an important step in maintaining oncogenesis, supporting the theory of ATC arising from PTC [20,21]. The epithelial–mesenchymal transformation is thought to be responsible for deregulated growth and the metastatic potential of the tumor. As the anaplastic component of the tumor increases, so does the tumor aggressiveness and its propensity for distant metastasis [22].

In recent years, various mutations have been recognized as potential targets for diagnosis and therapy. The well studied mutations found in ATC are TP53 (50–80%), CTNNB1 (5–60%), BRAF (20–40%), RAS (20–40%), PIK3CA (10–20%), PTEN (5–15%), and AKT1(5–10%) [23]. The BRAF oncogene, as a part of the RAS–RAF–MEK–ERK pathway, is an attractive target. A specific BRAF mutation, BRAFV600E, is known to cause constitutive activation of the MAPK pathway. The consequences are increased tumor growth and aggressiveness and reduced Sodium–Iodide symporter gene expression [24], which correlates with radioiodine resistance. This mutation, therefore, represents a potential target [25], and reintroduction of the NIS gene has been proposed as a part of gene therapy.

The PIK3CA mutations activate the PI3K/Akt/mammalian Target of Rapamycin (mTOR) pathway that leads to increased growth. The AKT1 mutation is prosurvival, leads to resistance toward conventional adjuvant therapy, and is another target under active investigation [26].

RET/PTC is a chimeric oncogene. It lies between RET and the promoter, which results in constitutive activation of the RET gene. Thirteen different RET/PTC rearrangements have been reported [27]. RAS is the next downstream effector in the pathway. All of these mutations cause chromosomal instability, which likely results in dedifferentiation [28].

TP53 is a well known tumor suppressor gene, a loss mutation causes increased proliferation, dedifferentiation, and angiogenesis. This is a key mutation in ATC, but unfortunately, there has been no effective clinical strategy to address this mutation at present.

CTNNB1 encodes β-catenin, which is a key downstream component of the Wnt pathway. The mutation causes activation of β-catenin via Wnt signaling and causes progression of the tumor. The antitumor effects of NSAIDs are through suppression of the aberrant Wnt pathways, which induces degradation of β-catenin. Other small molecules, such as lithium chloride and Wnt-blocking antibodies, have been tried to modulate Wnt function [29].

Methylation of PTEN causes loss of function and leads to progression of an adenoma to ATC. The mutation is thought to cause further genetic changes in the downstream PI3K/Akt/mTOR pathways, leading to increased proliferation [26]. There have been no effective drugs to restore the loss of PTEN function.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor subfamily. Two new point mutations, exclusively found in ATC, but not in WDTC, are C3592T and G3602A in exon 23 of the ALK gene with a prevalence of 11%. The ALK gene mutation leads to dual activation of the PI3K/Akt and MAPK pathways [30]. This mutation causes multilayer and anchorage independent tumor growth. ALK inhibitors represent a new option for therapy [30].

PPAR γ has growth regulatory properties, as it induces terminal-cell differentiation, cell-cycle arrest, apoptosis induction, and inhibition of angiogenesis. However, rearrangement of PPAR γ and the PAX8 gene results in a fusion protein. This fusion protein is antagonistic to PPAR γ, encourages accelerated growth, and functions as an oncogene. PAX8 is being recognized as a marker for ATC, as it is more consistently expressed than thyroglobulin and thyroid transcription factor 1. Interestingly, patients who express PAX8 were found to have better overall survival (OS). Hence, PAX8 is not only a diagnostic marker, but could also serve as a marker for prognosis. Another marker, β-HCG, was seen in a minority of ATC patients (17%) and was coexpressed with PAX8 in two of the five cases in the same study. It has been hypothesized that these tumors could indicate treatment responsiveness [31]. PPAR γ agonists have been tried to suppress tumor growth with promising results seen in vitro[32]. A phase 1 clinical trial using efatutazone, an oral PPAR γ agonist, in combination with paclitaxel, was shown to have some biological activity against ATC [33].

Proteosome inhibitors, such as bortezomib, have been shown to aid apoptosis and decrease tumor proliferation in preclinical studies [34].

Chrysin, a naturally occurring compound, has shown good activity against xenografts. It acts through activation of Notch1 signaling and redifferentiation [35].

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RECENT CLINICAL TRIALS

The therapeutic role of combrestatin-A4P (fosbretabulin), a tubulin binding protein that acts as a vascular disrupting agent targeting tumor neovascularity, was studied in one of the largest prospective, randomized, multi-institutional clinical trials. The primary objective was OS. The secondary objectives were patient safety, 1-year survival, and progression-free survival (PFS). Fosbretabulin administered in combination with paclitaxel and carboplatin was the study arm, whereas patients in the control arm did not receive fosbretabulin. Patients in the fosbretabulin arm had a median survival of 5.2 months, compared with 4 months in the control arm, and a 1-year survival of 25.9%, versus 8% in the control arm; however, the median PFS was similar. However, none of the results achieved statistical significance and the patients in both arms did not achieve complete response. The safety profile of the drug was acceptable. In spite of not achieving the primary objective of OS due to low accrual, this trial is significant because of the study design and is a good precedent for future studies [36]. Crobulin, a microtubulin inhibitor similar to CA4P, along with cisplatin is currently being evaluated (clinicaltrials.gov identifier NCT01240590).

Sorafenib is a tyrosine kinase inhibitor and blocks vascular endothelial growth factor receptor 2 and platelet derived growth factor receptor beta and inhibits protein kinases as BRAF, RET, VEGFR, c-KIT and PDGFRA. A phase II trial of sorafenib in patients with advanced ATC attempted to assess the response rate and consisted of only a single treatment arm. The median survival was 3.9 months. Sorafenib seems to act on the papillary component in the ATC, and is, therefore, not very effective in ATC [37]. A phase 2 trial evaluating a combination of sorafenib and everolimus, which targets mTOR, a kinase, and MLN0128, another agent targeting the same pathway, is currently underway (clinicaltrials.gov identifier NCT01141309 and NCT02244463).

A trial evaluating the role of imantinib (clinicaltrials.gov identifier NCT00115739) had shown some interesting results but was terminated due to slow accrual. Another study, which is underway utilizes pazopanib as a synergizer for paclitaxel therapy when administered in conjunction with intensity modulated radiotherapy (clinicaltrials.gov identifier NCT01236547). A summary of the important trials regarding ATC is outlined in Table 1[36–38].

Table 1

Table 1

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CONCLUSION

Complete surgical control of the central compartment, combined with adjuvant therapy, is still the cornerstone in the management of ATC. However, the majority of patients present with locally advanced or inoperable disease. Newer biological agents are the hope in those with inoperable disease and recurrence. As several studies have been terminated due to slow accrual, there is the need for wider global collaboration and coordination of high volume cancer centers when conducting clinical trials. The efficient sharing of preclinical data is another area that requires consideration, so as to accelerate drug development of agents that have shown early promise. The ethical issues associated with tracheostomy and best supportive care in patients with ATC will likely persist.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

anaplastic; anaplastic thyroid cancer; cancer; novel therapies; thyroid

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