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New Directions in the Systemic Treatment of Metastatic Thyroid Cancer

New Directions in the Systemic Treatment of Metastatic Thyroid Cancer

ABSTRACT: Medical oncologists have traditionally had little to offer patients with metastatic radioactive iodine–resistant thyroid cancer. The 3-year survival rate of patients with differentiated thyroid cancer is less than 50%, with little response obtained from standard cytotoxic chemotherapies. In recent years, however, huge advances have been made in understanding the molecular pathways and cellular pathogenesis of this disease. This knowledge has in turn led to the development of a range of targeted therapies, some specific to thyroid cancer genetic alterations such as the RET/PTC translocation, and others that exploit general malignant properties such as angiogenesis. This review highlights novel targeted agents for the treatment of differentiated and medullary thyroid cancers being studied at this time, and the results of recently published trials. We propose that such patients should be managed, whenever possible, within a clinical trial, in order to access the most promising new drugs for thyroid cancer. In cases where trials are unavailable, we recommend off-label use of the currently available oral multikinase inhibitors such as sorafenib and sunitinib rather than traditional chemotherapies.

About 30,000 new cases of thyroid cancer are diagnosed annually in the United States.[1] The incidence among men has risen more dramatically than any other malignancy in recent years (2.4% annual increase).[2] Thyroid cancers arise from one of two cell types, namely follicular and parafollicular cells.

Differentiated and undifferentiated tumors originate in follicular cells. Fortunately, the majority of patients present with differentiated carcinoma, which includes papillary, follicular, and Hrthle cell variants. The poorly differentiated or undifferentiated category includes anaplastic thyroid cancer, an aggressive tumor that is largely chemotherapy resistant. Medullary thyroid cancer arises from parafollicular or C cells and may be familial or sporadic.

Most patients with differentiated thyroid cancer are managed successfully with a combination of surgery, radioactive iodine (RAI), and long-term thyroid hormone–suppression therapy. This has led to a 20-year overall survival rate of almost 90% for thyroid cancers.[3] The prognosis is grim, however, for patients with poorly differentiated thyroid cancers, which have less RAI avidity (and therefore less sensitivity), and for those with anaplastic/undifferentiated tumors, which are refractory to RAI. Locoregional control of relapsed thyroid cancer is best managed by a multidisciplinary team and can include therapies such as surgery, endobronchial laser ablations, and external-beam radiation with or without chemotherapy.

Over time, 25% to 50% of metastatic differentiated thyroid cancers can lose functional iodine-concentrating ability and become insensitive to treatment with RAI.[4] Less than 50% of this subgroup of patients is alive at 3 years.[5-7] These same patients have historically obtained little benefit from cytotoxic chemotherapy,[8] augmenting the need for novel therapies.

This review will focus on systemic treatments for patients with radioactive iodine–resistant thyroid cancer that has metastasized distantly.

Radioactive Iodine

Both normal and malignant differentiated thyroid cells possess a unique sodium iodide symporter which allows concentration of beta-emitting radiolabeled iodine. The symporter is found at lower levels within malignant thyroid tissue[9] and therefore iodine depletion and thyroid-stimulating hormone (TSH) elevation are used to achieve sufficient uptake of iodine to ensure effective therapy.

Radioactive iodine (RAI) has no activity in undifferentiated thyroid cancer but can prolong disease-free and overall survival in patients with metastatic differentiated thyroid cancer, in whom its use is associated with 5-year survival rates of about 50%.[10-13] However, approximately 25% of patients will have persistent disease after initial therapy.[14] Additional responses can be seen with re-treatment.[15] Treatment works best when the volume of disease is small or microscopic.[4,16] RAI has limited efficacy against central nervous system metastases,[17] and at the doses usually used in the treatment of metastatic thyroid cancer, can have several significant side effects including salivary gland dysfunction, bone marrow suppression, and secondary hematopoietic malignancies.[14,18]

Radioactive Iodine Resistance, an Evolving Role for Positron-Emission Tomography

It is important both prognostically and therapeutically to define RAI resistance, and this is currently done in one of two ways. The first is in the setting of a negative RAI whole-body scan obtained after TSH stimulation. Care should be taken to avoid close or contemporaneous use of iodinated contrast with computed tomography and RAI scanning, as this can cause false-negative results. TSH elevation can be induced by either thyroid hormone withdrawal or by administration of human recombinant TSH (thyrotropin alfa, Thyrogen).

More recently, investigators have used 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) to localize distant sites of disease and thereby diagnose RAI resistance. Thyroid carcinomas with low iodine avidity tend to have a higher glucose metabolism and are more likely to be positive on FDG-PET imaging. RAI has been shown to have little or no therapeutic effect on FDG-avid tumors.[19] Conversely, tumors that concentrate RAI well are unlikely to be active on FDG-PET.[19,20] FDG avidity may be the most practical and reproducible definition of RAI-resistant disease and has a reported median sensitivity and specificity of 77% and 78%, respectively.[21,22]

Molecular Pathways in Thyroid Cancer

Thyroid cancer provides an excellent model for the study of tumor-initiating genetic events. Cancers of this area harbor several highly prevalent genetic alterations, some of which are unique. A well known example is the RET proto-oncogene, which codes for a cell membrane receptor tyrosine kinase. RET is expressed in parafollicular C cells but not in follicular cells. However, in follicular cells it can be activated by a chromosomal translocation known as the RET/PTC rearrangement.[23,24] RET/PTC is found in approximately 20% of adult sporadic papillary carcinomas.[25,26] A point mutation in RET is found commonly in parafollicular C cell–derived medullary thyroid carcinomas.

FIGURE 1
MAPK Signaling Pathway

An activation mutation in the gene encoding for the B-type Raf kinase (BRAF) can lead to activation of the mitogen-activated protein kinase (MAPK) signaling pathway (Figure 1, Table 1). Point mutations of the BRAF gene are found in 45% of thyroid papillary carcinomas.[27,28] This mutation is mutually exclusive with other common genetic alterations, supporting an independent oncogenic role.

The RAS gene also activates MAPK, among other signaling pathways. In malignant cells, point mutations within discrete domains of the RAS gene result in permanent activation of the mutant protein and corresponding activation of downstream signaling pathways. Point mutations of RAS seem to occur in all types of thyroid follicular cell-derived adenomas and carcinomas, suggesting that RAS mutations represent an early event in thyroid tumorigenesis.[29]

TABLE 1
Average Prevalence of Mutations in Thyroid Cancer and Potential Drugs Targeting the Mutations

Together, mutations involving one of these three genes (RET/PTC, BRAF, or RAS) are found in > 70% of papillary carcinomas and they rarely overlap in the same tumor.[28,30,31] The prevalence of mutations commonly found in thyroid cancers is shown in Table 1.

PAX8-PPAR is a rearrangement leading to the fusion of the PAX8 gene, which encodes a paired domain transcription factor and the peroxisome proliferator-activated receptor PPAR gene.[32] PAX8-PPAR is found in about 35% of follicular carcinomas and a small number of Hrthle cell (oncocytic) carcinomas.[33-35] It has been suggested that follicular carcinomas may develop by at least two distinct molecular pathways, initiated by either PAX8-PPAR or RAS mutations, because these two are rarely seen in the same tumor.[34]

Inactivating point mutations of the tumor-suppressor gene p53 are rare in patients with differentiated thyroid carcinomas but are commonly seen in anaplastic thyroid cancer.[36,37] Deregulation of intracellular levels of beta-catenin is an early event in the development of a variety of cancers. Beta-catenin mutations are mostly found in undifferentiated thyroid carcinomas.[38]

The pathways that are deregulated due to activation and or inactivation by the genes outlined above provide attractive therapeutic targets for thyroid cancer. These have been the basis for many rational clinical trials and drug development in recent years. Interest has also grown in several modulators of angiogenesis that have been successfully exploited in other cancers. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Elevated levels of VEGF are seen in thyroid cancers compared with normal thyroid tissue.[39-41] Higher VEGF levels correlate with later disease stage, large tumor size, nodal involvement, extrathyroidal invasion, and distant metastases.[42]

Investigators have also studied the expression of epidermal growth factor receptor (EGFR) in anaplastic thyroid cancer cell lines and have highlighted the potential of EGFR-targeting therapies.[43] Activation of EGFR signaling can upregulate the production of VEGF in human cancer cells.[44,45] EGFR overexpression has been shown to correlate with a decrease in recurrence-free thyroid cancer survival.[46]

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