There is no effective chemotherapeutic regimen for thyroid cancer. As mentioned earlier, chemotherapy is an established component of the multimodality therapy for ATC, but there appears to be no role for monotherapy. In contrast to ATC, chemotherapy has no role in the treatment of MTC or differentiated follicular cell-derived cancers, and no regimen has shown a promising response rate. Doxorubicin(Drug information on doxorubicin) has been used as monotherapy, but response is poor. A combined chemotherapeutic regimen consisting of doxorubicin plus cisplatin(Drug information on cisplatin) showed a combined complete plus partial response rate of 26% in one study. Another study evaluated the response of a regimen of doxorubicin, cisplatin, and vindesine(Drug information on vindesine), but found minor responses only in three of eight patients. Some clinicians have attempted to use chemotherapy in the setting of poorly differentiated non-radioiodine-avid tumors, but promising results are lacking thus far.
External-beam radiotherapy (EBRT) can be considered for those patients with inoperable, locally invasive, or recurrent thyroid cancers. It is also worth considering for those patients with poorly differentiated or undifferentiated (anaplastic) cancers. External-beam radiotherapy is usually employed only when other modalities have failed or are ineffective. In these rare cases EBRT can be considered, but should probably be used as a last resort only since its use often complicates or obviates subsequent reoperation due to the development of fibrotic scarring after radiation treatment. An example of when EBRT may be beneficial is when there is known residual or recurrent disease that cannot be resected, and radioiodine uptake scanning is negative. External-beam radiotherapy is also commonly part of neoadjuvant therapy for patients with anaplastic cancer.
Targeted Therapy for Thyroid Cancer
• Novel Targets—Despite the many modalities available for the treatment of thyroid cancer, overall survival for this malignancy has not seen an improvement in the past 20 years. For this reason there is interest in novel targeted therapies for thyroid cancer, including gene therapy and redifferentiation therapy. The therapeutic targets described below have shown some promise in preclinical trials or experimental models, but are not being used routinely in the clinical setting.
The past decade has seen a surge of research on targeted therapies aimed at protooncogenes, signal transduction pathways, or oncoproteins that are specific to cancer, but do not affect normal cells. Radioiodine ablation is an example of targeted therapy. Since the sodium-iodine symporter (NIS) is expressed almost exclusively on thyroid cells, only those tissues that are capable of concentrating radioiodine (normal thyroid and thyroid cancer) are exposed to lethal doses of radiation. Some thyroid cancers of follicular cell origin and all medullary thyroid cancers have no ability to concentrate radioiodine, making radioiodine ablation ineffective for these tumors. Therapy targeted toward novel pathways may be particularly important in the treatment of these radioiodine-negative, poorly differentiated or dedifferentiated thyroid cancers.
Pathways sought for targeted therapy are usually those related to the early events in oncogenesis. Cancers of follicular cell origin are believed to develop from multiple genetic alterations as opposed to a single gene mutation. Activating mutations in genes encoding tyrosine kinases are believed to be common early events in thyroid oncogenesis. Pathways germane to the early events in papillary thyroid oncogenesis include the RET/PTC rearrangement, which results in constitutive activation of the RET tyrosine kinase; mutations in H, K, and N-RAS, which lead to constitutive G protein activation; and BRAF mutations affecting the mitogen-activated protein kinase (MAPK) pathway.
The RET protooncogene has been shown to play a role in the pathogenesis of both papillary and medullary thyroid cancer. Several specific rearrangements of RET through either inversion or translocation have been observed; this occurs in about one-third of PTC cases. In PTCs arising following exposure to ionizing radiation, RET/PTC1 or RET/PTC3 rearrangements are more common.[33,34] MEN 2 and familial MTC are caused by germline point mutations in the RET protooncogene.[35-37] Sporadic MTC has also been linked to somatic RET mutations.
Mutations in H, K, and N-RAS are oncogenic when they lead to constitutive activation of the G proteins to which RAS binds. RAS mutations are thought to be early events in the oncogenesis of follicular, papillary, and Hürthle cell cancers. The prevalence of the RAS oncogene is believed to be highest in follicular cancers.
The translocation of PAX-8 (a thyroid transcription factor) to peroxisome proliferator-activated receptor (PPAR) γ1 (a nuclear hormone receptor) has been implicated in the oncogenesis of follicular cancers. These PAX-8/PPARγ rearrangements have been found in many follicular carcinomas, but only rarely in follicular adenomas.[39,40]
BRAF is a serine/threonine kinase thought to play a role in proliferation, differentiation, and apoptosis through its effects on the MAPK pathway. A high prevalence of BRAF mutations (36% to 69%) has been identified in papillary thyroid cancers.[41-44] The tall cell variant of PTC has a high prevalence of BRAF mutations as do poorly differentiated or anaplastic cancers arising from PTC.
Epidermal growth factor receptor (EGFR/ErbB1) and HER2/neu (ErbB2) are commonly overexpressed in PTC.[45-47] Because of this, treatment with humanized monoclonal anti-ErbB2 (trastuzumab [Herceptin]) and anti-ErbB1 (cetuximab [Erbitux]) is being explored.
• Redifferentiation—As discussed above, about 2% to 5% of all thyroid cancers dedifferentiate over time. In those patients with persistent or recurrent thyroid cancer, dedifferentiation occurs at a more alarming rate of about 30%. During dedifferentiation the thyroid cancer loses the ability to express thyroid-specific genes such as NIS, TSH-R, and thyroglobulin. This loss of NIS makes the use of radioiodine ineffective. Loss of TSH-R makes TSH suppression ineffective, and the loss of thyroglobulin expression prevents its use as a tumor marker. Redifferentiation therapy targets these thyroid-specific genes in order to restore expression and thereby allow the use of conventional treatments such as radioiodine and TSH suppression. Retinoids, aromatic fatty acids, PPARΥ agonists, histone deacetylase inhibitors, and HMG-CoA reductase inhibitors have been used in preclinical studies.
Retinoic acids are biologically active derivatives of vitamin A that have been shown to regulate cellular differentiation and growth in many human cancers. In some studies retinoic acids have been shown to increase NIS mRNA expression and radioiodine uptake in vitro.[50-52] Other studies have been less promising. In one clinical trial retinoic acid induced iodine(Drug information on iodine) uptake in 50% of subjects. Unfortunately, these effects have not been durable in most reports, and have not led to dramatic clinical responses.
The aromatic fatty acids phenylacetate and phenylbutyrate have been shown to induce growth inhibition and redifferentiation in several human cancers including thyroid cancer. In vitro studies have shown that phenylacetate induces growth inhibition and decreased VEGF secretion in thyroid cancer cell lines. Phenylacetate has also been shown to enhance the antiproliferative effect of retinoic acid in FTC cell lines.
PPARγ agonists have been shown to inhibit cellular proliferation and induce apoptosis. The PPARγ agonists that have received the most attention are the antidiabetic drugs which are derivatives of thiazolidinedione: rosiglitazone(Drug information on rosiglitazone) (Avandia), pioglitazone(Drug information on pioglitazone) (Actos), ciglitazone, and troglitazone. Thiazolidinedione derivatives have antiproliferative effects in many human cancers, including thyroid cancer. Troglitazone has had antiproliferative effects in PTC, FTC, HCC, and ATC cell lines.[58-61] The mechanism of action for PPARΥ agonists has not yet been elucidated.
Histone deacetylase (HDAC) inhibitors modulate the acetylation of histones and other intracellular molecular targets pertinent to cell growth and division. Examples of HDAC inhibitors under investigation include depsipeptide, trichostatin A, and suberoylanilide hydroxamic acid. Histone deacetylase inhibition can induce differentiation and apoptosis in thyroid cancer cell lines. NIS mRNA expression has also been shown to be upregulated by depsipeptide and trichostatin A in vitro.[62,63] If HDAC inhibition leads to significantly increased uptake of iodine, their use could lead to improved effectiveness of RAI in poorly differentiated tumors.
The HMG-CoA reductase inhibitors are popular cholesterol-lowering drugs commonly known as statins. HMG-CoA reductase inhibitors have been shown to have antiproliferative effects and promote differentiation in several human cancer cell lines. Lovastatin(Drug information on lovastatin) has been shown to inhibit cell proliferation and induce apoptosis in thyroid cancer cells.[64,65] In one study lovastatin was shown to induce redifferentiation of ATC in vitro in low doses.
• Gene Therapy—Gene therapy is the offspring of translational research into the molecular mechanisms of oncogenesis. Gene therapy may be expedient in thyroid cancer because of the expression of thyroid specific genes. The sodium iodide symporter, TSH receptor, thyroglobulin, thyroid peroxidase, TTF-1, and TTF-2 are examples of thyroid-specific genes. Gene therapy can be broken down into three broad approaches: corrective, cytoreductive, and immunomodulatory.
The goal of corrective gene therapy is to replace a defective gene, restore a deleted gene, or abrogate the effect of an oncogene. Perhaps the most obvious example of a target for corrective gene therapy is the RET protooncogene in MTC. The p53 tumor suppressor gene, tyrosine phosphatase η , and Gadd45Υ have all been implicated in ATC and have been used as targets for corrective gene therapy as well.[68-73]
The goal of cytoreductive gene therapy is to deliver a gene that leads to cell death or makes the cell susceptible to cytotoxic drugs. The most common strategy is suicide gene therapy by the introduction of viral thymidine kinase followed by the administration of ganciclovir(Drug information on ganciclovir), which leads to selective killing of cells that express the viral thymidine kinase. This strategy has been effective in ATC cell lines and in nude mice.[74-76]
Perhaps one of the most promising new strategies is the reintroduction of a functioning NIS gene in NIS-deficient thyroid cancers in order to restore iodine concentrating capacity. Medullary thyroid cancer does not express NIS and poorly differentiated and anaplastic cancers often have lost the cell surface expression of NIS, rendering radioiodine scanning and ablation ineffective for these tumors. The reintroduction of a functional NIS gene might make radioiodine treatment effective in these cancers. In experimental models the NIS gene has been transfected into NIS-defective thyroid cancer cells, and has resulted in restoration of the ability to accumulate iodine both in vitro and in vivo.[77-79] Successful NIS gene transfer has been demonstrated in both follicular cell-derived and medullary cancers.
The goal of immunomodulatory gene therapy is the introduction of genes that will enhance the immune system's response to the tumor and increase the immunogenicity of the tumor. The expression of cytokines with antitumor activity such as interleukin (IL)-2 (Proleukin) and IL-12 has been the main focus of immunomodulatory gene therapy thus far. IL-2 and IL-12 have been used alone or in conjunction with suicide gene therapy or tissue-specific promoters and have shown promise in vitro and in vivo for both follicular cell-derived and medullary cancers.[80-83]
The majority of thyroid cancers are slow-growing and easily treatable, with an excellent prognosis after appropriate surgical and medical therapy. Despite this, there has been no improvement in overall survival for thyroid cancer in the past 20 years. Unfortunately, 10% to 15% of thyroid cancers do not follow an indolent course, and exhibit aggressive behavior. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences, and most will be diagnosed within the first 10 years after treatment. Dedifferentiation occurs in about 30% of patients with persistent or recurrent thyroid cancer leading to poorer responses to conventional therapy and difficulty monitoring tumor burden. Distant metastases are present in about 20% of those who recur. Overall, about 50% of patients with distant metastases die within 5 years.
Clinicians need to be able to identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Novel therapies utilizing molecular targets, redifferentiation agents, and gene therapy are exciting potential therapeutic options on the horizon.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.