Surgery, radioactive iodine (I-131), thyroid hormone suppressive therapy, and radiotherapy are standard treatment modalities that can be employed in most cases of thyroid cancer. However, the efficacy of these treatment modalities remains limited for patients with metastatic, progressive and/or symptomatic disease thyroid cancer. In such cases, available treatment options include observation, targeted therapy with kinase inhibitors, and traditional cytotoxic chemotherapy.
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The new approach based upon targeting a genetic modification characteristic of cancer cells, for example, a mutation in the BRAF, RET/PTC, and NRAS genes or other kinase enzymes that are involved in the proliferation of cancer cells, is emerging as an effective treatment modality for progressive, symptomatic thyroid cancer.
In most thyroid cancers, kinase enzymes act as important signaling intermediates that stimulate the proliferation, angiogenesis, invasion, and spread of cancer cells or inhibit cancer cell death. Many drugs targeting these signaling kinase enzymes have been studied for the treatment of advanced-stage thyroid cancer.
Most of the available/tested drugs partially inhibit multiple tyrosine kinases affecting multiple signaling pathways. Newer agents are being developed that have more selective action against particular kinases, such as BRAF, mitogen-activated extracellular signal-regulated kinase (MEK), and phosphatidylinositol 3-kinase (PI3K).
Currently, researchers are focusing on developing targeted drugs to treat medullary thyroid cancer (MTC), anaplastic thyroid cancer (ATC), or other aggressive thyroid cancer types.
Following is the list of various targeted drugs that are currently approved or have shown potential for the treatment of thyroid cancer:
Lenvatinib is an orally active, small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR) 1 to 3, platelet-derived growth factor receptor (PDGFR) alpha, RET, stem cell factor receptor (KIT) and fibroblast growth factor receptor (FGFR) 1 to 4 kinases.
These kinases have been implicated to promote angiogenesis, growth, and progression of thyroid cancer cells. Lenvatinib is the preferred targeted agent and has been approved by US FDA for the treatment of patients with locally recurrent or metastatic, progressive differentiated thyroid cancer (DTC [including papillary, follicular, and poorly differentiated subtypes]) that is not responding to radioactive iodine treatment. It has been reported that patients whose tumors contain a RAS mutation have significantly better clinical outcome compared to those who lack this mutation.
Adverse events associated with the drug include high blood pressure, fatigue, diarrhea, pain in the bones and muscles, decreased appetite, decreased weight, nausea, mouth ulcers, headache, vomiting, abdominal pain, and speech disorders.
Sorafenib is an orally active, small-molecule inhibitor of multiple kinases including VEGFR 1 to 3, PDGFR beta, KIT, RET/PTC, and less potently, BRAF. Sorafenib has been approved by the US FDA for the treatment of patients with locally recurrent or metastatic, progressive Differentiated Thyroid Cancer that is not responding to radioactive iodine treatment. It has been reported that the presence/absence of a BRAF or RAS mutation is not predictive of clinical outcome.
Sorafenib may cause adverse events like diarrhea, fatigue, infection, hair loss, hand-foot skin reaction, rash, decreased weight, decreased appetite, nausea, abdominal pain, high blood pressure, and bleeding.
Sunitinib is an orally active, small-molecule inhibitor of multiple kinases including PDGFR alpha, PDGFR beta, VEGFR 1 to 3, KIT, RET/PTC subtypes 1 and 3, and others. Various clinical trials have shown the efficacy of sunitinib in the treatment of patients with MTC. Although not approved for the treatment of DTC, it can be used in the case of progressive and/or symptomatic metastatic disease when no appropriate clinical trial or preferred TKI agents are available.
Side effects of sunitinib include fatigue, diarrhea, mouth ulcers, nausea, decreased appetite, vomiting, abdominal pain, hand-foot reaction, high blood pressure, bleeding, taste changes, and low platelet counts.
Pazopanib is an orally active, small-molecule inhibitor of multiple kinases including VEGFR 1 to 3, PDGFR alpha and beta, and KIT; but it does not have a significant inhibitory activity against the RET, RET/PTC, or BRAF kinases. Thus, it seems to exert its anti-thyroid cancer effect primarily via inhibiting the formation of new blood vessels. Similar to sunitinib, it can be used in the case of progressive and/or symptomatic metastatic disease when no appropriate clinical trial or preferred TKI agents are available.
Side effects of pazopanib include fatigue, diarrhea, nausea, decreased weight, high blood pressure, decreased appetite, hair color changes, vomiting, headache, pain in bones and muscles, abdominal pain, and problem in breathing.
Vandetanib is an orally active, small-molecule inhibitor of multiple kinases including VEGFR, RET/PTC, epidermal growth factor receptor (EGFR), and others. It is considered the preferred treatment option and has been approved by US FDA for patients with unresectable, locally advanced or metastatic MTC that is either symptomatic or progressive. It helps in controlling the progression of cancer; however, overall survival advantage is not yet proved in the clinical trials.
Side effects of vandetanib include diarrhea, rash, high blood pressure, nausea, headache, infection, decreased appetite, arrhhythmias and abdominal pain.
Cabozantinib is an orally active, small-molecule inhibitor that targets VEGFR 1 to 3, RET/PTC, KIT, c-MET and others. Similar to vandetanib, it is considered the preferred treatment option and has been approved by US FDA for patients with unresectable, locally advanced or metastatic Medullary Thyroid Cancer that is either symptomatic or progressive. Cabozantinib can also be employed for the treatment of patients with radioiodine-refractory DTC who have progressed on previous anti-VEGFR therapy.
Side effects of the drug include diarrhea, mouth sores, decreased appetite, nausea, weight loss, fatigue, high blood pressure, hair color changes, hand-foot reaction, constipation, abdominal pain and bleeding.
Efatutazone is an orally active agonist of peroxisome proliferator-activated (PPAR)-gamma receptor. In combination with paclitaxel (chemotherapeutic drug), it could be helpful in the treatment of patients with advanced-stage Anaplastic Thyroid Cancer unresponsive to standard therapy.
Dabrafenib & Trametinib combination treatment
Dabrafenib is a BRAF kinase inhibitor and Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK)-1 and -2 inhibitor. ATCs frequently have mutations in the BRAF V600E gene and other mutations that lead to the activation of the mitogen-activated protein kinase (MAPK) and other proteins.
These proteins promote cellular growth and proliferation. The combination of dabrafenib and Trametinib has been approved by US FDA for the treatment of patients with locally advanced or metastatic ATC that possess BRAF V600E mutation and for whom no other satisfactory locoregional treatment is currently available.
Side effects of the combined treatment regimen include dry skin, rash, itching or other skin problems, sensitivity to the sunlight, headache, fever, chills, joint or muscle pain, fatigue, cough, hair loss, nausea, diarrhea, and high blood pressure.
Selumetinib is an orally active, small-molecule, selective inhibitor of MEK 1 and MEK 2. It has been reported to increase the radio-iodine uptake by thyroid cancer cells. Thus, it is deemed to be efficacious in the treatment of patients with radioiodine-refractory thyroid cancer. Mainly, patients with NRAS mutation positive thyroid cancer were reported to derive the benefit of selumetinib treatment.
Vemurafenib is an orally active, small-molecule, selective inhibitor of BRAF serine-threonine kinase including BRAF V600E and other kinases that are involved in abnormal cellular proliferation and metastasis. It has shown some activity for the treatment of patients with progressive radioiodine-refractory BRAF V600-mutant thyroid cancer who have previously received treatment with antiangiogenic kinase inhibitors including sorafenib.
Patients with any component of squamous differentiation within the primary or secondary papillary thyroid cancer lesion may confront disease progression with this drug. Thus, caution should be taken in such patients. Adverse events of the drug included rash, itching, sensitivity to sunlight, fatigue, weight loss, taste alteration, and hair loss.
Some other drugs, such as motesanib, axitinib, bevacizumab, lenalidomide, everolimus and drugs that inhibit specific signaling pathways involving phosphatidylinositol 3-kinase (PI3K), tropomyosin receptor kinase (TRK), and anaplastic lymphoma kinase are under clinical investigation and hold potential for the treatment of advanced-stage thyroid cancer possessing specific genetic mutations.
The introduction of multitargeted kinase inhibitors has transformed the treatment landscape of thyroid cancer and these agents are now being employed for locally advanced or metastatic disease.