Based on the type of cells affected, level of differentiation, appearance of cells under the microscope, and disease prognosis, thyroid cancers are divided mainly into 3 types: Differentiated (including papillary, follicular and Hrthle cell), Medullary, and Anaplastic thyroid cancers.
Read about Staging of Thyroid Cancer here.
Following are the treatment options for these 3 types of thyroid cancer-
Treatment of Differentiated Thyroid Cancer (DTC)
These cancer cells appear similar to normal thyroid cells under the microscope and arise from follicular cells. These can be further divided into following 3 subtypes:
- Papillary Carcinoma: This is the most common type of thyroid cancer, representing about 80% of all cases. Papillary carcinoma tends to grow slowly and can be treated successfully in most of the cases. Some variants of papillary carcinoma include mixed papillary-follicular, columnar, tall cell, insular, and diffuse sclerosing carcinomas. These variants (except mixed papillary-follicular) are sometimes referred to as poorly differentiated carcinomas and they tend to grow and spread rapidly.
- Follicular Carcinoma: This is the second most common type of thyroid cancer, representing about 10% of all cases. Prognosis of follicular carcinoma is not as good as of papillary carcinoma but they can also be treated successfully in most cases.
- Hrthle (Hurthle) cell Carcinoma: This type of thyroid cancer is rare and is harder to recognize and treat. They have worse prognosis among all differentiated thyroid cancers.
Stage I-II DTCs
Stage I-II DTCs are generally treated with surgery (lobectomy or total thyroidectomy) with or without radioiodine therapy (depending on the size of tumor and extent of invasion) as the standard treatment.
Stage III DTCs
Stage III DTCs are generally treated with surgery (total thyroidectomy) along with radioiodine therapy (if the disease is iodine-sensitive) or external beam radiation therapy (EBRT) as the standard treatment.
Stage IV DTCs
Stage IV DTCs sensitive to iodine are generally treated with radioiodine therapy as the standard treatment. Stage IV DTCs that are not sensitive to iodine therapy can be treated with thyroid-suppression therapy, targeted therapy, or EBRT as per physician’s discretion. Surgery and EBRT may also be employed for palliation of symptoms of advanced disease.
Treatment of Medullary Thyroid Cancer (MTC)
These cancers arise from parafollicular cells (or C-cells) and account for about 4% of all thyroid cancers. They are also referred to as neuroendocrine tumors and generally secrete calcitonin. They do not have a good prognosis as they grow and spread rapidly. They are mainly divided into following 2 subtypes:
- Sporadic MTC: They accounts for about 80% of all MTCs. They are not generally inherited and mostly affect one lobe of the thyroid gland.
- Familial MTC: They comprises about 20% of all MTCs and are generally inherited. They are generally bilateral or multicentric in occurrence.
Stage I-II MTCs
Stage I-II MTCs are generally treated with surgery (total thyroidectomy) with or without EBRT as the standard treatment.
Stage III-IV MTCs
Stage III-IV MTCs are generally treated with surgery (total thyroidectomy) along with thyroid hormone therapy and EBRT or targeted therapy as the standard treatment. Palliative chemotherapy may also be employed for palliation of symptoms of advanced disease. Genetic testing is generally recommended in MTCs so that other family members can also be screened and treated, as appropriate.
Treatment of Anaplastic (Undifferentiated) Thyroid Cancer
These cancers also arise from follicular cells and is a rare form of thyroid cancer accounting for about 2% of all cases. Anaplastic cancer cells do not look like normal cells under the microscope and known as undifferentiated cells. These are the most aggressive form of thyroid cancer and are harder to treat.
Stage IV Anaplastic thyroid cancer
Anaplastic thyroid cancers are generally already widespread at the time of diagnosis. Rarely, when the disease is confined to locoregional area, surgery (total thyroidectomy) to remove the thyroid and regional lymph nodes can be performed. For extensive disease, EBRT and/or chemotherapy are generally employed as standard treatment.
Role of Surgery
Surgery is the treatment of choice for most early-stage DTCs and MRCs and some cases of anaplastic thyroid cancers that have not spread to distant body parts and can be completely removed by a surgical procedure. The main objective of surgery is to remove the primary tumor tissue along with some affected lymph nodes (if detected by imaging tests or during the procedure). Following are some commonly employed surgical procedures for the treatment of thyroid cancer:
In this surgical procedure, only the affected lobe of the thyroid gland is removed (generally along with the isthmus). This surgery is usually employed for low-risk, small DTCs (<1 cm) confined to one lobe of the thyroid gland without any lymph node involvement.
The advantage of this procedure is that the patient can retain one lobe of the thyroid gland and will not require thyroid hormone supplementation after surgery. Radioiodine therapy cannot be given after this surgery as most of the iodine will be absorbed by the remnant thyroid.
In this surgical procedure, the entire thyroid gland is removed. Some of the suspected lymph nodes may also be removed during this procedure, especially in case of medullary or anaplastic thyroid cancers. Since all of the thyroid tissue is removed, thyroid supplementation is required after this surgery.
The advantage of this procedure is that radioiodine therapy can be employed for ablation of any remaining (or recurrent) disease. Surgery for thyroid cancer may be associated with the risk of complications, such as temporary or permanent hoarseness or loss of voice, damage to the parathyroid glands leading to low blood calcium level and associated symptoms, infection, excessive bleeding, blood clots in the neck, etc.
Role of Radioiodine (RAI) Therapy
In this technique, the therapeutic dose of radioiodine I-131 (much higher than that used for radioiodine scan) is administered to the patient. The iodine is taken up by the thyroid cancer cells (including the normal cells if any). The radiation from the iodine can destroy the thyroid cells that have concentrated the radioiodine, without much effect on the nearby healthy cells.
This treatment is usually employed for destroying any remaining thyroid cells after total thyroidectomy or iodine-sensitive advanced-stage disease. The radioiodine therapy can only work in the presence of a sufficiently high level of TSH, which is achieved by the administration of thyrotropin.
Radioiodine therapy may be associated with side-effects like nausea, vomiting, swelling or tenderness in the neck or salivary glands, dry mouth, low sperm count in males, and irregularity in menstrual cycles in females.
Thyroid Hormone Therapy
This treatment approach includes taking thyroid hormones at slightly higher dose than normal daily after surgical removal of the thyroid gland. This serves two purposes, first it provides necessary thyroid hormone supplementation for maintaining body’s normal metabolism, and secondly, it helps in reducing the growth of any remaining/recurrent thyroid cancer cells by decreasing the TSH level in blood.
It can also be combined with other treatment modalities such as EBRT or chemotherapy for the treatment of some locally advanced or metastatic thyroid cancers. Side-effects of prolonged thyroid hormone therapy may include rapid or irregular heartbeat and osteoporosis.
Radiation therapy uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancerous cells. EBRT is generally used when radioiodine therapy cannot be used for the treatment, for example, in the case of MTCs, anaplastic thyroid cancers, and iodine resistant advanced stage DTCs.
Sometimes, EBRT is used as palliative therapy to relieve pain, bleeding, and obstructive symptoms associated with the advanced-stage disease.
Targeted Therapy for Thyroid Cancer
Targeted drugs are designed to target a specific gene or protein characteristic of the thyroid cancer cells. 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.
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.
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.
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 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.
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.
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.
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.
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.
Role of Chemotherapy
Chemotherapy may be employed for the treatment of anaplastic thyroid cancers or for some advanced-stage MTCs that has spread to distant body parts. Depending on the physician’s preference and patient’s condition, it may also be combined with EBRT to accelerate the benefit achievement.