Editor's Note: Only 2%-8% of the estimated 62,980 thyroid cancers diagnosed in the United States in 2014 were of the medullary subtype. This cancer varies greatly from differentiated types of thyroid cancer in terms of cell of origin, etiology, incidence, and outcome, and revised guidelines were recently published updating the workup and management of this presentation. Medullary thyroid carcinomas (MTCs), which originate from parafollicular cells, are more aggressive and spread quickly to the lymph nodes and distant organs such as the lungs, liver, and bones over the course of the disease. Unlike the differentiated types, which originate from follicular cells of the thyroid, they do not absorb iodine and therefore do not respond to radioactive iodine (RAI) therapy.
In an interview with Medscape, Manisha H. Shah, MD, a medical oncologist in the Department of Internal Medicine at the Ohio State University Comprehensive Cancer Center, discussed the genetic risk factors of medullary thyroid carcinoma; the current FDA-approved tyrosine kinase inhibitors (TKIs) to treat advanced-stage, metastatic disease; and the advantages of dealing with a molecularly well-characterized malignancy.
No Known Risk Factors
Medscape: Specifically with MTC, what are the risk factors involved and which prognostic factors are the most telling?
Dr Shah: Approximately 25% of MTCs are genetic and fall under the setting of hereditary syndromes; these include MEN2A [multiple endocrine neoplasia], MEN2B, and familial medullary thyroid carcinoma.[2,3] Outside of this, there are no known risk factors. So, sporadic medullary thyroid cancer patients—the other 75%—do not have any known risk factors.[2,3] In other words, smoking, alcohol, and environmental factors are not known to be associated with this disease. Basically, we don't really know why they occur.
As for prognostic factors, like most other cancers, we typically stratify medullary thyroid carcinomas by stage. The worst prognostic sign would be widespread stage IV disease—that includes metastases to the lymph nodes, liver, lungs, bones, etc. This cancer likes to spread to the organs quickly, so by the time most patients are diagnosed, they already have stage IV cancer. If they are diagnosed with early-stage disease, then the tumor markers calcitonin and carcinoembryonic antigen (CEA) are the prognostic indicators. For calcitonin and CEA, the shorter that the doubling time values, the faster the cancer is growing.Stage and tumor marker status are the two prognostic factors. Other thyroid cancers are divided into poorly or well-differentiated subtypes. For medullary thyroid carcinoma, we don't have that kind of differentiation.
Medscape: The vast majority of medullary thyroid carcinomas are asymptomatic, but are there any subtle signs or symptoms that might indicate abnormal growth or malignancy during a patient's evaluation at a primary care visit?
Dr Shah: Thyroid cancer usually attracts our initial attention as a lump in the neck. We then do an ultrasound and fine-needle aspiration of the thyroid, and that's basically how the diagnosis is made. In typical practices, however, if someone has a lump in the neck, it is attributed to an enlarged lymph node from infection, which is a common occurrence. You may give the patient antibiotics for a couple of weeks, but if the lump doesn't shrink, then a follow-up workup including ultrasound or CT imaging is entertained. If you see a lump for an extended period of time, it is most likely not an infection.
In patients with symptoms, there's nothing subtle about them. This cancer can produce specific hormones, which can lead to symptoms of flushing and diarrhea. These are chronic symptoms. This is diarrhea that goes on for month after month. These patients may get diarrhea 15-20 times a day year after year. Such symptoms have an adverse impact on the quality of life of these patients, and treatment of such intractable symptoms is being investigated.
RET Testing Is the Gold Standard
Medscape: When do you recommend genetic testing for the RET (rearranged during transfection) proto-oncogene mutation?
Dr Shah: Because approximately 25% of medullary-type thyroid cancers are genetic, every patient diagnosed with the disease is required to undergo genetic testing. Genetic testing is the gold standard. If I have a patient who is diagnosed with medullary thyroid carcinoma and doesn't have a family history of the disease, I would still recommend genetic testing for RET mutation. It's a simple blood test and unique to this cancer in that, unlike other cancers, a genetic test is performed even when there is no indication of a family history of disease. The RET gene is long and can be mutated at several places along the gene. Depending on where it's mutated, we can predict the likelihood that someone will develop medullary thyroid carcinoma, the age of onset, and how aggressive the disease will be, all based on genotype-phenotype correlation.[5,6]
When someone has a positive genetic test, what needs to be done is well defined. The person is basically followed by a genetics team and recommendations are immediately made to test their children, parents, and siblings. If any of them have a positive genetic test, it means they already have medullary thyroid cancer or they are going to get it. They are at very high risk. For example, if I have a 25-year-old patient with a positive test and she has a newborn baby, we will recommend testing for the newborn baby. If the test comes back positive, we would recommend that the child's thyroid be removed by the age of 3 or 5, depending on what component of their genetic test is off.
Medscape: You briefly touched upon this already, but can you tell us more about when a prophylactic thyroidectomy should be considered in children? How would you approach that discussion with a patient or parent?
Dr Shah: This question is applicable mostly to the pediatric field. There are standard guidelines by several organizations, including the American Thyroid Association. For a young child, let's say a 2-year-old, if the child has had a positive genetic test, based on the guidelines you would recommend to the parents that the child undergo a thyroidectomy; it will prevent the child from getting medullary thyroid cancer. If the cancer is already present, a thyroidectomy might prevent metastases. Once the cancer metastasizes, it is no longer curable. It's very clear that if you have the gene, you're going to get the cancer. It's only a matter of at what age and how aggressive the cancer will be.
TKIs Approved for Use; Combinations May Prove Advantageous
Medscape: What are the standard treatments for this cancer? And what promising therapies and approaches are being examined in trials?
Dr Shah: Although this is a rare cancer, it is well characterized molecularly and genetically. And despite the rarity of it, it has two FDA-approved TKIs—the first systemic therapies ever approved for the treatment of medullary thyroid cancer. One is vandetanib (Caprelsa®), which was approved in 2011, and the other is cabozantinib (Cometriq®), approved in 2012. Both of them showed significant improvement in progression-free survival but no increase in overall survival.[7,8] However, it's hard to show overall survival differences for several reasons. The vandetanib trial was not even designed to look at overall survival. The cabozantinib trial was designed to look at overall survival, but when a patient who might be on placebo goes off a trial, they are usually put on another medication that might help and affect how long they live.
The recently revised ATA Guidelines for the Management of Medullary Thyroid Carcinoma recommend the use of TKIs for patients with advanced MTC. Single-agent vandetanib or cabozantinib is considered first-line systemic therapy in patients with advanced progressive MTC.
Sorafenib (Nexavar®) and pazopanib (Votrient®) are also TKIs, and they work similarly to vandetanib and cabozantinib by targeting the angiogenesis pathways. They inhibit the RET receptor, PDGF, and so forth. Sorafenib has shown modest responses in phase 2 trials.[9,10] Ponatinib is a more potent RET inhibitor currently being looked at in a phase 2 trial, with an estimated study completion date in 2016.
Our group here at Ohio State is working on combination therapies. We want to find out why sorafenib, vandetanib, and the other TKIs stop working after a couple of years. We want to use an antibiotic, infectious disease-type model, like that used for tuberculosis, in which you use several drugs all at once instead of one at a time.
Overall, this disease strikes people of any age and most are diagnosed at advanced stage, so drugs that work only for a couple of years are not good enough. We need to find better, longer-lasting systemic therapies. The clinical trial is the name of the game. We don't have a cure, and the two FDA-approved drugs are of similar caliber. This is a great first step, but we need to keep working at making therapies better and longer-lasting while at the same time improving quality of life for these patients.
Medscape Oncology © 2015 WebMD, LLC
Cite this: Medullary Thyroid Cancer: Progress in Rare Tumor - Medscape - Apr 16, 2015.