Sejal Saraiya, PharmD

Each year approximately 63,000 persons in the United States will be diagnosed with thyroid cancer, placing it among the top 10 most common cancers in the country. Moreover, it is the fastest rising cancer diagnosis in the US, coinciding with increased detection.

Several theories have been offered to explain the overall increased incidence of thyroid cancer, as well as why its incidence has been increasing at a relatively faster pace in certain parts of the country.

There are 4 main types of malignant thyroid tumors, most of which are differentiated cancers. Papillary thyroid cancer has the highest incidence, accounting for roughly 8 of 10 thyroid cancers. These cancers often grow slowly and typically reside in just 1 lobe of the thyroid gland, but they can spread to the lymph nodes in the neck. With a high potential for cure, papillary cancers are rarely fatal.

The second most common subtype is follicular thyroid cancer, accounting for 10% of thyroid cancer diagnoses. Normally localized to the thyroid, follicular thyroid cancer can metastasize to other organs such as the lungs or bones. Two rare forms of thyroid cancer are medullary thyroid cancer and anaplastic thyroid cancer, which make up 4% and 2% of thyroid cancer diagnoses, respectively.

Evaluation of data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute between 1973 and 2002 indicated that thyroid cancer diagnosis rates have been rising.

In the US, rates increased by 5.4% per year in men and by 6.5% per year in women between 2006 and 2010.

The incidence of thyroid cancer increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a statistically significant 2.4-fold increase. During the same period, the rate of papillary cancer increased from 2.7 to 7.7 per 100,000a 2.9-fold increase.

While several other developed nations, such as Scotland, France, and Canada, have seen similar increases,4-6 the debate persists: is the increasing incidence in cancer rates real, or is it a consequence of increased diagnostic scrutiny made possible by tools and techniques developed over the past few decades?

The argument that the rising incidence really reflects increased detection has merit. In fact, thyroid cancer has been a common autopsy finding for more than 50 years.

The 2 main diagnostic techniques that have been instrumental in the increased detection of thyroid cancer prior to autopsy are ultrasonography and fine-needle aspiration. Both techniques allow for the diagnosis of a much smaller tumor size. A 2006 study found that smaller papillary cancers had the largest increase in incidence among thyroid cancers.

Of the 4 main histologies of thyroid cancer, papillary cancer was the only subtype that had a significant change in the rate of incidence. Since 1988, almost half of the papillary thyroid cancer tumors identified have been 1 cm or less, and almost 90% were 2 cm or less.

These small sizes would prevent most physicians from diagnosing through palpation, leading many tumors to go unnoticed without the newer diagnostic techniques. If the incidence of thyroid cancer were truly increasing, one could expect that the rate of mortality associated with thyroid cancer would also be increasing. However, the mortality from thyroid cancer has remained stable. In both 1975 and 2009, thyroid cancer-specific mortality was approximately 0.5 deaths per 100,000 persons.

A way to assess the argument of &lsquo;overdiagnosis&rsquo; in thyroid cancer would be to look at how increased access to care influences the diagnosis rate. Upon examining 2 cohorts of patients with differing health insurance accessthose 65 years and older, who have near-universal health insurance coverage, and those under 65 years of age, who have varying rates of access&mdash;it was observed that those with universal access had higher papillary thyroid cancer rates.

An obvious assumption is that increased age could influence the rate of thyroid cancer development; however, before 1990, the incidence rate of papillary thyroid cancer among people 65 years and older (4 to 6 per 100,000) was only marginally higher than that of patients who were not of Medicare-eligible age (2 to 5 per 100,000). Since the early 1990s, the incidence rates have diverged; in 2009, Medicare patients had an incidence of 18.5 per 100,000 compared with an incidence of 11.6 per 100,000 in the under-65-years-old cohort.

&lsquo;Hot Spot&rsquo; Locations and Proximity to Nuclear Reactors

In addition to age, an environmental influence may be suspect as a cause because there are &lsquo;hot spots&rsquo; around the country that have a higher thyroid cancer incidence.

An analysis of data from the Centers for Disease Control and Prevention (CDC), which contains information on state thyroid cancer incidence for 45 states and the District of Columbia, reveals distinct areas of the country with much higher rates of thyroid cancer than others. Of the 7 states with the highest incidence, 5 are located in the northeastern US. These states, in decreasing order of incidence rate, are Pennsylvania, Massachusetts, New Jersey, Connecticut, and Rhode Island, with the highest rates in counties in the contiguous states of New Jersey, New York, and Pennsylvania.

One important characteristic of these counties is there is no other area in the US with a greater concentration of nuclear reactors. The high-incidence counties encompass an area within a 90-mile radius that houses 7 nuclear power plants, which contain 16 nuclear reactors.

Lehigh County in Pennsylvania is one of the referenced counties within 90 miles of a nuclear reactor. The thyroid cancer incidence rate in Lehigh County was 21.4 per 100,000, based on the data extracted from 2001 to 2005. This was significantly higher than the average US thyroid cancer rate of 8.9 per 100,000 during that same period.

Because it is well established that exposure to radiation is a risk factor for thyroid cancer, a result of radioactive iodine (I-131) being incorporated into the thyroid cells, it is hard to ignore the correlation between proximity to nuclear reactors and a much higher incidence of thyroid cancer.

As previously noted, the mortality rate has not changed in 30 years, despite the increase in incidence. If thyroid cancer incidence continues to increase, it may be necessary to determine a more cautious diagnostic approach, focusing more on symptomatic thyroid nodules rather than on just the presence of thyroid cancers, especially for those smaller than 1 cm. This is especially important in that the current standard of care remains the same as it was 2 decades ago and can be fairly invasive for the patient. The evidence-based guidelines released separately by the American Thyroid Association (ATA) and the National Comprehensive Cancer Network for the management of differentiated thyroid cancer both provide a clear recommendation for the use of surgery,

based on the extent of the disease, the patient&rsquo;s age, and the presence of comorbid conditions.

The ATA provides an aggressive prophylactic approach, recommending that a central neck dissection may be performed in patients with advanced papillary cancer even in the absence of clinical evidence of nodal involvement; the ATA guidelines also recommend near-total or total thyroidectomies for all tumors greater than 1 cm.

Although thyroidectomies are often seen as a low-risk surgery, they can have a major impact on a patient&rsquo;s life, requiring a daily thyroid hormone supplement for the rest of his or her life.

Thyroid Cancer is the fastest rising cancer diagnosis in the US.

Incidence of thyroid cancer increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002.

Mortality from thyroid cancer has remained stable.

Thyroid cancer has been a common autopsy finding for more than 50 years.

Northeastern US has the highest thyroid cancer incidence, with Pennsylvania, Massachusetts, New Jersey, Connecticut, and Rhode Island, ranking highest.

Northeastern US has the greatest concentration of nuclear reactors.

A more cautious diagnostic approach may focus on symptomatic thyroid nodules.

ATA guidelines recommend near-total or total thyroidectomies for all tumors greater than 1 cm.

Another medication often used after a thyroidectomy in patients with differentiated thyroid cancer is radioactive iodine. It is used as an adjuvant for the ablation of residual thyroid tissue and possible microscopic residual cancer, as imaging for possible metastatic disease, and as treatment of known residual or metastatic thyroid cancer.

Other approaches to treating thyroid cancer include external beam radiation and chemotherapy.

Four medications are approved in the US for the treatment of thyroid cancer. In chronologic order as approved by the US Food and Drug Administration (FDA), these medications are thyrotropin alfa, vandetanib, cabozantinib, and sorafenib.

Thyrotropin alfa is a thyroid-stimulating hormone that is used as an adjunct diagnostic tool for serum thyroglobulin testing, and also as an adjunct treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer.

Sorafenib, a kinase inhibitor used to treat kidney and liver cancer, is also indicated for differentiated thyroid cancer refractory to radioactive iodine treatment.16 Two other kinase inhibitors, vandetanib and cabozantinib, are approved for the treatment of progressive, metastatic medullary thyroid cancer.

A medication that was recently evaluated for thyroid cancer in the phase III SELECT trial is now under FDA review.

The compounda multikinase inhibitor called lenvatinib&mdash;was evaluated in I-131refractory differentiated thyroid cancer.

Driven by increased diagnostic scrutiny and possible environmental factors, rates of thyroid cancer diagnosis continue to climb. Treatment for thyroid cancer has not changed much over the past few decades, and it is still considered a disease that requires surgery. With an increased diagnosis of small tumors, reevaluation of the treatment algorithm may be merited. Questions should be asked about what the best treatment options are, and whether or not the potential surgical complications of a thyroidectomy pose more of a health risk than does a watch-and-wait approach for smaller tumors.

Cancer Facts and Figures 2014. American Cancer Society web site. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed August 26, 2014.

Thyroid Cancer Overview. American Cancer Society web site. http://www.cancer.org/cancer/thyroidcancer/overviewguide/index. Accessed August 18, 2014.

Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002.

Reynolds RM, Weir J, Stockton DL, Brewster DH, Sandeep TC, Strachan MW. Changing trends in incidence and mortality in Scotland.

Leenhardt L, Grosclaude P, Cherie-Challine L; Thyroid Cancer Committee. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects?

Liu S, Semenciw R, Ugnat AM, et al. Increasing thyroid cancer incidence in Canada 1970-1996: time trends and age-period-cohort effects.

Mangano J. Geographic variation in U.S. thyroid cancer incidence, and a cluster near nuclear reactors in New Jersey, New York, and Pennsylvania.

VanderLaan W. The occurrence of carcinoma of the thyroid gland in autopsy material.

Morris L, Sikora A, Tosteson T, Davies L. The increasing incidence of thyroid cancer: the influence of access to care.

Ron E, Lubin J, Shore RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies.

American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.

Tuttle R, Haddad R, Ball D, et al. Thyroid carcinoma version 2.2014. National Comprehensive Cancer Network web site. https://www.nccn.org/store/logi/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed August 18, 2014.

Thyrogen [package insert]. Cambridge, MA: Genzyme Corporation; 2014.

Caprelsa [package insert]. Wilmington, DE: AstraZeneca; 2014.

Cometriq [package insert]. San Francisco, CA: Exelixis, Inc; 2012.

Nexavar [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.

Inman S. FDA approval sought for lenvatinib in differentiated thyroid cancer. OncLive web site. http://www.onclive.com/web-exclusives/FDA-Approval-Sought-for-Lenvatinib-in-Differentiated-Thyroid-Cancer. Published August 31, 2014. Accessed September 2, 2014.

A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of lenvatinib (E7080) in 131I-refractory differentiated thyroid cancer. ClinicalTrials.gov web site. http://clinicaltrials.gov/show/NCT01321554. Updated April 18, 2014. Accessed August 30, 2014.

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Each year approximately 63,000 persons in the US will be diagnosed with thyroid cancer, placing it among the top 10 most common cancers in the country.

Sejal Saraiya, PharmD | Authors

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National Surge in Thyroid Cancer Under Scrutiny