Thyroid Cancer: Increased Incidence or Improved Diagnosis?

Each year approximately 63,000 individuals in the United States will be told that they have thyroid cancer. This places thyroid cancer among the top 10 most common cancers based on incidence in the United States. It will continue to move up that list, being the fastest rising cancer diagnosis in the United States, the most significant reason being increased detection.¹ However, thyroid cancer is not in the spotlight to the same extent as other cancers that are associated with a larger number of fatalities.

The story of thyroid cancer over the past few decades is an interesting one. Several different theories attempt 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.

With the number of thyroid cancer diagnoses increasing, healthcare professionals need to have a keen understanding of thyroid cancer and its different subtypes. There are 4 main types of malignant thyroid tumors, a majority of which are differentiated cancers. Papillary thyroid cancer has the highest incidence, with roughly 8 out of 10 thyroid cancers being papillary in nature. These cancers often grow very slowly and normally 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 include medullary thyroid cancer and anaplastic thyroid cancer, which make up 4% and 2% of thyroid cancer diagnoses, respectively.²

Incidence

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Evaluation of SEER data between 1973-2002 indicated that thyroid cancer diagnosis rates have been on the rise.³ In the United States, rates increased by 5.4% per year in men and by 6.5% year in women between 2006 and 2010.1 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?^3,7 The argument that the rising incidence is reflective of increased detection, as opposed to an increase in true occurrences, has merit. In fact, thyroid cancer has been a common autopsy finding for over 50 years.⁸ The 2 main diagnostic techniques that have given rise to 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 in crease in incidence among the other types of thyroid cancers. 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. Of the 4 main histologies of thyroid cancer, papillary cancer was the only subtype which 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 in size, and almost 90% were 2 cm or less.³ These small sizes would prevent the majority of physicians from diagnosing through palpation, leading many 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.⁹

Diagnosis Rate

A way to strengthen the argument of “overdiagnosis” in thyroid cancer, meaning the identification of a disease that would not cause symptoms or death to a patient if left undetected, 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—it was observed that those with universal access had higher papillary thyroid cancer rates.⁹ 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.⁹ Despite the logic behind the “overdiagnosis” theory and that there is simply an apparent increase in cancer rate, there is still reason to suspect an environmental influence, as there are “hot spots” around the country that have a higher thyroid cancer incidence.⁷

“Hot Spot” Locations, and Proximity to Nuclear Assets

An analysis of data from the 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 United States. These states, in decreasing order of incidence rate, are Pennsylvania, Massachusetts, New Jersey, Connecticut, and Rhode Island. A more granular look at incidence data counties are in the contiguous states of New Jersey, New York, and Pennsylvania.⁷ One important characteristic of these counties is there is no other area in the United States 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 United States thyroid cancer rate of 8.9 per 100,000 during that same period of time.⁷ As 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.^7,10

Standard of Care

It is important to take in the entirety of information regarding the surge in thyroid cancer incidence and what this means for the patient. As previously noted, the mortality rate has not changed in the past 30 years, despite the elevating 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 than 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.^11,12 Treating with surgery should be individualized to the patient, focusing on the extent of the disease, the patient’s age, and the presence of comorbid conditions. The ATA provides an aggressive prophylactic approach, stating that a central neck dissection may be performed in patients with advanced papillary cancer even in the absence of clinical evidence of nodal involvement, and also recommends near-total or total thyroidectomies for all tumors greater than 1 cm.¹¹ Although thyroidectomies are often seen as a low-risk surgery, they can have a major impact on a patient’s life, as the patient will be required to take a daily thyroid hormone supplement for the rest of his or her life.² Another medication often used post 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, imaging for possible metastatic disease, and treatment of known residual or metastatic thyroid cancer.¹¹ Other approaches to treating thyroid cancer include using external beam radiation and chemotherapy.²

Four medications are currently approved in the United States with a labeled indication for thyroid cancer. In chronological order of FDA approval, these medications are thyrotropin alfa, vandetanib, cabozantinib, and sorafenib.^13-17 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 neartotal or total thyroidectomy for well-differentiated thyroid cancer.¹³ Sorafenib, a kinase inhibitor used to treat kidney and liver cancer, is also indicated for differentiated thyroid carcinoma refractory to

radioactive iodine treatment.16 Two other kinase inhibitors, vandetanib and cabozantinib, are specifically approved for the treatment of progressive, metastatic medullary thyroid cancer.^14-15 Additionally, 1 other medication that was recently evaluated for thyroid cancer in a phase 3 SELECT trial is now under FDA review. The compound—a multi-kinase inhibitor called lenvatinib—was evaluated in I-131—refractory differentiated thyroid cancer,¹⁷ and is now under FDA review.¹⁸

Summary

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Driven by increased diagnostic scrutiny and potential environmental factors, rates of thyroid cancer diagnosis continue to climb. As the disease becomes more prevalent, it will be important to study this condition and its potentially causative factors more thoroughly. Treatment for thyroid cancer has not changed very much over the past few decades, and it is still considered a disease that requires surgery. With an increased diagnosis of small tumors, it could not hurt to reevaluate the treatment algorithm. Questions should be asked regarding what the best possible treatment options are on an individual basis, and whether or not the potential surgical complications of a thyroidectomy pose more of a health risk over leaving a small papillary thyroid tumor alone. This is very much a changing disease landscape for many reasons, and care for this condition should adapt accordingly. References

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

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

3. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-2167.

4. Reynolds RM, Weir J, Stockton DL, Brewster DH, Sandeep TC, Strachan MW. Changing trends in incidence and mortality in Scotland. Clin Endocrinol. 2005;62(2):156-162.

5. 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? Thyroid. 2004;14(12):1056-1060.

6. Liu S, Semenciw R, Ugnat AM, et al. Increasing thyroid cancer incidence in Canada 1970-1996: time trends and age-period-cohort effects. Br J Cancer. 2001;85(9):1335-1339.

7. Mangano J. Geographic variation in U.S. thyroid cancer incidence, and a cluster near nuclear reactors in New Jersey, New York, and Pennsylvania. Int J Health Serv. 2009;39(4):643-661.

8. VanderLaan W. The occurrence of carcinoma of the thyroid gland in autopsy material. N Engl J Med. 1947;237:221-222.

9. Morris L, Sikora A, Tosteson T, Davies L. The increasing incidence of thyroid cancer: the influence of access to care. Thyroid. 2013;23(7):885-891.

10. Ron, E, Lubin, J, Shore, RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res. 1995;141:259-277.

11. 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. Thyroid. 2009;19(11):1167-1214.

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

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

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

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

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

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

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

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