Getting Back To The Scientific Principles in Clinical Decision Makings

Surge of thyroid cancer

Like many other cancers, thyroid cancer incidence tends to be higher in wealthier regions of the world. The most recent results from International Agency for Research on Cancer (IARC), a cancerspecialized arm of World Health Organization (WHO), confirms that thyroid cancer incidence is higher in North America, Europe, Australia, Japan, and Korea compared to other parts of the world, even with the adjustment of age difference in the populations (1).

Further, incidence of thyroid cancer has been increasing in many parts of the world. Surveillance, Epidemiology, and End Results Program (SEER), a cancer statistics program in National Cancer Institute, reported that age-adjusted incidence rate of thyroid cancer rose to 14.2 per 100,000 people in 2011 from 7.5 per 100,000 people in 2000 (2). SEER estimates that 566,708 people are living with thyroid cancer in the United States as of 2011. SEER also estimates that 62,980 new cases of thyroid cancer will be diagnosed in 2014. Thyroid cancer is now 10th most common cancer in the United Cancer.

The high rate and the shear increase of thyroid cancer incidence in U.S., however, are no matches for the incidence and the increase thereof in Korea. IARC reported that the age-adjusted incidence rate of thyroid cancer in Korea is 6.4 per 100,000 men and 37.4 per 100,000 women based on cancer cases diagnosed in 2003–2007 (3). The most recent figures from Korean cohort are far worse than these figures. Agestandardized incidence rate of thyroid cancer in Korea, standardized against Korea’s population of year 2000, is 24.0 per 100,000 men, 113.8 per 100,000 women, and 68.7 per 100,000 people in year 2011 (4). The average annual increase rate of thyroid cancer incidence is 23.7% during the period from 1999 to 2011 - whopping 9.5 times increase over the 12 year period.

Why is thyroid cancer on the rise?

Facing this unprecedented and unusual increase of thyroid cancer incidence, many clinicians and epidemiologists have tried to answer the question of why thyroid cancer is on the rise. Risk factors like medical X-ray use, diet, life styles, obesity and environmental pollutants have been studied (Table 1). None of the suggested risk factors, however, could explain the surge of thyroid cancer.

The single most plausible explanation so far is over-diagnosis. Based on a survey on general adult population, Han et al. (2011) reported that 13.2% (8.4% men and 16.4% women) of Korean adults underwent thyroid ultrasonography (5). The authors reasoned that the relative easiness of thyroid sonography both by patient and physician’s perspective would play a role in this surprisingly high rate of thyroid sonography in Korea. Thyroid sonography does not require difficult preparations such as fasting and it is relatively easy to perform. Ahn and Park (2009) reported that doctors find thyroid nodules among 22 to 41% of general population using sonography. They also reported that 12% to 22% of people underwent thyroid sonography ended up with the diagnosis of thyroid cancer. With this higher rate of thyroid ultrasonography and surprisingly high rate of discovering thyroid cancer it seems that it is indeed inevitable but ends up with the astronomical incidence of thyroid cancer.

To elucidate the drivers of thyroid cancer screening, Lee et al. (2012) compared the data from 34 wealthier nations (7). They suggested that difference of healthcare system is a factor behind the higher incidence of thyroid cancer. The authors pointed out that a low share of public health expenditure and heavy dependence on patients’ direct payment is associated with a high incidence of thyroid cancer. A recent paper noted that the surge of thyroid cancer in Korea began with the screening program initiated and promoted by the Korean government since 1999 (8). The authors also reported a good correlation between percentage of adults reporting being screened for thyroid cancer and incidence of thyroid cancer in Korea.

What are the current recommendations?

In 1996, lacking any controlled study demonstrating that asymptomatic persons detected by screening have a better outcome than those who present with clinical symptoms or signs, the U.S. Preventive Services Task Forces concluded that screening asymptomatic adults or children for thyroid cancer using either neck palpation or ultrasonography is not recommended (9).

Over-diagnosis can cause problems not just through increase of healthcare burdens but also through potential complications associated with the treatment modalities. Potential complication of thyroid surgery includes hematoma, infection, permanent recurrent laryngeal nerve palsy, and permanent hypocalcemia. Further, some patients have to be on lifelong thyroid-replacement therapy following thyroid surgery. Although severe complications are infrequent, one can easily imagine that the actual number of complication is not low given large number of thyroid procedures and burden on patients are severe.

Concerning over potential harm of over-diagnosis Korean experts weighed it against potential gain of thyroid screening. Due to lack of quality evidences showing the harms, however, Korea’s experts published relatively moderate and somewhat vague conclusion, “Thyroid cancer screening using ultrasonography in asymptomatic adults is generally not recommended due to insufficient medical and scientific evidences for or against the screening.” (10)

Remaining controversies

Despite no recommendation of thyroid cancer screening by both U.S. and Korean experts, there is no sign of changes in clinical practice. Some clinicians advocated the current zealous screening practice and subsequent surgical strategies (11). Some clinicians dismissed the guidelines as unfounded and wrote that patient care should only be based on patient safety not on effectiveness researches (12). Other author recommended downsizing the treatment and suggested use of intervention radiology to manage thyroid cancer instead of opposing routing thyroid cancer screening on a proposition that over-diagnosis is currently unavoidable (13).

The authors arguing for status quo of zealous thyroid screening practices confused on various factors (Table 2).

According to Korean Central Cancer Registry data, 5 year survival rate of thyroid cancer is improved to 99.8% during the period of 2006 to 2010 from 94.9% during the period of 1996 to 2000 (14). Some authors incorrectly attributed this improvement as an effect of early detection and improvement of surgical technique. This improvement in 5 year survival rate is, however, a classic example of lead time bias.

We should note that mortality rate of thyroid cancer in Korea, about 0.5 per 100,000 people, has not been changed over the last decade. A dramatic improvement of survival rate is a consequence of 9.5 times increase in diagnosis of thyroid cancer which has very little impact on mortality rather than a true improvement of survival. In fact, because of the possibility of lead time bias, survival rate is better used in clinical trials where different treatments are compared in similar time period rather than in an evaluation of a cancer prognosis in general without comparison. According to the most recent data of Korean Central Cancer Registry, relative 5 year thyroid cancer survival, a prognosis measure taking into account the effect of deaths from all other causes – is 100.0 percent during the period of 2007 to 2011 (15).

Issue of lead time bias becomes more complicated when combined with other biases or confusions.

Researchers have reported high prevalence of occult prostate cancer – up to 70% for men older than 65, and occult thyroid cancer – up to 36% at autopsy (16 - 18). Because of relative high prevalence in the general population, the likelihood of being identified as a case increases proportionally with the effort to identify the cancer.

Getting back to science

In addition to clinical implications, issues of over-diagnosis can arise in other settings such as lawsuits claiming adverse health effect of alleged exposure to chemicals, radiations, heavy metals, and dusts. The studies performed to identify the factors associated with the cancers are often afflicted with multiple comparisons without proper adjustment. Statistical significance does not necessarily mean that the effect is real. By chance alone about one in 20 attempts will yield a positive finding in popular 95% confidence interval statistical tests.

It seems that some clinicians are frustrated with the new thyroid screening guidelines. But they have to understand that comparative effectiveness research and the guidelines based on careful examination of W those studies are one way to ensure a better patient care. Cancer screening is worth only if it detects life threatening cancers among asymptomatic people at a stage when lesions are treatable, and if the benefit from treatment outweighs the potential of harm. As both U.S and Korean experts noted, reliable evidences of benefit from zealous thyroid screening do not exist. The ongoing epidemics of thyroid cancer in both U.S. and Korea are likely an epidemic of diagnosis rather than an epidemic of disease (8, 19). In contentious areas, clinicians and other stakeholders in health should stand firmly on sound scientific principles guarding against common misconceptions.

References

1. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012.

2. SEER Stat Fact Sheets: Thyroid Cancer. Available at: http://seer.cancer.gov/statfacts/html/thyro.html

3. Age-standardized incidence and cumulative incidence rates and standard errors. Available at: http://ci5.iarc.fr/CI5I-X/old/ vol10/CI5-X-All-bySite.pdf

4. National Cancer Information Center of Korea. Cancer Incidence Trend Analysis. Available at: http://www.cancer.go.kr/mbs/ cancer/subview.jsp?id=cancer_040104000000

5. Han MA et al. Current Status of Thyroid Cancer Screening in Korea: Results From a Nationwide Interview Survey. Asian Pacific J Cancer Prev. 2011;12:1657-1663

6. Ahn HW and Park YJ. Incidence and clinical characteristics of thyroid cancer in Korea. The Korean Journal of Medicine. 2009;77(5):537-542

7. Lee TJ et al. The Incidence of Thyroid Cancer Is Affected by the Characteristics of a Healthcare System. J Korean Med Sci. 2012; 27: 1491-1498

8. Ahn HY et al. N Engl J Eed. 2014;371(19):1765-1767

9. The U.S. Preventive Services Task Force. Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd Edition.

10. Committee on Revision of Thyroid Cancer Screening Guideline. Thyroid Cancer Screening Guideline (Draft). August 2014.

11. Doctor’s News. Thyroid Cancer Guideline, Wrong From the First Button. Available at: http://www.doctorsnews.co.kr/news/ articleView.html?idxno=98646

12. Chung JH 2014. A Refutation against Unfounded Reports on Thyroid Cancer. J Korean Thyroid Assoc. 2014;7(1):1-6

13. Mauri G 2013. In response to Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumours. BMJ 2013; 347. Available at: http://www.bmj.com/content/347/bmj.f4706/rr/663585

14. National Cancer Information Center. Treatment situation. Available at: http://www.cancer.go.kr/mbs/cancer/jsp/cancer/ cancer.jsp?cancerSeq=3341&menuSeq=3360&viewType=all&id=cancer_020112000000

15. Korean Central Cancer Registry. National Cancer Registry Statistics 2011.

16. Haas GP et al. The Worldwide Epidemiology of Prostate Cancer: Perspectives from Autopsy Studies. Can J Urol. 2008;15(1):3866–3871

17. Harach HR et al. Occult papillary carcinoma of the thyroid: a “normal” finding in Finland — a systematic autopsy study. Cancer 1985;56:531-8

18. Yamamoto Y et al. Occult papillary carcinoma of the thyroid: a study of 408 autopsy cases. Cancer 1990;65:1173-9

19. Davies L and Welch HG. Current Thyroid Cancer Trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014;140(4):317-322

November 3, 2014

Doug Yoon, MD, PhD, MBA

Founder, Washington Scientific

Dr. Yoon is the Founder and Chief Scientist of Washington Scientific. Washington Scientific specializes in application of scientific principles and risk management strategies to medical, environmental health, and pharmaceutical areas. Dr. Yoon provides critical scientific insights to clients, often in a multinational and multicultural setting, by utilizing his medical and epidemiological expertise. Dr. Yoon’s work includes evaluation of epidemiological studies involving cancer or other chronic diseases; developing strategies to estimate health outcomes using health insurance claim data; evaluation of specificity and alternative causes of medical conditions; analyzing environmental exposure modelings; evaluation of admissibility of scientific evidences in courts based on human, animal and in vitro evidences; examination of causation criteria and disease susceptibility claims; and evaluation of medical treatments or guidelines through the principles of evidence based medicine.

Dr. Yoon is a strong advocate for humanitarian actions. He has participated and led medical relief actions responding various disasters including the 2005 tsunami and the 2006 earthquake. As of November 2014, Dr. Yoon is selected as a member of the Korean government’s effort to fight against the Ebola outbreak in West Africa.