Hematology/Oncology

The number of newly diagnosed thyroid cancers has more than doubled during the last 3 decades, leaving no question that the incidence of thyroid cancer is rising. The answer as to why these numbers continue to increase eludes cancer specialists and endocrinologists.

“This is not just a little squeak up in the numbers,” R. Michael Tuttle, MD, professor of medicine and attending physician of endocrinology service at Memorial Sloan-Kettering Cancer Center, told HemOnc Today. “This is a real increase that is being felt by thyroid surgeons, endocrinologists, nuclear medicine doctors and those in other specialties as well.”

Current data from the NCI’s SEER database show that the incidence of thyroid cancer in 1975 was 4.85 cases per 100,000 people. By 2007, this figure jumped to 11.99 per 100,000 people. And, although data are not yet available for the past year, it is estimated that 44,670 men and women were diagnosed with thyroid cancer in 2010.

R. Michael Tuttle, MD, discussed the growing incidence of thyroid cancer in the United States and issues in diagnosis and treatment. Photo credit: Richard DeWitt, Memorial Sloan-Kettering Cancer Center

Mortality rates, however, have declined slightly from 0.55 deaths per 100,000 in 1975 to 0.47 per 100,000 in 2007, according to SEER data, leading physicians to wonder whether these increases are simply related to better detection of less invasive tumors and, if this is the case, how best to approach treatment.

“As the numbers of thyroid cancers being diagnosed are increasing every year, we should not treat every patient with radioiodine. We really need additional research to determine how to predict which patients are truly low risk and do not need radioiodine ablation from those patients with a high risk of recurrence so we do not overtreat the disease,”

Stephanie L. Lee, MD, PhD, associate chief in the section of endocrinology, diabetes and nutrition and associate professor of medicine at Boston Medical Center, said in an interview.

Advent of improved detection methods

Small papillary tumors comprise most thyroid cancers that physicians diagnose and treat, but thyroid cancers of all sizes have also sustained the greatest increase in incidence since the 1970s.

One paper published in the Journal of the American Medical Association in 2006 highlights this upsurge, and researchers suggested that the dramatic increase in thyroid cancer cases may actually only reflect the mounting number of patients with papillary tumors.

In the study, Louise Davies, MD, MS, and H. Gilbert Welch, MD, MPH, of the VA Outcomes Group at the Department of Veterans Affairs Medical Center in White River Junction, Vt., analyzed information from the SEER database and determined that 49% of the increase in incidence between 1988 and 2002 was attributable to tumors smaller than 1 cm and 87% was attributable to tumors smaller than 2 cm.

These data led Davies and Welch to conclude that a combination of heightened awareness and the advent of improved diagnostic techniques, such as ultrasound and fine-needle aspiration, led to “overdiagnosis” of thyroid cancer. Physicians, for example, are now able to identify smaller tumors that would have otherwise remained imperceptible to former modes of examination.

“The increasing incidence of thyroid cancer in the United States is predominantly due to the increased detection of small papillary cancers,” Davies and Welch wrote. “These trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable mortality, suggest that increasing incidence reflects increased detection of subclinical disease, not an increase in the true occurrence of thyroid cancer.”

Although many physicians agree that earlier detection of smaller nodules contributes significantly to the rising incidence of cancer, some take issue with calling these tumors subclinical.

Ernest L. Mazzaferri Sr., MD, MACE, emeritus professor of medicine at The Ohio State University and courtesy professor of medicine at the University of Florida in Gainesville, said actual numbers instead of percentages may help describe a different situation.

Ernest L. Mazzaferri

As an example, Mazzaferri referenced a study of about 52,000 patients conducted by Karl Y. Bilimoria, MD, of the Feinberg School of Medicine at Northwestern University, Chicago, and colleagues. Data revealed that tumors smaller than 1 cm had a 5% 10-year recurrence rate and tumors measuring 1 cm to 2 cm had a 7% 10-year recurrence rate. In the same study, 2% of patients died from tumors smaller than 1 cm and 1.6% died from tumors measuring 1 cm to 2 cm.

“Roughly, 1,000 patients died of tumors less than a centimeter, and about 1,500 died from tumors ranging from 1 cm to 2 cm.

“The message here is that this disease has lots of recurrence and a reasonably high number of deaths. It is small in terms of percentages but large in terms of patient numbers. This is not a completely benign disease; it is a real entity,” Mazzaferri said.

Increases in tumors of all sizes

Some physicians whom HemOnc Today interviewed acknowledge that simply pointing the finger at micropapillary tumors ignores several other studies that indicate increases in more invasive thyroid cancers and larger tumors.

“If the higher incidence was exclusively attributable to detection, then it would be expected that only the number of patients with smaller tumors and early stage disease would be increasing,” Kenneth Burman, MD, chief of endocrinology section at Washington Hospital Center, said in an interview. “However, that is not exclusively what we are seeing.”

Instead, Burman said, the rates of distant metastases in men have more than doubled from 4% to 9%. The annual percentage change of thyroid cancer mortality in men was 2.4% from 1990 to 2000 — the largest increase of any type of cancer during that time period. Comparable rises have also been noted among women, he said.

Two studies that also examined SEER data offer similar information. Amy Y. Chen, MD, MPH, FACS, associate professor in the department of otolaryngology-head and neck surgery at Emory University, and colleagues identified considerable increases in tumors measuring at least 4 cm as well as increases in localized, regional and distant stage tumors among men and women from 1988 to 2005. Their data were published in the journal Cancer.

“Our findings suggest that the increasing incidence is not just overdiagnosis,” Chen, who is also director of the Thyroid Multidisciplinary Conference at Emory University and director of health services research at the American Cancer Society, told HemOnc Today. “They suggest that there may be something else that is predisposing individuals to getting thyroid cancers.”

A second study, which involved SEER data from 1973 to 2006, delved deeper into pathological characteristics of thyroid cancer in light of rising incidence.

“We found that well-differentiated thyroid cancers of all sizes, even those larger than 6 cm, have at least doubled in incidence over 30 years,” said study researcher Luc G.T. Morris, MD, of the New York University Cancer Institute. “Also, we found that cancers with extrathyroidal extension and cancers with lymph node metastases have dramatically increased in incidence.”

Because of the size and nature of these tumors, Morris, like Chen, said early detection or overdiagnosis could not account for all of the findings regarding rising incidence.

“The data in our paper are cause for caution — the notion that all of the extra thyroid cancers we are finding came from a ‘subclinical reservoir’ that was always there is probably true to a large extent, but it cannot explain 100% of what we are seeing,” he said.

Unclear causes

Although calling attention to the issue, research into the incidence of these cancers has done little to answer the overarching question about the potential risk factors for thyroid cancer and what is responsible for driving up the number of new cases.

Radiation, particularly during childhood, remains the only identifiable cause, according to Mazzaferri. A multitude of studies have delineated the connection between various exposures, including Chernobyl and nuclear weapon testing sites, and the development of cancer.

Of more current concern, however, is the amount of radiation a person receives while undergoing common tests, such as X-rays and CT scans.

“Several studies show staggering numbers of the amount of radiation that adults and children receive,” Mazzaferri said. Reports cited in an Archives of Internal Medicine commentary written by Rita F. Redberg, MD, MSc, of the University of California, San Francisco, for example, indicate that median doses of radiation received during CT scans were four times higher than they should be.

Additional areas of investigation include genetics and close examination of family history of the disease.

“One of the most intriguing things we have found is an increased incidence of familial papillary thyroid cancer that we did not recognize until the last 2 decades,” Mazzaferri said, noting that several groups of researchers have been exploring this subject. “There is pretty good evidence that this is genetic, but we have not yet identified the gene.”

Other factors, such as iodine intake, may also affect the development of thyroid cancer, according to Burman, although he noted that additional studies are required. “The reason for the rising incidence is largely unknown and needs to be investigated further,” he said.

Tuttle, who urged physicians and researchers to be open-minded, said initial arguments refused to accept radiation as a potential cause of thyroid cancer during the 1950s.

“We may find that it is something else that we exposed our children to 20 or 30 years ago,” he said, citing multiple paradigm shifts in parenting, such as switching to plastic bottles or flame retardant bedding, as potential influences on the development of cancer. “We have to look at nontraditional potential risk factors, including the environment, medicines used, food, clothing and other things that children were universally exposed to at the time.”

Tuttle also said a completely unexpected factor may be to blame.

“Clearly, early detection, screening and diagnosis account for a large part of this, but there is probably a secondary underlying cause that we just do not yet understand,” he said.

Changing approach to diagnosis, treatment

The swelling statistics have altered some physicians’ approach to diagnosing and treating thyroid cancer.

“Coincident with the increasing numbers of cancers, we are also realizing that thyroid nodules are very common. In fact, we are being somewhat bombarded,” Lee said. “There are both too many nodules and too many cancers, which has changed our practice of who gets biopsied for thyroid nodules.”

Many unanswered questions arise when it comes to diagnosis in this context, Burman said. Most nodules are small, and even if they are cancerous, they may not cause significant clinical problems, and the course of disease may depend on the clinical and pathologic circumstances. Additionally, the high cost of assessing and biopsying so many nodules has become a concern. The major question of whether physicians are actually improving the quality of life, morbidity and mortality of these patients remains in the back of physicians’ minds.

Kenneth Burman

Many have set these issues aside, however, and follow the “Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer” published in Thyroid in 2009, according to Burman. Dependent upon clinical and sonographic characteristics, the guidelines recommend aspirating most nodules larger than 1 cm as well as some nodules measuring between 6 mm and 10 mm in patients considered at high risk for cancer who also have worrisome characteristics identified via sonogram.

“Most of us feel, and the ATA guidelines indicate, that since you cannot determine which nodules will be cancer or which cancers will be more aggressive, we tend to be conservative and approach most thyroid nodules and cancers as potentially significant clinical issues and we tend to follow the ATA guidelines,” Burman said.

Occasionally, Tuttle said, ultrasound will identify clinically significant disease, which helps the physician properly diagnose and treat the patient.

“It is important to remember that every 5-cm tumor was originally a micropapillary,” he said. “At this point, we cannot accurately predict based on our initial assessment whether or not the cancer may develop into clinically significant disease.”

Tuttle said the ATA guidelines serve another purpose: They give physicians permission not to biopsy. Pressure to perform imaging tests, even if unnecessary, is often driven by fear of lawsuits, he said, noting that the threshold for additional testing is much lower in the United States compared with other countries.

“Very often, doctors feel that they have to prove that a patient does not have cancer, as opposed to proving that they do,” Tuttle said. Therefore, he explained that the guidelines set a standard to which a physician can refer in case of a legal conflict. He said, however, conservative adherence to the guidelines is important.

Heightened awareness of increasing incidence can also create a different type of roadblock that prevents providers and patients from approaching the possibility of disease objectively. This is especially true for physicians who previously stumbled upon a diagnosis of thyroid cancer as opposed to actively searching for the disease.

“It is sort of a self-fulfilling prophecy,” Tuttle said. “Once a physician finds one patient with thyroid cancer, they may think to look for it more in the next patients that they see. Similarly, patients also find out that incidence is rising, and where physicians could once say, ‘This is a rare disease, don’t worry about it,’ they now find themselves in a position where that is not possible.”

Consequently, even though physicians may want to perform fewer screening tests, this becomes progressively more difficult, Tuttle said.

Benefits, risks of treating thyroid cancer

Surgery and radioactive iodine therapy have long been the cornerstones of treatment for thyroid cancer, but increases in the number of small papillary cancers have physicians interviewed by HemOnc Today weighing the benefits and the risks of these therapies when caring for low-risk patients.

Although some concern persists over whether too many surgeries occur, thyroidectomy is considered appropriate and patients generally respond well to the treatment. Furthermore, the ATA guidelines contain specific recommendations defining when surgery as an intervention is appropriate. Patients with benign but growing nodules, for instance, may qualify for this procedure as do those with indeterminate tumors larger than 4 cm or indeterminate tumors that are marked suspicious. Thyroidectomy of varying degrees may also benefit patients with a family history disease, distant metastases, locoregional metastases and those aged older than 45 years.

The use of radioactive iodine therapy (I-131) after surgery for remnant ablation, however, can be a point of contention among physicians.

“We are finding lots of little nodules in many young people,” Lee said. “Coincident with that, we are now realizing there are serious morbidities that occur after high-dose radioactive iodine therapy.”

Lee said most physicians are concerned about second primary malignancies, such as tumors in the gastrointestinal tract or colon and leukemia, as well as other negative adverse events, including permanent dry mouth. With these risks in mind, the question becomes whether I-131 is appropriate for low-risk patients with smaller cancers, she said.

Others deem that the treatment is suitable, according to Lee, especially in light of the use of lower doses.

Mazzaferri agreed, emphasizing the fact that the risk for developing second primary malignancies is minimized when the amount of cumulative radiation is limited. Further, combining I-131 with recombinant human thyroid-stimulating hormone optimizes the treatment’s potential to prevent recurrence while curtailing the risk for adverse events.

Although these issues are extremely important to monitoring and treating the disease, Tuttle said one of the most burdensome decisions that a physician faces is handing down the diagnosis of cancer to the patient. That patient, he said, will not only bear at least some of the costs of the initial diagnosis, multiple ultrasounds and fine-needle aspirations and surgery, but will require thyroid hormone therapy for the rest of his or her life.

“Then, even more importantly, you have labeled somebody as a cancer survivor,” Tuttle said. “Most of my cancer patients tell me that they divide their lives up into two parts: before thyroid cancer and after thyroid cancer. It is no longer divided around marriage or the birth of a child or college graduation. There is an emotional toll that goes with this as well.”

Nevertheless, until research yields more clearly defined information about the causes of thyroid cancer and which nodules require more aggressive treatment, physicians will remain cautious.

“We know if we go looking for these little thyroid cancers, we can find them,” Tuttle said. “But the question is: Do we really have to treat every one of them? We are in a situation in which we are trying to figure out how to manage very, very low-risk thyroid cancer. We recognize that this very low-risk disease is unlikely to be life-threatening, but we have all had a patient who did poorly despite presenting with a small tumor. And that is what we are struggling with right now.” – by Melissa Foster

For more information:

• Bilimoria KY. Surgery. 2007;142:906-913.
• Chen AY. Cancer. 2009;115:3801-3807.
• Cooper DS. Thyroid. 2009:19:1167-1214.
• Davies L. JAMA. 2006;295:2164-2167.
• Morris LGT. Am J Surg. 2010;200:454-461.
• Redberg RF. Arch Intern Med. 2009;169:2049-2050.
• For more information on the SEER database, visit www.seer.cancer.gov

Disclosures: Drs. Burman, Chen, Lee, Mazzaferri and Morris report no relevant financial disclosures. Dr. Tuttle reports a direct financial interest in Thyrogen. He is a paid consultant for the Genzyme Corporation.

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When is radioactive iodine therapy appropriate?

Physicians should carefully weigh benefits and risks before treatment

Radioactive iodine is a wonderful therapy and has been a kind of magic bullet in thyroid cancer for 60 years. For many patients, it remains an effective way to prevent recurrence and eases monitoring and follow-up of those treated for thyroid cancer. Nevertheless, data from the past 10 to 15 years have also shown that the therapy is not as innocuous as physicians initially believed.

Bryan Haugen

The primary concern is the heightened risk of causing other cancers. Although the absolute risk is very small, the relative risk is solid. Furthermore, some people are genetically more susceptible to cancers, and we are often unaware of this before treatment unless they already have other cancers. Additionally, there is potential for developing dry mouth from even modest doses. Other problems, such as decreasing sperm count in men, reproductive issues in women and damaging a patient’s tear ducts, are rarer and of lesser concern, but they do happen.

Patients with stage III and stage IV disease who have higher risks of both recurrence and dying will likely experience improved survival as a result of receiving radioiodine and, consequently, the benefits of treatment outweigh the risks in these cases.

Patients with stage I and stage II disease, however, fall into a grayer area. In these situations, I explain to the patient that, although radioactive iodine therapy facilitates monitoring of the disease, newer tools, such as ultrasound and thyroglobulin blood tests, allow us to effectively follow them without treatment. I also tell these low-risk patients that radioiodine does not improve their already low risk of dying and recurrence.

Radioactive iodine therapy, however, is a valuable treatment and I consider its use with all of my patients because risk of adverse events remains low. Yet, if I do not see a reasonable benefit, I will not put my patients at risk.

Bryan Haugen, MD, is a professor of medicine and pathology and head of the division of endocrinology, metabolism and diabetes at the University of Colorado School of Medicine in Aurora. Disclosure: Dr. Haugen reports no relevant financial disclosures.

Changes in therapy and physician’s comfort level influence the decision to treat

The ATA guidelines identify certain groups of patients in whom radioactive iodine therapy is strongly recommended, as well as those groups for whom data do not support its use. The majority of patients, however, fall into the ‘selective use’ category. To determine which patients warrant treatment, physicians must consider the importance of ablation.

Radioiodine is an attractive option because it facilitates initial staging and follow-up. Currently, physicians use neck ultrasound and thyroglobulin measurements to determine whether a patient is free of disease; detailed guidelines exist to facilitate this thought process. However, in the absence of ablation, there are limited data and no explicit guidelines on how changes in thyroglobulin measurements during follow-up reflect status of the disease. Although some physicians are comfortable with monitoring a patient in this manner, others feel that ablation simplifies the process.

Richard T. Kloos

Research also suggests that possibility of clinical benefits of ablation, with a large meta-analysis demonstrating its ability to help decrease the recurrence of distant metastases in patients with thyroid cancer.

Recently, physicians have become cautious about the possible link between radioiodine and other malignancies. Current studies, however, suggest that increased risks for these uncommon adverse events were related to the use of high-treatment radioiodine activities. Now that we use lower doses, we suspect that harm is greatly reduced, although more research into long-term follow-up after low-dose ablation is required.

The increased use of Thyrogen-assisted ablation (Genzyme), allowing patients to maintain their normal thyroid status and more rapidly excrete radioiodine from their tissues as opposed to when they are hypothyroid, is also likely to decrease harm. Even with equal amounts of radioiodine, patients receiving Thyrogen get less radiation exposure to their bone marrow and may therefore be less likely to develop hematologic malignancies.

Consequently, with both Thyrogen and lower doses decreasing the risk of negative effects, the treatment risk-benefit consideration becomes even more favorable. Even the lowest-risk patients, whose disease outcomes will most likely not be directly affected by radioiodine, may benefit from the therapy’s ability to simplify follow-up.

Richard T. Kloos, MD, is secretary and chief operating officer of the American Thyroid Association. He is also co-director of The Ohio State University Thyroid Cancer Unit and professor in the divisions of endocrinology and nuclear medicine. Disclosure: Dr. Kloos reports no relevant financial disclosures.