Thyroid cancer care no longer ‘one-size-fits-all’

Thyroid cancer is ranked the ninth most common cancer in the United States, but the number of deaths associated with the disease is relatively small when compared with other common cancer types such as melanoma and lung cancers.

On average, 1.1% of US adults will be diagnosed with thyroid cancer at some point during their lifetimes, and in 2014 alone, there will be 62,980 new cases of thyroid cancer and roughly 1,890 deaths from the disease, according to most recent Surveillance, Epidemiology and End Results (SEER) data.

Although the incidence of follicular, medullary and anaplastic thyroid cancers have remained steady during the past 30 years, the incidence of papillary thyroid cancer has increased threefold in the United States within the past 4 decades — from 3.6 cases per 100,000 in 1973 to 11.6 cases per 100,000 in 2009.

“The data demonstrate that papillary thyroid cancer incidence is rising in the US and worldwide,” Matthew Ringel, MD, professor in the divisions of endocrinology and oncology and director of the division of endocrinology, diabetes and metabolism at the Ohio State University Wexner Medical Center, told Endocrine Today. “It has really picked up in terms of frequency since the late ’80s and early ’90s, which coincides with the more frequent use of neck and thyroid ultrasound.”

Endocrine Today spoke with several experts about the ‘epidemic of overdiagnosis,’the ‘treatment vs. watch-and-wait debate’ and how new genetic information may reshape the treatment and follow-up care of thyroid cancer in coming years.

“We don’t want to overtreat patients and put them at risk for complications, but on the other hand, we don’t want to miss anything that will have life-threatening impact. The number of patients with small thyroid tumors who have an aggressive clinical course is minor, but the number isn’t zero, so the question from the research world and patient perspective is, how we can best individualize care for these patients so that we don’t overtreat, but so we don’t miss a diagnosis as well? This is a very important question that affects a lot of people,” Ringel said.

‘Epidemic of overdiagnosis‘

Thyroid cancer appears to be diagnosed more often, some say due to newer screening modalities. However, at early stages, diagnosis is often not a danger to the patient’s health.

Ringel said when looking at the epidemiology of thyroid cancer, the increase appears to occur across the spectrum of thyroid cancer, but most frequently in small, stage 1 papillary thyroid cancer. Although there are several suggestions of why this is so, according to Ringel, one reason is related to the use of ultrasound and ultrasound-guided fine-needle aspiration — the ability to detect and biopsy thyroid nodules that are smaller and, therefore, detect thyroid cancers earlier.

“While this may be a good thing for some patients, it raises the potential for overdiagnosis, which further leads to unneeded surgery and subsequent therapies,” he said.

Megan Haymart, MD, assistant professor of medicine in the division of metabolism, endocrinology and diabetes and of hematology/oncology at the University of Michigan Health System, said the higher incidence can mostly be attributed to the increase in small tumors.

“There is controversy surrounding the etiology of the rise in thyroid cancer incidence. Many believe that there is this reservoir of indolent disease that we are dipping into and, by doing so, we end up with overdiagnosis,” she said. “Others argue that the reason for the increase in thyroid cancer is due to a new environmental exposure. It’s still a debated topic, but there is concern that we are picking up more low-risk disease — disease that some patients could potentially live their full-life and not die from.”

According to data from a 2013 study published in the British Medical Journal, technological advances have led to a dramatic increase in the detection of low-risk papillary thyroid cancers, which expose patients to unnecessary and potentially harmful treatments.

As previously reported, the number of thyroidectomies performed to treat thyroid cancer in the United States has increased by more than 60%, from 16,377 in 1996 to 27,493 in 2006.

In the study, Juan P. Brito, MD, a fellow of the division of endocrinology, diabetes, metabolism and nutrition at Mayo Clinic in Rochester, Minn., and colleagues reported that these procedures cost an estimated $416 million per year, and patients who undergo thyroidectomies are at a 1% to 6% risk for further complications. Additionally, the use of radioactive iodine significantly increased from one in 300 patients in 1973 to two in five patients in 2006.

“The advances in detection are unlikely to offer any benefit, as the death rate has not changed despite the increased trend of thyroid cancer,” Brito told Endocrine Today. “Increasingly, patients are diagnosed with conditions that are not destined to cause harm, putting them at risk for unnecessary, costly and harmful tests and interventions.”

Radioactive iodine

In years past, most patients with thyroid cancer received radioactive iodine as part of their cancer care. However, the pendulum has shifted more recently and the use of radioactive iodine varies widely across US health care institutions, according to Haymart.

“There is a large variation in the use of radioactive iodine in the United States,” she said. “It depends on where — region and hospital — the patient is treated whether or not radioactive iodine will be part of the treatment plan.”

Haymart and colleagues sought to identify the factors physicians utilize in determining the use of radioactive iodine after total thyroidectomy in 189,219 patients treated across 981 hospitals affiliated with the National Cancer Database from 1990 to 2008.

The results, published in 2011 in JAMA, indicated there was a significant increase in radioactive iodine use among the population of patients with well-differentiated thyroid cancer (P<.001). Specifically, a significant difference was observed in radioactive iodine use between patients with American Joint Committee on Cancer stages I and IV (OR=0.34) but not between stages II/III and IV (for stage II vs. stage IV, OR=0.97; for stage III vs. stage IV, OR=1.06).

Although 21.1% of the variation in radioactive iodine use was attributed to patient and tumor characteristics, 17.1% was associated with hospital type and volume. When the researchers later adjusted for available patient, tumor and hospital characteristics, 29.1% of variations were attributable to unexplained hospital characteristics.

“Among patients treated for well-differentiated thyroid cancer at hospitals in the National Cancer Database, there was an increase in the proportion receiving radioactive iodine between 1990 and 2008; much of the variation in use was associated with hospital characteristics,” Haymart and colleagues wrote.

Watch-and-wait

Although the watch-and-wait approach is not commonly used in the United States, data from a study conducted in Japan indicate that patients with papillary microcarcinomas that are <1 cm may be candidates for observation, regardless of patient background and clinical features.

“If there are subsequent signs of progression, such as tumor enlargement and novel nodal metastasis, it would not be too late to perform surgical treatment. Even though the primary tumor is small, careful surgical treatment including therapeutic modified neck dissection is necessary for lateral node metastasis papillary microcarcinoma patients,” the researchers wrote.

The study by Ito and colleagues, published in 2010 in World Journal of Surgery, included 340 patients who underwent observation and 1,055 who underwent surgical treatment without observation in Japan between 1993 and 2004.

At a follow-up of 5 years, 6.4% of patients had growth in their papillary microcarcinoma by 3 mm, which increased to 15.9% at the 10-year follow-up. Further, only 1.4% had new nodal metastasis at 5 years, and only 3.4% at the 10-year follow-up.

Patient background was not associated with risk nor were clinical features associated with tumor growth or novel nodal metastasis. Of the 109 patients included in the observation arm who later underwent surgical treatment for various reasons, none experienced disease recurrence. Researchers identified male gender and clinically apparent lateral node metastasis as independent prognostic factors for disease-free survival in those who underwent immediate surgical treatment.

“Most of the small, papillary cancers stayed stable, but a percentage grew,” Ringel said. “The question is: How do we identify the group destined to grow? Is it safe to say we are going to monitor this by ultrasound and go to surgery after growth has occurred or should all patients have early surgery? The answer at the present moment is not entirely clear, and this is an intriguing question. It is difficult for patients and physicians to feel comfortable about being monitored without surgery when a papillary cancer has been identified. What it comes down to is developing better biomarkers to accurately predict which nodules are more likely to progress vs. which ones are likely to remain stable over time.”

BRAF, RAS and RET/PTC mutations

Haymart said although the field of genetic markers is a ‘hot new area’ in thyroid cancer, it is unclear whether it will actually have clinical implications for this population of patients.

R. Michael Tuttle, MD, professor of medicine at Memorial Sloan Kettering Cancer Center, said the tremendous amount of new genetic information is causing a lot of confusion.

“We are all excited about [the new genetic information], and it’s amazing how much molecular data we currently have,” he said. “What we are trying to figure out is when specific molecular findings will offer prognostic information that goes beyond traditional anatomic staging. For example, many patients with aggressive BRAF tumors present with extrathyroidal extension and extensive lymph node metastases, so we already know they are a high-risk tumor. On the other hand, when BRAF mutations are identified in smaller tumors that are appropriately treated, the patients do well, despite having a potentially aggressive mutational profile. So, we are trying to figure out where, in the broad range of thyroid cancer patients, is knowledge of the specific genetic profile of the individual tumor going to provide clinically meaningful information.”

Although it is known that BRAF, RAS and RET/PTC are genetic mutations often identified in thyroid cancer, the mutations all have a particular link to a specific etiology, according to Yuri E. Nikiforov, MD, of the department of pathology at the University of Pittsburgh.

Nikiforov and colleagues aimed to analyze trends in demographic, clinical, pathologic and molecular characteristics among 469 consecutive cases of papillary thyroid carcinoma.

The results, published in The Journal of Clinical Endocrinology & Metabolism, indicated that the increase in papillary thyroid carcinoma incidence during the previous 40 years could be characterized by increased age at diagnosis as well as the detection of smaller-sized, intrathyroidal papillary thyroid carcinomas.

“Molecular profiles of thyroid cancer have changed over the last 40 years and the increase is very unlikely due to radiation exposure,” Nikiforov said in an interview. “For example, with the Chernobyl explosion, there was a fear of radiation exposure, but incidence of RET/PTC mutations, a marker of radiation-induced carcinogenesis is decreasing, not increasing.”

Conversely, there appears to be a marked increase in RAS mutations, according to Nikiforov.

“New etiologies are involved, we do not know what these etiologies are, but there’s a very big difference from 30 years ago when we had almost no RAS to now almost 35% of thyroid cancers include this mutation. It may be what we eat and the air we breathe — this probably has something to do with the increase in thyroid cancer,” Nikiforov said.

Team approach

Experts said a team approach is crucial when treating the patient with thyroid cancer.

“I fully believe that the best care of the thyroid cancer patient is when the surgeon, endocrinologist and nuclear medicine physician all work closely with one another as a team,” Tuttle said. “In the past, thyroid cancer was treated as a ‘one-size-fits-all’ — everyone received the same treatment and follow-up. However, we cannot be further from that now.”

Thomas J. Giordano, MD, PhD, professor in the department of pathology, and director of tissue and molecular pathology core at the University of Michigan Health System, said oncologists do not normally provide care for thyroid patients until they have progressed from the well-differentiated thyroid cancer category.

“Well-differentiated cancers are normally treated by surgeons, endocrinologists and nuclear medicine physicians. If the tumors evolve or progress to the other categories, then oncologists are brought in,” Giordano said. “Therefore, a lot of oncologists do not know thyroid cancer very well because it falls under the domain of endocrinology; they just do not see much well-differentiated thyroid cancer in their training.”

The Cancer Genome Atlas

Giordano is a leader in the team effort to map the genetic changes in thyroid cancer via The Cancer Genome Atlas — “a comprehensive effort to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies, specifically large-scale genome sequencing.”

Thyroid cancer is one of the 20 various cancer types chosen for the project launched in 2005 by the National Cancer Institute and the National Human Genome Research Institute.

During a 3-year study period, Giordano and colleagues assessed the genomic data on 500 papillary carcinomas and reinforced the concept that tumors, driven by RAS mutations, tend to have a follicular architecture and are relatively indolent compared to tumors driven by BRAF mutations.

“Our large study with The Cancer Genome Atlas suggests papillary carcinoma tumors with RAS and BRAF mutations are definitely biologically distinct,” he said. “Our paper, which has been submitted for publication, suggests there may be a re-classification of RAS-driven tumors and also suggests that maybe the tumors we are calling ‘follicular-variant of papillary’ may actually be more closely related to follicular carcinomas.”

Giordano said he and colleagues plan to propose in a subsequent paper that encapsulated noninvasive follicular variant papillary carcinomas should be placed into a follicular carcinoma in situ category.

“This would send the message that they are less likely to metastasize, much like ductal carcinoma of the breast is less likely to metastasize,” he said. “The bottom line is that our paper will trigger a discussion on what is the most appropriate classification of thyroid cancer. This has implications for the watch-and-wait approach because if we come up with a more meaningful classification, then it will change practice patterns. This is what we are hopeful for and where we are headed. We are at this golden age of thyroid genotyping and diagnostics and prognostics where we will continue to see them through in the years to come. It’s really a fun time for the thyroid field.” — by Jennifer Southall

Should endocrinologists learn to use end-stage oncology drugs for treating advanced thyroid cancer?

Oncologic endocrinologists are equipped to deliver the full spectrum of medical care, including oncology drugs.

Oncologic endocrinologists with particular training and expertise are equipped to deliver the full spectrum of medical care, including oncology drugs, for patients with advanced thyroid cancer. After all, physicians in subspecialties such as gynecology oncology, rheumatology, and in some cases, dermatology, are trained to administer biologics and chemotherapy.

Historically, oncology training programs provide limited exposure to thyroid cancer, while endocrinology programs are heavily weighted in this area. An understanding of the natural history of thyroid cancer is critical for the management of this disorder. In order to achieve this, it is necessary to be exposed to the disorder early during its development as well as later during its natural history, including its metastatic phase. When to utilize a given treatment for thyroid cancer, and more importantly, when not to, is an important aspect that endocrinologists are exposed to.

Many patients with advanced differentiated thyroid cancer (DTC) can benefit from radioactive iodine (RAI), and the ones who don’t often times have indolent disease controlled with suppression of the thyroid-stimulating hormone, not requiring systemic chemotherapy. Medullary thyroid cancer (MTC) patients, as well, often have indolent disease, but the standard treatment is different from DTC.

Once patients are ready to begin systemic therapy, they should be referred to an oncologic endocrinologist or oncologist. Oncologic endocrinology programs, such as the one at MD Anderson Cancer Center, train endocrinologists to care for the full spectrum of these diseases, including symptom management from advanced disease, systemic therapies, management of adverse events related to systemic therapies and end-of-life care. In addition, they are attuned to the special needs of thyroid cancer patients such as monitoring and dosing of thyroid hormone, management of post-thyroidectomy complications exacerbated by multikinase inhibitors (such as hypoparathyroidism), and treatment of Cushings syndrome in the case of MTC patients. Recently, MEK inhibitors have been used in an attempt to restore RAI uptake. If these drugs prove to be effective, oncologic endocrinologists would be well positioned to coordinate this type of care.

As more and more thyroid cancer patients will be referred for systemic therapy, it will be imperative to cross-train both the endocrinology and oncology fellow in the care and appropriate management of the patient with advanced thyroid cancer.

Maria E. Cabanillas, MD, FACE, is an associate professor and faculty director of clinical research in the department of endocrine neoplasia and hormonal disorders at the University of Texas M.D. Anderson Cancer Center. Cabanillas reports no relevant financial disclosures.

Just because the new kinase inhibitors are easy to prescribe does not mean that everyone should give these agents.

We can now treat advanced thyroid cancer with oral therapy, free of the need of infusion suites and thus, these drugs might be prescribed by an endocrinologist or an oncologist. However, just because the new kinase inhibitors are easy to prescribe does not mean that everyone should give these agents.

In general, in the United States, those specializing in medical oncology spend considerable time learning how to use many types of anticancer therapies and how to best manage the toxicities. This equips them with not just knowledge, but experience to handle the most complicated of patients and the toxicities that arise in the setting of kinase inhibitor treatment. In addition, most patients will experience progression on at least first-line and likely second- and third-line therapies, and there will likely be additional options, such as those available in the context of a clinical trial, of which the vast majority are available only through an oncologic practice.

Supportive care, such as infusions of zolidronic acid, are routinely given in the infusion suites of oncologists office, and palliative care, nutritional support and other supportive services are central to oncology care. Finally, most oncologist’s office have facilities and resources to allow 24-hour support by a certified nurse practitioner or an oncologic nurse. This provides critical identification and support to the patients if they encounter life threatening toxicities, as well as the ability to handle them quickly and effectively.

On many occasions, we have encountered patients referred to us because of “progression on a kinase inhibitor” only to find that they are still responsive to the agent and that inexperience in using these agents resulted in premature dose reductions or treatment discontinuation resulting in compromised results.

Over the past 5 years, virtually all endocrinologists that I have met in the U.S. have said that they do not have the resources or the desire to treat patients with this high acuity. While there are exceptions to this rule in a few medical centers that offer multidisciplinary cancer care (and thus have the resources necessary to support the more advanced patients), endocrinologists in the community need to be informed that there are options for these patients.

Thus, it is crucial that they identify an oncologist that has dedicated time to learn the issues specific to the care of thyroid cancer patients with advanced disease (ideally one who has taken time to understand the particular needs of thyroid cancer patients). In summary, with extremely few exceptions, in the interest of patient safety and improved outcomes and access to patient support services , patients with advanced thyroid cancer should be treated in the setting of an oncologist’s office.

Marcia S. Brose, MD, PhD, is an associate professor and director of the thyroid cancer theraputics program at the Abramson Cancer Center at the University of Pennsylvania. Brose reports no relevant financial disclosures.