Thyroid cancer treatment no longer ‘one-size-fits-all’ approach

Thyroid cancer incidence is increasing faster than any other malignancy in the United States.

Rates nearly tripled during the past four decades, climbing from 4.9 per 100,000 people in 1975 to 14.3 per 100,000 people in 2009, according to a study published in April in JAMA Otolaryngology — Head and Neck Surgery.

A closer look at the statistics, however, reveals several intriguing trends.

For example, incidence of follicular, medullary and anaplastic thyroid cancers have remained steady for the past 30 years. Meanwhile, incidence of papillary thyroid cancer — a slow-growing tumor that accounts for about 85% of all thyroid cancer cases in the United States — increased threefold since the early 1970s, according to a study published last year in BMJ.

“The data demonstrate that papillary thyroid cancer incidence is rising in the United States and worldwide,” Matthew Ringel, MD, professor in the divisions of oncology and endocrinology and director of the division of endocrinology, diabetes and metabolism at Ohio State University Wexner Medical Center, told HemOnc Today. “It has really picked up in terms of frequency since the late 1980s and early 1990s, which coincides with the more frequent use of neck and thyroid ultrasound.”

Despite the increased incidence of thyroid cancer, the death rate has remained stable at 0.5 per 100,000 since the late 1970s. Some researchers suggest rapidly improving technology has dramatically increased the detection of low-risk cancers that may never cause harm.

“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,” Ringel said. “The number of patients with small thyroid tumors who have an aggressive clinical course is [low], but the number isn’t zero. The question from the research world and patient perspective is: How we can best individualize care for these patients so we don’t overtreat, but so we don’t miss a diagnosis?”

HemOnc Today spoke with several experts about the potential for overdiagnosis, the evolving debate about treatment vs. watch-and-wait strategies, and how the increasing availability of genomic data may reshape the treatment and follow-up care offered to patients with thyroid cancer.

‘Epidemic in diagnosis’

The overall increase in thyroid cancer incidence appears driven largely by diagnosis of small, stage I papillary thyroid cancers.

“There is controversy surrounding the etiology of the rise in thyroid cancer incidence,” Megan Haymart, MD, assistant professor of medicine in the division of hematology/oncology and the division of metabolism, endocrinology and diabetes at University of Michigan Health System, told HemOnc Today. “Many believe that there is this reservoir of indolent disease that we are dipping into and, by doing so, we end up with overdiagnosis. 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 [with which] some patients could potentially live their full lives and not die from.”

In a study published last year in BMJ, Juan P. Brito, MD, a fellow in the division of endocrinology, diabetes, metabolism and nutrition at Mayo Clinic in Rochester, Minn., and colleagues suggested “zealous imaging” and the power of improved technologies to detect smaller lesions have combined to fuel an “epidemic in diagnosis” of low-risk papillary thyroid cancers.

For example, the use of ultrasound and ultrasound-guided fine-needle aspiration has improved clinicians’ abilities to detect and biopsy smaller thyroid nodules. This helps to detect thyroid cancers at an earlier stage, but it also exposes patients to unnecessary treatments and potential complications.

The number of thyroidectomies performed to treat thyroid cancer in the United States increased by more than 60% — from 16,377 per year to 27,493 per year — from 1996 to 2006, according to Brito and colleagues. These procedures cost an estimated $416 million per year, and patients who undergo thyroidectomies face a 1% to 6% risk for further complications.

Additionally, the use of radioactive iodine significantly increased during the past four decades, 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 HemOnc Today when the BMJ study was published. “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 underwent treatment with radioactive iodine, which can destroy the thyroid gland and thyroid cells without harming the rest of the body.

However, considerable uncertainty exists about the appropriate indications for radioactive iodine in thyroid cancer treatment, and the pendulum has shifted.

“There is a large variation in the use of radioactive iodine in the United States,” Haymart said. “It depends on where — region and hospital — the patient is treated whether radioactive iodine will be part of the treatment plan.”

Haymart and colleagues sought to identify the factors that influenced use of radioactive iodine after total thyroidectomy in 189,219 patients treated at 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 patients with well-differentiated thyroid cancer (P<.001). Researchers observed a significant difference in radioactive iodine use between patients with American Joint Committee on Cancer stages I and IV disease (OR=0.34; 95% CI, 0.31-0.37), but not between stages II and IV (OR=0.97; 95% CI, 0.88-1.07) or between stages III and IV (OR=1.06; 95% CI, 0.95-1.17).

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

“The significant between-hospital variation in radioactive iodine use suggests clinical uncertainty about the role of radioactive iodine in thyroid cancer management,” Haymart and colleagues concluded. “Of concern, for patients with thyroid cancer, the hospital where care is received has a substantial influence on treatment with radioactive iodine after total thyroidectomy, even after accounting for patient and tumor characteristics.”

Watch and wait

Although a watch-and-wait strategy is not commonly employed for thyroid cancer in the United States, results of a study conducted in Japan suggest patients with papillary microcarcinomas (PMC) that are <1 cm may be candidates for observation, regardless of patient background and clinical features.

Ito and colleagues evaluated 340 patients who underwent observation and 1,055 who underwent surgical treatment without observation between 1993 and 2004. Mean follow-up was 74 months (range, 18-187).

The results, published in 2010 in World Journal of Surgery, showed PMCs enlarged by 3 mm or more in 6.4% of patients by 5 years. The rate increased to 15.9% at 10 years. Researchers observed new nodal metastasis in 1.4% of patients at 5 years and 3.4% of patients at 10 years.

Researchers determined no factors related to clinical features or patient background predicted tumor growth or nodal metastasis. They also reported that 109 of the 340 patients assigned observation ultimately underwent surgery, and none showed recurrence.

“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,” Ito and colleagues wrote.

Although most of the small papillary cancers stayed stable, it is important to emphasize that some did grow, 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?” Ringel said. “The answer … 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.”

Team approach

Regardless of the reasons for increased thyroid cancer incidence, a team approach is essential to ensure proper treatment, according to R. Michael Tuttle, MD, professor of medicine at Memorial Sloan Kettering Cancer Center.

“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,” Tuttle said in an interview. “In the past, thyroid cancer was treated as ‘one-size-fits-all’ — everyone received the same treatment and follow-up. However, we cannot be further from that now.”

Patients with well-differentiated thyroid cancers typically are treated by surgeons, endocrinologists and nuclear medicine physicians. Oncologists typically do not provide care for patients with thyroid cancer unless their disease progresses beyond well-differentiated thyroid cancer, according to Thomas J. Giordano, MD, PhD, professor in the department of pathology and director of the tissue and molecular pathology core at the University of Michigan Health System.

“Therefore, a lot of oncologists do not know thyroid cancer very well because it falls under the domain of endocrinology,” Giordano said. “They just do not see much well-differentiated thyroid cancer in their training.”

Genetic markers

As in all types of cancers, tremendous emphasis has been placed on efforts to identify genetic markers that drive the development and progression of thyroid cancers.

However, the clinical implications of this effort remains unclear.

“We are all excited about [the new genetic information], and it’s amazing how much molecular data we currently have,” Tuttle 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-mutated tumors present with extrathyroidal extension and extensive lymph node metastases, and it is well understood that those patients have high-risk tumors.

“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,” Tuttle said. “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.”

BRAF, RAS and RET/PTC mutations often are identified in thyroid cancer, but 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 analyzed trends in demographic, clinical, pathologic and molecular characteristics among 469 consecutive cases of papillary thyroid carcinoma from 1974 to 2009. They assessed BRAF and RAS mutations, as well as RET/PTC rearrangements, among the 341 tumors that were at least 0.3 cm in size.

The results, published in February in The Journal of Clinical Endocrinology & Metabolism, indicated 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. “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.”

Nikiforov and colleagues determined the proportion of BRAF mutations remained stable during the study period, but the researchers observed a sharp increase in RAS mutations after 2000.

“New etiologies are involved,” Nikiforov said. “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, [when] 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.”

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, which the NIH describes as “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 was one of 20 cancer types chosen for the project, launched in 2005 by the NCI and the National Human Genome Research Institute.

During a 3-year study period, Giordano and colleagues assessed genomic data on 500 papillary carcinomas. Their findings reinforced the understanding 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 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,” Giordano 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

References:

Brito JP. BMJ. 2013;347:f4706.

Davies L. JAMA Otolaryngol Head Neck Surg. 2014;140:317-322.

Haymart MR. JAMA. 2011;306:721-728.

Ito Y. World J Surg. 2010;34:28-35.

Jung CK. J Clin Endocrinol Metab. 2014;99:e276-285.

For more information:

Thomas J. Giordano, MD, PhD, can be reached at The University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; email: giordano@med.umich.edu.

Megan Haymart, MD, can be reached The University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; email: meganhay@med.umich.edu.

Yuri E. Nikiforov, MD, PhD, can be reached at The University of Pittsburgh, 4200 Fifth Ave., Pittsburgh, PA 15260; email: nikiforovye@upmc.edu.

Matthew Ringel, MD, can be reached at The Ohio State University, 565 McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210.

R. Michael Tuttle, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065.

Disclosure: Giordano, Haymart, Nikiforov, Ringel and Tuttle report no relevant financial disclosures. Disclosure: Brose reports no relevant financial disclosures.

 

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

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, whereas 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 to which endocrinologists are exposed.

Many patients with advanced differentiated thyroid cancer (DTC) can benefit from radioactive iodine (RAI). The ones who don’t often have indolent disease controlled with suppression of the thyroid-stimulating hormone, thereby not requiring systemic chemotherapy. Patients with medullary thyroid cancer (MTC) 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 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 (such as hypoparathyroidism) exacerbated by multikinase inhibitors, and treatment of Cushing’s 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 endocrinology and oncology fellows 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 MD Anderson Cancer Center. She can be reached at mcabani@mdanderson.org. Disclosure: Cabanillas reports no relevant financial disclosures.

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.

We can now treat advanced thyroid cancer with oral therapy, free of the need of infusion suites. 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 who specialize 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 knowledge and 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 likely will be additional options — such as those available in the context of a clinical trial — the vast majority of which are available only through an oncologic practice.

Supportive care, such as infusions of zoledronic acid, are routinely given in the infusion suites of an oncologist’s office, and palliative care, nutritional support and other supportive services are central to oncology care. Finally, most oncologists’ offices 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 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, leading to compromised results.

Over the past 5 years, virtually all endocrinologists I have met in the United States have said they do not have the resources or the desire to treat patients with this high acuity. Although 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 who 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.

 

Marcia S. Brose, MD, PhD, is an associate professor and director of the thyroid cancer therapeutics program at Abramson Cancer Center at the University of Pennsylvania. She can be reached at brosem@mail.med.upenn.edu. Disclosure: Brose reports no relevant financial disclosures.