Delivering Targeted Therapy for Advanced Thyroid Cancer

Considerable progress in understanding the molecular basis of rare thyroid cancer cases has led to the introduction of new drugs that target specific genetic mutations, enabling personalized care and improved survival.

with Trevor Angell, MD, Elena A. Christofides, MD, Gary Clayman, MD

The therapeutic advances and the benefits of personalized treatments in advanced thyroid cancer were reviewed by Cabanillas et al,1 in a review article published in the journal, Endocrine Reviews.

The discussion addressed the increasing reliance of targeted therapies for a small percentage of patients with advanced thyroid cancers. The question of who should be delivering these targed drugs seems to raise greater consideration than which drug for which patient. 

Aggressive thyroid cancers are rare and often fatal but new drugs hold promise.

Rare Thyroid Cancers Require New Drugs to Improve Survival 

Despite an anticipated decline in the number of diagnosed cases of thyroid cancer diagnoses of 1,920 this year, the number of deaths are expected to increase by 5.3%, or 2,170 individuals in the same time period. This follows a trend in which the rate of thyroid cancer deaths has been gradually increasing over the past few years.1

In addition, the increased use of high-resolution imaging which is able to detect small thyroid nodules not otherwise detected with prior imaging approaches has led to a tripling in rate of diagnosed cases of thyroid related cancers in the past 30 years,1 according to the American Cancer Society.

For the majority of patients diagnosed with thyroid cancer, the prognosis remains excellent, with an overall disease-specific survival of greater than 90%. This is hold true particularly for patients with differentiated thyroid cancers (DTCs), which represent about 85% of thyroid cancers.1

“Surgery remains the mainstay treatment for all thyroid cancers. Control of disease in the neck is the primary priority for all patients with thyroid cancer. However, this article highlights new therapies that have clinical efficacy against some of the most challenging thyroid cancers – that may be inoperable or have significant progressing distant disease,”said Gary Clayman, MD, founder and director of the Clayman Thyroid Center at Tampa General Hospital in Florida, and professor emeritus at the University of Texas MD Anderson Medical Center in Houston, in reviewing the article for EndocrineWeb. “These rare thyroid cancers require a very knowledgeable interdisciplinary team that understands how to control disease in the neck.”

In an effort to identify possible prognostic factors for the more aggressive thyroid cancers, a team of investigators examined data from nearly 60,000 patients from the Surveillance, Epidemiology, and End Result (SEER) database.2

The mean overall survival for patients with advanced thyroid cancers ranges from less than six months to about five years, with age at diagnosis being the major factor in thyroid-specific cancer survival,2 reported Hai-Yan Zhang and colleagues.

Consider Range of Factors Influencing Prognosis

While several factors were identified as contributing to a worse prognosis, particulalry clinical-patholgoical features and treatment approach, age at diagnosis (> 65 years) regardless of surgical approach (ie, thyroidectomy, lobectomy) proved most influential (P = 0.01). In this older age group, faxtos such as gender (ie, being male), follicular subtype, and aged tumor grade and stage, arose as the most influential characteristics. In general, men with differentiated thyroid cancer had a poorer outcomes than women with undifferentiated thyroid cancers. 2

For the few individuals with a diagnosis of  locally invasive and/or distant metastatic DTCs, advanced medullary thyroid cancer (MTC)—which represents about 5% of all thyroid cancers, nearly one-third of which are hereditary­—or anaplastic (undifferentiated) thyroid cancer (ATC)—reflecting fewer than 1% of all thyroid cancers that are nearly always fatal.  

Currently, the major targets for advanced thyroid cancers involve antiangiogenic tyrosine kinase inhibitor (TKI) drugs, such as the Food and Drug Administration-approved agents: cabozantinib, lenvatinib, sorafenib, and vandetanib.

Aggressive Thyroid Cancer Cases Challenge Clinical Practice

“Until recently, patients with more rapidly progressing cancers who did not respond to radioactive iodine or surgery had few other treatment options; however, the introduction of the TKI drugs has afforded patients an effective treatment alternative” said Trevor E. Angell, MD, associate medical director of the thyroid center and assistant professor of clinical medicine at the Univesity of Southern California Keck School of Medicine in Los Angeles, California. However, these agents are not curative and the thyroid cancers likely will progress.

There are currently two FDA-approved drugs for MTC, and emerging agents in the pipeline include one that targets the RET receptor as well as Peptide Receptor Radionucleotide therapies.3[Cabanillas 2019] Personalized agents have also been develop—some of which are now FDA-approved—for differentiated thyroid cancer. A drug combination of BRAF and MEK inhibitor dabrafenib and trametinib) for BRAF mutated anaplastic thyroid cancers has also received FDA approval to which seven in 10 patients demonstrated good response.4

“This article creates a conundrum,” said Elena A. Christofides, MD, FACE, CEO of Endocrinology Associations Inc, and clinical associate professor of endocrinology at Ohio University College of Medicine in Columbua, in an interview with EndocrineWeb, “in that community-based endocrinologists, who are primarily responsible for the diagnosis and management of the majority of thyroid cancers, as well as many hospital pathologists, do not have ready access to this level of molecular testing. Consequently, patients who might benefit from the testing are not receiving it and thus may not be receiving the most targeted, individualized treatment.”

Dr. Angell told EndocrineWeb: “Any community-based endocrinologists who can and do prescribe these drugs, must be able to provide the necessary monitoring for adverse effects.” However, “much of the substantial information disseminated in this article may not be as clinically relevant to [private practice clinicians] as perhaps to academic endocrinologists and/or oncologists who are more likely to treat such patients with rare, advanced thyroid cancers.”  

Specialized Genetic Testing, Intensive Follow-Up for Advanced Thyroid Cancer

Both Dr. Angell and Dr. Clayman agreed that community-based endocrinologists are rarely positioned to genotype the more resistant cancers, match them with the new systemic therapies, and provide the intensive monitoring and follow-up that is needed during treatment with the therapies.  In addition, “it may be difficult to know exactly when to start the therapy as some advanced cancers may remain stable for a long time without progressing,” Dr. Angell added.

“When our patients with thyroid cancer are not optimally responding to the available treatments (eg, radioactive iodine, thyroid hormones, or surgery), we send them to academic centers. But what if the nearest center is six or eight hours away by car? Do we just keep doing surgery because our patients cannot access the testing needed to enable us to prescribe the newer, more effective therapy that specifically targets their type of thyroid cancer?,” said Dr. Angell.

“Wouldn’t it be great if all of us could do the testing ourselves and refer the patient, if needed, to tertiary care centers already armed with knowledge about their rare genetic mutation?” said Dr. Angell, “However, a thyroidectomy specimen might not be representative of the molecular fingerprint of the cancer in the metastasis, which may be more challenging for most endocrinologists to obtain for biopsy.”

Dr. Clayman recommends that in these rare cases, clinicians refer their patients to the closest Center of Excellence or academic institution where the endocrinology staff are equipped to diagnose and treat aggressive cancers using personalized medicine.

While the majority of community-based endocrinologists are unlikely to manage these patients,  Dr. Christofides hopes the article may “energize and arm community-based physicians (and their patients) with the information necessary to advocate for having greater access to the molecular tests, and thus to the more personalized treatments.”

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