MEDULLARY CANCER GUIDELINES

The newly released Revised American Thyroid Association (ATA) Guidelines for the Management of Medullary Thyroid Carcinoma are an update to the guidelines first published in 2009 and cover everything from a novel risk-category classification to new drugs for advanced disease. Still, more research is needed to improve treatment, the authors state.

The document is available on the ATA website and was published March 26, 2015 in Thyroid. Its 67 recommendations "address every aspect of clinical practice" for clinicians treating patients with medullary thyroid cancer, guideline task force chair Samuel A. Wells, Jr, MD, of the National Institutes of Health in Bethesda, Maryland, told Medscape Medical News.

The guidelines needed to be updated "because of recent significant advances in clinical research, especially the results of clinical trials of new molecular targeted therapeutics in patients with advanced [medullary thyroid cancer], improved methods of diagnosis and treatment of patients with [this cancer], and the need to consider a new classification for multiple endocrine neoplasia type 2 [MEN2] syndromes," he added.

Asked to comment, ATA President Robert C. Smallridge, MD, professor of medicine and former chair of the endocrinology Division at the Mayo Clinic in Jacksonville, Florida, said that the document "should be a valuable reference for all clinicians who are involved in the care of patients with this disorder."

According to Dr Smallridge, key recommendations include those "describing a change in risk category classification, a reclassification of MEN2A, an update on genetic testing, and a discussion of the role of genetic counseling."

The guidelines also do a good job of explaining "the effect of age on calcitonin levels, the extent of surgery ... and the new aspect of systemic treatment for progressive metastatic disease," he added.

Multidisciplinary Approach

The guidelines taskforce included international scientists working in endocrinology, ethics, genetics, molecular biology, medical oncology, pathology, pediatrics, nuclear medicine, radiation oncology, and surgery.

They reviewed relevant literature published from January 1980 to April 2014 to develop evidence-based recommendations for diagnosing and treating patients with medullary thyroid cancer, including sporadic or hereditary MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC).

Virtually all patients with MEN2A and MEN2B, have RET (rearranged during transfection) oncogene germline mutations, and half of patients with the sporadic form of the cancer have these mutations.

The current guidelines aimed to clear up confusion about classification. The original ATA guidelines classified cancers based on the RET mutations into categories A, B, C, or D, which indicated increasingly aggressive cancers. However other groups, such as the North American Neuroendocrine Tumor Society and National Comprehensive Cancer Network, use the TNM classification of the American Joint Committee on Cancer or terms such as level I, II, and III, or "high," "higher," and "highest," which was confusing.

The new guidelines have replaced ATA risk categories for hereditary medullary thyroid cancer as follows: categories A and B are now "moderate risk," category C is now "high risk," and category D is now "highest risk."

MEN2 syndromes are now subdivided into MEN2A (which account for 95% of cases) and MEN2B. Classical MEN2A includes medullary thyroid cancer plus less frequent pheochromocytoma or hyperparathyroidism or both. There are also three other less common MEN2A types.

The guidelines also describe how to manage patients with a thyroid nodule and a histological diagnosis of medullary thyroid carcinoma.

"The new methods of diagnosis and treatment regard primarily the use of advanced molecular testing in patients at risk for developing medullary thyroid carcinoma," said Dr Wells.

"This involves both the molecular analysis of the RET proto-oncogene and special immunohistochemical studies of medullary thyroid carcinoma tissue samples," he explained.

Significant Advances, Yet Much Remains to Be Done

Since the previous guidelines were published, two new therapies have become available. "On the basis of recently completed phase 3 clinical trials, the US Food and Drug Administration and European Medicines Agency approved two orally administered tyrosine kinase inhibitors, vandetanib in 2011and cabozantinib in 2012, for the treatment of patients with advanced progressive medullary thyroid carcinoma," Dr Wells and colleagues write.

Based on these trials, vandetanib and cabozantinib showed the potential to provide high rates of disease control with durable responses and a highly significant improvement of progression-free survival, the authors write.

However, the drugs have to be given daily and chronically to maintain tumor control; short-term toxicity is significant; and there are few data on long-term toxicity and no data on overall survival. Thus, currently the drugs are indicated only in patients with significant tumor burden and documented tumor progression.

Therefore, "despite significant advances in the diagnosis and treatment of patients with medullary thyroid carcinoma, much remains to be done," the authors write in an epilogue.

For example, there is a critical need for more effective therapies for patients with advanced medullary thyroid carcinoma, they note. Vandetanib and cabozantinib have increased progression-free survival compared with placebo in such patients, but over time the cancer becomes resistant to treatment and the disease progresses.

"Although new molecular targeted therapeutics will be evaluated in clinical trials, it is unlikely that a single compound will be curative," according to Dr Wells and colleagues.

However, ongoing animal research may lead to better therapies in the future. "Hopefully, preclinical studies of tumor cells and animal models of medullary thyroid carcinoma, and especially molecular analysis of tumor tissues collected from patients in tyrosine kinase inhibitor clinical trials, will lead to an understanding of the mechanisms of tumor resistance, and thereby the development of effective combinatorial therapies," the authors conclude.

Dr Wells has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. 

Thyroid. Published online March 26, 2015. Full article