Management of medullary thyroid cancer remains challenging

Annual Meeting of the ATA

INDIAN WELLS, Calif. — Medullary thyroid cancer is a complex disease that presents unique challenges, speakers said here. Careful consideration of its molecular components and insight into management issues, however, can help clinicians overcome these hurdles.

Although genetic defects are involved in all types of cancer, approximately 25% of cases of medullary thyroid carcinoma are caused by inherited, or germline, mutations, according to Gilbert Cote, PhD, of the MD Anderson Cancer Center. For hereditary medullary thyroid cancer, three major subtypes exist: multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B) and familial medullary thyroid carcinoma, he said during a presentation. These forms of disease often arise from inherited mutations in the RET gene. Cote said, however, that knowing the specific mutation is critical for characterizing risk levels for patients.

Role of genetic mutations

According to risk classifications outlined by the ATA, level D mutations carry the highest risk for developing aggressive medullary thyroid carcinoma, whereas levels A and B mutations are associated with lower risk for aggressive disease. The current guidelines recommend that patients with level D mutations undergo thyroidectomy as early as possible.

Prophylactic thyroidectomy generally appears to offer a cure for these patients, Cote noted, citing a study published by Roehmer et al in the Journal of Clinical Endocrinology & Metabolism showing that more patients with RET mutations were disease-free after the introduction of genetic testing.

Nevertheless, questions remain, Cote said. For example, clinicians are asking whether genetic analysis of mutations can be beneficial for treatment of patients with sporadic disease or whether RET should be the therapeutic target. Despite these uncertainties, the important role that RET mutations play in familial and sporadic medullary thyroid carcinoma is clear.

“Molecular typing of tumors has the potential to enhance therapeutic decision-making,” he said.

Surgical management

Surgery for medullary thyroid cancer is complicated, but can lead to successful management of the disease, according to Douglas B. Evans, MD, of the Medical College of Wisconsin.

“Many patients with MEN2A are in well-described families, so with proper genetic counseling and medical attention, prophylactic thyroidectomy can occur,” he said. “With MEN2B, this is not the case. It is very rare and is often a spontaneous mutation.”

For example, Evans noted that few patients are diagnosed early and even fewer undergo thyroidectomy during early childhood. “It is important to remember that, unfortunately, it is rarely recognized on time.”

Assessing lymph nodes in children and adolescents can also be difficult, Evans pointed out. He said that he typically removes the lymph nodes, even if examinations yield indeterminate results. The recurrent nerves in children with MEN2B are actually quite large, he noted, and the neck tends to make adhesions, making going back into the neck much more problematic.

Evans also explained that prophylactic neck dissection is usually appropriate, except in cases of MEN2A or familial medullary thyroid cancer and N0 neck; when calcitonin is lower than 40 pg/mL; and when a patient has a normal thyroid ultrasound or a nodule smaller than 5 mm. ATA guidelines, however, do not typically recommend prophylactic lateral neck dissections.

“The current guidelines recommend that the lateral neck be dissected only if imaging is positive,” Evans said. “The logic is that most patients postoperatively are not rendered biochemically cured.”

Knowing the mutation status is also helpful, according to Evans. A mutation associated with MEN2A vs. MEN2B, for instance, may alter how the disease is managed.

Finally, Evans said, clinicians can consider external beam radiation in appropriate circumstances, but they should ensure that the patient has had maximal surgical treatment first.

On the horizon

At present, several novel therapies for treatment of medullary thyroid cancer are being investigated, including those that target intervention at the RET protein, Douglas W. Ball, MD, of Johns Hopkins University School of Medicine, said.

Of the many multikinase inhibitors being evaluated, vandetanib (Caprelsa, AstraZeneca) recently received FDA approval in April 2011. The agency’s decision was based on a randomized, placebo-controlled clinical trial, published online this week in the Journal of Clinical Oncology, involving 331 patients with unresectable, locally advanced or metastatic medullary thyroid cancer showing a significant improvement in progression-free survival and no data for overall survival. Serious adverse events, including diarrhea, colitis, nausea, headache, rash and, most concerning, the second highest degree of QT prolongation of any FDA-approved drug, were observed during the trial. Consequently, the agency requires prescribers to take an online course educating them about potential issues and what they need to monitor in patients taking this medication.

Ball also highlighted promising results from phase 1 and phase 3 studies of the multikinase inhibitor cabozantinib (XL184) and pointed out that trials involving lenvatinib are ongoing. Still, new ideas are needed.

“Preclinically, we need genetic discovery to expand potential targets and better model systems. Too long have we relied on the TT line or additional tumor lines,” Ball said. “Clinically, we need better pharmacodynamic assessments, better understanding of patterns of failure and some insight into appropriate sequencing of agents, time of therapy and novel approaches.”

For more information:

• Kloos RT. Early riser symposium: Management of medullary thyroid cancer from diagnosis to therapeutic trials. Presented at: the 81st Annual Meeting of the American Thyroid Association; Oct. 26-30, 2011; Indian Wells, Calif.

Richard T. Kloos, MD

I thought this session was tremendous. We heard experts in their field present data that’s published, but we also saw new research that has just emerged during the past week and the past several months. We also heard their thoughts on directions forward and about results of potentially two new studies that may direct our patient care. We have one FDA-approved drug, which is new compared to a year ago. We heard some warnings about its potential side effects and the need for special training, with the FDA requesting that providers register to be able to write this prescription. It’s fairly easy to get approved, but it’s a nice reminder that these drugs have side effects. We also heard a call for further investigation because there are a number of areas that we don’t quite understand completely. There were descriptions of gene mutations, about whether they could even be new targets for therapy, so I think that these sessions were incredibly informative for me. They were also informative because the speakers presented questions to the audience before their sessions began and received some clearly wrong answers from the audience. I interpret that as the fact that this is a rare disease, and most people in the audience don’t see hundreds of these patients. So, it’s an educational opportunity for us to go forward, to see those errors and think about what we can help do to further educate everyone.

- Richard T. Kloos, MD

Secretary and Chief Operating Officer
American Thyroid Association

Disclosure: Dr. Kloos reports no relevant financial disclosures.

This was an unbelievably good presentation, very clear, and it helped to clarify how genetic testing in not only familial cases but also sporadic cases can help direct therapy and clarify the correct surgical approach, and the hope with some of the new chemotherapy agents.

- Carol Greenlee, MD

Western Slope Endocrinology
Grand Junction, CO

Disclosure: Dr. Greenlee reports no relevant financial disclosures.