CHICAGO — An individually tailored approach to providing thyroid hormone replacement in thyroid cancer patients should be guided by the findings of several key studies, according to endocrinologist Giuseppe Barbesino.
The evidence at hand doesn't permit sweeping generalizations about what the target TSH level should be, said Dr. Barbesino of Harvard University, Boston.
He said that one important study that has influenced his thinking was led by Dr. Jacqueline Jonklaas of Georgetown University, Washington. She and her coinvestigators analyzed a prospective multicenter registry and showed for the first time that it isn't necessary to drive TSH levels below 0.1 mIU/L to improve overall survival in patients with stage II thyroid cancer. Survival can be improved in such patients with moderate TSH suppression in the range of 0.1 but less than 0.5 mIU/L (Thyroid 2006;16:1229–42).
That's an important observation because aggressive TSH suppression to less than 0.1 mIU/L in patients with differentiated thyroid cancer carries several downsides. It is associated with an increased risk of new-onset atrial fibrillation, an increase in left ventricular mass index and other echocardiographic abnormalities, and some as-yet-inconclusive evidence suggesting increased risks of cardiovascular mortality, fracture, and decreased bone mineral density, Dr. Barbesino noted at a satellite symposium held in conjunction with the annual meeting of the American Thyroid Association.
The abnormalities of cardiac structure and function associated with TSH suppression in thyroid cancer patients are subtle. Their clinical significance remains unclear, he said. But it's noteworthy that investigators at the University of Cagliari (Italy) have demonstrated that these abnormalities—including left ventricular posterior wall thickening, increased intraventricular septum thickness, increased left ventricular end-diastolic dimension, and an associated diminished exercise tolerance—are reversible by titrating the levothyroxine dose down to the minimum still capable of inducing TSH suppression (J. Clin. Endocrinol. Metab. 2000;85:159–64). This is a practice well worth following, the endocrinologist continued at the symposium supported by Abbott Laboratories, maker of a test for TSH.
Whether TSH suppression with levothyroxine does indeed reduce bone mineral density and increase fracture risk remains an open question.
“I've looked at meta-analyses that included studies from the same period and came to almost diametrically opposite conclusions as to whether TSH suppression is a serious risk factor for fractures,” Dr. Barbesino said.
He suggested the following individually tailored approach to TSH suppression in thyroid cancer patients: Reserve aggressive TSH suppression to less than 0.1 mIU/L for patients with high-risk stage III-IV or incurable tumors, since that approach has been shown to improve overall survival.
Consider a target level of 0.1 to less than 0.5 mIU/L in patients with low-risk tumors prior to restaging, and in patients with high-risk tumors who have had several years with no disease activity, particularly if the patients are over age 60, when the increased risk of atrial fibrillation and other side effects associated with aggressive TSH suppression are likely to be most damaging.
Reserve mild TSH suppression to a target of 0.5 to less than 2.5 mIU/L for patients with microcarcinomas or tumors who are deemed low risk following negative restaging.
Dr. Barbesino added that he tries to avoid TSH levels of 2.5 mIU/L or more in thyroid cancer patients. He said he is especially careful to keep levels under 5.0 mIU/L because values above that are associated with rapid growth of metastases.
Naturally occurring hyperthyroidism has been far more extensively studied than TSH suppression with levothyroxine in thyroid cancer patients. Key unresolved questions for future research include whether the clinical impact of these two forms of TSH suppression is similar, whether TSH suppression in cancer patients can be stopped at some point without increasing the risk of relapse, and whether the adverse effects of TSH suppression in cancer patients can be mitigated with β-blockers, bisphosphonates, or other therapies, Dr. Barbesino said.
He disclosed having received honoraria from Genzyme Corp., maker of Thyrogen (thyrotropin alfa for injection).