Thyroid Hormone Suppression Therapy— Less is More for Thyroid Cancer

Aggressive TSH suppression offers little to no benefit in patients with differentiated thyroid cancer patients at low risk of recurrence and death based on a comprehensive review of the literature.

With David S. Cooper, MD, and Bryan R. Haugen, MD

For patients who undergo a total thyroidectomy or thyroid lobectomy, the need for long-term thyroid hormone replacement to maintain normal serum thyroid-stimulating (TSH) hormone levels, is the most notable post-surgical side effect.

Conversely, patients with differentiated thyroid cancer (DTC) may be treated with thyroid hormone suppression as a therapeutic strategy to reduce TSH levels, with the aim of improving outcomes.

The benefit studies on TSH replacement therapy have gone back and forth, with conflicting findings about the worth of that strategy, said David S. Cooper, MD, professor of medicine in the division of endocrinology, diabetes and metabolism at Johns Hopkins University School of Medicine in Baltimore.

For years, he said, the party line has been: "We want TSH low so as not to stimulate the growth of cancer." However, it appears that we may have been oversimplifying the treatment strategy such that from a systematic review of the research, published in Endocrinology and Metabolism Clinics of North America,1 Dr. Cooper said, the findings point to a need to individualize therapy.

Dissenting Opinions on Suppressing and Replacing TSH

"It turns out that most individuals with differentiated thyroid cancer are at low risk [for recurrence] to begin with, and don't have residual [cancer cells],'' he said. “So there would be no reason to maintain a low TSH level in these patients. However, for the small fraction of patients with more advanced thyroid cancers, there is some evidence that TSH therapy might result in an improved outlook. But for the vast majority of patients, TSH therapy really won’t matter," Dr. Cooper told EndocrineWeb.

Among the many studies cited by Dr. Cooper is a meta-analysis of 10 studies on which the researchers concluded that suppression therapy helped reduce morbidity and mortality  (relative risk 0.71, P < 0.05) for adverse events pertaining to combined disease progression/recurrence and death. However, these older studies failed to differentiate thyroid hormone replacement from thyroid hormone suppression; and, modern technology such as ultrasound and thyroglobulin measurement were also lacking, he said.

Results of studies falling under the umbrella of the National Thyroid Cancer Treatment Cooperative Study Group suggest that the most aggressive suppression therapy ''was of no value in patients at low risk for recurrence but was of benefit in high-risk patients."3,4

In a more recent research analysis,5 however, following nearly 5,000 thyroid cancer patients, moderate suppression (0.1 to 4 mU/L) led to improved outcomes in patients at all stages of thyroid cancer progression as compared to TSH levels kept in the normal to elevated range. However, any benefits disappeared after five years of follow-up.

Potential adverse events to consider include effects of suppressive therapy with levothyroxine. When patients with DTC were given excessive L-T4 doses, serum free thyroxine (fT4) was often at the upper limit of the reference range or even elevated.6-8  

This condition is termed exogenous subclinical hyperthyroidism, which may be linked with symptoms and signs of hyperthyroidism, including increased risk of cardiovascular morbidity and mortality as well as osteoporosis and fractures.9

Thyroid Hormone Suppression for Thyroid Cancer

After evaluating the amassed evidence for and against suppression therapy, and factoring in potential adverse effects, Dr. Cooper said since the average patient with DTC is at low risk for recurrence, the takeaway message for clinicians is that the TSH for these patients does not need to be suppressed.

The goal should be to achieve a TSH level at the low end of the normal range, he told EndocrineWeb. As such, Dr. Cooper suggests following the graded algorithm cited in the American Thyroid Association (ATA) guidelines with consideration given to the potential for benefits of therapy balanced against any individual cardiovascular and skeletal risks.10

According to the ATA guidelines,10 serum TSH levels should be maintained between 0.5 and 2 mU/L in low and intermediate risk patients with the expectation of an excellent response to treatment. Mild TSH suppression is recommended when TSH is at 0.1 to 0.5 mU/L in high risk patients with excellent response, meaning negative imaging and undetectable suppressed thyroglobulin.

Mild suppression is also recommended for patients with a biochemically incomplete response. In particular, patients with residual structural disease or a biochemically incomplete response if they are young or at low risk of complications may need more robust TSH suppression—to less than 0.1 mU/L but not necessarily undetectable.10

Other factors to consider when determining an individualized treatment strategy: age of the patient, menopausal status, osteoporosis diagnosis or CVD diagnosis.1

Tailored Thyroid Hormone Suppression Therapy in Patients with Differentiated Thyroid Tumors

The report is ''a very nice summary of the potential benefits and harms of using TSH-suppression thyroid hormone therapy in patients with differentiated thyroid cancer," said Bryan Haugen, MD, professor of medicine and pathology, and head of the division of endocrinology, metabolism and diabetes at the University of Colorado in Denver. He reviewed the report for EndocrineWeb and chaired the 2015 ATA Thyroid Guidelines. In fact, the recommendations given in this paper, he said, “offer a reasoned overview for thyroid cancer treatment, which is supported by many experts in the field."

The messages are clear, he said, for both endocrinologists and primary care providers (PCP). For endocrinologists, Dr. Haugen told EndocrineWeb, the bottom line is that ''one size thyroid hormone therapy and TSH target ranges does not fit all differentiated thyroid cancer patients. The TSH target should be based on the severity of the disease and most importantly, the response to therapy weighted against the individual's risk factors for taking excess thyroid hormone therapy."

For PCPs, he said, the clinical takeaway is that "thyroid cancer patients can have different TSH targets than patients who do not have cancer but are taking thyroid hormone therapy." Dr. Haugen said that PCPs should not adjust thyroid therapy in a patient with DTC unless they are familiar with the guidelines from ATA. "If unsure, work with the patient’s endocrinologist to adjust the thyroid hormone therapy," he said.

Dr. Cooper's final comment: "Our findings support that for the average person who has thyroid cancer, thyroid suppression therapy isn’t necessary."

Neither Dr. Cooper nor Dr. Haugen has any relevant financial disclosures with regard to this study.

Continue Reading:
Challenging ATA Guidelines on Thyroid Cancer Treatment
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