Suppressing TSH May Harm Low-Risk Thyroid-Cancer Patients

Miriam E Tucker

March 25, 2015

Thyrotropin suppression does more harm than good in thyroid-cancer patients who aren't at high risk for tumor recurrence following thyroidectomy, a new study suggests.

The findings, from chart reviews of more than 700 low- and intermediate-risk differentiated–thyroid-carcinoma patients who underwent total thyroidectomy, were published in the March issue of Thyroid by Laura Y Wang, MD, from Memorial Sloan Kettering Cancer Center, New York, and colleagues.

Compared with low- to moderate-risk patients who had not received levothyroxine suppression of thyrotropin (TSH) following surgery, there were no differences in tumor recurrence or disease-free survival over 6.5 years among those who had received suppression.

But the risk for osteoporosis was more than threefold greater and increased further with age among women who had received thyrotropin suppression compared with those who hadn't.

"We have a one-size-fits-all approach, where we administer thyrotropin suppression to every patient with thyroid cancer after they have undergone thyroidectomy and radioactive iodine.…They are often on lifetime suppression.…We do that on purpose, to stop the growth of thyroid cancer," senior author Laura Boucai, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, told Medscape Medical News.

However, the recurrence rates of thyroid cancer are extremely low, and the question is "whether we truly need to give medications to these [lower-risk] patients forever to keep them at a level where they are overmedicated, when the real risk of the tumor coming back in the neck is very small," she added.

In fact, the thinking has been shifting in this direction in recent years, and the overall findings were no surprise to David S Cooper, MD, director of the thyroid clinic at Johns Hopkins University School of Medicine, Baltimore, Maryland.

"I think this is probably what you would expect. It's been known for over 100 years that people who have endogenous hyperthyroidism have low bone density.…So, if TSH is suppressed in cancer patients and they're made mildly hyperthyroid, it makes sense that they also would have lower bone density."

However, he noted that the paper did include a surprising finding: the risk for osteoporosis was elevated even among people who fell into what is considered the normal TSH range (0.4 to 4.0 mIU/L). "That to me is the most interesting finding, that you saw this risk even when the TSH wasn't below normal but in low end of normal range."

New ATA Guidelines Due, but Doctors Not Even Heeding Old Ones

The 2009 American Thyroid Association (ATA) guidelines — for which Dr. Cooper was the task-force chair — recommend lifelong TSH suppression to less than 0.1 mIU/L in patients at high risk for tumor recurrence but lower levels of suppression among patients deemed to be at low or moderate risk and only for a year in the lower-risk group to ensure there is no residual cancer.

The new ATA guidelines, expected to be released in 2015, will advise no postthyroidectomy TSH suppression in low-risk patients, Dr Cooper told Medscape Medical News.

"Low-risk patients are probably cured with surgery, so keeping TSH low won't help, because they don't have any more cancer….It's not benefiting them and might be harming if they're elderly. If they're even mildly hyperthyroid, you're making their bones leach calcium," he explained.

Despite the ATA's previous risk-based guidance, the information hasn't yet reached many front-line endocrinologists, who continue to apply the same treatment to all postthyroidectomy patients, Dr Boucai told Medscape Medical News.

She noted that her group's current paper is the first to quantify the adverse event risk in low- to moderate-risk patients.

"We have evolved our thought process to suppressing people much less frequently for a shorter period of time and with less medication. This is totally new. It has evolved over the past couple of years and is not something that everybody does….It has to be publicized."

She said that the overtreatment and consequent osteoporosis — as well as potential other complications — may represent significant healthcare costs, given the recent exploding increase in identification of small thyroid tumors.

"The implications of this are that you run into much higher costs. We haven't done a cost/benefit analysis, but if you look at the people we harm by overprescribing thyroid medication causing osteoporosis, that's where the clinical relevance comes….If we continue to treat everybody with thyroidectomy, radioactive iodine, and TSH suppression when they actually don't need it, that's where it becomes a problem. So, we want to stop the train much earlier [because] this can potentially become a real public-health issue."

No Reduction Seen in Recurrence, Survival

The investigators analyzed a total of 771 patients who underwent thyroidectomy for differentiated thyroid cancer at Memorial Sloan Kettering between 2000 and 2006 and who were deemed to be at low or intermediate risk of tumor recurrence based on the ATA's criteria (ie, they did not have macroscopic tumor invasion, gross residual disease, or distant metastases). None had recorded diagnoses of osteoporosis or atrial fibrillation at baseline.

Of the total 771 patients, 465 had suppressed TSH levels (0.4 mIU/L or less), while the other 306 were not suppressed (TSH greater than 0.4 mIU/L). Patients who had been given suppression were younger and more likely to have tumor size greater than 1 cm and to have received radioactive iodine therapy (all P < .01).

Over a median follow-up of 6.5 years, 4.9% of the nonsuppressed group experienced tumor recurrence, compared with 6.0% of the suppressed group, a nonsignificant difference. Disease-free survival also did not differ between the two groups (hazard ratio [HR], 1.02, P = .956).

Even after adjustment for age, sex, receipt of radioactive iodine, and ATA risk category (low vs intermediate), TSH suppression still did not significantly decrease the risk for recurrence (HR, 0.88, P = .692). Furthermore, propensity scoring to account for indication biases at the time of prescribing levothyroxine still did not change the results, Dr Wang and colleagues report.

Bone Toxicity Increased

The patients who were treated to a median TSH of 0.4 mIU/L or less (suppressed) had a 2.1 times greater risk of developing either osteoporosis or atrial fibrillation (P = .05).

But when the 2.3% of the total group who had developed atrial fibrillation were examined separately, there was no significant difference between the suppressed and nonsuppressed groups (HR, 0.78, P = .63).

However, for the 5.4% women who developed osteoporosis out of the 537 total women in the study (men weren't included because they're not usually screened for osteoporosis), the risk was 3.5 times greater for those who were suppressed compared with those who weren't (P = .023).

In multivariate analysis adjusting for age, the suppressed women had a 4.3 times greater risk for osteoporosis (P = .009), "suggesting that TSH suppression in elderly women may cause even greater bone toxicity," the authors write.

What Is the Optimal TSH Level?

The authors plotted the risks for osteoporosis and tumor recurrence as a function of median TSH level. "Interestingly," they note, the data suggest that even at the lower limit of normal TSH — between 0.5 and 0.7 mIU/L — there is still an increased risk of osteoporosis.

In contrast, "It would appear that a TSH level around 0.9 or 1 mIU/L is optimal for maintenance treatment of ATA low- to intermediate-risk patients, as the risk of osteoporosis disappears, yet the risk of recurrence remains unchanged."

Dr Boucai told Medscape Medical News, "When you keep patients in the upper limit of normal, you're still causing harm. Even when you think you're not overtreating, you're causing this increased risk of osteoporosis." Rather than treating to a range, she advised, "Focus on the exact target [1.0 mIU/L]."

The main message, she said, is "Stop prescribing thyroid hormone when it's not needed….Stop doing harm."

The study authors and Dr. Cooper have no relevant financial relationships.

Thyroid. 2015;25:300-307. Article


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