No Advantage for Aggressive TSH Suppression for Thyroid Cancer

Nancy A Melville

November 03, 2014

SAN DIEGO — Treatment of differentiated thyroid cancer with aggressive thyroid-stimulating hormone (TSH) suppressive therapy is not better than moderate TSH suppressive therapy, even among patients diagnosed with distant metastatic disease in follow-up, according to a large new study following up nearly 5000 thyroid-cancer patients over a median of 6 years.

"Aggressive [TSH] suppression confers no additional survival advantage as compared with moderate suppression in differentiated thyroid cancer — even when limiting the analysis to patients with distant metastatic disease, which remains particularly relevant, given the risks associated with long-term thyrotoxicosis," said Dr Aubrey Carhill (University of Texas MD Anderson Cancer Center, Houston).

The findings, presented here at the 2014 Annual Meeting of the American Thyroid Association (ATA), contradict recommendations in thyroid cancer, including ATA guidelines, which recommend aggressive TSH suppression to undetectable subnormal levels (<0.1 mU/L), maintained indefinitely, for long-term follow-up of patients with persistent disease.

The approach has been the subject of debate, however, as clinicians grapple with the numerous pros and cons of TSH suppression therapy, including cardiovascular and fracture risks.

"The challenge for physicians is balancing the risk of more aggressive therapies — and the potential for long-term thyrotoxicosis — with the potential benefits of treatment, and the choice is not always clear, especially when patients are at a very low risk for cancer-specific mortality," said Dr Carhill.

These new findings may therefore signal a significant change in the management of thyroid-cancer patients, said Dr Irwin Klein (New York University School of Medicine).

"I think that there is no question that all physicians caring for thyroid-cancer patients will relax the dose of T4 to allow the previous targets of TSH <0.1 to drift north" to moderate TSH suppression, defined as hormone levels at "subnormal" values of 0.1 to 1.0 mU/L, he told Medscape Medical News.

"These data are very important, as they challenge the long-held notion that aggressive TSH suppression was both necessary and desirable," he remarked.

Aggressive TSH Suppression Leads to Worse Survival Than Moderate

Dr Carhill explained that in the absence of prospective trials of initial treatments for patients with differentiated thyroid cancer, debate continues on the appropriate extent of surgery (total or near-total thyroidectomy) and the role of postoperative radioiodine (RAI), and TSH-suppressive therapy.

She and her colleagues reported updated analyses of prospectively collected data related to clinical outcomes following initial treatment in 4941 patients with differentiated thyroid cancer from the National Thyroid Cancer Treatment Cooperative Study Group (NTCTCSG), a multicenter registry, between 1987 and 2012, who were treated per local standard of care (6 years' median follow-up; 34,631 person-years of documented follow-up time).

Overall and disease-free survival was assessed by multivariate analyses. The NTCTCSG staging system was applied.

The results show that in stage III patients, thyroidectomy or near-total thyroidectomy was not independently predictive of overall survival; however, RAI did continue to remain as an independent predictor of survival. In stage IV patients, combined thyroidectomy or near-total thyroidectomy with RAI continued to show improvement in overall survival.

In terms of TSH suppression, worse outcomes were seen in low-risk patients with stage I and II cancers who did not have suppressed TSH therapy; however, outcomes did not differ between moderately and aggressively suppressed patients.

And in contrast with previous reports, no significant difference in outcomes was seen between moderate vs aggressive TSH suppression in higher-risk patients with stage III and stage IV cancers.

A lower initial stage of disease was also independently predictive of overall survival, and among patients who were disease-free following their initial therapy, moderate TSH suppression independently predicted improved disease-free survival for at least 3 years of follow-up.

Moderate, but not aggressive, suppression was associated with significantly improved overall survival in all cancer stages (RR in: stage I, 0.13; stage II, 0.09; stage III, 0.13; and stage IV, 0.33). Similar results were seen with moderate, but not aggressive, suppression for disease-free survival (RR in: stage I, 0.52; stage II, 0.40; stage III 0.18).

A comparison of all three of the therapies (thyroidectomy or near-total thyroidectomy, RAI, and TSH suppression) showed only TSH suppression to be independently predictive of improved overall and disease-free survival.

"We report for the first time that in multivariate analysis of primary treatments for differentiated thyroid cancer in all stages, only TSH suppression was associated with both improved overall and disease-free survival," Dr Carhill said.

"In contrast with our earlier reports, only moderate TSH suppression is associated with better outcomes in all stages (including low-risk stage I patients), and aggressive TSH suppression may not be warranted even in patients diagnosed with distant metastatic disease during follow-up. Moderate TSH suppression continued at least 3 years after diagnosis may be indicated in higher-risk patients," she and her colleagues conclude.

Dr Klein agrees: The researchers show, "as we had previously suggested, that aggressive TSH suppression not only has theoretical risk but in fact leads to lowered overall survival when compared with more moderate suppression."

The study received support from Genzyme and Pfizer. Dr Carhill and Dr. Klein reported they have no relevant financial relationships.

2014 Annual Meeting of the American Thyroid Association; October 30, 2014; San Diego, CA. Abstract 11.

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