Pituitary, Thyroid & Adrenal Disorders

Discontinuing antithyroid drugs during early pregnancy is linked to a possible rebound of hyperthyroidism and a high risk of adverse pregnancy outcomes, new research shows.

“Our study provides preliminary evidence that the risk of rebound increases in women with subnormal thyroid-stimulating hormone (TSH) and/or positive thyrotropin receptor antibody (TRAb) who stop antithyroid drugs in early pregnancy,” first author Xin Hou told this news organization.

“When discussing the pros and cons of antithyroid drug withdrawal early in pregnancy [clinicians] should consider the level of TSH and TRAb in early pregnancy,” said Hou, of the department of endocrinology and metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang.

Suvi Turunen, MD, of the University of Oulu (Finland), who has also conducted research on the issue, said the study adds important insights.

“I find this study very interesting,” Dr. Turunen said in an interview. “It is well known that medical treatment of hyperthyroidism outweighs the potential harms of antithyroid treatment.”

The new findings add to the evidence, she added. “I think that withdrawal of antithyroid drugs should be carefully considered, especially with autoantibody-positive patients,” Dr. Turunen said.
 

Hyperthyroidism a risk in pregnancy – with or without treatment

The potential risks of hyperthyroidism in pregnancy are well established and can range from preeclampsia to premature birth or miscarriage.

However, antithyroid drugs, including methimazole and propylthiouracil, carry their own risks. In crossing the placental barrier, the drugs can increase the risk of birth defects, particularly during 6-10 weeks of gestation, yet their discontinuation is linked to as much as a 50%-60% risk of relapse, the authors explain.

Because of the risks, the American Thyroid Association recommends that “women with a stable euthyroid state on 5-10 mg methimazole per day achieved within a few months, and a falling TRAb level, are likely candidates to withdraw from antithyroid drug therapy in early pregnancy,” the authors noted.

However, as the recommendations for women who are already pregnant are largely based on evidence from nonpregnant patients, Hou and colleagues sought to evaluate withdrawal among women who were pregnant.

For the study, published in Thyroid, they enrolled 63 women who were pregnant and part of an outpatient service of the department of endocrinology and metabolism at The First Affiliated Hospital of China Medical University, between September 2014 and March 2017, who had well-controlled hyperthyroidism in early pregnancy and discontinued the drugs.

The women were an average age of 27 years, and 28 were multigravida. Twenty-two had a history of miscarriage.

A follow-up of the patients until the end of their pregnancy showed that, overall, 20 (31.7%) had a rebound of hyperthyroidism during their pregnancy after withdrawing from the drugs.

Key factors associated with the highest risk of a rebound after discontinuation included having subnormal TSH levels (TSH < 0.35 mIU/L; odds ratio, 5.12; P  = .03) or having positive TRAb (TRAb > 1.75 IU/L; OR, 3.79; P = .02) at the time of medication withdrawal, compared with those with either normal TSH levels or negative TRAb.

The combination of both subnormal TSH and positive TRAb at the time of antithyroid medication withdrawal further boosted the risk of hyperthyroidism rebound (83.3%, 5 of 6), compared with those who had both normal TSH and negative TRAb (13%, 3 of 23; OR, 33.33; P = .003).

Adverse pregnancy outcomes increased

Importantly, among the 20 patients who had a rebound, 11 (55%) had adverse pregnancy outcomes, including miscarriage, premature birth, induced labor, gestational hypertension, and gestational diabetes, compared with only 4 (9.3%) of the 43 who had no rebound (OR, 11.92; P = .0002).

Neonatal abnormalities were also higher among those experiencing a rebound (20% vs. 4.7%), however, the authors noted that “larger prospective studies are required to conclude whether antithyroid drug withdrawal affects fetal outcome.”

In the rebound group, the mean duration of antithyroid medication use was 24.7 months versus 35.1 months in the nonrebound group, however, the difference was not statistically significant (P = .07). And 40% of the rebound group had a history of miscarriage versus 32.6% in the non-rebound group, but was also not significantly different (P = .56).

The authors noted that half of those in the rebound group developed hyperthyroidism more than 4 weeks after their withdrawal from antithyroid medications, “which seemed to have circumvented the most sensitive period of teratogenesis between 6 and 10 weeks of pregnancy.”

Hou added that restarting antithyroid medication did not increase the risk of adverse outcomes for offspring.

“A low dose of antithyroid medications may be a good choice for women with subnormal TSH and/or positive TRAb in early pregnancy,” Hou concluded. “Because of the small size of our study, a larger prospective study is needed to overcome the potential selection bias and to verify the conclusions.”
 

Findings consistent with Finnish study

In her own recent study, which included 2,144 women in Finland who experienced hyperthyroidism during pregnancy, Dr. Turunen and colleagues found that having hyperthyroidism, with or without antithyroid drug treatment, was associated with an increased odds of pregnancy and/or prenatal complications, compared with those without thyroid disease.

“In our study, we observed an increased risk of adverse pregnancy outcomes also in mothers with previous diagnosis and/or treatment of hyperthyroidism, not only with overt hyperthyroidism treated with antithyroid drugs,” she told this news organization.

“I think that especially those patients with positive antibodies [TRAbs] are at risk even if they are euthyroid,” she noted. “Withdrawal of antithyroid drugs in these patients is a risk.”

“Probably continuing antithyroid treatment with low dose is a better option,” she said.

The authors and Dr. Turunen reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Discontinuing antithyroid drugs during early pregnancy is linked to a possible rebound of hyperthyroidism and a high risk of adverse pregnancy outcomes, new research shows.

“Our study provides preliminary evidence that the risk of rebound increases in women with subnormal thyroid-stimulating hormone (TSH) and/or positive thyrotropin receptor antibody (TRAb) who stop antithyroid drugs in early pregnancy,” first author Xin Hou told this news organization.

“When discussing the pros and cons of antithyroid drug withdrawal early in pregnancy [clinicians] should consider the level of TSH and TRAb in early pregnancy,” said Hou, of the department of endocrinology and metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang.

Suvi Turunen, MD, of the University of Oulu (Finland), who has also conducted research on the issue, said the study adds important insights.

“I find this study very interesting,” Dr. Turunen said in an interview. “It is well known that medical treatment of hyperthyroidism outweighs the potential harms of antithyroid treatment.”

The new findings add to the evidence, she added. “I think that withdrawal of antithyroid drugs should be carefully considered, especially with autoantibody-positive patients,” Dr. Turunen said.
 

Hyperthyroidism a risk in pregnancy – with or without treatment

The potential risks of hyperthyroidism in pregnancy are well established and can range from preeclampsia to premature birth or miscarriage.

However, antithyroid drugs, including methimazole and propylthiouracil, carry their own risks. In crossing the placental barrier, the drugs can increase the risk of birth defects, particularly during 6-10 weeks of gestation, yet their discontinuation is linked to as much as a 50%-60% risk of relapse, the authors explain.

Because of the risks, the American Thyroid Association recommends that “women with a stable euthyroid state on 5-10 mg methimazole per day achieved within a few months, and a falling TRAb level, are likely candidates to withdraw from antithyroid drug therapy in early pregnancy,” the authors noted.

However, as the recommendations for women who are already pregnant are largely based on evidence from nonpregnant patients, Hou and colleagues sought to evaluate withdrawal among women who were pregnant.

For the study, published in Thyroid, they enrolled 63 women who were pregnant and part of an outpatient service of the department of endocrinology and metabolism at The First Affiliated Hospital of China Medical University, between September 2014 and March 2017, who had well-controlled hyperthyroidism in early pregnancy and discontinued the drugs.

The women were an average age of 27 years, and 28 were multigravida. Twenty-two had a history of miscarriage.

A follow-up of the patients until the end of their pregnancy showed that, overall, 20 (31.7%) had a rebound of hyperthyroidism during their pregnancy after withdrawing from the drugs.

Key factors associated with the highest risk of a rebound after discontinuation included having subnormal TSH levels (TSH < 0.35 mIU/L; odds ratio, 5.12; P  = .03) or having positive TRAb (TRAb > 1.75 IU/L; OR, 3.79; P = .02) at the time of medication withdrawal, compared with those with either normal TSH levels or negative TRAb.

The combination of both subnormal TSH and positive TRAb at the time of antithyroid medication withdrawal further boosted the risk of hyperthyroidism rebound (83.3%, 5 of 6), compared with those who had both normal TSH and negative TRAb (13%, 3 of 23; OR, 33.33; P = .003).

Adverse pregnancy outcomes increased

Importantly, among the 20 patients who had a rebound, 11 (55%) had adverse pregnancy outcomes, including miscarriage, premature birth, induced labor, gestational hypertension, and gestational diabetes, compared with only 4 (9.3%) of the 43 who had no rebound (OR, 11.92; P = .0002).

Neonatal abnormalities were also higher among those experiencing a rebound (20% vs. 4.7%), however, the authors noted that “larger prospective studies are required to conclude whether antithyroid drug withdrawal affects fetal outcome.”

In the rebound group, the mean duration of antithyroid medication use was 24.7 months versus 35.1 months in the nonrebound group, however, the difference was not statistically significant (P = .07). And 40% of the rebound group had a history of miscarriage versus 32.6% in the non-rebound group, but was also not significantly different (P = .56).

The authors noted that half of those in the rebound group developed hyperthyroidism more than 4 weeks after their withdrawal from antithyroid medications, “which seemed to have circumvented the most sensitive period of teratogenesis between 6 and 10 weeks of pregnancy.”

Hou added that restarting antithyroid medication did not increase the risk of adverse outcomes for offspring.

“A low dose of antithyroid medications may be a good choice for women with subnormal TSH and/or positive TRAb in early pregnancy,” Hou concluded. “Because of the small size of our study, a larger prospective study is needed to overcome the potential selection bias and to verify the conclusions.”
 

Findings consistent with Finnish study

In her own recent study, which included 2,144 women in Finland who experienced hyperthyroidism during pregnancy, Dr. Turunen and colleagues found that having hyperthyroidism, with or without antithyroid drug treatment, was associated with an increased odds of pregnancy and/or prenatal complications, compared with those without thyroid disease.

“In our study, we observed an increased risk of adverse pregnancy outcomes also in mothers with previous diagnosis and/or treatment of hyperthyroidism, not only with overt hyperthyroidism treated with antithyroid drugs,” she told this news organization.

“I think that especially those patients with positive antibodies [TRAbs] are at risk even if they are euthyroid,” she noted. “Withdrawal of antithyroid drugs in these patients is a risk.”

“Probably continuing antithyroid treatment with low dose is a better option,” she said.

The authors and Dr. Turunen reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Discontinuing antithyroid drugs during early pregnancy is linked to a possible rebound of hyperthyroidism and a high risk of adverse pregnancy outcomes, new research shows.

“Our study provides preliminary evidence that the risk of rebound increases in women with subnormal thyroid-stimulating hormone (TSH) and/or positive thyrotropin receptor antibody (TRAb) who stop antithyroid drugs in early pregnancy,” first author Xin Hou told this news organization.

“When discussing the pros and cons of antithyroid drug withdrawal early in pregnancy [clinicians] should consider the level of TSH and TRAb in early pregnancy,” said Hou, of the department of endocrinology and metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang.

Suvi Turunen, MD, of the University of Oulu (Finland), who has also conducted research on the issue, said the study adds important insights.

“I find this study very interesting,” Dr. Turunen said in an interview. “It is well known that medical treatment of hyperthyroidism outweighs the potential harms of antithyroid treatment.”

The new findings add to the evidence, she added. “I think that withdrawal of antithyroid drugs should be carefully considered, especially with autoantibody-positive patients,” Dr. Turunen said.
 

Hyperthyroidism a risk in pregnancy – with or without treatment

The potential risks of hyperthyroidism in pregnancy are well established and can range from preeclampsia to premature birth or miscarriage.

However, antithyroid drugs, including methimazole and propylthiouracil, carry their own risks. In crossing the placental barrier, the drugs can increase the risk of birth defects, particularly during 6-10 weeks of gestation, yet their discontinuation is linked to as much as a 50%-60% risk of relapse, the authors explain.

Because of the risks, the American Thyroid Association recommends that “women with a stable euthyroid state on 5-10 mg methimazole per day achieved within a few months, and a falling TRAb level, are likely candidates to withdraw from antithyroid drug therapy in early pregnancy,” the authors noted.

However, as the recommendations for women who are already pregnant are largely based on evidence from nonpregnant patients, Hou and colleagues sought to evaluate withdrawal among women who were pregnant.

For the study, published in Thyroid, they enrolled 63 women who were pregnant and part of an outpatient service of the department of endocrinology and metabolism at The First Affiliated Hospital of China Medical University, between September 2014 and March 2017, who had well-controlled hyperthyroidism in early pregnancy and discontinued the drugs.

The women were an average age of 27 years, and 28 were multigravida. Twenty-two had a history of miscarriage.

A follow-up of the patients until the end of their pregnancy showed that, overall, 20 (31.7%) had a rebound of hyperthyroidism during their pregnancy after withdrawing from the drugs.

Key factors associated with the highest risk of a rebound after discontinuation included having subnormal TSH levels (TSH < 0.35 mIU/L; odds ratio, 5.12; P  = .03) or having positive TRAb (TRAb > 1.75 IU/L; OR, 3.79; P = .02) at the time of medication withdrawal, compared with those with either normal TSH levels or negative TRAb.

The combination of both subnormal TSH and positive TRAb at the time of antithyroid medication withdrawal further boosted the risk of hyperthyroidism rebound (83.3%, 5 of 6), compared with those who had both normal TSH and negative TRAb (13%, 3 of 23; OR, 33.33; P = .003).

Adverse pregnancy outcomes increased

Importantly, among the 20 patients who had a rebound, 11 (55%) had adverse pregnancy outcomes, including miscarriage, premature birth, induced labor, gestational hypertension, and gestational diabetes, compared with only 4 (9.3%) of the 43 who had no rebound (OR, 11.92; P = .0002).

Neonatal abnormalities were also higher among those experiencing a rebound (20% vs. 4.7%), however, the authors noted that “larger prospective studies are required to conclude whether antithyroid drug withdrawal affects fetal outcome.”

In the rebound group, the mean duration of antithyroid medication use was 24.7 months versus 35.1 months in the nonrebound group, however, the difference was not statistically significant (P = .07). And 40% of the rebound group had a history of miscarriage versus 32.6% in the non-rebound group, but was also not significantly different (P = .56).

The authors noted that half of those in the rebound group developed hyperthyroidism more than 4 weeks after their withdrawal from antithyroid medications, “which seemed to have circumvented the most sensitive period of teratogenesis between 6 and 10 weeks of pregnancy.”

Hou added that restarting antithyroid medication did not increase the risk of adverse outcomes for offspring.

“A low dose of antithyroid medications may be a good choice for women with subnormal TSH and/or positive TRAb in early pregnancy,” Hou concluded. “Because of the small size of our study, a larger prospective study is needed to overcome the potential selection bias and to verify the conclusions.”
 

Findings consistent with Finnish study

In her own recent study, which included 2,144 women in Finland who experienced hyperthyroidism during pregnancy, Dr. Turunen and colleagues found that having hyperthyroidism, with or without antithyroid drug treatment, was associated with an increased odds of pregnancy and/or prenatal complications, compared with those without thyroid disease.

“In our study, we observed an increased risk of adverse pregnancy outcomes also in mothers with previous diagnosis and/or treatment of hyperthyroidism, not only with overt hyperthyroidism treated with antithyroid drugs,” she told this news organization.

“I think that especially those patients with positive antibodies [TRAbs] are at risk even if they are euthyroid,” she noted. “Withdrawal of antithyroid drugs in these patients is a risk.”

“Probably continuing antithyroid treatment with low dose is a better option,” she said.

The authors and Dr. Turunen reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.

amenic181/Getty Images

Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.

Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.

Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.

And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
 

Liquid thyroxine may be less affected by food/drink but is expensive

Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.

“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.

When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”

Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.

However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”

And the higher cost of the liquid products is a major issue, he noted. 

A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.

In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.

“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
 

Bioequivalence with shorter versus longer waits before coffee/breakfast

The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.

Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.

There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.

In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.

Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.

Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.

There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
 

Similar findings for Tirosint-SOL but longer-term studies needed

The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.

Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.

Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”

However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.

“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”

Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.

amenic181/Getty Images

Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.

Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.

Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.

And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
 

Liquid thyroxine may be less affected by food/drink but is expensive

Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.

“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.

When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”

Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.

However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”

And the higher cost of the liquid products is a major issue, he noted. 

A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.

In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.

“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
 

Bioequivalence with shorter versus longer waits before coffee/breakfast

The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.

Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.

There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.

In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.

Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.

Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.

There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
 

Similar findings for Tirosint-SOL but longer-term studies needed

The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.

Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.

Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”

However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.

“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”

Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.

amenic181/Getty Images

Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.

Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.

Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.

And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
 

Liquid thyroxine may be less affected by food/drink but is expensive

Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.

“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.

When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”

Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.

However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”

And the higher cost of the liquid products is a major issue, he noted. 

A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.

In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.

“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
 

Bioequivalence with shorter versus longer waits before coffee/breakfast

The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.

Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.

There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.

In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.

Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.

Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.

There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
 

Similar findings for Tirosint-SOL but longer-term studies needed

The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.

Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.

Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”

However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.

“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”

Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Suboptimal treatment of primary hypothyroidism may increase the risk of worse hospital outcomes, new research suggests.

The risks, including longer length of stay (LOS) and higher readmission rates, were no longer present in patients with adequately treated hypothyroidism, and in fact, appeared better than among those without hypothyroidism.

“Unfortunately, suboptimal treatment is common amongst the patient population with hypothyroidism,” wrote Matthew D. Ettleson, MD, of the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago, and colleagues.

“It is important for both patients and physicians to know that maintaining optimal thyroid hormone replacement is important to minimize length of hospital stays and hospital readmission. It is particularly important for planned admissions where thyroid hormone replacement can be adjusted if needed prior to admission,” said Dr. Ettleson in a press release from the Endocrine Society.
 

More evidence of adverse effects of suboptimal treatment

The findings, from a large U.S. claims database, “add to the growing body of evidence demonstrating the serious adverse short- and long-term health effects associated with suboptimal treatment of hypothyroidism,” the authors write in their article, published online  in the Journal of Clinical Endocrinology and Metabolism. Dr. Ettleson will also present the data on June 11 at the ENDO 2022 meeting.

Thyroid hormone replacement therapy – generally levothyroxine – is given for primary hypothyroidism with the aim of maintaining serum thyroid-stimulating hormone (TSH) within the normal reference range.

TSH is inversely related to the level of circulating thyroid hormone, so low levels of TSH indicate overtreatment of thyroid disease and high levels indicate undertreatment.

Worse hospital outcomes associated with high TSH

In their study, Dr. Ettleson and colleagues retrospectively examined IBM MarketScan claims for 43,478 privately insured patients younger than age 65 years and hospitalized for medical or surgical reasons in 2008-2015.

Of those, 8,873 met the criteria for primary hypothyroidism based on a pre-admission prescription claim for levothyroxine, TSH > 10.00 mIU/L, confirmed diagnosis of hypothyroidism during hospitalization, or chronic lymphocytic thyroiditis. Of those, 4,770 (53.8%) had a prescription claim for levothyroxine.  

Patients who met the clinical criteria for hypothyroidism were divided into four subgroups based on prehospitalization TSH level: low (< 0.40 mIU/L), normal (0.40-4.50 mIU/L), intermediate (4.51-10.00 mIU/L), and high (> 10.00 mIU/L).

The median length of time between TSH collection and hospital admission was 56 days in the hypothyroidism group and 63 days in the control group.

There were no differences in hospital outcomes between those with and without hypothyroidism among those who had low or intermediate TSH levels, in a multivariate analysis that used propensity-score matching.

In those with normal TSH levels, those with hypothyroidism actually had a lower risk of in-hospital death (risk ratio, 0.46; P = .004) and 90-day readmission rate (RR, 0.92; P = .02) than controls.

And those in the high TSH level subgroup had longer length of stay (+1.2 days; P = .003) and higher risk of 30-day readmission (RR, 1.49; P < .001) and 90-day readmission (RR, 1.43; P < .001), compared with balanced controls.
 

Public health effort needed to improve quality of care

There are multiple reasons why those with undertreated or undiagnosed hypothyroidism might have worse hospital outcomes, the authors say.

A bit more puzzling is why those with well-controlled hypothyroidism appeared to do better than those without hypothyroidism, given that thyroid hormone replacement isn’t likely to provide an advantage over normal, endogenous thyroid hormone production.

Dr. Ettleson and colleagues speculate that in-range TSH values may be a surrogate for regular health care and adherence to medical therapy, which likely leads to better hospital outcomes.

“The long- and short-term adverse health effects associated with off-target treatment of hypothyroidism, coupled with the high frequency of off-target treatment amongst the millions of patients in the United States on thyroid hormone, suggest that a public health effort to improve the quality of care of hypothyroidism is necessary,” Dr. Ettleson and colleagues write.

However, they note that there is currently no quality measure regarding appropriate treatment of hypothyroidism within the Merit-Based Incentive Payment System of the Centers for Medicare & Medicaid Services.

“The presence of guidelines alone may not be sufficient, as demonstrated by the inadequate application of guidelines for the use of levothyroxine in the treatment of thyroid cancer, a serious but much less common disease than clinical hypothyroidism,” the authors add.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Dr. Ettleson has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Suboptimal treatment of primary hypothyroidism may increase the risk of worse hospital outcomes, new research suggests.

The risks, including longer length of stay (LOS) and higher readmission rates, were no longer present in patients with adequately treated hypothyroidism, and in fact, appeared better than among those without hypothyroidism.

“Unfortunately, suboptimal treatment is common amongst the patient population with hypothyroidism,” wrote Matthew D. Ettleson, MD, of the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago, and colleagues.

“It is important for both patients and physicians to know that maintaining optimal thyroid hormone replacement is important to minimize length of hospital stays and hospital readmission. It is particularly important for planned admissions where thyroid hormone replacement can be adjusted if needed prior to admission,” said Dr. Ettleson in a press release from the Endocrine Society.
 

More evidence of adverse effects of suboptimal treatment

The findings, from a large U.S. claims database, “add to the growing body of evidence demonstrating the serious adverse short- and long-term health effects associated with suboptimal treatment of hypothyroidism,” the authors write in their article, published online  in the Journal of Clinical Endocrinology and Metabolism. Dr. Ettleson will also present the data on June 11 at the ENDO 2022 meeting.

Thyroid hormone replacement therapy – generally levothyroxine – is given for primary hypothyroidism with the aim of maintaining serum thyroid-stimulating hormone (TSH) within the normal reference range.

TSH is inversely related to the level of circulating thyroid hormone, so low levels of TSH indicate overtreatment of thyroid disease and high levels indicate undertreatment.

Worse hospital outcomes associated with high TSH

In their study, Dr. Ettleson and colleagues retrospectively examined IBM MarketScan claims for 43,478 privately insured patients younger than age 65 years and hospitalized for medical or surgical reasons in 2008-2015.

Of those, 8,873 met the criteria for primary hypothyroidism based on a pre-admission prescription claim for levothyroxine, TSH > 10.00 mIU/L, confirmed diagnosis of hypothyroidism during hospitalization, or chronic lymphocytic thyroiditis. Of those, 4,770 (53.8%) had a prescription claim for levothyroxine.  

Patients who met the clinical criteria for hypothyroidism were divided into four subgroups based on prehospitalization TSH level: low (< 0.40 mIU/L), normal (0.40-4.50 mIU/L), intermediate (4.51-10.00 mIU/L), and high (> 10.00 mIU/L).

The median length of time between TSH collection and hospital admission was 56 days in the hypothyroidism group and 63 days in the control group.

There were no differences in hospital outcomes between those with and without hypothyroidism among those who had low or intermediate TSH levels, in a multivariate analysis that used propensity-score matching.

In those with normal TSH levels, those with hypothyroidism actually had a lower risk of in-hospital death (risk ratio, 0.46; P = .004) and 90-day readmission rate (RR, 0.92; P = .02) than controls.

And those in the high TSH level subgroup had longer length of stay (+1.2 days; P = .003) and higher risk of 30-day readmission (RR, 1.49; P < .001) and 90-day readmission (RR, 1.43; P < .001), compared with balanced controls.
 

Public health effort needed to improve quality of care

There are multiple reasons why those with undertreated or undiagnosed hypothyroidism might have worse hospital outcomes, the authors say.

A bit more puzzling is why those with well-controlled hypothyroidism appeared to do better than those without hypothyroidism, given that thyroid hormone replacement isn’t likely to provide an advantage over normal, endogenous thyroid hormone production.

Dr. Ettleson and colleagues speculate that in-range TSH values may be a surrogate for regular health care and adherence to medical therapy, which likely leads to better hospital outcomes.

“The long- and short-term adverse health effects associated with off-target treatment of hypothyroidism, coupled with the high frequency of off-target treatment amongst the millions of patients in the United States on thyroid hormone, suggest that a public health effort to improve the quality of care of hypothyroidism is necessary,” Dr. Ettleson and colleagues write.

However, they note that there is currently no quality measure regarding appropriate treatment of hypothyroidism within the Merit-Based Incentive Payment System of the Centers for Medicare & Medicaid Services.

“The presence of guidelines alone may not be sufficient, as demonstrated by the inadequate application of guidelines for the use of levothyroxine in the treatment of thyroid cancer, a serious but much less common disease than clinical hypothyroidism,” the authors add.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Dr. Ettleson has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Suboptimal treatment of primary hypothyroidism may increase the risk of worse hospital outcomes, new research suggests.

The risks, including longer length of stay (LOS) and higher readmission rates, were no longer present in patients with adequately treated hypothyroidism, and in fact, appeared better than among those without hypothyroidism.

“Unfortunately, suboptimal treatment is common amongst the patient population with hypothyroidism,” wrote Matthew D. Ettleson, MD, of the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago, and colleagues.

“It is important for both patients and physicians to know that maintaining optimal thyroid hormone replacement is important to minimize length of hospital stays and hospital readmission. It is particularly important for planned admissions where thyroid hormone replacement can be adjusted if needed prior to admission,” said Dr. Ettleson in a press release from the Endocrine Society.
 

More evidence of adverse effects of suboptimal treatment

The findings, from a large U.S. claims database, “add to the growing body of evidence demonstrating the serious adverse short- and long-term health effects associated with suboptimal treatment of hypothyroidism,” the authors write in their article, published online  in the Journal of Clinical Endocrinology and Metabolism. Dr. Ettleson will also present the data on June 11 at the ENDO 2022 meeting.

Thyroid hormone replacement therapy – generally levothyroxine – is given for primary hypothyroidism with the aim of maintaining serum thyroid-stimulating hormone (TSH) within the normal reference range.

TSH is inversely related to the level of circulating thyroid hormone, so low levels of TSH indicate overtreatment of thyroid disease and high levels indicate undertreatment.

Worse hospital outcomes associated with high TSH

In their study, Dr. Ettleson and colleagues retrospectively examined IBM MarketScan claims for 43,478 privately insured patients younger than age 65 years and hospitalized for medical or surgical reasons in 2008-2015.

Of those, 8,873 met the criteria for primary hypothyroidism based on a pre-admission prescription claim for levothyroxine, TSH > 10.00 mIU/L, confirmed diagnosis of hypothyroidism during hospitalization, or chronic lymphocytic thyroiditis. Of those, 4,770 (53.8%) had a prescription claim for levothyroxine.  

Patients who met the clinical criteria for hypothyroidism were divided into four subgroups based on prehospitalization TSH level: low (< 0.40 mIU/L), normal (0.40-4.50 mIU/L), intermediate (4.51-10.00 mIU/L), and high (> 10.00 mIU/L).

The median length of time between TSH collection and hospital admission was 56 days in the hypothyroidism group and 63 days in the control group.

There were no differences in hospital outcomes between those with and without hypothyroidism among those who had low or intermediate TSH levels, in a multivariate analysis that used propensity-score matching.

In those with normal TSH levels, those with hypothyroidism actually had a lower risk of in-hospital death (risk ratio, 0.46; P = .004) and 90-day readmission rate (RR, 0.92; P = .02) than controls.

And those in the high TSH level subgroup had longer length of stay (+1.2 days; P = .003) and higher risk of 30-day readmission (RR, 1.49; P < .001) and 90-day readmission (RR, 1.43; P < .001), compared with balanced controls.
 

Public health effort needed to improve quality of care

There are multiple reasons why those with undertreated or undiagnosed hypothyroidism might have worse hospital outcomes, the authors say.

A bit more puzzling is why those with well-controlled hypothyroidism appeared to do better than those without hypothyroidism, given that thyroid hormone replacement isn’t likely to provide an advantage over normal, endogenous thyroid hormone production.

Dr. Ettleson and colleagues speculate that in-range TSH values may be a surrogate for regular health care and adherence to medical therapy, which likely leads to better hospital outcomes.

“The long- and short-term adverse health effects associated with off-target treatment of hypothyroidism, coupled with the high frequency of off-target treatment amongst the millions of patients in the United States on thyroid hormone, suggest that a public health effort to improve the quality of care of hypothyroidism is necessary,” Dr. Ettleson and colleagues write.

However, they note that there is currently no quality measure regarding appropriate treatment of hypothyroidism within the Merit-Based Incentive Payment System of the Centers for Medicare & Medicaid Services.

“The presence of guidelines alone may not be sufficient, as demonstrated by the inadequate application of guidelines for the use of levothyroxine in the treatment of thyroid cancer, a serious but much less common disease than clinical hypothyroidism,” the authors add.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Dr. Ettleson has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who receive parathyroidectomy for mild primary hyperparathyroidism show no benefits in survival or morbidity, including fractures, cancer, or cardiovascular outcomes over more than 10 years, compared with those not receiving the surgery, results from a randomized, prospective trial show.

“In contrast to existing data showing increased mortality and cardiovascular morbidity in mild primary hyperparathyroidism, we did not find any treatment effect of parathyroidectomy on these important clinical endpoints,” report the authors of the study, published in the Annals of Internal Medicine.
 

Reason to evaluate and revise current recommendations?

With mild primary hyperparathyroidism becoming the predominant form of hyperparathyroidism, the results suggest rethinking the current recommendations for the condition, the study authors note. 

“Over the years, more active management of mild primary hyperparathyroidism has been recommended, with a widening of criteria for parathyroidectomy,” they write.

“With the low number of kidney stones (n = 5) and no effect of parathyroidectomy on fractures, there may be a need to evaluate and potentially revise the current recommendations.”

The authors of an accompanying editorial agree that “the [results] provide a strong rationale for nonoperative management of patients with mild primary hyperparathyroidism.”

“The findings suggest that most patients can be managed nonoperatively, with monitoring of serum calcium levels every 1 to 2 years or if symptoms occur,” write the editorial authors, Mark J. Bolland, PhD, and Andrew Grey, MD, of the department of medicine, University of Auckland, New Zealand.

Although parathyroidectomy is recommended for the treatment in patients with hyperparathyroidism with severe hypercalcemia or overt symptoms, there has been debate on the long-term benefits of surgery among those with milder cases.  

Most previous studies that have shown benefits, such as reductions in the risk of fracture with parathyroidectomy, have importantly not distinguished between mild and more severe primary hyperparathyroidism, the authors note.
 

No significant differences in mortality between surgery, nonsurgery groups

For the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, first author Mikkel Pretorius, MD, Oslo University Hospital and Faculty of Medicine, University of Oslo, and colleagues enrolled 191 patients between 1998 and 2005 in Sweden, Norway, and Denmark, who were aged 50-80 years and had mild primary hyperparathyroidism, defined as serum calcium levels of 10.42-11.22 mg/dL.

Participants were randomized to receive surgery (n = 95) or nonoperative observation without intervention (n = 96).

After a 10-year follow-up, 129 patients had completed the final visit. The overall death rate was 7.6%, and, with eight deaths in the surgery group and seven in the nonsurgery group, there were no significant differences between groups in terms of mortality (HR, 1.17; P = .76).

During an extended observation period that lasted until 2018, mortality rates increased by 23%, but with a relatively even distribution of 24 deaths in the surgery group and 20 among those with no surgery.

Chronic hypercalcemia related to primary hyperparathyroidism has been debated as being associated with an increased risk of cardiovascular disease or cancer, however, “the absolute numbers for these and the other disease-specific causes of death were nearly identical between groups,” the authors write, with 17 deaths from cardiovascular disease, eight from cancer, and eight from cerebrovascular disease.

In terms of morbidity, including cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones, there were 101 events overall, with 52 in the parathyroidectomy group and 49 in the nonsurgery group, which again, was not a significant difference.

Sixteen vertebral fractures occurred overall in 14 patients, which were evenly split at seven patients in each group.

The authors note that “the incidence of peripheral fractures for women in our study was around 2,900 per 100,000 person-years, in the same range as for 70-year-old women in a study in Gothenburg, Sweden (about 2,600 per 100,000 person-years).”

There were no between-group differences in terms of time to death or first morbidity event for any of the prespecified events.

Of the 96 patients originally assigned to the nonsurgery group, 17 (18%) had surgery during follow-up, including three for serious hypercalcemia, three by their own choice, two for decreasing bone density, one for kidney stones, and the others for unclear or unrelated reasons.

Study limitations include that only 26 men (13 in each group) were included, and only 16 completed the study. “The external validity for men based on this study is therefore limited,” the authors note.

And although most people with primary hyperparathyroidism are adults, the older age of participants suggests the results should not be generalized to younger patients with benign parathyroid tumors.

The editorialists note that age should be one of the few factors that may, indeed, suggest appropriate candidates for parathyroidectomy.

“Younger patients (aged < 50 years) may have more aggressive disease,” they explain.

In addition, “patients with serum calcium levels above 3 mmol/L (> 12 mg/dL) are at greater risk for symptomatic hypercalcemia, and patients with a recent history of kidney stones may have fewer future stones after surgical cure.”

“Yet, such patients are a small minority of those with primary hyperparathyroidism,” they note.

The study authors underscore that “our data add evidence to guide the decisionmaking process in deliberative dialogue between clinicians and patients.”

The study received funding from Swedish government grants, the Norwegian Research Council, and the South-Eastern Norway Regional Health Authority.

A version of this article first appeared on Medscape.com.

Patients who receive parathyroidectomy for mild primary hyperparathyroidism show no benefits in survival or morbidity, including fractures, cancer, or cardiovascular outcomes over more than 10 years, compared with those not receiving the surgery, results from a randomized, prospective trial show.

“In contrast to existing data showing increased mortality and cardiovascular morbidity in mild primary hyperparathyroidism, we did not find any treatment effect of parathyroidectomy on these important clinical endpoints,” report the authors of the study, published in the Annals of Internal Medicine.
 

Reason to evaluate and revise current recommendations?

With mild primary hyperparathyroidism becoming the predominant form of hyperparathyroidism, the results suggest rethinking the current recommendations for the condition, the study authors note. 

“Over the years, more active management of mild primary hyperparathyroidism has been recommended, with a widening of criteria for parathyroidectomy,” they write.

“With the low number of kidney stones (n = 5) and no effect of parathyroidectomy on fractures, there may be a need to evaluate and potentially revise the current recommendations.”

The authors of an accompanying editorial agree that “the [results] provide a strong rationale for nonoperative management of patients with mild primary hyperparathyroidism.”

“The findings suggest that most patients can be managed nonoperatively, with monitoring of serum calcium levels every 1 to 2 years or if symptoms occur,” write the editorial authors, Mark J. Bolland, PhD, and Andrew Grey, MD, of the department of medicine, University of Auckland, New Zealand.

Although parathyroidectomy is recommended for the treatment in patients with hyperparathyroidism with severe hypercalcemia or overt symptoms, there has been debate on the long-term benefits of surgery among those with milder cases.  

Most previous studies that have shown benefits, such as reductions in the risk of fracture with parathyroidectomy, have importantly not distinguished between mild and more severe primary hyperparathyroidism, the authors note.
 

No significant differences in mortality between surgery, nonsurgery groups

For the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, first author Mikkel Pretorius, MD, Oslo University Hospital and Faculty of Medicine, University of Oslo, and colleagues enrolled 191 patients between 1998 and 2005 in Sweden, Norway, and Denmark, who were aged 50-80 years and had mild primary hyperparathyroidism, defined as serum calcium levels of 10.42-11.22 mg/dL.

Participants were randomized to receive surgery (n = 95) or nonoperative observation without intervention (n = 96).

After a 10-year follow-up, 129 patients had completed the final visit. The overall death rate was 7.6%, and, with eight deaths in the surgery group and seven in the nonsurgery group, there were no significant differences between groups in terms of mortality (HR, 1.17; P = .76).

During an extended observation period that lasted until 2018, mortality rates increased by 23%, but with a relatively even distribution of 24 deaths in the surgery group and 20 among those with no surgery.

Chronic hypercalcemia related to primary hyperparathyroidism has been debated as being associated with an increased risk of cardiovascular disease or cancer, however, “the absolute numbers for these and the other disease-specific causes of death were nearly identical between groups,” the authors write, with 17 deaths from cardiovascular disease, eight from cancer, and eight from cerebrovascular disease.

In terms of morbidity, including cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones, there were 101 events overall, with 52 in the parathyroidectomy group and 49 in the nonsurgery group, which again, was not a significant difference.

Sixteen vertebral fractures occurred overall in 14 patients, which were evenly split at seven patients in each group.

The authors note that “the incidence of peripheral fractures for women in our study was around 2,900 per 100,000 person-years, in the same range as for 70-year-old women in a study in Gothenburg, Sweden (about 2,600 per 100,000 person-years).”

There were no between-group differences in terms of time to death or first morbidity event for any of the prespecified events.

Of the 96 patients originally assigned to the nonsurgery group, 17 (18%) had surgery during follow-up, including three for serious hypercalcemia, three by their own choice, two for decreasing bone density, one for kidney stones, and the others for unclear or unrelated reasons.

Study limitations include that only 26 men (13 in each group) were included, and only 16 completed the study. “The external validity for men based on this study is therefore limited,” the authors note.

And although most people with primary hyperparathyroidism are adults, the older age of participants suggests the results should not be generalized to younger patients with benign parathyroid tumors.

The editorialists note that age should be one of the few factors that may, indeed, suggest appropriate candidates for parathyroidectomy.

“Younger patients (aged < 50 years) may have more aggressive disease,” they explain.

In addition, “patients with serum calcium levels above 3 mmol/L (> 12 mg/dL) are at greater risk for symptomatic hypercalcemia, and patients with a recent history of kidney stones may have fewer future stones after surgical cure.”

“Yet, such patients are a small minority of those with primary hyperparathyroidism,” they note.

The study authors underscore that “our data add evidence to guide the decisionmaking process in deliberative dialogue between clinicians and patients.”

The study received funding from Swedish government grants, the Norwegian Research Council, and the South-Eastern Norway Regional Health Authority.

A version of this article first appeared on Medscape.com.

Patients who receive parathyroidectomy for mild primary hyperparathyroidism show no benefits in survival or morbidity, including fractures, cancer, or cardiovascular outcomes over more than 10 years, compared with those not receiving the surgery, results from a randomized, prospective trial show.

“In contrast to existing data showing increased mortality and cardiovascular morbidity in mild primary hyperparathyroidism, we did not find any treatment effect of parathyroidectomy on these important clinical endpoints,” report the authors of the study, published in the Annals of Internal Medicine.
 

Reason to evaluate and revise current recommendations?

With mild primary hyperparathyroidism becoming the predominant form of hyperparathyroidism, the results suggest rethinking the current recommendations for the condition, the study authors note. 

“Over the years, more active management of mild primary hyperparathyroidism has been recommended, with a widening of criteria for parathyroidectomy,” they write.

“With the low number of kidney stones (n = 5) and no effect of parathyroidectomy on fractures, there may be a need to evaluate and potentially revise the current recommendations.”

The authors of an accompanying editorial agree that “the [results] provide a strong rationale for nonoperative management of patients with mild primary hyperparathyroidism.”

“The findings suggest that most patients can be managed nonoperatively, with monitoring of serum calcium levels every 1 to 2 years or if symptoms occur,” write the editorial authors, Mark J. Bolland, PhD, and Andrew Grey, MD, of the department of medicine, University of Auckland, New Zealand.

Although parathyroidectomy is recommended for the treatment in patients with hyperparathyroidism with severe hypercalcemia or overt symptoms, there has been debate on the long-term benefits of surgery among those with milder cases.  

Most previous studies that have shown benefits, such as reductions in the risk of fracture with parathyroidectomy, have importantly not distinguished between mild and more severe primary hyperparathyroidism, the authors note.
 

No significant differences in mortality between surgery, nonsurgery groups

For the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, first author Mikkel Pretorius, MD, Oslo University Hospital and Faculty of Medicine, University of Oslo, and colleagues enrolled 191 patients between 1998 and 2005 in Sweden, Norway, and Denmark, who were aged 50-80 years and had mild primary hyperparathyroidism, defined as serum calcium levels of 10.42-11.22 mg/dL.

Participants were randomized to receive surgery (n = 95) or nonoperative observation without intervention (n = 96).

After a 10-year follow-up, 129 patients had completed the final visit. The overall death rate was 7.6%, and, with eight deaths in the surgery group and seven in the nonsurgery group, there were no significant differences between groups in terms of mortality (HR, 1.17; P = .76).

During an extended observation period that lasted until 2018, mortality rates increased by 23%, but with a relatively even distribution of 24 deaths in the surgery group and 20 among those with no surgery.

Chronic hypercalcemia related to primary hyperparathyroidism has been debated as being associated with an increased risk of cardiovascular disease or cancer, however, “the absolute numbers for these and the other disease-specific causes of death were nearly identical between groups,” the authors write, with 17 deaths from cardiovascular disease, eight from cancer, and eight from cerebrovascular disease.

In terms of morbidity, including cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones, there were 101 events overall, with 52 in the parathyroidectomy group and 49 in the nonsurgery group, which again, was not a significant difference.

Sixteen vertebral fractures occurred overall in 14 patients, which were evenly split at seven patients in each group.

The authors note that “the incidence of peripheral fractures for women in our study was around 2,900 per 100,000 person-years, in the same range as for 70-year-old women in a study in Gothenburg, Sweden (about 2,600 per 100,000 person-years).”

There were no between-group differences in terms of time to death or first morbidity event for any of the prespecified events.

Of the 96 patients originally assigned to the nonsurgery group, 17 (18%) had surgery during follow-up, including three for serious hypercalcemia, three by their own choice, two for decreasing bone density, one for kidney stones, and the others for unclear or unrelated reasons.

Study limitations include that only 26 men (13 in each group) were included, and only 16 completed the study. “The external validity for men based on this study is therefore limited,” the authors note.

And although most people with primary hyperparathyroidism are adults, the older age of participants suggests the results should not be generalized to younger patients with benign parathyroid tumors.

The editorialists note that age should be one of the few factors that may, indeed, suggest appropriate candidates for parathyroidectomy.

“Younger patients (aged < 50 years) may have more aggressive disease,” they explain.

In addition, “patients with serum calcium levels above 3 mmol/L (> 12 mg/dL) are at greater risk for symptomatic hypercalcemia, and patients with a recent history of kidney stones may have fewer future stones after surgical cure.”

“Yet, such patients are a small minority of those with primary hyperparathyroidism,” they note.

The study authors underscore that “our data add evidence to guide the decisionmaking process in deliberative dialogue between clinicians and patients.”

The study received funding from Swedish government grants, the Norwegian Research Council, and the South-Eastern Norway Regional Health Authority.

A version of this article first appeared on Medscape.com.

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

A version of this article first appeared on Medscape.com.

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

A version of this article first appeared on Medscape.com.

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

The global burden of thyroid cancer is substantial, and incidence rates are increasing in many developed countries, including the Unites States, concluded a new analysis based on 30 years of observational data.

“We report overall increases in the burden of thyroid cancer across the majority of EU15+ countries between 1990 and 2019, evidenced by plateaus in incidence rates and reductions in mortality and DALY [disability-adjusted life-years] rates,” the authors reported.

“However, in a number of countries, including the U.S., there are unfavorable increasing mortality and DALY trends over this time period ... [and] a better understanding of the trends in the disease burden of thyroid cancer may help to inform future health system planning,” they added.

The study was published online March 10, 2022, in JAMA Otolaryngology–Head & Neck Surgery.
 

Trends in thyroid cancer

For the analysis, James Schuster-Bruce, MBChB, from St. George’s University Hospital NHS Foundation Trust, London, and colleagues compared trends in thyroid cancer across 30 years of follow-up among 15 countries of the (pre-2004) European Union as well as those in the United States, Australia, Canada, and Norway (EU15+).

Data from the Global Burden of Disease study database were used to track these trends. “We extracted age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and DALYs for thyroid cancer from EU15+ countries between 1990 and 2019 using the dedicated GBD study results tool,” the investigators explained.

In 2019, ASIRs were highest in Italy at 6.36 per 100,000 population, followed by the United States at a rate of 5.59 per 100,000 population – although incidence rates of thyroid cancer have actually recently decreased in U.S. women, they noted.

“Thirteen of 19 countries showed an average annual percentage increase in ASIR across the study period,” the investigators added. Out of all the EU15+ countries, the average annual percentage change (AAPC) was the highest in Australia at 2.5 per 100,000 population and the United States at 1.2 per 100,000.

On the other hand, a largely plateauing trend in incidence rates across the majority of EU15+ nations has been observed since 1990, as reflected by incidence rates ranging from –0.8 to 0.8 per 100,000 in the most recent period, the researchers added. ASMRs ranged from a 0.40 per 100,000 in Greece to 0.57 per 100,000 in Luxembourg.

In the United States, the ASMR in 2019 was 0.43 per 100,000 population while the ASMR was the lowest in the United Kingdom in the same year at 0.38 per 100,000 population.

Australia, Denmark, and the United States were the only countries showing positive AAPC changes, the team observed. For example, in the most recent period to 2019, Denmark and Australia had reductions in ASMR trends, whereas in the United States, the trend was toward increasing ASMRs 

In 2019, the DALYs of the EU15+ nations ranged from 9.63 per 100,000 in the United Kingdom to 14.46 per 100,000 in Luxembourg. In the most recent period, a downward trend in DALYs was observed in Australia and Denmark while it plateaued in the United States.

“Overall, we identified improvements in thyroid cancer mortality and DALYs, but overall increases in thyroid cancer incidence in EU15+ countries over the past 3 decades,” the investigators commented.

It has been widely suggested that improvements in diagnostic techniques have contributed significantly to increasing incidence rates of thyroid cancer, but there is concern about overdiagnosis.  Newer diagnostic techniques detect significant numbers of slow-growing, subclinical papillary thyroid cancers that make up at least one quarter of all thyroid cancer subtypes, the authors pointed out.

“It has therefore been suggested that an increase in subclinical disease has inflated the data to look more substantial than the clinical reality,” the authors wrote. However, they insisted that overdiagnosis alone is unlikely to account entirely for increasing incidence trends in the current analysis.

Rather, their concern for countries with high incidence rates of thyroid cancer is the surveillance burden of disease that does not affect mortality. “Close observation of future time trends in thyroid cancer disease burden should be performed in the context of recent changes in international clinical practice guidelines, which have suggested more conservative diagnostic and management strategies,” the authors suggested.

“In the context of the more conservative treatment guidelines and reported increase in true disease, it is important to closely observe mortality and DALYs over the coming years to ensure optimum thyroid cancer management in these nations,” they added.

The study had no specific funding. Dr. Schuster-Bruce disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The global burden of thyroid cancer is substantial, and incidence rates are increasing in many developed countries, including the Unites States, concluded a new analysis based on 30 years of observational data.

“We report overall increases in the burden of thyroid cancer across the majority of EU15+ countries between 1990 and 2019, evidenced by plateaus in incidence rates and reductions in mortality and DALY [disability-adjusted life-years] rates,” the authors reported.

“However, in a number of countries, including the U.S., there are unfavorable increasing mortality and DALY trends over this time period ... [and] a better understanding of the trends in the disease burden of thyroid cancer may help to inform future health system planning,” they added.

The study was published online March 10, 2022, in JAMA Otolaryngology–Head & Neck Surgery.
 

Trends in thyroid cancer

For the analysis, James Schuster-Bruce, MBChB, from St. George’s University Hospital NHS Foundation Trust, London, and colleagues compared trends in thyroid cancer across 30 years of follow-up among 15 countries of the (pre-2004) European Union as well as those in the United States, Australia, Canada, and Norway (EU15+).

Data from the Global Burden of Disease study database were used to track these trends. “We extracted age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and DALYs for thyroid cancer from EU15+ countries between 1990 and 2019 using the dedicated GBD study results tool,” the investigators explained.

In 2019, ASIRs were highest in Italy at 6.36 per 100,000 population, followed by the United States at a rate of 5.59 per 100,000 population – although incidence rates of thyroid cancer have actually recently decreased in U.S. women, they noted.

“Thirteen of 19 countries showed an average annual percentage increase in ASIR across the study period,” the investigators added. Out of all the EU15+ countries, the average annual percentage change (AAPC) was the highest in Australia at 2.5 per 100,000 population and the United States at 1.2 per 100,000.

On the other hand, a largely plateauing trend in incidence rates across the majority of EU15+ nations has been observed since 1990, as reflected by incidence rates ranging from –0.8 to 0.8 per 100,000 in the most recent period, the researchers added. ASMRs ranged from a 0.40 per 100,000 in Greece to 0.57 per 100,000 in Luxembourg.

In the United States, the ASMR in 2019 was 0.43 per 100,000 population while the ASMR was the lowest in the United Kingdom in the same year at 0.38 per 100,000 population.

Australia, Denmark, and the United States were the only countries showing positive AAPC changes, the team observed. For example, in the most recent period to 2019, Denmark and Australia had reductions in ASMR trends, whereas in the United States, the trend was toward increasing ASMRs 

In 2019, the DALYs of the EU15+ nations ranged from 9.63 per 100,000 in the United Kingdom to 14.46 per 100,000 in Luxembourg. In the most recent period, a downward trend in DALYs was observed in Australia and Denmark while it plateaued in the United States.

“Overall, we identified improvements in thyroid cancer mortality and DALYs, but overall increases in thyroid cancer incidence in EU15+ countries over the past 3 decades,” the investigators commented.

It has been widely suggested that improvements in diagnostic techniques have contributed significantly to increasing incidence rates of thyroid cancer, but there is concern about overdiagnosis.  Newer diagnostic techniques detect significant numbers of slow-growing, subclinical papillary thyroid cancers that make up at least one quarter of all thyroid cancer subtypes, the authors pointed out.

“It has therefore been suggested that an increase in subclinical disease has inflated the data to look more substantial than the clinical reality,” the authors wrote. However, they insisted that overdiagnosis alone is unlikely to account entirely for increasing incidence trends in the current analysis.

Rather, their concern for countries with high incidence rates of thyroid cancer is the surveillance burden of disease that does not affect mortality. “Close observation of future time trends in thyroid cancer disease burden should be performed in the context of recent changes in international clinical practice guidelines, which have suggested more conservative diagnostic and management strategies,” the authors suggested.

“In the context of the more conservative treatment guidelines and reported increase in true disease, it is important to closely observe mortality and DALYs over the coming years to ensure optimum thyroid cancer management in these nations,” they added.

The study had no specific funding. Dr. Schuster-Bruce disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The global burden of thyroid cancer is substantial, and incidence rates are increasing in many developed countries, including the Unites States, concluded a new analysis based on 30 years of observational data.

“We report overall increases in the burden of thyroid cancer across the majority of EU15+ countries between 1990 and 2019, evidenced by plateaus in incidence rates and reductions in mortality and DALY [disability-adjusted life-years] rates,” the authors reported.

“However, in a number of countries, including the U.S., there are unfavorable increasing mortality and DALY trends over this time period ... [and] a better understanding of the trends in the disease burden of thyroid cancer may help to inform future health system planning,” they added.

The study was published online March 10, 2022, in JAMA Otolaryngology–Head & Neck Surgery.
 

Trends in thyroid cancer

For the analysis, James Schuster-Bruce, MBChB, from St. George’s University Hospital NHS Foundation Trust, London, and colleagues compared trends in thyroid cancer across 30 years of follow-up among 15 countries of the (pre-2004) European Union as well as those in the United States, Australia, Canada, and Norway (EU15+).

Data from the Global Burden of Disease study database were used to track these trends. “We extracted age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and DALYs for thyroid cancer from EU15+ countries between 1990 and 2019 using the dedicated GBD study results tool,” the investigators explained.

In 2019, ASIRs were highest in Italy at 6.36 per 100,000 population, followed by the United States at a rate of 5.59 per 100,000 population – although incidence rates of thyroid cancer have actually recently decreased in U.S. women, they noted.

“Thirteen of 19 countries showed an average annual percentage increase in ASIR across the study period,” the investigators added. Out of all the EU15+ countries, the average annual percentage change (AAPC) was the highest in Australia at 2.5 per 100,000 population and the United States at 1.2 per 100,000.

On the other hand, a largely plateauing trend in incidence rates across the majority of EU15+ nations has been observed since 1990, as reflected by incidence rates ranging from –0.8 to 0.8 per 100,000 in the most recent period, the researchers added. ASMRs ranged from a 0.40 per 100,000 in Greece to 0.57 per 100,000 in Luxembourg.

In the United States, the ASMR in 2019 was 0.43 per 100,000 population while the ASMR was the lowest in the United Kingdom in the same year at 0.38 per 100,000 population.

Australia, Denmark, and the United States were the only countries showing positive AAPC changes, the team observed. For example, in the most recent period to 2019, Denmark and Australia had reductions in ASMR trends, whereas in the United States, the trend was toward increasing ASMRs 

In 2019, the DALYs of the EU15+ nations ranged from 9.63 per 100,000 in the United Kingdom to 14.46 per 100,000 in Luxembourg. In the most recent period, a downward trend in DALYs was observed in Australia and Denmark while it plateaued in the United States.

“Overall, we identified improvements in thyroid cancer mortality and DALYs, but overall increases in thyroid cancer incidence in EU15+ countries over the past 3 decades,” the investigators commented.

It has been widely suggested that improvements in diagnostic techniques have contributed significantly to increasing incidence rates of thyroid cancer, but there is concern about overdiagnosis.  Newer diagnostic techniques detect significant numbers of slow-growing, subclinical papillary thyroid cancers that make up at least one quarter of all thyroid cancer subtypes, the authors pointed out.

“It has therefore been suggested that an increase in subclinical disease has inflated the data to look more substantial than the clinical reality,” the authors wrote. However, they insisted that overdiagnosis alone is unlikely to account entirely for increasing incidence trends in the current analysis.

Rather, their concern for countries with high incidence rates of thyroid cancer is the surveillance burden of disease that does not affect mortality. “Close observation of future time trends in thyroid cancer disease burden should be performed in the context of recent changes in international clinical practice guidelines, which have suggested more conservative diagnostic and management strategies,” the authors suggested.

“In the context of the more conservative treatment guidelines and reported increase in true disease, it is important to closely observe mortality and DALYs over the coming years to ensure optimum thyroid cancer management in these nations,” they added.

The study had no specific funding. Dr. Schuster-Bruce disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with low-risk differentiated thyroid cancer (DTC) undergoing thyroidectomy show no improvements in outcomes with the use of postoperative radioiodine ablation compared to those who do not receive this therapy, suggesting these patients can be spared the previously common treatment.

The study’s take-home message for clinicians should be to “stop systematic radioiodine ablation administration in low-risk thyroid cancer patients,” lead author Sophie Leboulleux, MD, PhD, said in an interview.

The results were first reported at ENDO 2021 and have now been published in the New England Journal of Medicine by Dr. Leboulleux, of the department of nuclear medicine and endocrine oncology, Gustave Roussy Cancer Institute, Villejuif, France, and colleagues.

While American Thyroid Association (ATA) guidelines already indicate that radioiodine ablation is not routinely recommended after thyroidectomy for patients with low-risk thyroid cancer, the guidance is only a “weak recommendation,” supported by “low-quality evidence.”  

However, the new findings should give that level of evidence a much-needed boost, said one expert. “I think the main contribution of this paper is to change the evidence level to ‘high quality,’ therefore making the recommendation ‘strong,’ rather than ‘weak,’ ” David S. Cooper, MD, said in an interview.

Dr. Cooper, professor of medicine and radiology at Johns Hopkins University, Baltimore, wrote an editorial that accompanies Dr. Leboulleux’s study.

The ability to safely spare patients the radioiodine ablation step after thyroidectomy has important benefits in terms of cost and convenience, Dr. Cooper stressed.
 

ESTIMABL2 trial

The new findings are from the prospective, randomized, phase 3 Essai Stimulation Ablation 2 (ESTIMABL2) trial, in which 730 patients at 35 centers in France with low-risk DTC scheduled to undergo thyroidectomy were enrolled between May 2013 and March 2017.

Patients were randomized to receive either postoperative radioiodine ablation (1.1 GBq) after injections of recombinant human thyrotropin (n = 363) or no postoperative radioiodine (n = 367).

Patients were a mean age of 52 years and 83% were women. About 96% had papillary tumors, and pathological tumor node (pTN) stages were mostly pT1b thyroid with a nodal status of N0 or Nx (81.1%). It is these patients in particular in whom retrospective studies of the use of radioiodine ablation have yielded inconsistent results, Dr. Leboulleux and colleagues noted. Hence, their decision to look at this prospectively.

Outcomes were based on the groups’ rates of events, defined as the presence of abnormal foci of radioiodine uptake on whole-body scanning that required treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or increased levels of thyroglobulin or thyroglobulin antibodies.

After a 3-year follow-up, the rates of having no events in both groups were very high – and nearly identical – at 95.6% among those receiving no radioiodine ablation and 95.9% in the radioiodine group, for a between-group difference of –0.3 percentage points, which met the criteria for noninferiority for the no-radioiodine group.

Likewise, the events that did occur were nearly equally split between the no-radioiodine group (16 events, 4.4%) and the radioiodine group (15 events, 4.1%).

Among patients who had events, subsequent treatments, including surgery, radioiodine administration, or both, were necessary for four patients in the no-radioiodine group and 10 in the radioiodine group, and additional treatments were not necessary for the other patients who experienced events.

There were no differences between those who did and did not experience events in terms of molecular alterations, and 50 of the tumors had BRAF mutations, with no significant differences between groups.

Of the adverse events that occurred in 30 patients, none were determined to be related to treatment, and there were no thyroid-related deaths.

The recurrence rates align with the rates observed overall with low-risk thyroid cancer, the authors noted. 

“We observed that less than 5% of the patients in the two groups had events that included abnormal findings on whole-body scanning or neck ultrasonography or elevated levels of thyroglobulin or thyroglobulin antibodies during the first 3 years of follow-up,” they reported.

“This rate is concordant with the definition of low-risk thyroid cancer, and our trial showed that the risk of events was not higher in the absence of postoperative administration of radioiodine.”
 

Patients spared costs, work losses

Dr. Cooper elaborated on the advantages, for patients, of avoiding radioiodine ablation.

For one thing, the recombinant human TSH that is necessary to prepare for radioiodine therapy is very expensive, ranging from $2,000 to $3,000, with patients often having a copay, he explained.

“Patients usually have to take time off work, which is also an expense to society and to them if they don’t get paid for days that they don’t work,” Dr. Cooper added.

A possible study limitation is the question of whether 3 years is an ample follow-up period to detect events. However, Dr. Cooper said he considers the period to be sufficient.

“As the authors point out, most recurrences of thyroid cancer are detected within the first 3-5 years of initial treatment, so ... the 3-year window is still clinically relevant,” he said.

Regarding the study’s inclusion of centers only in France, Dr. Cooper added, “I do not think that this is a study limitation. There is nothing specific about the French population that would lead me to conclude that the results were not generalizable to all populations with low-risk papillary thyroid cancer.”
 

Some continue radioiodine use, but lobectomies add to decline

Despite the mounting evidence of the lack of benefit of radioiodine ablation in low-risk patients, some centers, particularly in Europe, continue the practice, which was standard in the treatment of DTC until relatively recently.

“[While] U.S. guidelines changed in 2015 in favor of no radioiodine in low-risk differentiated thyroid cancer patients, this study should help to change European guidelines,” Dr. Leboulleux said. “The results will help to change practice both in the U.S. and in Europe.”

In addition to awareness of guidelines and new evidence, another reason for the decline in radioiodine ablation for low-risk DTC is the increasing use of thyroid lobectomy, which does not involve the use of radioiodine ablation, rather than total thyroidectomy, Dr. Cooper noted.

“The [new] NEJM paper will hopefully decrease the inappropriate use of radioiodine in low-risk patients even further,” he concluded.

The study received support from the French Ministry of Health through a grant from the National Cancer Institute. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with low-risk differentiated thyroid cancer (DTC) undergoing thyroidectomy show no improvements in outcomes with the use of postoperative radioiodine ablation compared to those who do not receive this therapy, suggesting these patients can be spared the previously common treatment.

The study’s take-home message for clinicians should be to “stop systematic radioiodine ablation administration in low-risk thyroid cancer patients,” lead author Sophie Leboulleux, MD, PhD, said in an interview.

The results were first reported at ENDO 2021 and have now been published in the New England Journal of Medicine by Dr. Leboulleux, of the department of nuclear medicine and endocrine oncology, Gustave Roussy Cancer Institute, Villejuif, France, and colleagues.

While American Thyroid Association (ATA) guidelines already indicate that radioiodine ablation is not routinely recommended after thyroidectomy for patients with low-risk thyroid cancer, the guidance is only a “weak recommendation,” supported by “low-quality evidence.”  

However, the new findings should give that level of evidence a much-needed boost, said one expert. “I think the main contribution of this paper is to change the evidence level to ‘high quality,’ therefore making the recommendation ‘strong,’ rather than ‘weak,’ ” David S. Cooper, MD, said in an interview.

Dr. Cooper, professor of medicine and radiology at Johns Hopkins University, Baltimore, wrote an editorial that accompanies Dr. Leboulleux’s study.

The ability to safely spare patients the radioiodine ablation step after thyroidectomy has important benefits in terms of cost and convenience, Dr. Cooper stressed.
 

ESTIMABL2 trial

The new findings are from the prospective, randomized, phase 3 Essai Stimulation Ablation 2 (ESTIMABL2) trial, in which 730 patients at 35 centers in France with low-risk DTC scheduled to undergo thyroidectomy were enrolled between May 2013 and March 2017.

Patients were randomized to receive either postoperative radioiodine ablation (1.1 GBq) after injections of recombinant human thyrotropin (n = 363) or no postoperative radioiodine (n = 367).

Patients were a mean age of 52 years and 83% were women. About 96% had papillary tumors, and pathological tumor node (pTN) stages were mostly pT1b thyroid with a nodal status of N0 or Nx (81.1%). It is these patients in particular in whom retrospective studies of the use of radioiodine ablation have yielded inconsistent results, Dr. Leboulleux and colleagues noted. Hence, their decision to look at this prospectively.

Outcomes were based on the groups’ rates of events, defined as the presence of abnormal foci of radioiodine uptake on whole-body scanning that required treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or increased levels of thyroglobulin or thyroglobulin antibodies.

After a 3-year follow-up, the rates of having no events in both groups were very high – and nearly identical – at 95.6% among those receiving no radioiodine ablation and 95.9% in the radioiodine group, for a between-group difference of –0.3 percentage points, which met the criteria for noninferiority for the no-radioiodine group.

Likewise, the events that did occur were nearly equally split between the no-radioiodine group (16 events, 4.4%) and the radioiodine group (15 events, 4.1%).

Among patients who had events, subsequent treatments, including surgery, radioiodine administration, or both, were necessary for four patients in the no-radioiodine group and 10 in the radioiodine group, and additional treatments were not necessary for the other patients who experienced events.

There were no differences between those who did and did not experience events in terms of molecular alterations, and 50 of the tumors had BRAF mutations, with no significant differences between groups.

Of the adverse events that occurred in 30 patients, none were determined to be related to treatment, and there were no thyroid-related deaths.

The recurrence rates align with the rates observed overall with low-risk thyroid cancer, the authors noted. 

“We observed that less than 5% of the patients in the two groups had events that included abnormal findings on whole-body scanning or neck ultrasonography or elevated levels of thyroglobulin or thyroglobulin antibodies during the first 3 years of follow-up,” they reported.

“This rate is concordant with the definition of low-risk thyroid cancer, and our trial showed that the risk of events was not higher in the absence of postoperative administration of radioiodine.”
 

Patients spared costs, work losses

Dr. Cooper elaborated on the advantages, for patients, of avoiding radioiodine ablation.

For one thing, the recombinant human TSH that is necessary to prepare for radioiodine therapy is very expensive, ranging from $2,000 to $3,000, with patients often having a copay, he explained.

“Patients usually have to take time off work, which is also an expense to society and to them if they don’t get paid for days that they don’t work,” Dr. Cooper added.

A possible study limitation is the question of whether 3 years is an ample follow-up period to detect events. However, Dr. Cooper said he considers the period to be sufficient.

“As the authors point out, most recurrences of thyroid cancer are detected within the first 3-5 years of initial treatment, so ... the 3-year window is still clinically relevant,” he said.

Regarding the study’s inclusion of centers only in France, Dr. Cooper added, “I do not think that this is a study limitation. There is nothing specific about the French population that would lead me to conclude that the results were not generalizable to all populations with low-risk papillary thyroid cancer.”
 

Some continue radioiodine use, but lobectomies add to decline

Despite the mounting evidence of the lack of benefit of radioiodine ablation in low-risk patients, some centers, particularly in Europe, continue the practice, which was standard in the treatment of DTC until relatively recently.

“[While] U.S. guidelines changed in 2015 in favor of no radioiodine in low-risk differentiated thyroid cancer patients, this study should help to change European guidelines,” Dr. Leboulleux said. “The results will help to change practice both in the U.S. and in Europe.”

In addition to awareness of guidelines and new evidence, another reason for the decline in radioiodine ablation for low-risk DTC is the increasing use of thyroid lobectomy, which does not involve the use of radioiodine ablation, rather than total thyroidectomy, Dr. Cooper noted.

“The [new] NEJM paper will hopefully decrease the inappropriate use of radioiodine in low-risk patients even further,” he concluded.

The study received support from the French Ministry of Health through a grant from the National Cancer Institute. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with low-risk differentiated thyroid cancer (DTC) undergoing thyroidectomy show no improvements in outcomes with the use of postoperative radioiodine ablation compared to those who do not receive this therapy, suggesting these patients can be spared the previously common treatment.

The study’s take-home message for clinicians should be to “stop systematic radioiodine ablation administration in low-risk thyroid cancer patients,” lead author Sophie Leboulleux, MD, PhD, said in an interview.

The results were first reported at ENDO 2021 and have now been published in the New England Journal of Medicine by Dr. Leboulleux, of the department of nuclear medicine and endocrine oncology, Gustave Roussy Cancer Institute, Villejuif, France, and colleagues.

While American Thyroid Association (ATA) guidelines already indicate that radioiodine ablation is not routinely recommended after thyroidectomy for patients with low-risk thyroid cancer, the guidance is only a “weak recommendation,” supported by “low-quality evidence.”  

However, the new findings should give that level of evidence a much-needed boost, said one expert. “I think the main contribution of this paper is to change the evidence level to ‘high quality,’ therefore making the recommendation ‘strong,’ rather than ‘weak,’ ” David S. Cooper, MD, said in an interview.

Dr. Cooper, professor of medicine and radiology at Johns Hopkins University, Baltimore, wrote an editorial that accompanies Dr. Leboulleux’s study.

The ability to safely spare patients the radioiodine ablation step after thyroidectomy has important benefits in terms of cost and convenience, Dr. Cooper stressed.
 

ESTIMABL2 trial

The new findings are from the prospective, randomized, phase 3 Essai Stimulation Ablation 2 (ESTIMABL2) trial, in which 730 patients at 35 centers in France with low-risk DTC scheduled to undergo thyroidectomy were enrolled between May 2013 and March 2017.

Patients were randomized to receive either postoperative radioiodine ablation (1.1 GBq) after injections of recombinant human thyrotropin (n = 363) or no postoperative radioiodine (n = 367).

Patients were a mean age of 52 years and 83% were women. About 96% had papillary tumors, and pathological tumor node (pTN) stages were mostly pT1b thyroid with a nodal status of N0 or Nx (81.1%). It is these patients in particular in whom retrospective studies of the use of radioiodine ablation have yielded inconsistent results, Dr. Leboulleux and colleagues noted. Hence, their decision to look at this prospectively.

Outcomes were based on the groups’ rates of events, defined as the presence of abnormal foci of radioiodine uptake on whole-body scanning that required treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or increased levels of thyroglobulin or thyroglobulin antibodies.

After a 3-year follow-up, the rates of having no events in both groups were very high – and nearly identical – at 95.6% among those receiving no radioiodine ablation and 95.9% in the radioiodine group, for a between-group difference of –0.3 percentage points, which met the criteria for noninferiority for the no-radioiodine group.

Likewise, the events that did occur were nearly equally split between the no-radioiodine group (16 events, 4.4%) and the radioiodine group (15 events, 4.1%).

Among patients who had events, subsequent treatments, including surgery, radioiodine administration, or both, were necessary for four patients in the no-radioiodine group and 10 in the radioiodine group, and additional treatments were not necessary for the other patients who experienced events.

There were no differences between those who did and did not experience events in terms of molecular alterations, and 50 of the tumors had BRAF mutations, with no significant differences between groups.

Of the adverse events that occurred in 30 patients, none were determined to be related to treatment, and there were no thyroid-related deaths.

The recurrence rates align with the rates observed overall with low-risk thyroid cancer, the authors noted. 

“We observed that less than 5% of the patients in the two groups had events that included abnormal findings on whole-body scanning or neck ultrasonography or elevated levels of thyroglobulin or thyroglobulin antibodies during the first 3 years of follow-up,” they reported.

“This rate is concordant with the definition of low-risk thyroid cancer, and our trial showed that the risk of events was not higher in the absence of postoperative administration of radioiodine.”
 

Patients spared costs, work losses

Dr. Cooper elaborated on the advantages, for patients, of avoiding radioiodine ablation.

For one thing, the recombinant human TSH that is necessary to prepare for radioiodine therapy is very expensive, ranging from $2,000 to $3,000, with patients often having a copay, he explained.

“Patients usually have to take time off work, which is also an expense to society and to them if they don’t get paid for days that they don’t work,” Dr. Cooper added.

A possible study limitation is the question of whether 3 years is an ample follow-up period to detect events. However, Dr. Cooper said he considers the period to be sufficient.

“As the authors point out, most recurrences of thyroid cancer are detected within the first 3-5 years of initial treatment, so ... the 3-year window is still clinically relevant,” he said.

Regarding the study’s inclusion of centers only in France, Dr. Cooper added, “I do not think that this is a study limitation. There is nothing specific about the French population that would lead me to conclude that the results were not generalizable to all populations with low-risk papillary thyroid cancer.”
 

Some continue radioiodine use, but lobectomies add to decline

Despite the mounting evidence of the lack of benefit of radioiodine ablation in low-risk patients, some centers, particularly in Europe, continue the practice, which was standard in the treatment of DTC until relatively recently.

“[While] U.S. guidelines changed in 2015 in favor of no radioiodine in low-risk differentiated thyroid cancer patients, this study should help to change European guidelines,” Dr. Leboulleux said. “The results will help to change practice both in the U.S. and in Europe.”

In addition to awareness of guidelines and new evidence, another reason for the decline in radioiodine ablation for low-risk DTC is the increasing use of thyroid lobectomy, which does not involve the use of radioiodine ablation, rather than total thyroidectomy, Dr. Cooper noted.

“The [new] NEJM paper will hopefully decrease the inappropriate use of radioiodine in low-risk patients even further,” he concluded.

The study received support from the French Ministry of Health through a grant from the National Cancer Institute. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Radiofrequency ablation (RFA) shows efficacy as a potential noninvasive option for the treatment of low-risk microcarcinomas in papillary thyroid cancer (PTC) when measures beyond active surveillance are warranted, results from a new review show.

“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.

Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.

“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.

However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.  
 

When active surveillance isn’t enough

Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.

Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.

In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.

Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
 

New meta-analysis

To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.

The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.

Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.

Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.

With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.

The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).

New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.

Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.

“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
 

Questions surrounding the 20% of patients who still had residual nodules

While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”

The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.

To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.

A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.

They add that core needle biopsy is believed to have higher accuracy.

While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”

And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.

To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
 

RFA an option for some patients

In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.

“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.

The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Radiofrequency ablation (RFA) shows efficacy as a potential noninvasive option for the treatment of low-risk microcarcinomas in papillary thyroid cancer (PTC) when measures beyond active surveillance are warranted, results from a new review show.

“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.

Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.

“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.

However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.  
 

When active surveillance isn’t enough

Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.

Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.

In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.

Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
 

New meta-analysis

To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.

The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.

Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.

Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.

With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.

The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).

New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.

Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.

“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
 

Questions surrounding the 20% of patients who still had residual nodules

While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”

The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.

To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.

A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.

They add that core needle biopsy is believed to have higher accuracy.

While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”

And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.

To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
 

RFA an option for some patients

In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.

“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.

The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Radiofrequency ablation (RFA) shows efficacy as a potential noninvasive option for the treatment of low-risk microcarcinomas in papillary thyroid cancer (PTC) when measures beyond active surveillance are warranted, results from a new review show.

“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.

Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.

“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.

However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.  
 

When active surveillance isn’t enough

Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.

Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.

In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.

Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
 

New meta-analysis

To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.

The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.

Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.

Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.

With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.

The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).

New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.

Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.

“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
 

Questions surrounding the 20% of patients who still had residual nodules

While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”

The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.

To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.

A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.

They add that core needle biopsy is believed to have higher accuracy.

While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”

And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.

To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
 

RFA an option for some patients

In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.

“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.

The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.