Pituitary, Thyroid & Adrenal Disorders

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

The women received 300-1,200
mg/day of mifepristone (Korlym) in the 24-
week open-label Study of the Effica­
cy and Safety of Mifepristone in the
Treatment of Endogenous Cushing’s
Syndrome ( SEISMIC) and in an ex­
tension of the study in 18 patients
who continued for a median of 27
months (range, 14-43 months). Korlym is indicated to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery, according to the product's labeling information.*

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

"Gynecologic consultation may be required in patients with persistent endometrial bleeding," said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

*Clarification, 8/22/2013: An earlier version of this story did not state that the brand of mifepristone used in this study was Korlym, which is indicated for treating Cushing's syndrome.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

The women received 300-1,200
mg/day of mifepristone (Korlym) in the 24-
week open-label Study of the Effica­
cy and Safety of Mifepristone in the
Treatment of Endogenous Cushing’s
Syndrome ( SEISMIC) and in an ex­
tension of the study in 18 patients
who continued for a median of 27
months (range, 14-43 months). Korlym is indicated to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery, according to the product's labeling information.*

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

"Gynecologic consultation may be required in patients with persistent endometrial bleeding," said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

*Clarification, 8/22/2013: An earlier version of this story did not state that the brand of mifepristone used in this study was Korlym, which is indicated for treating Cushing's syndrome.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

The women received 300-1,200
mg/day of mifepristone (Korlym) in the 24-
week open-label Study of the Effica­
cy and Safety of Mifepristone in the
Treatment of Endogenous Cushing’s
Syndrome ( SEISMIC) and in an ex­
tension of the study in 18 patients
who continued for a median of 27
months (range, 14-43 months). Korlym is indicated to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery, according to the product's labeling information.*

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

"Gynecologic consultation may be required in patients with persistent endometrial bleeding," said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

*Clarification, 8/22/2013: An earlier version of this story did not state that the brand of mifepristone used in this study was Korlym, which is indicated for treating Cushing's syndrome.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

"Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed," he observed. "I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic."

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

"I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome," the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that "by far" the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

"They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis," he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the "buffalo hump," supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

"Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed," he observed. "I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic."

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

"I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome," the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that "by far" the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

"They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis," he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the "buffalo hump," supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

"Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed," he observed. "I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic."

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

"I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome," the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that "by far" the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

"They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis," he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the "buffalo hump," supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

Ketoconazole tablets should not be used as a first-line treatment for fungal infections because treatment has been associated with an increased risk of adrenal insufficiency, potentially fatal hepatotoxicity, and drug interactions, the Food and Drug Administration has announced.

Marketed as Nizoral, oral ketoconazole is no longer indicated for the treatment of Candida and dermatophyte infections and "should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated," according to the MedWatch safety alert issued on July 26.

In addition, oral ketoconazole should not be used to treat fungal infections of the skin and nails, and is only indicated for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis "in patients in whom other treatments have failed or who are intolerant to other therapies," according to the label, which has been modified to reflect these risks and recommendations.

There is now a Medication Guide that will be provided to patients with each filled prescription of oral ketoconazole, explaining the risks.

Because oral ketoconazole has been associated with hepatoxicity that can result in liver transplantation or death, it is now contraindicated in patients with acute or chronic liver disease. The label also now recommends that patients be assessed and monitored for liver toxicity. Monitoring of adrenal function also is now recommended in patients who take the oral formulation of the drug and have adrenal problems or "are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital."

In addition, coadministration of ketoconazole – a potent inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) – with certain drugs is either restricted or contraindicated because of the increase in drug concentrations and increased risk of QT prolongation and other serious reactions. Contraindicated drugs include dofetilide, quinidine, pimozide, and cisapride.

The FDA changes are based on risk-benefit analyses of data that include reports made to the FDA’s Adverse Events Reporting System.

On July 26, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) announced that it has concluded that the risk of hepatoxicity with oral ketoconazole products was greater than the benefits in treating fungal infections and recommended that these products no longer be marketed in the European Union.

Creams, shampoos, and other topical ketoconazole formulations have not been associated with these problems, according to the FDA.

The updated label is available here. Serious adverse events associated with ketoconazole should be reported to the FDA at 800-332-1088 or MedWatch.

emechcatie@frontlinemedcom.com

Ketoconazole tablets should not be used as a first-line treatment for fungal infections because treatment has been associated with an increased risk of adrenal insufficiency, potentially fatal hepatotoxicity, and drug interactions, the Food and Drug Administration has announced.

Marketed as Nizoral, oral ketoconazole is no longer indicated for the treatment of Candida and dermatophyte infections and "should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated," according to the MedWatch safety alert issued on July 26.

In addition, oral ketoconazole should not be used to treat fungal infections of the skin and nails, and is only indicated for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis "in patients in whom other treatments have failed or who are intolerant to other therapies," according to the label, which has been modified to reflect these risks and recommendations.

There is now a Medication Guide that will be provided to patients with each filled prescription of oral ketoconazole, explaining the risks.

Because oral ketoconazole has been associated with hepatoxicity that can result in liver transplantation or death, it is now contraindicated in patients with acute or chronic liver disease. The label also now recommends that patients be assessed and monitored for liver toxicity. Monitoring of adrenal function also is now recommended in patients who take the oral formulation of the drug and have adrenal problems or "are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital."

In addition, coadministration of ketoconazole – a potent inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) – with certain drugs is either restricted or contraindicated because of the increase in drug concentrations and increased risk of QT prolongation and other serious reactions. Contraindicated drugs include dofetilide, quinidine, pimozide, and cisapride.

The FDA changes are based on risk-benefit analyses of data that include reports made to the FDA’s Adverse Events Reporting System.

On July 26, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) announced that it has concluded that the risk of hepatoxicity with oral ketoconazole products was greater than the benefits in treating fungal infections and recommended that these products no longer be marketed in the European Union.

Creams, shampoos, and other topical ketoconazole formulations have not been associated with these problems, according to the FDA.

The updated label is available here. Serious adverse events associated with ketoconazole should be reported to the FDA at 800-332-1088 or MedWatch.

emechcatie@frontlinemedcom.com

Ketoconazole tablets should not be used as a first-line treatment for fungal infections because treatment has been associated with an increased risk of adrenal insufficiency, potentially fatal hepatotoxicity, and drug interactions, the Food and Drug Administration has announced.

Marketed as Nizoral, oral ketoconazole is no longer indicated for the treatment of Candida and dermatophyte infections and "should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated," according to the MedWatch safety alert issued on July 26.

In addition, oral ketoconazole should not be used to treat fungal infections of the skin and nails, and is only indicated for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis "in patients in whom other treatments have failed or who are intolerant to other therapies," according to the label, which has been modified to reflect these risks and recommendations.

There is now a Medication Guide that will be provided to patients with each filled prescription of oral ketoconazole, explaining the risks.

Because oral ketoconazole has been associated with hepatoxicity that can result in liver transplantation or death, it is now contraindicated in patients with acute or chronic liver disease. The label also now recommends that patients be assessed and monitored for liver toxicity. Monitoring of adrenal function also is now recommended in patients who take the oral formulation of the drug and have adrenal problems or "are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital."

In addition, coadministration of ketoconazole – a potent inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) – with certain drugs is either restricted or contraindicated because of the increase in drug concentrations and increased risk of QT prolongation and other serious reactions. Contraindicated drugs include dofetilide, quinidine, pimozide, and cisapride.

The FDA changes are based on risk-benefit analyses of data that include reports made to the FDA’s Adverse Events Reporting System.

On July 26, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) announced that it has concluded that the risk of hepatoxicity with oral ketoconazole products was greater than the benefits in treating fungal infections and recommended that these products no longer be marketed in the European Union.

Creams, shampoos, and other topical ketoconazole formulations have not been associated with these problems, according to the FDA.

The updated label is available here. Serious adverse events associated with ketoconazole should be reported to the FDA at 800-332-1088 or MedWatch.

emechcatie@frontlinemedcom.com

LONDON – Women with hypothyroidism can achieve good results following fertility treatment if they maintain low levels of thyroid-stimulating hormone before assisted conception, according to findings of a 3-year retrospective study.

"An adequate treatment maintaining serum TSH levels below the threshold value of 2.5 mIU/L seems to fully overcome the detrimental effects of hypothyroidism on the rate of success of IVF [in vitro fertilization] and ICSI [intracytoplasmic sperm injection]," Dr. Andrea Busnelli reported at the annual meeting of the European Society of Human Reproduction and Embryology.

"Therefore, women scheduled for IVF-ICSI with adequately treated hypothyroidism can be reassured regarding the success of the procedure[s]," Dr. Busnelli of IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy, added.

Previous research has shown that women with hypothyroidism have less chance of becoming pregnant after assisted conception than those with normal thyroid function. Subsequent findings conflict on whether levothyroxine treatment may (Hum. Reprod. Update 2013;19:251-8) or may not (Thyroid 2012;22:631-6) improve pregnancy rates.

These studies have been performed in a small number of women and TSH levels achieved with levothyroxine therapy were higher than recently recommended (J. Clin. Endocrinol. Metab. 2012;97:2543-65).

The current study therefore looked at whether "adequate" levothyroxine treatment, meaning that which ensured the level of TSH before conception was 2.5 mIU/L or lower, would be able to compensate for the reduced fertility success reported previously.

A total of 137 women with clinical or subclinical treated hypothyroidism participated in the study. At recruitment, their baseline TSH was between 0.4 and 2.5 mIU/L. Each case was age matched to two women with normal thyroid function as a control (n = 274).

Ultrasound was used to confirm any pregnancy, defined as a vital embryo within an intrauterine gestational sac at 4-5 weeks after embryo transfer.

The average age of cases and controls was approximately 35 years, body mass index in both groups was approximately 22 kg/m², and there were no significant differences in the number of previous deliveries, serum hormone levels, or the cause of infertility leading to fertility treatment. Preconception TSH levels were approximately 1.5 mIU/L.

Looking at the number of assisted reproduction cycles, Dr. Busnelli noted that the duration of controlled ovarian hyperstimulation (COH) was longer for women with hypothyroidism than for their euthyroid counterparts: COH was 10.9 days in cases and 10.1 days in controls (P = .001).

Hyperthyroid women also had a higher chance of cancelled treatment cycles because of a poor response (3.6% vs. 0.7% in euthyroid women, P = .04). Failure to obtain viable embryos also occurred more frequently in hyperthyroid than in euthyroid women, at 17% and 7%, respectively (P = .006). Fertilization rates were also lower (75% vs. 80%; P = .017).

However, there was no difference between cases and controls in terms of the implantation (28% vs. 22%; P = .11), clinical pregnancy (36% vs. 34%; P = .93), or live delivery rates (30% vs. 25%; P = .5).

The presence of antithyroid antibodies did not influence the rates of implantation or termination. There was also no difference in the results comparing women with overt versus subclinical hypothyroidism.

Dr. Busnelli noted, however, that anti-TPO, anti-TG antibodies were not screened for in control women, so this limits the study findings as some in the control population could have had thyroid autoimmunity.

"Our observations suggest that the level of thyroxine may constitute a functional reserve in patients with positive TPO/TG antibodies which is able to compensate for the increased request typical of controlled ovarian hyperstimulation and pregnancy," Dr. Busnelli said.

The study received no commercial financial support. Dr. Busnelli reported having no relevant financial disclosures.

LONDON – Women with hypothyroidism can achieve good results following fertility treatment if they maintain low levels of thyroid-stimulating hormone before assisted conception, according to findings of a 3-year retrospective study.

"An adequate treatment maintaining serum TSH levels below the threshold value of 2.5 mIU/L seems to fully overcome the detrimental effects of hypothyroidism on the rate of success of IVF [in vitro fertilization] and ICSI [intracytoplasmic sperm injection]," Dr. Andrea Busnelli reported at the annual meeting of the European Society of Human Reproduction and Embryology.

"Therefore, women scheduled for IVF-ICSI with adequately treated hypothyroidism can be reassured regarding the success of the procedure[s]," Dr. Busnelli of IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy, added.

Previous research has shown that women with hypothyroidism have less chance of becoming pregnant after assisted conception than those with normal thyroid function. Subsequent findings conflict on whether levothyroxine treatment may (Hum. Reprod. Update 2013;19:251-8) or may not (Thyroid 2012;22:631-6) improve pregnancy rates.

These studies have been performed in a small number of women and TSH levels achieved with levothyroxine therapy were higher than recently recommended (J. Clin. Endocrinol. Metab. 2012;97:2543-65).

The current study therefore looked at whether "adequate" levothyroxine treatment, meaning that which ensured the level of TSH before conception was 2.5 mIU/L or lower, would be able to compensate for the reduced fertility success reported previously.

A total of 137 women with clinical or subclinical treated hypothyroidism participated in the study. At recruitment, their baseline TSH was between 0.4 and 2.5 mIU/L. Each case was age matched to two women with normal thyroid function as a control (n = 274).

Ultrasound was used to confirm any pregnancy, defined as a vital embryo within an intrauterine gestational sac at 4-5 weeks after embryo transfer.

The average age of cases and controls was approximately 35 years, body mass index in both groups was approximately 22 kg/m², and there were no significant differences in the number of previous deliveries, serum hormone levels, or the cause of infertility leading to fertility treatment. Preconception TSH levels were approximately 1.5 mIU/L.

Looking at the number of assisted reproduction cycles, Dr. Busnelli noted that the duration of controlled ovarian hyperstimulation (COH) was longer for women with hypothyroidism than for their euthyroid counterparts: COH was 10.9 days in cases and 10.1 days in controls (P = .001).

Hyperthyroid women also had a higher chance of cancelled treatment cycles because of a poor response (3.6% vs. 0.7% in euthyroid women, P = .04). Failure to obtain viable embryos also occurred more frequently in hyperthyroid than in euthyroid women, at 17% and 7%, respectively (P = .006). Fertilization rates were also lower (75% vs. 80%; P = .017).

However, there was no difference between cases and controls in terms of the implantation (28% vs. 22%; P = .11), clinical pregnancy (36% vs. 34%; P = .93), or live delivery rates (30% vs. 25%; P = .5).

The presence of antithyroid antibodies did not influence the rates of implantation or termination. There was also no difference in the results comparing women with overt versus subclinical hypothyroidism.

Dr. Busnelli noted, however, that anti-TPO, anti-TG antibodies were not screened for in control women, so this limits the study findings as some in the control population could have had thyroid autoimmunity.

"Our observations suggest that the level of thyroxine may constitute a functional reserve in patients with positive TPO/TG antibodies which is able to compensate for the increased request typical of controlled ovarian hyperstimulation and pregnancy," Dr. Busnelli said.

The study received no commercial financial support. Dr. Busnelli reported having no relevant financial disclosures.

LONDON – Women with hypothyroidism can achieve good results following fertility treatment if they maintain low levels of thyroid-stimulating hormone before assisted conception, according to findings of a 3-year retrospective study.

"An adequate treatment maintaining serum TSH levels below the threshold value of 2.5 mIU/L seems to fully overcome the detrimental effects of hypothyroidism on the rate of success of IVF [in vitro fertilization] and ICSI [intracytoplasmic sperm injection]," Dr. Andrea Busnelli reported at the annual meeting of the European Society of Human Reproduction and Embryology.

"Therefore, women scheduled for IVF-ICSI with adequately treated hypothyroidism can be reassured regarding the success of the procedure[s]," Dr. Busnelli of IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy, added.

Previous research has shown that women with hypothyroidism have less chance of becoming pregnant after assisted conception than those with normal thyroid function. Subsequent findings conflict on whether levothyroxine treatment may (Hum. Reprod. Update 2013;19:251-8) or may not (Thyroid 2012;22:631-6) improve pregnancy rates.

These studies have been performed in a small number of women and TSH levels achieved with levothyroxine therapy were higher than recently recommended (J. Clin. Endocrinol. Metab. 2012;97:2543-65).

The current study therefore looked at whether "adequate" levothyroxine treatment, meaning that which ensured the level of TSH before conception was 2.5 mIU/L or lower, would be able to compensate for the reduced fertility success reported previously.

A total of 137 women with clinical or subclinical treated hypothyroidism participated in the study. At recruitment, their baseline TSH was between 0.4 and 2.5 mIU/L. Each case was age matched to two women with normal thyroid function as a control (n = 274).

Ultrasound was used to confirm any pregnancy, defined as a vital embryo within an intrauterine gestational sac at 4-5 weeks after embryo transfer.

The average age of cases and controls was approximately 35 years, body mass index in both groups was approximately 22 kg/m², and there were no significant differences in the number of previous deliveries, serum hormone levels, or the cause of infertility leading to fertility treatment. Preconception TSH levels were approximately 1.5 mIU/L.

Looking at the number of assisted reproduction cycles, Dr. Busnelli noted that the duration of controlled ovarian hyperstimulation (COH) was longer for women with hypothyroidism than for their euthyroid counterparts: COH was 10.9 days in cases and 10.1 days in controls (P = .001).

Hyperthyroid women also had a higher chance of cancelled treatment cycles because of a poor response (3.6% vs. 0.7% in euthyroid women, P = .04). Failure to obtain viable embryos also occurred more frequently in hyperthyroid than in euthyroid women, at 17% and 7%, respectively (P = .006). Fertilization rates were also lower (75% vs. 80%; P = .017).

However, there was no difference between cases and controls in terms of the implantation (28% vs. 22%; P = .11), clinical pregnancy (36% vs. 34%; P = .93), or live delivery rates (30% vs. 25%; P = .5).

The presence of antithyroid antibodies did not influence the rates of implantation or termination. There was also no difference in the results comparing women with overt versus subclinical hypothyroidism.

Dr. Busnelli noted, however, that anti-TPO, anti-TG antibodies were not screened for in control women, so this limits the study findings as some in the control population could have had thyroid autoimmunity.

"Our observations suggest that the level of thyroxine may constitute a functional reserve in patients with positive TPO/TG antibodies which is able to compensate for the increased request typical of controlled ovarian hyperstimulation and pregnancy," Dr. Busnelli said.

The study received no commercial financial support. Dr. Busnelli reported having no relevant financial disclosures.

SAN FRANCISCO – Nonwhite patients with well-differentiated thyroid cancer were at least 36% more likely than were whites to present with metastatic disease, and these significant racial disparities could not be explained fully by differences in socioeconomic status or other obvious factors in a study of 25,945 California cases.

The risk of remote (metastatic) disease at presentation was 89% higher in Hispanics, 82% higher in Asians or Pacific Islanders, and 36% higher in non-Hispanic blacks than in whites, Dr. Avital Harari and her associates reported at the Endocrine Society’s Annual Meeting. The investigators adjusted for the effects of age, socioeconomic status, sex, and type of insurance when assessing the effects of race on disease stage at presentation.

The odds of regional-stage disease at presentation also were significantly higher compared with whites among Hispanics (a 59% higher likelihood of regional disease) and Asian/Pacific Islanders (32% higher).

Compared with patients with the highest socioeconomic status, those with the lowest socioeconomic status were 45% more likely to present with remote disease, a significant difference. Patients who were poorly insured, uninsured, or covered by Medicaid insurance were more than twice as likely to present with remote disease as were privately insured patients. Age and sex increased risk too, with double the odds of metastatic disease at presentation in patients who were male or at least 45 years old.

"Despite the fact that three races seem to have presented with more remote disease than white patients, their survival analysis differs from what we might expect," Dr. Harari said. Asian/Pacific Islanders were significantly less likely than whites to die (a 14% lower odds ratio), and Hispanics had essentially the same overall survival rates as whites. The risk of death was significantly higher in black patients, who were 38% more likely than whites to die, after adjustment for the effects of age, sex, and comorbidities, said Dr. Harari, an endocrine surgeon at the University of California, Los Angeles.

Remote disease quadrupled the odds of dying and regional disease increased the risk of death by 46% compared with localized disease at presentation. Older age significantly increased the risk of death by 7%.

Among patients with metastatic disease at presentation, overall survival rates were not significantly different between racial groups after adjustment for age, sex, and comorbidity. Older age significantly increased the risk of death by 5%.

The chances of dying of thyroid cancer, however, were significantly greater for blacks than for patients of other races.

Differences in the biology of thyroid disease by race, disparities in access to care and resources that might delay diagnosis and treatment, and inherent provider bias are likely at play, said Dr. Harari.

"I challenge you to think about how you might change your practice in regard to the information noted here," she said.

Dr. Harari and her colleagues analyzed data on all new cases of thyroid cancer during 1999-2008 from the California Cancer Registry, a population-based cancer surveillance system. Cases were excluded if they were not well differentiated, had unknown stage at diagnosis, or were second cases in patients already in the registry. The researchers scored socioeconomic status using Yost’s index and scored comorbidity using the Charlson system.

The cohort was 57% white, 24% Hispanic, 15% Asian/Pacific Islander, and 4% black. The racial groups differed significantly by mean age, sex, mean comorbidity score, and socioeconomic score.

Hispanics were younger at diagnosis (mean age, 44 years) compared with Asian/Pacific Islanders (48 years) or whites or Hispanics (50 years each). Hispanics were less likely to be male (18%) than were whites (26%). Mean Charlson comorbidity scores were highest for blacks (0.69) compared with whites (0.41), Hispanics (0.39), and Asian/Pacific Islanders (0.34). Overall, black patients were more likely to be older and to have higher comorbidity scores than other patients, she said.

The two highest quintiles of socioeconomic scores included 60% of whites and 55% of Asian/Pacific Islanders. The two lowest quintiles of socioeconomic scores included 55% of Hispanics and 47% of blacks.

The results support a 2012 review by the Endocrine Society in which people with low socioeconomic status were more likely than more affluent groups to present with advanced thyroid cancer. That study also found that racial minorities had less access to high-volume thyroid surgeons (J. Clin. Endocrinol. Metab. 2012;97:E1579-639).

Dr. Harari reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Nonwhite patients with well-differentiated thyroid cancer were at least 36% more likely than were whites to present with metastatic disease, and these significant racial disparities could not be explained fully by differences in socioeconomic status or other obvious factors in a study of 25,945 California cases.

The risk of remote (metastatic) disease at presentation was 89% higher in Hispanics, 82% higher in Asians or Pacific Islanders, and 36% higher in non-Hispanic blacks than in whites, Dr. Avital Harari and her associates reported at the Endocrine Society’s Annual Meeting. The investigators adjusted for the effects of age, socioeconomic status, sex, and type of insurance when assessing the effects of race on disease stage at presentation.

The odds of regional-stage disease at presentation also were significantly higher compared with whites among Hispanics (a 59% higher likelihood of regional disease) and Asian/Pacific Islanders (32% higher).

Compared with patients with the highest socioeconomic status, those with the lowest socioeconomic status were 45% more likely to present with remote disease, a significant difference. Patients who were poorly insured, uninsured, or covered by Medicaid insurance were more than twice as likely to present with remote disease as were privately insured patients. Age and sex increased risk too, with double the odds of metastatic disease at presentation in patients who were male or at least 45 years old.

"Despite the fact that three races seem to have presented with more remote disease than white patients, their survival analysis differs from what we might expect," Dr. Harari said. Asian/Pacific Islanders were significantly less likely than whites to die (a 14% lower odds ratio), and Hispanics had essentially the same overall survival rates as whites. The risk of death was significantly higher in black patients, who were 38% more likely than whites to die, after adjustment for the effects of age, sex, and comorbidities, said Dr. Harari, an endocrine surgeon at the University of California, Los Angeles.

Remote disease quadrupled the odds of dying and regional disease increased the risk of death by 46% compared with localized disease at presentation. Older age significantly increased the risk of death by 7%.

Among patients with metastatic disease at presentation, overall survival rates were not significantly different between racial groups after adjustment for age, sex, and comorbidity. Older age significantly increased the risk of death by 5%.

The chances of dying of thyroid cancer, however, were significantly greater for blacks than for patients of other races.

Differences in the biology of thyroid disease by race, disparities in access to care and resources that might delay diagnosis and treatment, and inherent provider bias are likely at play, said Dr. Harari.

"I challenge you to think about how you might change your practice in regard to the information noted here," she said.

Dr. Harari and her colleagues analyzed data on all new cases of thyroid cancer during 1999-2008 from the California Cancer Registry, a population-based cancer surveillance system. Cases were excluded if they were not well differentiated, had unknown stage at diagnosis, or were second cases in patients already in the registry. The researchers scored socioeconomic status using Yost’s index and scored comorbidity using the Charlson system.

The cohort was 57% white, 24% Hispanic, 15% Asian/Pacific Islander, and 4% black. The racial groups differed significantly by mean age, sex, mean comorbidity score, and socioeconomic score.

Hispanics were younger at diagnosis (mean age, 44 years) compared with Asian/Pacific Islanders (48 years) or whites or Hispanics (50 years each). Hispanics were less likely to be male (18%) than were whites (26%). Mean Charlson comorbidity scores were highest for blacks (0.69) compared with whites (0.41), Hispanics (0.39), and Asian/Pacific Islanders (0.34). Overall, black patients were more likely to be older and to have higher comorbidity scores than other patients, she said.

The two highest quintiles of socioeconomic scores included 60% of whites and 55% of Asian/Pacific Islanders. The two lowest quintiles of socioeconomic scores included 55% of Hispanics and 47% of blacks.

The results support a 2012 review by the Endocrine Society in which people with low socioeconomic status were more likely than more affluent groups to present with advanced thyroid cancer. That study also found that racial minorities had less access to high-volume thyroid surgeons (J. Clin. Endocrinol. Metab. 2012;97:E1579-639).

Dr. Harari reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Nonwhite patients with well-differentiated thyroid cancer were at least 36% more likely than were whites to present with metastatic disease, and these significant racial disparities could not be explained fully by differences in socioeconomic status or other obvious factors in a study of 25,945 California cases.

The risk of remote (metastatic) disease at presentation was 89% higher in Hispanics, 82% higher in Asians or Pacific Islanders, and 36% higher in non-Hispanic blacks than in whites, Dr. Avital Harari and her associates reported at the Endocrine Society’s Annual Meeting. The investigators adjusted for the effects of age, socioeconomic status, sex, and type of insurance when assessing the effects of race on disease stage at presentation.

The odds of regional-stage disease at presentation also were significantly higher compared with whites among Hispanics (a 59% higher likelihood of regional disease) and Asian/Pacific Islanders (32% higher).

Compared with patients with the highest socioeconomic status, those with the lowest socioeconomic status were 45% more likely to present with remote disease, a significant difference. Patients who were poorly insured, uninsured, or covered by Medicaid insurance were more than twice as likely to present with remote disease as were privately insured patients. Age and sex increased risk too, with double the odds of metastatic disease at presentation in patients who were male or at least 45 years old.

"Despite the fact that three races seem to have presented with more remote disease than white patients, their survival analysis differs from what we might expect," Dr. Harari said. Asian/Pacific Islanders were significantly less likely than whites to die (a 14% lower odds ratio), and Hispanics had essentially the same overall survival rates as whites. The risk of death was significantly higher in black patients, who were 38% more likely than whites to die, after adjustment for the effects of age, sex, and comorbidities, said Dr. Harari, an endocrine surgeon at the University of California, Los Angeles.

Remote disease quadrupled the odds of dying and regional disease increased the risk of death by 46% compared with localized disease at presentation. Older age significantly increased the risk of death by 7%.

Among patients with metastatic disease at presentation, overall survival rates were not significantly different between racial groups after adjustment for age, sex, and comorbidity. Older age significantly increased the risk of death by 5%.

The chances of dying of thyroid cancer, however, were significantly greater for blacks than for patients of other races.

Differences in the biology of thyroid disease by race, disparities in access to care and resources that might delay diagnosis and treatment, and inherent provider bias are likely at play, said Dr. Harari.

"I challenge you to think about how you might change your practice in regard to the information noted here," she said.

Dr. Harari and her colleagues analyzed data on all new cases of thyroid cancer during 1999-2008 from the California Cancer Registry, a population-based cancer surveillance system. Cases were excluded if they were not well differentiated, had unknown stage at diagnosis, or were second cases in patients already in the registry. The researchers scored socioeconomic status using Yost’s index and scored comorbidity using the Charlson system.

The cohort was 57% white, 24% Hispanic, 15% Asian/Pacific Islander, and 4% black. The racial groups differed significantly by mean age, sex, mean comorbidity score, and socioeconomic score.

Hispanics were younger at diagnosis (mean age, 44 years) compared with Asian/Pacific Islanders (48 years) or whites or Hispanics (50 years each). Hispanics were less likely to be male (18%) than were whites (26%). Mean Charlson comorbidity scores were highest for blacks (0.69) compared with whites (0.41), Hispanics (0.39), and Asian/Pacific Islanders (0.34). Overall, black patients were more likely to be older and to have higher comorbidity scores than other patients, she said.

The two highest quintiles of socioeconomic scores included 60% of whites and 55% of Asian/Pacific Islanders. The two lowest quintiles of socioeconomic scores included 55% of Hispanics and 47% of blacks.

The results support a 2012 review by the Endocrine Society in which people with low socioeconomic status were more likely than more affluent groups to present with advanced thyroid cancer. That study also found that racial minorities had less access to high-volume thyroid surgeons (J. Clin. Endocrinol. Metab. 2012;97:E1579-639).

Dr. Harari reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Patients with acromegaly struggle with issues that they often don’t share with their physicians, and they have specific suggestions about actions that health care providers can take to help them cope with their disease, a qualitative study of 19 patients found.

Most described a long journey to a correct diagnosis, and other data suggest that an acromegaly diagnosis typically is delayed by 4-10 years. The delay is frustrating for patients but is followed by relief when they finally have a name for their disease, Michelle H. Gurel, R.N., reported at the Endocrine Society’s Annual Meeting.

She and her associates conducted online interviews with 10 patients recruited through AcromegalyCommunity.com and live interviews with 9 patients at the 2012 Acromegaly Community Conference.

The patients said they were shocked at the idea of needing "brain surgery" (pituitary surgery) when discussing treatment with their physicians, and that they felt unsatisfied or left out of the treatment decision process.

Acromegaly is a rare chronic disease characterized by abnormal skeletal growth and soft tissue enlargement caused by excessive secretion of growth hormone by a pituitary adenoma.

Patients also hesitated to raise quality-of-life issues with their physicians and said they were concerned that health care providers did not care about quality of life. "Patients said that they were uncomfortable bringing this up; so you have to open the discussion," said Ms. Gurel of the neuroendocrine unit at Massachusetts General Hospital, Boston.

For a successful physician-patient partnership, patients want to feel that they are being listened to and treated as a person first and as someone with a disease second, they said. Health care providers should take the time to explain in detail the disease and treatment options, covering a slew of questions that patients had in four main categories: What is acromegaly? Will I ever feel like myself again? What is treatment like, and what will I experience? How do I survive financially?

Patients want to know why they are experiencing symptoms, feel bad, and no longer look like themselves, they said. They wonder if their levels of growth hormone and insulin-like growth factor 1 will return to normal, if symptoms will resolve, if the pain will stop, and if the disease can be cured. They question whether they will ever look like themselves again, feel energetic, live a normal life, and be able to forget, even for a moment, that they have acromegaly.

When discussing treatment, patients want to know why "brain surgery" is needed and how it will feel, as well as the pros and cons of radiation. They wonder why they have to take medications, and how to cope with side effects. Most of the medical therapies are expensive, raising questions about whether insurance will cover the costs, how to afford copays, and what happens if patients lose or change insurance.

Patients said they do want to be asked detailed questions about their quality of life during follow-up visits. They want health care providers who are educated about acromegaly and up-to-date in their knowledge of treatments, which they found mainly at Centers of Excellence and at pituitary centers, Ms. Gurel said. Patients wanted physicians to be aggressive in treatment without downplaying the patient’s physical, emotional, and psychological pain and suffering. "They felt stronger support from health care providers if they thought the physician cared," she said.

Nonphysician staff also are key to a successful partnership, patients said. Having a well-run office with courteous, friendly, and competent staff who can help patients with financial questions is important, from a patient’s point of view.

Participants in the study had a mean age of 43 years, and 12 of the 19 were female, although acromegaly generally affects men and women at the same rate. Among 10 patients who described their presenting symptoms, the most common were acral changes or changes in height, in six patients (60%). The disease presented with joint or muscle pain, diabetes, weight gain, headaches, and amenorrhea or an irregular menstrual cycle in 30% of patients each, and hypertension or visual changes affected 20% each at presentation. (Some patients had more than one symptom.)

Twelve of the 19 patients were currently being treated with somatostatin analogues (63%) and 3 with growth hormone receptor antagonists (16%), while 4 patients were not receiving medical therapy (21%) because they had been cured after surgery and/or radiation or because they had not yet chosen a medical therapy. Most medical therapies for acromegaly are expensive and are administered through injection, Ms. Gurel noted.

"(Patients) felt stronger support from health care providers if they thought the physician cared."

Treatment histories from 10 patients showed that 9 had undergone surgery since diagnosis, 2 had radiotherapy, 3 were treated with one medication, 4 had tried two medications, 1 patient had been treated with three drugs, and 2 patients had gone through four medications. (Patients could report more than one treatment category.)

Because patients felt left out of the treatment decision process, they felt motivated to talk to other patients, and many used online resources for support such as AcromegalyCommunity.com or other disease-specific websites. Patients who were not connected to a patient support group reported feeling lonely and helpless. Many of the patients expressed a desire to help improve knowledge about acromegaly in order to shorten the time to diagnosis for future patients.

Acromegaly typically appears in the fourth decade of life, with an annual incidence of 3 or 4 patients per million and a prevalence of 40-90 cases per million people. People with acromegaly are more likely to develop hypertension and heart disease, cardiovascular events and headaches, arthritis and acral changes, sleep apnea, and insulin-resistant diabetes. The disease is associated with premature death, with a doubling or tripling of mortality risk.

Most patients with acromegaly are treated with surgery. Medical therapies include the somatostatin analogues lanreotide and octreotide, the growth hormone receptor antagonist pegvisomant, or the dopamine agonist cabergoline.

The study was funded by Ipsen Biopharmaceuticals, which makes lanreotide (Somatuline). Ms. Gurel reported having no other financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Patients with acromegaly struggle with issues that they often don’t share with their physicians, and they have specific suggestions about actions that health care providers can take to help them cope with their disease, a qualitative study of 19 patients found.

Most described a long journey to a correct diagnosis, and other data suggest that an acromegaly diagnosis typically is delayed by 4-10 years. The delay is frustrating for patients but is followed by relief when they finally have a name for their disease, Michelle H. Gurel, R.N., reported at the Endocrine Society’s Annual Meeting.

She and her associates conducted online interviews with 10 patients recruited through AcromegalyCommunity.com and live interviews with 9 patients at the 2012 Acromegaly Community Conference.

The patients said they were shocked at the idea of needing "brain surgery" (pituitary surgery) when discussing treatment with their physicians, and that they felt unsatisfied or left out of the treatment decision process.

Acromegaly is a rare chronic disease characterized by abnormal skeletal growth and soft tissue enlargement caused by excessive secretion of growth hormone by a pituitary adenoma.

Patients also hesitated to raise quality-of-life issues with their physicians and said they were concerned that health care providers did not care about quality of life. "Patients said that they were uncomfortable bringing this up; so you have to open the discussion," said Ms. Gurel of the neuroendocrine unit at Massachusetts General Hospital, Boston.

For a successful physician-patient partnership, patients want to feel that they are being listened to and treated as a person first and as someone with a disease second, they said. Health care providers should take the time to explain in detail the disease and treatment options, covering a slew of questions that patients had in four main categories: What is acromegaly? Will I ever feel like myself again? What is treatment like, and what will I experience? How do I survive financially?

Patients want to know why they are experiencing symptoms, feel bad, and no longer look like themselves, they said. They wonder if their levels of growth hormone and insulin-like growth factor 1 will return to normal, if symptoms will resolve, if the pain will stop, and if the disease can be cured. They question whether they will ever look like themselves again, feel energetic, live a normal life, and be able to forget, even for a moment, that they have acromegaly.

When discussing treatment, patients want to know why "brain surgery" is needed and how it will feel, as well as the pros and cons of radiation. They wonder why they have to take medications, and how to cope with side effects. Most of the medical therapies are expensive, raising questions about whether insurance will cover the costs, how to afford copays, and what happens if patients lose or change insurance.

Patients said they do want to be asked detailed questions about their quality of life during follow-up visits. They want health care providers who are educated about acromegaly and up-to-date in their knowledge of treatments, which they found mainly at Centers of Excellence and at pituitary centers, Ms. Gurel said. Patients wanted physicians to be aggressive in treatment without downplaying the patient’s physical, emotional, and psychological pain and suffering. "They felt stronger support from health care providers if they thought the physician cared," she said.

Nonphysician staff also are key to a successful partnership, patients said. Having a well-run office with courteous, friendly, and competent staff who can help patients with financial questions is important, from a patient’s point of view.

Participants in the study had a mean age of 43 years, and 12 of the 19 were female, although acromegaly generally affects men and women at the same rate. Among 10 patients who described their presenting symptoms, the most common were acral changes or changes in height, in six patients (60%). The disease presented with joint or muscle pain, diabetes, weight gain, headaches, and amenorrhea or an irregular menstrual cycle in 30% of patients each, and hypertension or visual changes affected 20% each at presentation. (Some patients had more than one symptom.)

Twelve of the 19 patients were currently being treated with somatostatin analogues (63%) and 3 with growth hormone receptor antagonists (16%), while 4 patients were not receiving medical therapy (21%) because they had been cured after surgery and/or radiation or because they had not yet chosen a medical therapy. Most medical therapies for acromegaly are expensive and are administered through injection, Ms. Gurel noted.

"(Patients) felt stronger support from health care providers if they thought the physician cared."

Treatment histories from 10 patients showed that 9 had undergone surgery since diagnosis, 2 had radiotherapy, 3 were treated with one medication, 4 had tried two medications, 1 patient had been treated with three drugs, and 2 patients had gone through four medications. (Patients could report more than one treatment category.)

Because patients felt left out of the treatment decision process, they felt motivated to talk to other patients, and many used online resources for support such as AcromegalyCommunity.com or other disease-specific websites. Patients who were not connected to a patient support group reported feeling lonely and helpless. Many of the patients expressed a desire to help improve knowledge about acromegaly in order to shorten the time to diagnosis for future patients.

Acromegaly typically appears in the fourth decade of life, with an annual incidence of 3 or 4 patients per million and a prevalence of 40-90 cases per million people. People with acromegaly are more likely to develop hypertension and heart disease, cardiovascular events and headaches, arthritis and acral changes, sleep apnea, and insulin-resistant diabetes. The disease is associated with premature death, with a doubling or tripling of mortality risk.

Most patients with acromegaly are treated with surgery. Medical therapies include the somatostatin analogues lanreotide and octreotide, the growth hormone receptor antagonist pegvisomant, or the dopamine agonist cabergoline.

The study was funded by Ipsen Biopharmaceuticals, which makes lanreotide (Somatuline). Ms. Gurel reported having no other financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Patients with acromegaly struggle with issues that they often don’t share with their physicians, and they have specific suggestions about actions that health care providers can take to help them cope with their disease, a qualitative study of 19 patients found.

Most described a long journey to a correct diagnosis, and other data suggest that an acromegaly diagnosis typically is delayed by 4-10 years. The delay is frustrating for patients but is followed by relief when they finally have a name for their disease, Michelle H. Gurel, R.N., reported at the Endocrine Society’s Annual Meeting.

She and her associates conducted online interviews with 10 patients recruited through AcromegalyCommunity.com and live interviews with 9 patients at the 2012 Acromegaly Community Conference.

The patients said they were shocked at the idea of needing "brain surgery" (pituitary surgery) when discussing treatment with their physicians, and that they felt unsatisfied or left out of the treatment decision process.

Acromegaly is a rare chronic disease characterized by abnormal skeletal growth and soft tissue enlargement caused by excessive secretion of growth hormone by a pituitary adenoma.

Patients also hesitated to raise quality-of-life issues with their physicians and said they were concerned that health care providers did not care about quality of life. "Patients said that they were uncomfortable bringing this up; so you have to open the discussion," said Ms. Gurel of the neuroendocrine unit at Massachusetts General Hospital, Boston.

For a successful physician-patient partnership, patients want to feel that they are being listened to and treated as a person first and as someone with a disease second, they said. Health care providers should take the time to explain in detail the disease and treatment options, covering a slew of questions that patients had in four main categories: What is acromegaly? Will I ever feel like myself again? What is treatment like, and what will I experience? How do I survive financially?

Patients want to know why they are experiencing symptoms, feel bad, and no longer look like themselves, they said. They wonder if their levels of growth hormone and insulin-like growth factor 1 will return to normal, if symptoms will resolve, if the pain will stop, and if the disease can be cured. They question whether they will ever look like themselves again, feel energetic, live a normal life, and be able to forget, even for a moment, that they have acromegaly.

When discussing treatment, patients want to know why "brain surgery" is needed and how it will feel, as well as the pros and cons of radiation. They wonder why they have to take medications, and how to cope with side effects. Most of the medical therapies are expensive, raising questions about whether insurance will cover the costs, how to afford copays, and what happens if patients lose or change insurance.

Patients said they do want to be asked detailed questions about their quality of life during follow-up visits. They want health care providers who are educated about acromegaly and up-to-date in their knowledge of treatments, which they found mainly at Centers of Excellence and at pituitary centers, Ms. Gurel said. Patients wanted physicians to be aggressive in treatment without downplaying the patient’s physical, emotional, and psychological pain and suffering. "They felt stronger support from health care providers if they thought the physician cared," she said.

Nonphysician staff also are key to a successful partnership, patients said. Having a well-run office with courteous, friendly, and competent staff who can help patients with financial questions is important, from a patient’s point of view.

Participants in the study had a mean age of 43 years, and 12 of the 19 were female, although acromegaly generally affects men and women at the same rate. Among 10 patients who described their presenting symptoms, the most common were acral changes or changes in height, in six patients (60%). The disease presented with joint or muscle pain, diabetes, weight gain, headaches, and amenorrhea or an irregular menstrual cycle in 30% of patients each, and hypertension or visual changes affected 20% each at presentation. (Some patients had more than one symptom.)

Twelve of the 19 patients were currently being treated with somatostatin analogues (63%) and 3 with growth hormone receptor antagonists (16%), while 4 patients were not receiving medical therapy (21%) because they had been cured after surgery and/or radiation or because they had not yet chosen a medical therapy. Most medical therapies for acromegaly are expensive and are administered through injection, Ms. Gurel noted.

"(Patients) felt stronger support from health care providers if they thought the physician cared."

Treatment histories from 10 patients showed that 9 had undergone surgery since diagnosis, 2 had radiotherapy, 3 were treated with one medication, 4 had tried two medications, 1 patient had been treated with three drugs, and 2 patients had gone through four medications. (Patients could report more than one treatment category.)

Because patients felt left out of the treatment decision process, they felt motivated to talk to other patients, and many used online resources for support such as AcromegalyCommunity.com or other disease-specific websites. Patients who were not connected to a patient support group reported feeling lonely and helpless. Many of the patients expressed a desire to help improve knowledge about acromegaly in order to shorten the time to diagnosis for future patients.

Acromegaly typically appears in the fourth decade of life, with an annual incidence of 3 or 4 patients per million and a prevalence of 40-90 cases per million people. People with acromegaly are more likely to develop hypertension and heart disease, cardiovascular events and headaches, arthritis and acral changes, sleep apnea, and insulin-resistant diabetes. The disease is associated with premature death, with a doubling or tripling of mortality risk.

Most patients with acromegaly are treated with surgery. Medical therapies include the somatostatin analogues lanreotide and octreotide, the growth hormone receptor antagonist pegvisomant, or the dopamine agonist cabergoline.

The study was funded by Ipsen Biopharmaceuticals, which makes lanreotide (Somatuline). Ms. Gurel reported having no other financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Administering daily hydrocortisone prescriptions in four divided doses, instead of three, can improve control of congenital adrenal hyperplasia and obviate the need for additional steroids, British researchers found in a retrospective cross-sectional study.

A decade ago, it was assumed that children with poorly controlled moderate-to-severe disease "needed higher doses rather than more frequent dosing; if patients were not controlled on three-times-a-day dosing, we’d increase the dose. Now, we go four times a day, and don’t necessarily have to increase the dose. We see better control with QID dosing," said lead investigator Dr. Anbezhil Subbarayan, a pediatric endocrinologist at Great Ormond Street Hospital for Children in London.

His team compared 107 children under treatment there with a similar cohort treated a decade ago and found that the approach led to a reduction in mean daily hydrocortisone doses from 17.5 mg/m² to 13.3 mg/m² and a drop in mean daily doses of 9 alpha-fludrocortisone, administered in one or two divided doses, from 112 mcg/m² to 102 mcg/m².

That led to a corresponding drop in the prevalence of steroid-induced systolic hypertension from 58% of patients to 21%; a drop in diastolic hypertension prevalence from 24% to 9%; and improvement in mean body mass index standard deviation scores (BMI-SDS) from 1.57 to 0.98. The results were also published online(Clin. Endocrinol [Oxf] 2013 [doi:10.1111/cen.12265]).

"Our message" is that "patients under poor control should [try] four-times-a-day" hydrocortisone dosing. With a half-life of just 4-6 hours, spacing out hydrocortisone administration "should improve control in patients with moderate-to-severe disease without increasing the need for steroids, which can worsen cardiovascular risk factors," Dr. Subbarayan said at the Endocrine Society’s annual meeting.

"Ideally, the first hydrocortisone dose should be given at 4:00 a.m. Some parents are motivated" to do that; for those who find it impractical, "we try to encourage giving hydrocortisone first thing in the morning, maybe at 6:00 a.m." For children with mild disease, divided doses three times a day might be enough, he said.

Despite reduced steroid doses and cardiovascular risk factors, obesity and systolic hypertension remain problematic in kids with congenital adrenal hyperplasia.

The team found that 24% of their children were obese (BMI-SDS greater than 2), and that BMI-SD scores were significantly higher, compared with British children overall. The mean systolic blood pressure of 108 mm Hg (SD 13.5) was higher, as well. Differences in diastolic pressure did not reach statistical significance.

The values were assessed during annual reviews when the children were admitted to the hospital for 24 hours for serial monitoring of cortisol levels and clinical parameters, and dose adjustments. The median age in the study was 9.2 years; 64% were girls.

The authors said they have no disclosures.

aotto@frontlinemedcom.com

SAN FRANCISCO – Administering daily hydrocortisone prescriptions in four divided doses, instead of three, can improve control of congenital adrenal hyperplasia and obviate the need for additional steroids, British researchers found in a retrospective cross-sectional study.

A decade ago, it was assumed that children with poorly controlled moderate-to-severe disease "needed higher doses rather than more frequent dosing; if patients were not controlled on three-times-a-day dosing, we’d increase the dose. Now, we go four times a day, and don’t necessarily have to increase the dose. We see better control with QID dosing," said lead investigator Dr. Anbezhil Subbarayan, a pediatric endocrinologist at Great Ormond Street Hospital for Children in London.

His team compared 107 children under treatment there with a similar cohort treated a decade ago and found that the approach led to a reduction in mean daily hydrocortisone doses from 17.5 mg/m² to 13.3 mg/m² and a drop in mean daily doses of 9 alpha-fludrocortisone, administered in one or two divided doses, from 112 mcg/m² to 102 mcg/m².

That led to a corresponding drop in the prevalence of steroid-induced systolic hypertension from 58% of patients to 21%; a drop in diastolic hypertension prevalence from 24% to 9%; and improvement in mean body mass index standard deviation scores (BMI-SDS) from 1.57 to 0.98. The results were also published online(Clin. Endocrinol [Oxf] 2013 [doi:10.1111/cen.12265]).

"Our message" is that "patients under poor control should [try] four-times-a-day" hydrocortisone dosing. With a half-life of just 4-6 hours, spacing out hydrocortisone administration "should improve control in patients with moderate-to-severe disease without increasing the need for steroids, which can worsen cardiovascular risk factors," Dr. Subbarayan said at the Endocrine Society’s annual meeting.

"Ideally, the first hydrocortisone dose should be given at 4:00 a.m. Some parents are motivated" to do that; for those who find it impractical, "we try to encourage giving hydrocortisone first thing in the morning, maybe at 6:00 a.m." For children with mild disease, divided doses three times a day might be enough, he said.

Despite reduced steroid doses and cardiovascular risk factors, obesity and systolic hypertension remain problematic in kids with congenital adrenal hyperplasia.

The team found that 24% of their children were obese (BMI-SDS greater than 2), and that BMI-SD scores were significantly higher, compared with British children overall. The mean systolic blood pressure of 108 mm Hg (SD 13.5) was higher, as well. Differences in diastolic pressure did not reach statistical significance.

The values were assessed during annual reviews when the children were admitted to the hospital for 24 hours for serial monitoring of cortisol levels and clinical parameters, and dose adjustments. The median age in the study was 9.2 years; 64% were girls.

The authors said they have no disclosures.

aotto@frontlinemedcom.com

SAN FRANCISCO – Administering daily hydrocortisone prescriptions in four divided doses, instead of three, can improve control of congenital adrenal hyperplasia and obviate the need for additional steroids, British researchers found in a retrospective cross-sectional study.

A decade ago, it was assumed that children with poorly controlled moderate-to-severe disease "needed higher doses rather than more frequent dosing; if patients were not controlled on three-times-a-day dosing, we’d increase the dose. Now, we go four times a day, and don’t necessarily have to increase the dose. We see better control with QID dosing," said lead investigator Dr. Anbezhil Subbarayan, a pediatric endocrinologist at Great Ormond Street Hospital for Children in London.

His team compared 107 children under treatment there with a similar cohort treated a decade ago and found that the approach led to a reduction in mean daily hydrocortisone doses from 17.5 mg/m² to 13.3 mg/m² and a drop in mean daily doses of 9 alpha-fludrocortisone, administered in one or two divided doses, from 112 mcg/m² to 102 mcg/m².

That led to a corresponding drop in the prevalence of steroid-induced systolic hypertension from 58% of patients to 21%; a drop in diastolic hypertension prevalence from 24% to 9%; and improvement in mean body mass index standard deviation scores (BMI-SDS) from 1.57 to 0.98. The results were also published online(Clin. Endocrinol [Oxf] 2013 [doi:10.1111/cen.12265]).

"Our message" is that "patients under poor control should [try] four-times-a-day" hydrocortisone dosing. With a half-life of just 4-6 hours, spacing out hydrocortisone administration "should improve control in patients with moderate-to-severe disease without increasing the need for steroids, which can worsen cardiovascular risk factors," Dr. Subbarayan said at the Endocrine Society’s annual meeting.

"Ideally, the first hydrocortisone dose should be given at 4:00 a.m. Some parents are motivated" to do that; for those who find it impractical, "we try to encourage giving hydrocortisone first thing in the morning, maybe at 6:00 a.m." For children with mild disease, divided doses three times a day might be enough, he said.

Despite reduced steroid doses and cardiovascular risk factors, obesity and systolic hypertension remain problematic in kids with congenital adrenal hyperplasia.

The team found that 24% of their children were obese (BMI-SDS greater than 2), and that BMI-SD scores were significantly higher, compared with British children overall. The mean systolic blood pressure of 108 mm Hg (SD 13.5) was higher, as well. Differences in diastolic pressure did not reach statistical significance.

The values were assessed during annual reviews when the children were admitted to the hospital for 24 hours for serial monitoring of cortisol levels and clinical parameters, and dose adjustments. The median age in the study was 9.2 years; 64% were girls.

The authors said they have no disclosures.

aotto@frontlinemedcom.com

PHOENIX – The majority of benign thyroid nodules treated with laser ablation shrunk by more than half and the procedures had a low complication rate, according to a 2-year randomized trial in four centers in Italy.

The 200-patient study showed that the procedure was fairly well tolerated without general anesthesia, and cost about $400 in disposables per procedures, Dr. Enrico Papini said at the annual meeting of the American Association of Clinical Endocrinologists.

Previous published studies by Dr. Papini (Thyroid 2007;17:229-35) and other European groups (Thyroid 2006;16:763-8) have shown good outcomes for laser ablation of cold thyroid nodules. However, minimally invasive procedures for treating benign or malignant thyroid nodules, including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), and laser ablation (LA), have not been widely adopted by U.S. specialists, said Dr. Hossein Gharib, president-elect of the American Thyroid Association and past-president of AACE. And experience matters.

"PEI should be first-line therapy for symptomatic, benign cysts," said Dr. Gharib, who was not involved in the study. "It is easy to do, safe and very effective. LA and RFA are more complicated and should be performed only by personnel with experience and equipment."

Dr. Papini said that the procedure is performed by interventional radiologists or endocrinologists "who are fairly experienced in percutaneous injections, or at least in the use of fine-needle aspiration biopsy." He added that it takes about a month of training to be effective in the procedure.

Dr. Papini and colleagues compared the clinical and ultrasound changes in benign thyroid nodules by ultrasound-guided LA with those who were follow-up only. They also assessed side effects and the efficacy of the technique in different centers.

Two hundred consecutive patients with a solid thyroid nodule with a volume of more than 5 mL and less than 18 mL were referred to four thyroid centers and randomly assigned to a single LA treatment (101 patients) or follow-up (100 patients).

In the treatment group, clinicians performed LA with a 1.064-nm neodymium yttrium-aluminum garnet laser with 2 fibers, and an output power of 3 watts. Energy delivery was 3,600 Joules for nodules up to 13 mL, and 7,200 J for nodules larger than 13 mL. The treatment was outpatient, took less than 30 minutes, and was fairly well tolerated, said Dr. Papini. Volume and local symptoms changes were evaluated 1, 6, 12, and 24 months after LA.

There was no need for general anesthesia.

"You don’t need anesthesia," said Dr. Papini of Regina Apostolorum Hospital, Rome. "It’s very important that the patient can tell you if he feels pain. Because you have pain only if the high temperature approaches the thyroid capsule, so you can stop one of the fibers that may be closer to the border of the nodule."

The control group received no treatment affecting the thyroid gland. Clinical, laboratory, and ultrasound control were performed at baseline and every 6 months thereafter for 3 years.

Results showed that a progressive nodule volume reduction was found at 6 months (–50.7%), 12 (–57.3%), and 24 (–60.9%) months (P < .001). A reduction of more than 50% was observed in 73.6% of the cases (P < .001).

Volume reduction in LA was progressive until 12 months and remained stable until 24 months. The 24-month mean volume reduction in the difference centers was 41.6%, 63.2%, 61.5%, and 58.7%.

Cost of disposables was about $400 for each procedure, and efficacy and side effects were similar in different centers, Dr. Papini reported.

The presence of pressure symptoms complaint decreased from 31% to 1% of the cases. There were four complications, including one case of self-resolving vocal cord paresis, one infection, and two fevers.

Meanwhile, the control group showed a 21.9% volume increase in 24 months, but local symptoms did not change significantly.

Although the procedure had several advantages, including no cosmetic damage and no risk of hypothyroidism, it’s not without drawbacks. Dr. Papini said that the nodules are persistent and need careful cytologic evaluation and follow-up. Also, the operator needs to be well trained, as complications can be severe during the learning period. There’s also a potential for regrowth, although none were reported during the trial’s 3-year follow-up.

"Currently, RFA is used in some centers for hepatic but not thyroid lesions," said Dr. Gharib, who practices at Mayo Clinic, Rochester, Minn. "It is likely that in the near future we will see the application of these techniques for thyroid masses."

Dr. Papini and Dr. Gharib had no relevant disclosures.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

PHOENIX – The majority of benign thyroid nodules treated with laser ablation shrunk by more than half and the procedures had a low complication rate, according to a 2-year randomized trial in four centers in Italy.

The 200-patient study showed that the procedure was fairly well tolerated without general anesthesia, and cost about $400 in disposables per procedures, Dr. Enrico Papini said at the annual meeting of the American Association of Clinical Endocrinologists.

Previous published studies by Dr. Papini (Thyroid 2007;17:229-35) and other European groups (Thyroid 2006;16:763-8) have shown good outcomes for laser ablation of cold thyroid nodules. However, minimally invasive procedures for treating benign or malignant thyroid nodules, including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), and laser ablation (LA), have not been widely adopted by U.S. specialists, said Dr. Hossein Gharib, president-elect of the American Thyroid Association and past-president of AACE. And experience matters.

"PEI should be first-line therapy for symptomatic, benign cysts," said Dr. Gharib, who was not involved in the study. "It is easy to do, safe and very effective. LA and RFA are more complicated and should be performed only by personnel with experience and equipment."

Dr. Papini said that the procedure is performed by interventional radiologists or endocrinologists "who are fairly experienced in percutaneous injections, or at least in the use of fine-needle aspiration biopsy." He added that it takes about a month of training to be effective in the procedure.

Dr. Papini and colleagues compared the clinical and ultrasound changes in benign thyroid nodules by ultrasound-guided LA with those who were follow-up only. They also assessed side effects and the efficacy of the technique in different centers.

Two hundred consecutive patients with a solid thyroid nodule with a volume of more than 5 mL and less than 18 mL were referred to four thyroid centers and randomly assigned to a single LA treatment (101 patients) or follow-up (100 patients).

In the treatment group, clinicians performed LA with a 1.064-nm neodymium yttrium-aluminum garnet laser with 2 fibers, and an output power of 3 watts. Energy delivery was 3,600 Joules for nodules up to 13 mL, and 7,200 J for nodules larger than 13 mL. The treatment was outpatient, took less than 30 minutes, and was fairly well tolerated, said Dr. Papini. Volume and local symptoms changes were evaluated 1, 6, 12, and 24 months after LA.

There was no need for general anesthesia.

"You don’t need anesthesia," said Dr. Papini of Regina Apostolorum Hospital, Rome. "It’s very important that the patient can tell you if he feels pain. Because you have pain only if the high temperature approaches the thyroid capsule, so you can stop one of the fibers that may be closer to the border of the nodule."

The control group received no treatment affecting the thyroid gland. Clinical, laboratory, and ultrasound control were performed at baseline and every 6 months thereafter for 3 years.

Results showed that a progressive nodule volume reduction was found at 6 months (–50.7%), 12 (–57.3%), and 24 (–60.9%) months (P < .001). A reduction of more than 50% was observed in 73.6% of the cases (P < .001).

Volume reduction in LA was progressive until 12 months and remained stable until 24 months. The 24-month mean volume reduction in the difference centers was 41.6%, 63.2%, 61.5%, and 58.7%.

Cost of disposables was about $400 for each procedure, and efficacy and side effects were similar in different centers, Dr. Papini reported.

The presence of pressure symptoms complaint decreased from 31% to 1% of the cases. There were four complications, including one case of self-resolving vocal cord paresis, one infection, and two fevers.

Meanwhile, the control group showed a 21.9% volume increase in 24 months, but local symptoms did not change significantly.

Although the procedure had several advantages, including no cosmetic damage and no risk of hypothyroidism, it’s not without drawbacks. Dr. Papini said that the nodules are persistent and need careful cytologic evaluation and follow-up. Also, the operator needs to be well trained, as complications can be severe during the learning period. There’s also a potential for regrowth, although none were reported during the trial’s 3-year follow-up.

"Currently, RFA is used in some centers for hepatic but not thyroid lesions," said Dr. Gharib, who practices at Mayo Clinic, Rochester, Minn. "It is likely that in the near future we will see the application of these techniques for thyroid masses."

Dr. Papini and Dr. Gharib had no relevant disclosures.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

PHOENIX – The majority of benign thyroid nodules treated with laser ablation shrunk by more than half and the procedures had a low complication rate, according to a 2-year randomized trial in four centers in Italy.

The 200-patient study showed that the procedure was fairly well tolerated without general anesthesia, and cost about $400 in disposables per procedures, Dr. Enrico Papini said at the annual meeting of the American Association of Clinical Endocrinologists.

Previous published studies by Dr. Papini (Thyroid 2007;17:229-35) and other European groups (Thyroid 2006;16:763-8) have shown good outcomes for laser ablation of cold thyroid nodules. However, minimally invasive procedures for treating benign or malignant thyroid nodules, including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), and laser ablation (LA), have not been widely adopted by U.S. specialists, said Dr. Hossein Gharib, president-elect of the American Thyroid Association and past-president of AACE. And experience matters.

"PEI should be first-line therapy for symptomatic, benign cysts," said Dr. Gharib, who was not involved in the study. "It is easy to do, safe and very effective. LA and RFA are more complicated and should be performed only by personnel with experience and equipment."

Dr. Papini said that the procedure is performed by interventional radiologists or endocrinologists "who are fairly experienced in percutaneous injections, or at least in the use of fine-needle aspiration biopsy." He added that it takes about a month of training to be effective in the procedure.

Dr. Papini and colleagues compared the clinical and ultrasound changes in benign thyroid nodules by ultrasound-guided LA with those who were follow-up only. They also assessed side effects and the efficacy of the technique in different centers.

Two hundred consecutive patients with a solid thyroid nodule with a volume of more than 5 mL and less than 18 mL were referred to four thyroid centers and randomly assigned to a single LA treatment (101 patients) or follow-up (100 patients).

In the treatment group, clinicians performed LA with a 1.064-nm neodymium yttrium-aluminum garnet laser with 2 fibers, and an output power of 3 watts. Energy delivery was 3,600 Joules for nodules up to 13 mL, and 7,200 J for nodules larger than 13 mL. The treatment was outpatient, took less than 30 minutes, and was fairly well tolerated, said Dr. Papini. Volume and local symptoms changes were evaluated 1, 6, 12, and 24 months after LA.

There was no need for general anesthesia.

"You don’t need anesthesia," said Dr. Papini of Regina Apostolorum Hospital, Rome. "It’s very important that the patient can tell you if he feels pain. Because you have pain only if the high temperature approaches the thyroid capsule, so you can stop one of the fibers that may be closer to the border of the nodule."

The control group received no treatment affecting the thyroid gland. Clinical, laboratory, and ultrasound control were performed at baseline and every 6 months thereafter for 3 years.

Results showed that a progressive nodule volume reduction was found at 6 months (–50.7%), 12 (–57.3%), and 24 (–60.9%) months (P < .001). A reduction of more than 50% was observed in 73.6% of the cases (P < .001).

Volume reduction in LA was progressive until 12 months and remained stable until 24 months. The 24-month mean volume reduction in the difference centers was 41.6%, 63.2%, 61.5%, and 58.7%.

Cost of disposables was about $400 for each procedure, and efficacy and side effects were similar in different centers, Dr. Papini reported.

The presence of pressure symptoms complaint decreased from 31% to 1% of the cases. There were four complications, including one case of self-resolving vocal cord paresis, one infection, and two fevers.

Meanwhile, the control group showed a 21.9% volume increase in 24 months, but local symptoms did not change significantly.

Although the procedure had several advantages, including no cosmetic damage and no risk of hypothyroidism, it’s not without drawbacks. Dr. Papini said that the nodules are persistent and need careful cytologic evaluation and follow-up. Also, the operator needs to be well trained, as complications can be severe during the learning period. There’s also a potential for regrowth, although none were reported during the trial’s 3-year follow-up.

"Currently, RFA is used in some centers for hepatic but not thyroid lesions," said Dr. Gharib, who practices at Mayo Clinic, Rochester, Minn. "It is likely that in the near future we will see the application of these techniques for thyroid masses."

Dr. Papini and Dr. Gharib had no relevant disclosures.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

pwendling@frontlinemedcom.com

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

pwendling@frontlinemedcom.com

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

pwendling@frontlinemedcom.com