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Sorafenib extends survival in differentiated thyroid cancer
CHICAGO – A new trial has found that sorafenib may help extend the survival of patients with differentiated thyroid cancer. In the phase-III DECISION trial, progression-free survival was extended by 5.8 months in patients treated with placebo and by 10.8 months in patients treated with sorafenib.
Dr. Marcia Brose discusses the new trial results in an interview at the annual meeting of the American Society of Clinical Oncology.
CHICAGO – A new trial has found that sorafenib may help extend the survival of patients with differentiated thyroid cancer. In the phase-III DECISION trial, progression-free survival was extended by 5.8 months in patients treated with placebo and by 10.8 months in patients treated with sorafenib.
Dr. Marcia Brose discusses the new trial results in an interview at the annual meeting of the American Society of Clinical Oncology.
CHICAGO – A new trial has found that sorafenib may help extend the survival of patients with differentiated thyroid cancer. In the phase-III DECISION trial, progression-free survival was extended by 5.8 months in patients treated with placebo and by 10.8 months in patients treated with sorafenib.
Dr. Marcia Brose discusses the new trial results in an interview at the annual meeting of the American Society of Clinical Oncology.
AT THE ASCO ANNUAL MEETING 2013
Case Report: Chronic marijuana use potential cause for hypopituitarism
PHOENIX – Chronic marijuana use can be a potential cause for hypopituitarism, according to an unpublished case report, which relied on existing data about the effect of cannabis on the hypothalamic-pituitary-gonadal axis.
The case hints at a largely underrepresented problem, researchers said, especially as various states contemplate legalizing marijuana, which is currently the most commonly used illicit drug in the nation, said Dr. Richard Pinsker at the annual meeting of the American Association of Clinical Endocrinologists.
The 37-year-old man arrived at the emergency department of Jamaica (N.Y.) Hospital Medical Center in Queens in late 2012 complaining of shortness of breath, increasing fatigue, and loss of libido. The patient had low blood pressure, and physical examination revealed gynecomastia, bilateral atrophied testis, and bibasilar rales. He disclosed that he had used marijuana daily for 15 years.
After ruling out hemochromatosis, conducting a battery of hormonal tests, and an MRI, Dr. Pinsker and his colleagues diagnosed the patient with hypopituitarism. The culprit? Chronic marijuana use, they concluded after finding no other potential cause.
"I think it’s a thought-provoking study," said Dr. R. Mack Harrell, who will be the president-elect of the AACE this year. "We’ve known for many years, if you use a lot of cannabis, it suppresses the gonadal axis, and it’s been assumed that [cannabis’] only effect was on the gonadal axis. This poster poses the question of whether other pituitary hormones may be affected, and whether every pituitary hormone is at risk, so it’s hypothesis generating."
Dr. Pinsker, who is a practicing endocrinologist and the internal medicine residency program director at Jamaica Hospital Medical Center, said that the finding – and high rate of marijuana use – call for further research on the effect of chronic marijuana use on the endocrine system. He added that that physicians need to do a better job of obtaining a social history from their patients.
Tetrahydrocannabinol, or THC, which is the psychoactive ingredient of marijuana, can alter the hypothalamic-pituitary-gonadal axis either by acting directly on the hypothalamus and altering the gonadotropin-releasing hormone (GnRH) or by altering neural transmitters in the central nervous system, which affect the hypothalamus. The result is lowered luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which lead to reduced testosterone production by Leydig cells of the testis.
Studies have shown cannabis exposure can result in impaired cortisol response to stress. Animal studies have shown that cannabinoids can suppress several hypothalamic-pituitary pathways, including the growth hormone, and the thyroid hormone, reported Dr. Hineshkumar Upadhyay, coauthor of the report.
Meanwhile, THC, which is lipid soluble, can remain stored in the fatty tissue and re-enter the blood stream at very low levels. This pharmacokinetics can cause chronic effect on organ systems even though it is used occasionally, researchers said.
In the case of the 37-year-old patient, researchers first suspected hemochromatosis, which they ruled out by iron studies and echocardiography. Hypopituitarism is rare in young people.
The patient had low levels of LH (0.2 mIU/mL), FSH (1.8 mIU/mL), and testosterone (22 ng/dL). His prolactin levels were high (53 ng/mL), an increase that confirms trouble in the hypothalamic-pituitary axis, said Dr. Pinsker.
Further endocrine chemistry showed that he had adrenocorticotropic hormone (ACTH) of 6 pg/mL and cortisol at 0 mcg/dL. At 60 minutes, following administration of cosyntropin, the levels changed to 6.4 pg/mL and 9.3 mcg/dL, respectively.
Additional tests revealed low levels of total T3 (30 ng/dL), high T3 resin reuptake (49%), low total T4 (3.94 mcg/dL), normal free T4 (0.97 ng/dL), and low TSH (0.22 mcIU/mL). Growth hormone was within normal limits (5.0 ng/mL), and insulinlike growth factor-1 was low (75 ng/mL; Z-score of –1.3).
MRI showed that the protuberant pituitary gland was slightly larger than the expected size, but there was no identified mass lesion, researchers reported.
Researchers started the patient on replacement hormones – 25 mg cortisone in the morning and 12.5 mg at bedtime, with 25 mcg levothyroxine daily. The patient’s fatigue and edema improved dramatically, they reported. As with other patients who abuse substances, they advised him to stop using marijuana.
Dr. Pinsker, who is also a colonel in the U.S. Army Reserve Medical Corps, said he was planning on collecting more cases before publishing the findings. He added the same mechanism could affect women as well. "We just haven’t looked at it," he said.
"I think it’ll be frightening if the use goes up" as more states make the drug legal "and the awareness does not follow it," he said.
Dr. Pinsker and Dr. Upadhyay had no disclosures.
On Twitter @NaseemSMiller
PHOENIX – Chronic marijuana use can be a potential cause for hypopituitarism, according to an unpublished case report, which relied on existing data about the effect of cannabis on the hypothalamic-pituitary-gonadal axis.
The case hints at a largely underrepresented problem, researchers said, especially as various states contemplate legalizing marijuana, which is currently the most commonly used illicit drug in the nation, said Dr. Richard Pinsker at the annual meeting of the American Association of Clinical Endocrinologists.
The 37-year-old man arrived at the emergency department of Jamaica (N.Y.) Hospital Medical Center in Queens in late 2012 complaining of shortness of breath, increasing fatigue, and loss of libido. The patient had low blood pressure, and physical examination revealed gynecomastia, bilateral atrophied testis, and bibasilar rales. He disclosed that he had used marijuana daily for 15 years.
After ruling out hemochromatosis, conducting a battery of hormonal tests, and an MRI, Dr. Pinsker and his colleagues diagnosed the patient with hypopituitarism. The culprit? Chronic marijuana use, they concluded after finding no other potential cause.
"I think it’s a thought-provoking study," said Dr. R. Mack Harrell, who will be the president-elect of the AACE this year. "We’ve known for many years, if you use a lot of cannabis, it suppresses the gonadal axis, and it’s been assumed that [cannabis’] only effect was on the gonadal axis. This poster poses the question of whether other pituitary hormones may be affected, and whether every pituitary hormone is at risk, so it’s hypothesis generating."
Dr. Pinsker, who is a practicing endocrinologist and the internal medicine residency program director at Jamaica Hospital Medical Center, said that the finding – and high rate of marijuana use – call for further research on the effect of chronic marijuana use on the endocrine system. He added that that physicians need to do a better job of obtaining a social history from their patients.
Tetrahydrocannabinol, or THC, which is the psychoactive ingredient of marijuana, can alter the hypothalamic-pituitary-gonadal axis either by acting directly on the hypothalamus and altering the gonadotropin-releasing hormone (GnRH) or by altering neural transmitters in the central nervous system, which affect the hypothalamus. The result is lowered luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which lead to reduced testosterone production by Leydig cells of the testis.
Studies have shown cannabis exposure can result in impaired cortisol response to stress. Animal studies have shown that cannabinoids can suppress several hypothalamic-pituitary pathways, including the growth hormone, and the thyroid hormone, reported Dr. Hineshkumar Upadhyay, coauthor of the report.
Meanwhile, THC, which is lipid soluble, can remain stored in the fatty tissue and re-enter the blood stream at very low levels. This pharmacokinetics can cause chronic effect on organ systems even though it is used occasionally, researchers said.
In the case of the 37-year-old patient, researchers first suspected hemochromatosis, which they ruled out by iron studies and echocardiography. Hypopituitarism is rare in young people.
The patient had low levels of LH (0.2 mIU/mL), FSH (1.8 mIU/mL), and testosterone (22 ng/dL). His prolactin levels were high (53 ng/mL), an increase that confirms trouble in the hypothalamic-pituitary axis, said Dr. Pinsker.
Further endocrine chemistry showed that he had adrenocorticotropic hormone (ACTH) of 6 pg/mL and cortisol at 0 mcg/dL. At 60 minutes, following administration of cosyntropin, the levels changed to 6.4 pg/mL and 9.3 mcg/dL, respectively.
Additional tests revealed low levels of total T3 (30 ng/dL), high T3 resin reuptake (49%), low total T4 (3.94 mcg/dL), normal free T4 (0.97 ng/dL), and low TSH (0.22 mcIU/mL). Growth hormone was within normal limits (5.0 ng/mL), and insulinlike growth factor-1 was low (75 ng/mL; Z-score of –1.3).
MRI showed that the protuberant pituitary gland was slightly larger than the expected size, but there was no identified mass lesion, researchers reported.
Researchers started the patient on replacement hormones – 25 mg cortisone in the morning and 12.5 mg at bedtime, with 25 mcg levothyroxine daily. The patient’s fatigue and edema improved dramatically, they reported. As with other patients who abuse substances, they advised him to stop using marijuana.
Dr. Pinsker, who is also a colonel in the U.S. Army Reserve Medical Corps, said he was planning on collecting more cases before publishing the findings. He added the same mechanism could affect women as well. "We just haven’t looked at it," he said.
"I think it’ll be frightening if the use goes up" as more states make the drug legal "and the awareness does not follow it," he said.
Dr. Pinsker and Dr. Upadhyay had no disclosures.
On Twitter @NaseemSMiller
PHOENIX – Chronic marijuana use can be a potential cause for hypopituitarism, according to an unpublished case report, which relied on existing data about the effect of cannabis on the hypothalamic-pituitary-gonadal axis.
The case hints at a largely underrepresented problem, researchers said, especially as various states contemplate legalizing marijuana, which is currently the most commonly used illicit drug in the nation, said Dr. Richard Pinsker at the annual meeting of the American Association of Clinical Endocrinologists.
The 37-year-old man arrived at the emergency department of Jamaica (N.Y.) Hospital Medical Center in Queens in late 2012 complaining of shortness of breath, increasing fatigue, and loss of libido. The patient had low blood pressure, and physical examination revealed gynecomastia, bilateral atrophied testis, and bibasilar rales. He disclosed that he had used marijuana daily for 15 years.
After ruling out hemochromatosis, conducting a battery of hormonal tests, and an MRI, Dr. Pinsker and his colleagues diagnosed the patient with hypopituitarism. The culprit? Chronic marijuana use, they concluded after finding no other potential cause.
"I think it’s a thought-provoking study," said Dr. R. Mack Harrell, who will be the president-elect of the AACE this year. "We’ve known for many years, if you use a lot of cannabis, it suppresses the gonadal axis, and it’s been assumed that [cannabis’] only effect was on the gonadal axis. This poster poses the question of whether other pituitary hormones may be affected, and whether every pituitary hormone is at risk, so it’s hypothesis generating."
Dr. Pinsker, who is a practicing endocrinologist and the internal medicine residency program director at Jamaica Hospital Medical Center, said that the finding – and high rate of marijuana use – call for further research on the effect of chronic marijuana use on the endocrine system. He added that that physicians need to do a better job of obtaining a social history from their patients.
Tetrahydrocannabinol, or THC, which is the psychoactive ingredient of marijuana, can alter the hypothalamic-pituitary-gonadal axis either by acting directly on the hypothalamus and altering the gonadotropin-releasing hormone (GnRH) or by altering neural transmitters in the central nervous system, which affect the hypothalamus. The result is lowered luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which lead to reduced testosterone production by Leydig cells of the testis.
Studies have shown cannabis exposure can result in impaired cortisol response to stress. Animal studies have shown that cannabinoids can suppress several hypothalamic-pituitary pathways, including the growth hormone, and the thyroid hormone, reported Dr. Hineshkumar Upadhyay, coauthor of the report.
Meanwhile, THC, which is lipid soluble, can remain stored in the fatty tissue and re-enter the blood stream at very low levels. This pharmacokinetics can cause chronic effect on organ systems even though it is used occasionally, researchers said.
In the case of the 37-year-old patient, researchers first suspected hemochromatosis, which they ruled out by iron studies and echocardiography. Hypopituitarism is rare in young people.
The patient had low levels of LH (0.2 mIU/mL), FSH (1.8 mIU/mL), and testosterone (22 ng/dL). His prolactin levels were high (53 ng/mL), an increase that confirms trouble in the hypothalamic-pituitary axis, said Dr. Pinsker.
Further endocrine chemistry showed that he had adrenocorticotropic hormone (ACTH) of 6 pg/mL and cortisol at 0 mcg/dL. At 60 minutes, following administration of cosyntropin, the levels changed to 6.4 pg/mL and 9.3 mcg/dL, respectively.
Additional tests revealed low levels of total T3 (30 ng/dL), high T3 resin reuptake (49%), low total T4 (3.94 mcg/dL), normal free T4 (0.97 ng/dL), and low TSH (0.22 mcIU/mL). Growth hormone was within normal limits (5.0 ng/mL), and insulinlike growth factor-1 was low (75 ng/mL; Z-score of –1.3).
MRI showed that the protuberant pituitary gland was slightly larger than the expected size, but there was no identified mass lesion, researchers reported.
Researchers started the patient on replacement hormones – 25 mg cortisone in the morning and 12.5 mg at bedtime, with 25 mcg levothyroxine daily. The patient’s fatigue and edema improved dramatically, they reported. As with other patients who abuse substances, they advised him to stop using marijuana.
Dr. Pinsker, who is also a colonel in the U.S. Army Reserve Medical Corps, said he was planning on collecting more cases before publishing the findings. He added the same mechanism could affect women as well. "We just haven’t looked at it," he said.
"I think it’ll be frightening if the use goes up" as more states make the drug legal "and the awareness does not follow it," he said.
Dr. Pinsker and Dr. Upadhyay had no disclosures.
On Twitter @NaseemSMiller
AT AACE ANNUAL MEETING
All glucocorticoids linked to increased risk of VTE
Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.
Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.
These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.
However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.
"Clinicians should be aware of this association," they noted.
Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.
A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.
All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.
Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)
Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.
New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).
In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.
The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.
In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.
The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.
"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.
This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.
This study provides strong evidence that glucocorticoids are linked to elevated risk of VTE, an association that is difficult to prove because some of the illnesses that are treated with these drugs may themselves cause VTE or may cause immobility that predisposes patients to VTE, said Dr. Mitchell H. Katz.
The findings don’t change the indications for prescribing glucocorticoids, but they "should remind us to always make sure that the potential benefits of treatment outweigh the risks, and to be prepared to diagnose and treat thromboembolism" in patients taking glucocorticoids, he said.
Dr. Mitchell H. Katz is a deputy editor of JAMA Internal Medicine. His remarks were taken from his editorial accompanying Ms. Johannesdottir’s report (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.93]).
This study provides strong evidence that glucocorticoids are linked to elevated risk of VTE, an association that is difficult to prove because some of the illnesses that are treated with these drugs may themselves cause VTE or may cause immobility that predisposes patients to VTE, said Dr. Mitchell H. Katz.
The findings don’t change the indications for prescribing glucocorticoids, but they "should remind us to always make sure that the potential benefits of treatment outweigh the risks, and to be prepared to diagnose and treat thromboembolism" in patients taking glucocorticoids, he said.
Dr. Mitchell H. Katz is a deputy editor of JAMA Internal Medicine. His remarks were taken from his editorial accompanying Ms. Johannesdottir’s report (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.93]).
This study provides strong evidence that glucocorticoids are linked to elevated risk of VTE, an association that is difficult to prove because some of the illnesses that are treated with these drugs may themselves cause VTE or may cause immobility that predisposes patients to VTE, said Dr. Mitchell H. Katz.
The findings don’t change the indications for prescribing glucocorticoids, but they "should remind us to always make sure that the potential benefits of treatment outweigh the risks, and to be prepared to diagnose and treat thromboembolism" in patients taking glucocorticoids, he said.
Dr. Mitchell H. Katz is a deputy editor of JAMA Internal Medicine. His remarks were taken from his editorial accompanying Ms. Johannesdottir’s report (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.93]).
Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.
Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.
These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.
However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.
"Clinicians should be aware of this association," they noted.
Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.
A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.
All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.
Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)
Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.
New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).
In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.
The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.
In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.
The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.
"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.
This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.
Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.
Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.
These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.
However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.
"Clinicians should be aware of this association," they noted.
Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.
A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.
All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.
Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)
Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.
New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).
In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.
The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.
In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.
The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.
"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.
This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.
FROM JAMA INTERNAL MEDICINE
Major Finding: New use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse.
Data Source: A national population-based case-control study involving 38,765 Danish adults who developed VTE in a 7-year period and 387,650 controls.
Disclosures: This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.
Subclinical hypothyroidism predicts cardiovascular mortality in NHANES
SAN FRANCISCO – Subclinical hypothyroidism is a strong independent predictor of cardiovascular mortality in a healthy population at baseline, a national study indicated.
Among 7,883 participants in the National Health and Nutrition Examination Survey III (NHANES III) who were over age 40 years and free of overt hyper- or hypothyroidism, 5.3% had subclinical hypothyroidism as defined by a thyroid-stimulating hormone level of 5-19.99 mIU/L and a thyroxine level of 5-12 mcg/dL. During a mean 12.3 years of follow-up, 25.2% of the subclinical hypothyroid group died of cardiovascular causes, compared with 16.9% of euthyroid controls, Dr. Tushar A. Tuliani reported at the annual meeting of the American College of Cardiology.
Similarly, death due specifically to ischemic heart disease occurred in 15.4% of the subjects with subclinical hypothyroidism, compared with 9.6% of euthyroid controls, added Dr. Tuliani of Wayne State University–Detroit Medical Center.
In a multivariate analysis that adjusted for standard cardiovascular risk factors and demographic variables, individuals with subclinical hypothyroidism had a 20% increased risk of all-cause mortality, a 24% increase in cardiovascular mortality, and a 34% increased risk of death from ischemic heart disease. All of these increases were statistically significant and clinically meaningful, he noted.
NHANES III is an in-depth weighted survey conducted by the Centers for Disease Control and Prevention in a nationally representative population.
Dr. Tuliani reported having no financial conflicts.
SAN FRANCISCO – Subclinical hypothyroidism is a strong independent predictor of cardiovascular mortality in a healthy population at baseline, a national study indicated.
Among 7,883 participants in the National Health and Nutrition Examination Survey III (NHANES III) who were over age 40 years and free of overt hyper- or hypothyroidism, 5.3% had subclinical hypothyroidism as defined by a thyroid-stimulating hormone level of 5-19.99 mIU/L and a thyroxine level of 5-12 mcg/dL. During a mean 12.3 years of follow-up, 25.2% of the subclinical hypothyroid group died of cardiovascular causes, compared with 16.9% of euthyroid controls, Dr. Tushar A. Tuliani reported at the annual meeting of the American College of Cardiology.
Similarly, death due specifically to ischemic heart disease occurred in 15.4% of the subjects with subclinical hypothyroidism, compared with 9.6% of euthyroid controls, added Dr. Tuliani of Wayne State University–Detroit Medical Center.
In a multivariate analysis that adjusted for standard cardiovascular risk factors and demographic variables, individuals with subclinical hypothyroidism had a 20% increased risk of all-cause mortality, a 24% increase in cardiovascular mortality, and a 34% increased risk of death from ischemic heart disease. All of these increases were statistically significant and clinically meaningful, he noted.
NHANES III is an in-depth weighted survey conducted by the Centers for Disease Control and Prevention in a nationally representative population.
Dr. Tuliani reported having no financial conflicts.
SAN FRANCISCO – Subclinical hypothyroidism is a strong independent predictor of cardiovascular mortality in a healthy population at baseline, a national study indicated.
Among 7,883 participants in the National Health and Nutrition Examination Survey III (NHANES III) who were over age 40 years and free of overt hyper- or hypothyroidism, 5.3% had subclinical hypothyroidism as defined by a thyroid-stimulating hormone level of 5-19.99 mIU/L and a thyroxine level of 5-12 mcg/dL. During a mean 12.3 years of follow-up, 25.2% of the subclinical hypothyroid group died of cardiovascular causes, compared with 16.9% of euthyroid controls, Dr. Tushar A. Tuliani reported at the annual meeting of the American College of Cardiology.
Similarly, death due specifically to ischemic heart disease occurred in 15.4% of the subjects with subclinical hypothyroidism, compared with 9.6% of euthyroid controls, added Dr. Tuliani of Wayne State University–Detroit Medical Center.
In a multivariate analysis that adjusted for standard cardiovascular risk factors and demographic variables, individuals with subclinical hypothyroidism had a 20% increased risk of all-cause mortality, a 24% increase in cardiovascular mortality, and a 34% increased risk of death from ischemic heart disease. All of these increases were statistically significant and clinically meaningful, he noted.
NHANES III is an in-depth weighted survey conducted by the Centers for Disease Control and Prevention in a nationally representative population.
Dr. Tuliani reported having no financial conflicts.
AT ACC 13
Major finding: Healthy adults with subclinical hypothyroidism had a 24% greater risk of cardiovascular death than did euthyroid individuals during a mean 12.3 years of follow-up.
Data source: Analysis of 7,883 participants in the National Health and Nutrition Examination Survey III, a weighted, nationally representative sample.
Disclosures: NHANES III is sponsored by the Centers for Disease Control and Prevention. The presenter reported having no relevant financial interests.
Cancer deaths declined 20% since 1991
Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.
The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.
The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.
The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.
Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.
Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."
Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.
The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."
The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.
On Twitter @aliciaault
Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.
The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.
The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.
The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.
Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.
Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."
Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.
The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."
The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.
On Twitter @aliciaault
Cancer deaths have declined 20% since 1991, which means there were 1.2 million fewer deaths from cancer in 2009, according to the American Cancer Society.
The overall cancer death rate decreased from 215 per 100,000 in 1991 to 173 per 100,000 in 2009. Death rates declined more sharply for cancers of the lung and prostate in men, for breast cancers in women, and for colon and rectal cancers for men and women. The ACS attributes the drops to decreases in smoking and improvements in early detection and treatment.
The most common causes of cancer death in Americans, accounting for 50% of cancer deaths, are cancers of the lung and bronchus, prostate, and colorectum in men; and cancers of the lung and bronchus, breast, and colorectum in women. This year, there will be 1.6 million cancer cases and 580,350 cancer deaths; lung cancers will account for 25% of cancer deaths in men and women this year, according to estimates from the ACS.
The mortality figures and incidence data are contained in two reports: Cancer Facts & Figures 2013 and Cancer Statistics 2013, both published in CA: A Cancer Journal for Clinicians. (doi:10.3322/caac.21166). The reports were published online on Jan. 18.
Incidence rates are on the decline for most cancers with the exception of melanoma, and liver, thyroid and pancreatic cancer.
Dr. Daniel M. Siegel, president of the American Academy of Dermatology, said in a statement that a rising incidence of melanoma "is particularly concerning because skin cancer can often be easily prevented and detected." Dr. Siegel said that the AAD and its members "are actively working to reduce the incidence of skin cancer and change society’s attitudes and behaviors toward sun exposure and tanning."
Death rates from pancreatic cancer have increased over the last decade, due to what the ACS called "a lack progress in primary prevention, early diagnosis, and treatment of this cancer." The ACS report included a special section devoted to updated information on the occurrence and treatment of pancreatic cancer. Most patients with pancreatic cancer die within a year of diagnosis; the 5-year survival rate is 6%.
The ACS also noted that the disparity in cancer outcomes based on ethnicity and income, "particularly [among] those diagnosed with colorectal or breast cancer where earlier detection and better treatments are credited for the improving trends," said John R. Seffrin, Ph.D., chief executive officer of the ACS, in a statement. "We can and must close this gap so that people are not punished for having the misfortune of being born poor and disadvantaged."
The 5-year survival rate in 2002-2008 for white women with breast cancer, for instance, was 92%, whereas for black women, it was 78%. For colon cancer, the 5-year survival rate was 66% for whites, but 55% for blacks.
On Twitter @aliciaault
FROM CA: A CANCER JOURNAL FOR CLINICIANS
Clinical guidelines for hypothyroidism 'take the middle ground' on TSH
The target range for serum thyrotropin levels in nonpregnant adults should be the normal range of a third-generation assay, and if an upper limit of normal for the assay is unspecified, the limit should be considered 4.12 mIU/L in iodine-sufficient areas, according to new clinical practice guidelines issued jointly by the American Association of Clinical Endocrinologists and the American Thyroid Association.
Thus, the new guidelines "take the middle ground" with respect to the controversy over what the upper limit of normal is for serum thyrotropin (TSH) levels, Dr. Hossein Gharib of the Mayo Clinic, Rochester, Minn., said in an interview.
The reference range is generally considered to be between 2.5 and 5 mIU/L by laboratories that perform the tests, he noted.
The recommendation (#17) is one of 34 main recommendations and 18 subrecommendations included in the new guidelines. It is a Grade B recommendation with a Best Evidence Level (BEL) of 2, indicating that the evidence is limited but based on prospective controlled trials with or without randomization.
The evidence-based guidelines, developed by a task force of expert clinicians appointed by the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA), represent a joint effort by these organizations to address the etiology and epidemiology of hypothyroidism, as well as clinical and laboratory evaluation, management, and consequences of hypothyroidism.
Topics addressed by the guidelines include everything from screening to treatment of subclinical disease to pregnancy-related concerns, according to lead author Dr. Jeffrey R. Garber, the task force chair, and his colleagues (Endocr. Pract. 2012;18:988-s4).
"We covered a wide range of issues important to clinical endocrinologists," said Dr. Gharib, a task force member as well as past president of the AACE and president-elect of the ATA.
Other recommendations within the guidelines that Dr. Gharib highlighted address the use of thyroxin monotherapy, management of subclinical disease, and management of hypothyroidism in pregnancy.
Thyroxin monotherapy
Thyroxin monotherapy, rather than combination therapy, is preferred in patients with hypothyroidism, according to the guidelines.
This represents an endorsement of current practice, Dr. Gharib said.
Specifically, recommendations 22.1 and 22.2 state that patients with hypothyroidism should be treated with L-thyroxine monotherapy and that the evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism (Grade A, BEL 1 [indicating the evidence is based on large, randomized controlled prospective trials] and Grade B, BEL 1, respectively).
Subclinical hypothyroidism
Subclinical hypothyroidism, defined by TSH above normal when T3 and T4 are normal, usually involves mildly elevated TSH at between 5 and 10 mIU/L. Controversy has existed over whether treatment or observation is best in these patients, Dr. Gharib explained.
Recommendation 16 of the guidelines states that treatment should definitely be considered in those with TSH above 10 mIU/L, particularly if the patient has symptoms suggestive of hypothyroidism; positive anti-microsomal/anti-thyroid peroxidase antibodies (TPOAb); or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases (Grade B, BEL 1).
Pregnancy
With respect to pregnancy, the new recommendations underscore the fact that TSH levels differ between pregnant and nonpregnant women, Dr. Gharib said.
Recommendation 18 states that reference levels should be adjusted based on trimester-specific TSH values. If trimester-specific reference ranges are not available from a given laboratory, the following upper-normal reference limits should be used: 2.5 mIU/L for the first trimester, 3.0 mIU/L for the second trimester, and 3.5 mIU/L for the third trimester (Grade C, BEL 2).
"These guidelines are a document that reflects the current state of the field and are intended to provide a working document for guideline updates since rapid changes in this field are expected in the future. We encourage medical professionals to use this information in conjunction with their best clinical judgment," the authors wrote, noting that the recommendations may not be appropriate in all situations.
"Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances," they added.
Areas for future research include the evaluation of possible cardiac and cognitive benefit from treating subclinical hypothyroidism, combination therapy for hypothyroidism, monotherapy with L-triiodothyronine, the use of thyroid hormone antagonists in therapy, screening for hypothyroidism in pregnancy, and agents and conditions impacting therapy and interpretation of thyroid tests, they noted.
These guidelines were cosponsored by the AACE and the ATA. One task force member, Dr. Jeffrey I. Mechanick, reported receiving speaker and program development honoraria from Abbott Nutrition. The remaining task force members reported having no disclosures.
The target range for serum thyrotropin levels in nonpregnant adults should be the normal range of a third-generation assay, and if an upper limit of normal for the assay is unspecified, the limit should be considered 4.12 mIU/L in iodine-sufficient areas, according to new clinical practice guidelines issued jointly by the American Association of Clinical Endocrinologists and the American Thyroid Association.
Thus, the new guidelines "take the middle ground" with respect to the controversy over what the upper limit of normal is for serum thyrotropin (TSH) levels, Dr. Hossein Gharib of the Mayo Clinic, Rochester, Minn., said in an interview.
The reference range is generally considered to be between 2.5 and 5 mIU/L by laboratories that perform the tests, he noted.
The recommendation (#17) is one of 34 main recommendations and 18 subrecommendations included in the new guidelines. It is a Grade B recommendation with a Best Evidence Level (BEL) of 2, indicating that the evidence is limited but based on prospective controlled trials with or without randomization.
The evidence-based guidelines, developed by a task force of expert clinicians appointed by the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA), represent a joint effort by these organizations to address the etiology and epidemiology of hypothyroidism, as well as clinical and laboratory evaluation, management, and consequences of hypothyroidism.
Topics addressed by the guidelines include everything from screening to treatment of subclinical disease to pregnancy-related concerns, according to lead author Dr. Jeffrey R. Garber, the task force chair, and his colleagues (Endocr. Pract. 2012;18:988-s4).
"We covered a wide range of issues important to clinical endocrinologists," said Dr. Gharib, a task force member as well as past president of the AACE and president-elect of the ATA.
Other recommendations within the guidelines that Dr. Gharib highlighted address the use of thyroxin monotherapy, management of subclinical disease, and management of hypothyroidism in pregnancy.
Thyroxin monotherapy
Thyroxin monotherapy, rather than combination therapy, is preferred in patients with hypothyroidism, according to the guidelines.
This represents an endorsement of current practice, Dr. Gharib said.
Specifically, recommendations 22.1 and 22.2 state that patients with hypothyroidism should be treated with L-thyroxine monotherapy and that the evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism (Grade A, BEL 1 [indicating the evidence is based on large, randomized controlled prospective trials] and Grade B, BEL 1, respectively).
Subclinical hypothyroidism
Subclinical hypothyroidism, defined by TSH above normal when T3 and T4 are normal, usually involves mildly elevated TSH at between 5 and 10 mIU/L. Controversy has existed over whether treatment or observation is best in these patients, Dr. Gharib explained.
Recommendation 16 of the guidelines states that treatment should definitely be considered in those with TSH above 10 mIU/L, particularly if the patient has symptoms suggestive of hypothyroidism; positive anti-microsomal/anti-thyroid peroxidase antibodies (TPOAb); or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases (Grade B, BEL 1).
Pregnancy
With respect to pregnancy, the new recommendations underscore the fact that TSH levels differ between pregnant and nonpregnant women, Dr. Gharib said.
Recommendation 18 states that reference levels should be adjusted based on trimester-specific TSH values. If trimester-specific reference ranges are not available from a given laboratory, the following upper-normal reference limits should be used: 2.5 mIU/L for the first trimester, 3.0 mIU/L for the second trimester, and 3.5 mIU/L for the third trimester (Grade C, BEL 2).
"These guidelines are a document that reflects the current state of the field and are intended to provide a working document for guideline updates since rapid changes in this field are expected in the future. We encourage medical professionals to use this information in conjunction with their best clinical judgment," the authors wrote, noting that the recommendations may not be appropriate in all situations.
"Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances," they added.
Areas for future research include the evaluation of possible cardiac and cognitive benefit from treating subclinical hypothyroidism, combination therapy for hypothyroidism, monotherapy with L-triiodothyronine, the use of thyroid hormone antagonists in therapy, screening for hypothyroidism in pregnancy, and agents and conditions impacting therapy and interpretation of thyroid tests, they noted.
These guidelines were cosponsored by the AACE and the ATA. One task force member, Dr. Jeffrey I. Mechanick, reported receiving speaker and program development honoraria from Abbott Nutrition. The remaining task force members reported having no disclosures.
The target range for serum thyrotropin levels in nonpregnant adults should be the normal range of a third-generation assay, and if an upper limit of normal for the assay is unspecified, the limit should be considered 4.12 mIU/L in iodine-sufficient areas, according to new clinical practice guidelines issued jointly by the American Association of Clinical Endocrinologists and the American Thyroid Association.
Thus, the new guidelines "take the middle ground" with respect to the controversy over what the upper limit of normal is for serum thyrotropin (TSH) levels, Dr. Hossein Gharib of the Mayo Clinic, Rochester, Minn., said in an interview.
The reference range is generally considered to be between 2.5 and 5 mIU/L by laboratories that perform the tests, he noted.
The recommendation (#17) is one of 34 main recommendations and 18 subrecommendations included in the new guidelines. It is a Grade B recommendation with a Best Evidence Level (BEL) of 2, indicating that the evidence is limited but based on prospective controlled trials with or without randomization.
The evidence-based guidelines, developed by a task force of expert clinicians appointed by the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA), represent a joint effort by these organizations to address the etiology and epidemiology of hypothyroidism, as well as clinical and laboratory evaluation, management, and consequences of hypothyroidism.
Topics addressed by the guidelines include everything from screening to treatment of subclinical disease to pregnancy-related concerns, according to lead author Dr. Jeffrey R. Garber, the task force chair, and his colleagues (Endocr. Pract. 2012;18:988-s4).
"We covered a wide range of issues important to clinical endocrinologists," said Dr. Gharib, a task force member as well as past president of the AACE and president-elect of the ATA.
Other recommendations within the guidelines that Dr. Gharib highlighted address the use of thyroxin monotherapy, management of subclinical disease, and management of hypothyroidism in pregnancy.
Thyroxin monotherapy
Thyroxin monotherapy, rather than combination therapy, is preferred in patients with hypothyroidism, according to the guidelines.
This represents an endorsement of current practice, Dr. Gharib said.
Specifically, recommendations 22.1 and 22.2 state that patients with hypothyroidism should be treated with L-thyroxine monotherapy and that the evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism (Grade A, BEL 1 [indicating the evidence is based on large, randomized controlled prospective trials] and Grade B, BEL 1, respectively).
Subclinical hypothyroidism
Subclinical hypothyroidism, defined by TSH above normal when T3 and T4 are normal, usually involves mildly elevated TSH at between 5 and 10 mIU/L. Controversy has existed over whether treatment or observation is best in these patients, Dr. Gharib explained.
Recommendation 16 of the guidelines states that treatment should definitely be considered in those with TSH above 10 mIU/L, particularly if the patient has symptoms suggestive of hypothyroidism; positive anti-microsomal/anti-thyroid peroxidase antibodies (TPOAb); or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases (Grade B, BEL 1).
Pregnancy
With respect to pregnancy, the new recommendations underscore the fact that TSH levels differ between pregnant and nonpregnant women, Dr. Gharib said.
Recommendation 18 states that reference levels should be adjusted based on trimester-specific TSH values. If trimester-specific reference ranges are not available from a given laboratory, the following upper-normal reference limits should be used: 2.5 mIU/L for the first trimester, 3.0 mIU/L for the second trimester, and 3.5 mIU/L for the third trimester (Grade C, BEL 2).
"These guidelines are a document that reflects the current state of the field and are intended to provide a working document for guideline updates since rapid changes in this field are expected in the future. We encourage medical professionals to use this information in conjunction with their best clinical judgment," the authors wrote, noting that the recommendations may not be appropriate in all situations.
"Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances," they added.
Areas for future research include the evaluation of possible cardiac and cognitive benefit from treating subclinical hypothyroidism, combination therapy for hypothyroidism, monotherapy with L-triiodothyronine, the use of thyroid hormone antagonists in therapy, screening for hypothyroidism in pregnancy, and agents and conditions impacting therapy and interpretation of thyroid tests, they noted.
These guidelines were cosponsored by the AACE and the ATA. One task force member, Dr. Jeffrey I. Mechanick, reported receiving speaker and program development honoraria from Abbott Nutrition. The remaining task force members reported having no disclosures.
FROM ENDOCRINE PRACTICE
FDA approves pasireotide for Cushing's, with postmarketing safety studies
Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."
Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.
t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.
In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.
Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).
The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.
In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.
Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.
The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.
Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.
The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.
Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."
Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.
t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.
In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.
Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).
The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.
In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.
Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.
The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.
Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.
The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.
Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."
Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.
t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.
In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.
Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).
The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.
In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.
Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.
The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.
Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.
The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.
Thyroid Hormone Replacement Benefits Subset of CKD Patients
SAN DIEGO – Chronic kidney disease patients with subclinical hypothyroidism who were treated with thyroid hormone had better preserved renal function than did those who did not receive the treatment, a study has shown.
In addition, thyroid hormone replacement therapy was an independent predictor of renal outcomes in this subset of patients, Dr. Shin-Wook Kang reported at Kidney Week 2012.
"Subclinical hyperthyroidism is not a rare disorder, especially in females and in the elderly, and it is frequently observed in CKD [chronic kidney disease] patients," said Dr. Kang of the department of internal medicine at Yonsei University College of Medicine, Seoul, Korea. "In contrast to overt hypothyroidism, thyroid hormone treatment is seldom necessary in patients with subclinical hypothyroidism. Even though previous studies have demonstrated that thyroid hormone improves cardiac dysfunction and reduces total and LDL cholesterol levels in patients with subclinical hypothyroidism, the impact of thyroid hormone replacement therapy on renal function has never been studied in these patients."
In an effort to investigate whether restoration of euthyroidism is beneficial in terms of preserving renal function in CKD patients with subclinical hypothyroidism, he and his associates retrospectively studied the medical records of 309 patients with stage 2-4 CKD who were diagnosed with subclinical hypothyroidism and treated at the college of medicine during 2005-2010. They assessed demographic, clinical, and biochemical data including levels of calcium/phosphorus, albumin, total cholesterol, and triglycerides and estimated glomerular filtration rate (GFR). The researchers used a linear mixed model to compare changes in estimated GFR over time between patients who received thyroid hormone replacement therapy and those who did not.
Of the 309 patients, 180 (58%) were treated with l-thyroxine at an initial dose of 25 mcg/day (treatment group) while the remaining 42% were not (nontreatment group). Among patients in the treatment group, the dose of l-thyroxine was adjusted 5-6 weeks after the start of therapy and then every 3 months based on the patient’s serum TSH levels.
At baseline, levels of serum cholesterol and triglyceride were significantly higher in the treatment vs. the nontreatment group (180.0 vs. 161.3 mg/dL and 162.7 vs. 125.6 mg/dL, respectively).
During a mean follow-up of 34.8 months, the overall rate of decline in estimated GFR was significantly greater in the nontreatment group than in the treatment group (–5.93 vs. –2.11 mL/min per year per 1.73 mm2). Dr. Kang also reported that a linear mixed model showed a significant difference in the rates of estimated GFR over time between the two groups, while Kaplan-Meier analysis also showed that renal event-free survival was significantly higher in the treatment group.
Multivariate Cox regression analysis revealed that thyroid hormone replacement therapy was an independent predictor of renal outcome (hazard ratio, 0.28; P =.01).
"Thyroid hormone therapy not only preserved renal function better but also was an independent predictor of renal outcome in CKD patients with subclinical hypothyroidism, suggesting that thyroid hormone replacement should be considered in these patients," Dr. Kang said.
Dr. Kang said he had no relevant financial conflicts to disclose.
SAN DIEGO – Chronic kidney disease patients with subclinical hypothyroidism who were treated with thyroid hormone had better preserved renal function than did those who did not receive the treatment, a study has shown.
In addition, thyroid hormone replacement therapy was an independent predictor of renal outcomes in this subset of patients, Dr. Shin-Wook Kang reported at Kidney Week 2012.
"Subclinical hyperthyroidism is not a rare disorder, especially in females and in the elderly, and it is frequently observed in CKD [chronic kidney disease] patients," said Dr. Kang of the department of internal medicine at Yonsei University College of Medicine, Seoul, Korea. "In contrast to overt hypothyroidism, thyroid hormone treatment is seldom necessary in patients with subclinical hypothyroidism. Even though previous studies have demonstrated that thyroid hormone improves cardiac dysfunction and reduces total and LDL cholesterol levels in patients with subclinical hypothyroidism, the impact of thyroid hormone replacement therapy on renal function has never been studied in these patients."
In an effort to investigate whether restoration of euthyroidism is beneficial in terms of preserving renal function in CKD patients with subclinical hypothyroidism, he and his associates retrospectively studied the medical records of 309 patients with stage 2-4 CKD who were diagnosed with subclinical hypothyroidism and treated at the college of medicine during 2005-2010. They assessed demographic, clinical, and biochemical data including levels of calcium/phosphorus, albumin, total cholesterol, and triglycerides and estimated glomerular filtration rate (GFR). The researchers used a linear mixed model to compare changes in estimated GFR over time between patients who received thyroid hormone replacement therapy and those who did not.
Of the 309 patients, 180 (58%) were treated with l-thyroxine at an initial dose of 25 mcg/day (treatment group) while the remaining 42% were not (nontreatment group). Among patients in the treatment group, the dose of l-thyroxine was adjusted 5-6 weeks after the start of therapy and then every 3 months based on the patient’s serum TSH levels.
At baseline, levels of serum cholesterol and triglyceride were significantly higher in the treatment vs. the nontreatment group (180.0 vs. 161.3 mg/dL and 162.7 vs. 125.6 mg/dL, respectively).
During a mean follow-up of 34.8 months, the overall rate of decline in estimated GFR was significantly greater in the nontreatment group than in the treatment group (–5.93 vs. –2.11 mL/min per year per 1.73 mm2). Dr. Kang also reported that a linear mixed model showed a significant difference in the rates of estimated GFR over time between the two groups, while Kaplan-Meier analysis also showed that renal event-free survival was significantly higher in the treatment group.
Multivariate Cox regression analysis revealed that thyroid hormone replacement therapy was an independent predictor of renal outcome (hazard ratio, 0.28; P =.01).
"Thyroid hormone therapy not only preserved renal function better but also was an independent predictor of renal outcome in CKD patients with subclinical hypothyroidism, suggesting that thyroid hormone replacement should be considered in these patients," Dr. Kang said.
Dr. Kang said he had no relevant financial conflicts to disclose.
SAN DIEGO – Chronic kidney disease patients with subclinical hypothyroidism who were treated with thyroid hormone had better preserved renal function than did those who did not receive the treatment, a study has shown.
In addition, thyroid hormone replacement therapy was an independent predictor of renal outcomes in this subset of patients, Dr. Shin-Wook Kang reported at Kidney Week 2012.
"Subclinical hyperthyroidism is not a rare disorder, especially in females and in the elderly, and it is frequently observed in CKD [chronic kidney disease] patients," said Dr. Kang of the department of internal medicine at Yonsei University College of Medicine, Seoul, Korea. "In contrast to overt hypothyroidism, thyroid hormone treatment is seldom necessary in patients with subclinical hypothyroidism. Even though previous studies have demonstrated that thyroid hormone improves cardiac dysfunction and reduces total and LDL cholesterol levels in patients with subclinical hypothyroidism, the impact of thyroid hormone replacement therapy on renal function has never been studied in these patients."
In an effort to investigate whether restoration of euthyroidism is beneficial in terms of preserving renal function in CKD patients with subclinical hypothyroidism, he and his associates retrospectively studied the medical records of 309 patients with stage 2-4 CKD who were diagnosed with subclinical hypothyroidism and treated at the college of medicine during 2005-2010. They assessed demographic, clinical, and biochemical data including levels of calcium/phosphorus, albumin, total cholesterol, and triglycerides and estimated glomerular filtration rate (GFR). The researchers used a linear mixed model to compare changes in estimated GFR over time between patients who received thyroid hormone replacement therapy and those who did not.
Of the 309 patients, 180 (58%) were treated with l-thyroxine at an initial dose of 25 mcg/day (treatment group) while the remaining 42% were not (nontreatment group). Among patients in the treatment group, the dose of l-thyroxine was adjusted 5-6 weeks after the start of therapy and then every 3 months based on the patient’s serum TSH levels.
At baseline, levels of serum cholesterol and triglyceride were significantly higher in the treatment vs. the nontreatment group (180.0 vs. 161.3 mg/dL and 162.7 vs. 125.6 mg/dL, respectively).
During a mean follow-up of 34.8 months, the overall rate of decline in estimated GFR was significantly greater in the nontreatment group than in the treatment group (–5.93 vs. –2.11 mL/min per year per 1.73 mm2). Dr. Kang also reported that a linear mixed model showed a significant difference in the rates of estimated GFR over time between the two groups, while Kaplan-Meier analysis also showed that renal event-free survival was significantly higher in the treatment group.
Multivariate Cox regression analysis revealed that thyroid hormone replacement therapy was an independent predictor of renal outcome (hazard ratio, 0.28; P =.01).
"Thyroid hormone therapy not only preserved renal function better but also was an independent predictor of renal outcome in CKD patients with subclinical hypothyroidism, suggesting that thyroid hormone replacement should be considered in these patients," Dr. Kang said.
Dr. Kang said he had no relevant financial conflicts to disclose.
AT KIDNEY WEEK 2012
Major Finding: During a mean follow-up of 34.8 months, the overall rate of decline in estimated GFR was significantly greater among chronic kidney disease patients who did not receive thyroid hormone replacement than in those who did (–5.93 vs. –2.11 mL/min per year per 1.73 mm2).
Data Source: Data are from a single-center Korean study of 309 patients with stage 2-4 chronic kidney disease who were diagnosed with subclinical hypothyroidism and treated during 2005-2010.
Disclosures: Dr. Kang said he had no relevant financial conflicts to disclose.
FDA Approves Second Drug for Rare Thyroid Cancer
Cabozantinib, a kinase inhibitor, has been approved for the treatment of progressive, metastatic medullary thyroid cancer, on the basis of the results of an international study of 330 patients, the Food and Drug Administration has announced.
This is the second drug approved by the FDA for this indication in the past 2 years; the first was vandetanib (Caprelsa), approved in April 2011. Before these approvals, "patients with this rare and difficult to treat disease had limited therapeutic treatment options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s Nov. 29 statement announcing the approval.
Cabozantinib will be marketed as Cometriq by Exelixis Inc. The recommended dose is 140 mg orally, without food (people taking the drug should not eat for at least 2 hours before and at least 1 hour after taking it). Exelixis is planning to make the drug available in late January, at an average wholesale price of $9,900 for a 28-day supply, according to the company.
In the EXAM study of 330 patients with metastatic medullary thyroid cancer, with evidence of actively progressive disease within 14 months of enrollment, the median progression-free survival was 11.2 months among those treated with cabozantinib, compared with 4 months among those on placebo, a statistically significant difference, according to the prescribing information. Partial responses were observed among 27% of those on cabozantinib but none of those on placebo, and the median duration of the objective response was 14.7 months among those on cabozantinib. At the planned interim analysis, there was no statistically significant difference in overall survival between the two groups.
The most common adverse events, reported in at least 25% of patients treated with cabozantinib, were diarrhea; stomatitis, palmar-plantar erythrodysesthesia syndrome; decreases in weight and appetite; nausea; fatigue; oral pain; hair color changes; dysgeusia; hypertension; abdominal pain; and constipation. The most common laboratory abnormalities, reported in at least 25% of patients, were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
The prescribing information includes a boxed warning about severe and sometimes fatal hemorrhage (3%), and gastrointestinal perforations (3%) and fistulas (1%) were reported in patients treated with the drug.
The review of this drug was a priority review, completed in 6 months, which is used for drugs "that may offer major advances in treatment or that provide a treatment when no adequate therapy exists," the FDA statement said. The drug has also been designated an orphan drug, because medullary thyroid cancer is considered a rare disease.
As part of its postmarketing commitments, the FDA has requested that the company submit the final overall survival results of the study, expected to be submitted in December 2014, according to the agency’s approval letter. The letter also lists other postmarketing commitments, including the completion of a study comparing the approved dose of "a biologically active and potentially safer lower daily cabozantinib dose" in patients with progressive medullary thyroid cancer.
Cabozantinib is a kinase inhibitor that inhibits the activity of RET, MET, and other tyrosine kinases, which "are involved in both normal cellular function, and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment," according to the Exelixis statement announcing approval
The company also announced on Nov. 29 that the application for approval of cabozantinib, also based on the EXAM study, has been accepted by the European Medicines Agency for approval in the European Union.
The FDA statement cites estimates from the National Cancer Institute that 56,460 people will be diagnosed with thyroid cancer this year in the United States, and 1,780 will die from the disease, and about 4% percent of thyroid cancers are medullary thyroid cancer.
The drug’s label is available on the FDA website. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch site or at 800-332-1088.
Cabozantinib, a kinase inhibitor, has been approved for the treatment of progressive, metastatic medullary thyroid cancer, on the basis of the results of an international study of 330 patients, the Food and Drug Administration has announced.
This is the second drug approved by the FDA for this indication in the past 2 years; the first was vandetanib (Caprelsa), approved in April 2011. Before these approvals, "patients with this rare and difficult to treat disease had limited therapeutic treatment options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s Nov. 29 statement announcing the approval.
Cabozantinib will be marketed as Cometriq by Exelixis Inc. The recommended dose is 140 mg orally, without food (people taking the drug should not eat for at least 2 hours before and at least 1 hour after taking it). Exelixis is planning to make the drug available in late January, at an average wholesale price of $9,900 for a 28-day supply, according to the company.
In the EXAM study of 330 patients with metastatic medullary thyroid cancer, with evidence of actively progressive disease within 14 months of enrollment, the median progression-free survival was 11.2 months among those treated with cabozantinib, compared with 4 months among those on placebo, a statistically significant difference, according to the prescribing information. Partial responses were observed among 27% of those on cabozantinib but none of those on placebo, and the median duration of the objective response was 14.7 months among those on cabozantinib. At the planned interim analysis, there was no statistically significant difference in overall survival between the two groups.
The most common adverse events, reported in at least 25% of patients treated with cabozantinib, were diarrhea; stomatitis, palmar-plantar erythrodysesthesia syndrome; decreases in weight and appetite; nausea; fatigue; oral pain; hair color changes; dysgeusia; hypertension; abdominal pain; and constipation. The most common laboratory abnormalities, reported in at least 25% of patients, were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
The prescribing information includes a boxed warning about severe and sometimes fatal hemorrhage (3%), and gastrointestinal perforations (3%) and fistulas (1%) were reported in patients treated with the drug.
The review of this drug was a priority review, completed in 6 months, which is used for drugs "that may offer major advances in treatment or that provide a treatment when no adequate therapy exists," the FDA statement said. The drug has also been designated an orphan drug, because medullary thyroid cancer is considered a rare disease.
As part of its postmarketing commitments, the FDA has requested that the company submit the final overall survival results of the study, expected to be submitted in December 2014, according to the agency’s approval letter. The letter also lists other postmarketing commitments, including the completion of a study comparing the approved dose of "a biologically active and potentially safer lower daily cabozantinib dose" in patients with progressive medullary thyroid cancer.
Cabozantinib is a kinase inhibitor that inhibits the activity of RET, MET, and other tyrosine kinases, which "are involved in both normal cellular function, and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment," according to the Exelixis statement announcing approval
The company also announced on Nov. 29 that the application for approval of cabozantinib, also based on the EXAM study, has been accepted by the European Medicines Agency for approval in the European Union.
The FDA statement cites estimates from the National Cancer Institute that 56,460 people will be diagnosed with thyroid cancer this year in the United States, and 1,780 will die from the disease, and about 4% percent of thyroid cancers are medullary thyroid cancer.
The drug’s label is available on the FDA website. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch site or at 800-332-1088.
Cabozantinib, a kinase inhibitor, has been approved for the treatment of progressive, metastatic medullary thyroid cancer, on the basis of the results of an international study of 330 patients, the Food and Drug Administration has announced.
This is the second drug approved by the FDA for this indication in the past 2 years; the first was vandetanib (Caprelsa), approved in April 2011. Before these approvals, "patients with this rare and difficult to treat disease had limited therapeutic treatment options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s Nov. 29 statement announcing the approval.
Cabozantinib will be marketed as Cometriq by Exelixis Inc. The recommended dose is 140 mg orally, without food (people taking the drug should not eat for at least 2 hours before and at least 1 hour after taking it). Exelixis is planning to make the drug available in late January, at an average wholesale price of $9,900 for a 28-day supply, according to the company.
In the EXAM study of 330 patients with metastatic medullary thyroid cancer, with evidence of actively progressive disease within 14 months of enrollment, the median progression-free survival was 11.2 months among those treated with cabozantinib, compared with 4 months among those on placebo, a statistically significant difference, according to the prescribing information. Partial responses were observed among 27% of those on cabozantinib but none of those on placebo, and the median duration of the objective response was 14.7 months among those on cabozantinib. At the planned interim analysis, there was no statistically significant difference in overall survival between the two groups.
The most common adverse events, reported in at least 25% of patients treated with cabozantinib, were diarrhea; stomatitis, palmar-plantar erythrodysesthesia syndrome; decreases in weight and appetite; nausea; fatigue; oral pain; hair color changes; dysgeusia; hypertension; abdominal pain; and constipation. The most common laboratory abnormalities, reported in at least 25% of patients, were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
The prescribing information includes a boxed warning about severe and sometimes fatal hemorrhage (3%), and gastrointestinal perforations (3%) and fistulas (1%) were reported in patients treated with the drug.
The review of this drug was a priority review, completed in 6 months, which is used for drugs "that may offer major advances in treatment or that provide a treatment when no adequate therapy exists," the FDA statement said. The drug has also been designated an orphan drug, because medullary thyroid cancer is considered a rare disease.
As part of its postmarketing commitments, the FDA has requested that the company submit the final overall survival results of the study, expected to be submitted in December 2014, according to the agency’s approval letter. The letter also lists other postmarketing commitments, including the completion of a study comparing the approved dose of "a biologically active and potentially safer lower daily cabozantinib dose" in patients with progressive medullary thyroid cancer.
Cabozantinib is a kinase inhibitor that inhibits the activity of RET, MET, and other tyrosine kinases, which "are involved in both normal cellular function, and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment," according to the Exelixis statement announcing approval
The company also announced on Nov. 29 that the application for approval of cabozantinib, also based on the EXAM study, has been accepted by the European Medicines Agency for approval in the European Union.
The FDA statement cites estimates from the National Cancer Institute that 56,460 people will be diagnosed with thyroid cancer this year in the United States, and 1,780 will die from the disease, and about 4% percent of thyroid cancers are medullary thyroid cancer.
The drug’s label is available on the FDA website. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch site or at 800-332-1088.
FDA Panel Backs Somatostatin Analogue for Cushing's
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
AT A MEETING OF THE FDA’S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE
