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Etomidate drip quickly curbs severe hypercortisolism
CHICAGO – Continuous intravenous infusion of etomidate safely and swiftly gains control of severe hypercortisolism in patients with adrenocorticotropic hormone–dependent Cushing’s syndrome when conventional presurgical oral treatment is problematic.
"From our cumulative experience, we have now developed a standardized titrated etomidate infusion protocol, which should provide clinicians with a simple, safe, and effective means to lower serum cortisol in patients with severe clinical, metabolic, and neuropsychiatric consequences of prodigious hypercortisolism as a bridge to definitive medical or surgical therapy," explained Dr. Katarzyna G. Zarnecki at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Etomidate (Amidate) is a sedative hypnotic agent with an excellent cardiovascular safety profile. It is widely used in emergency settings, such as reduction of dislocated joints and cardioversion. It suppresses adrenal steroidogenesis by potently inhibiting 11-beta hydroxylase. Fortunately for endocrinologic purposes, etomidate suppresses cortisol synthesis even at subhypnotic doses. In using it off label for management of severe hypercortisolism, it’s essential to keep the drug at subhypnotic doses, meaning not more than 0.3 mg/kg per hour, emphasized Dr. Zarnecki of the University of Wisconsin, Milwaukee.
Dr. Zarnecki and her coworkers utilize as their standard etomidate infusion protocol an initial 5-mg bolus followed by an infusion at 0.02 mg/kg per hour, with dose titration in increments of 0.01-0.02 mg/kg per hour every 4-6 hours based on changes in serum cortisol level. The goal is to bring the cortisol down to a target range of 10-20 mcg/dL.
She presented an illustrative six-patient series in which she and her colleagues turned to continuous infusion of etomidate because conventional oral therapy would have taken too long to rein in the severe hypercortisolism or because medication side effects were intolerable.
Mean baseline pretreatment serum cortisol was 138 mcg/dL, with an adrenocorticotropic hormone level of 419 pg/mL. Five of the six patients reached the goal of 10-20 mcg/dL in an average time of 64 hours. The mean rate of serum cortisol reduction was 1.93 mcg/dL per hour. The average etomidate infusion rate at the time the target level was reached was 0.07 mg/kg per hour, with a maximum rate of 0.1 mg/kg per hour. Monitoring via the Richmond Agitation Sedation Scale confirmed that none of the patients experienced sedative effects.
In the sole patient who didn’t reach goal, etomidate therapy was suspended because the patient entered palliative care because of extensive tumor progression.
Dr. Zarnecki reported having no financial conflicts of interest.
CHICAGO – Continuous intravenous infusion of etomidate safely and swiftly gains control of severe hypercortisolism in patients with adrenocorticotropic hormone–dependent Cushing’s syndrome when conventional presurgical oral treatment is problematic.
"From our cumulative experience, we have now developed a standardized titrated etomidate infusion protocol, which should provide clinicians with a simple, safe, and effective means to lower serum cortisol in patients with severe clinical, metabolic, and neuropsychiatric consequences of prodigious hypercortisolism as a bridge to definitive medical or surgical therapy," explained Dr. Katarzyna G. Zarnecki at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Etomidate (Amidate) is a sedative hypnotic agent with an excellent cardiovascular safety profile. It is widely used in emergency settings, such as reduction of dislocated joints and cardioversion. It suppresses adrenal steroidogenesis by potently inhibiting 11-beta hydroxylase. Fortunately for endocrinologic purposes, etomidate suppresses cortisol synthesis even at subhypnotic doses. In using it off label for management of severe hypercortisolism, it’s essential to keep the drug at subhypnotic doses, meaning not more than 0.3 mg/kg per hour, emphasized Dr. Zarnecki of the University of Wisconsin, Milwaukee.
Dr. Zarnecki and her coworkers utilize as their standard etomidate infusion protocol an initial 5-mg bolus followed by an infusion at 0.02 mg/kg per hour, with dose titration in increments of 0.01-0.02 mg/kg per hour every 4-6 hours based on changes in serum cortisol level. The goal is to bring the cortisol down to a target range of 10-20 mcg/dL.
She presented an illustrative six-patient series in which she and her colleagues turned to continuous infusion of etomidate because conventional oral therapy would have taken too long to rein in the severe hypercortisolism or because medication side effects were intolerable.
Mean baseline pretreatment serum cortisol was 138 mcg/dL, with an adrenocorticotropic hormone level of 419 pg/mL. Five of the six patients reached the goal of 10-20 mcg/dL in an average time of 64 hours. The mean rate of serum cortisol reduction was 1.93 mcg/dL per hour. The average etomidate infusion rate at the time the target level was reached was 0.07 mg/kg per hour, with a maximum rate of 0.1 mg/kg per hour. Monitoring via the Richmond Agitation Sedation Scale confirmed that none of the patients experienced sedative effects.
In the sole patient who didn’t reach goal, etomidate therapy was suspended because the patient entered palliative care because of extensive tumor progression.
Dr. Zarnecki reported having no financial conflicts of interest.
CHICAGO – Continuous intravenous infusion of etomidate safely and swiftly gains control of severe hypercortisolism in patients with adrenocorticotropic hormone–dependent Cushing’s syndrome when conventional presurgical oral treatment is problematic.
"From our cumulative experience, we have now developed a standardized titrated etomidate infusion protocol, which should provide clinicians with a simple, safe, and effective means to lower serum cortisol in patients with severe clinical, metabolic, and neuropsychiatric consequences of prodigious hypercortisolism as a bridge to definitive medical or surgical therapy," explained Dr. Katarzyna G. Zarnecki at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Etomidate (Amidate) is a sedative hypnotic agent with an excellent cardiovascular safety profile. It is widely used in emergency settings, such as reduction of dislocated joints and cardioversion. It suppresses adrenal steroidogenesis by potently inhibiting 11-beta hydroxylase. Fortunately for endocrinologic purposes, etomidate suppresses cortisol synthesis even at subhypnotic doses. In using it off label for management of severe hypercortisolism, it’s essential to keep the drug at subhypnotic doses, meaning not more than 0.3 mg/kg per hour, emphasized Dr. Zarnecki of the University of Wisconsin, Milwaukee.
Dr. Zarnecki and her coworkers utilize as their standard etomidate infusion protocol an initial 5-mg bolus followed by an infusion at 0.02 mg/kg per hour, with dose titration in increments of 0.01-0.02 mg/kg per hour every 4-6 hours based on changes in serum cortisol level. The goal is to bring the cortisol down to a target range of 10-20 mcg/dL.
She presented an illustrative six-patient series in which she and her colleagues turned to continuous infusion of etomidate because conventional oral therapy would have taken too long to rein in the severe hypercortisolism or because medication side effects were intolerable.
Mean baseline pretreatment serum cortisol was 138 mcg/dL, with an adrenocorticotropic hormone level of 419 pg/mL. Five of the six patients reached the goal of 10-20 mcg/dL in an average time of 64 hours. The mean rate of serum cortisol reduction was 1.93 mcg/dL per hour. The average etomidate infusion rate at the time the target level was reached was 0.07 mg/kg per hour, with a maximum rate of 0.1 mg/kg per hour. Monitoring via the Richmond Agitation Sedation Scale confirmed that none of the patients experienced sedative effects.
In the sole patient who didn’t reach goal, etomidate therapy was suspended because the patient entered palliative care because of extensive tumor progression.
Dr. Zarnecki reported having no financial conflicts of interest.
AT ICE/ENDO 2014
Key clinical point: The anesthetic induction agent etomidate is a potent suppressor of cortisol synthesis in the adrenal cortex at subhypnotic doses, making it a safe and effective agent for management of severe hypercortisolism in Cushing’s syndrome.
Major finding: Continuous infusion of etomidate using a standardized protocol resulted in a reduction in serum cortisol from a mean of 138 mcg/dL to a goal range of 10-20 mcg/dL in an average of 64 hours.
Data source: This was a retrospective case series involving six patients with severe hypercortisolism caused by adrenocorticotropic hormone–dependent Cushing’s syndrome.
Disclosures: The study was carried out with institutional funds. The presenter reported having no financial conflicts.
VIDEO: Use late-night salivary cortisol to catch recurrent Cushing’s
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ICE/ENDO 2014
VIDEO: Use late-night salivary cortisol to catch recurrent Cushing’s
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Late-night salivary cortisol exceeded normal limits in 10 women with recurrent Cushing’s disease a mean of 3.5 years after transsphenoidal surgery, but their urinary free cortisol remained in normal limits, according to a retrospective review from the Medical College of Wisconsin, Milwaukee.
That adds strength to the notion that late-night salivary cortisol (LNSC) catches recurrent Cushing’s that’s missed by urinary free cortisol, even though UFC remains a standard screening approach in some places.
The study is tiny and retrospective, but at the joint meeting of the International Congress of Endocrinology and the Endocrine Society, lead investigator Dr. Ty Carroll explained why the findings still matter, and also why two LNSC measurements are better than one.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ICE/ENDO 2014
Acromegaly: Look closely for sleep-disordered breathing
CHICAGO – Roughly 80% of patients with newly diagnosed and as-yet untreated acromegaly already have obstructive sleep apnea, according to the findings of what’s believed to be the largest-ever polysomnography study in such subjects.
Importantly, this study showed that the common practice of screening for sleep-disordered breathing with the Epworth Sleepiness Scale (ESS) and overnight oximetry to measure the desaturation index will greatly underdiagnose this important condition in patients with acromegaly. These are poor screening tools in this setting. They need to be supplemented by polysomnography, with the diagnosis of obstructive sleep apnea (OSA) hinging upon the finding of an abnormal apnea-hypopnea index, Dr. Andrew S. Powlson asserted at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Dr. Powlson of the University of Cambridge (U.K.), reported on 40 consecutive patients with newly diagnosed, treatment-naive acromegaly who were evaluated by the ESS, desaturation index, and polysomnography. The study’s purpose was to shed light on a controversy: Is sleep-disordered breathing an inherent feature of acromegaly or a secondary side effect of its treatment? The question takes on added clinical relevance in light of OSA’s known predisposition to premature cardiovascular and metabolic disease, motor vehicle accidents, and impaired quality of life.
Of the 40 patients, 31 (78%) met diagnostic criteria for OSA by polysomnography. The OSA was defined on the basis of the apnea-hypopnea index as mild in 12, moderate in 5, and severe in 14.
In contrast, the ESS performed dismally as a screening instrument: Only 12 of the 31 patients with OSA had an ESS score greater than 11, which is the standard threshold for further investigation. Moreover, measurement of the diffusion index during overnight oximetry identified only 21 patients as having OSA: 11 rated mild, 7 moderate, and 3 severe, as compared to 14 patients classified as having severe OSA by polysomnography.
Patients with acromegaly displayed an increased sleep arousal index and more periodic limb movements during sleep than in reference norms, which translates into marked disruption of the normal sleep cycle. Of note, however, polysomnography showed that sleep latency – that is, the time it takes to fall asleep – and total sleep time were normal in the acromegaly patients with OSA.
Instead, the predominant pattern was one of disrupted sleep architecture. Twenty-seven acromegaly patients spent longer than expected in stage-1 sleep, while the deeper sleep stages were dramatically diminished. Indeed, 26 patients had reduced stage-2 sleep, 31 had reduced REM sleep, and 26 had shortened slow wave sleep.
Dr. Powlson reported having no financial disclosures in connection with this study, conducted with institutional funds.
CHICAGO – Roughly 80% of patients with newly diagnosed and as-yet untreated acromegaly already have obstructive sleep apnea, according to the findings of what’s believed to be the largest-ever polysomnography study in such subjects.
Importantly, this study showed that the common practice of screening for sleep-disordered breathing with the Epworth Sleepiness Scale (ESS) and overnight oximetry to measure the desaturation index will greatly underdiagnose this important condition in patients with acromegaly. These are poor screening tools in this setting. They need to be supplemented by polysomnography, with the diagnosis of obstructive sleep apnea (OSA) hinging upon the finding of an abnormal apnea-hypopnea index, Dr. Andrew S. Powlson asserted at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Dr. Powlson of the University of Cambridge (U.K.), reported on 40 consecutive patients with newly diagnosed, treatment-naive acromegaly who were evaluated by the ESS, desaturation index, and polysomnography. The study’s purpose was to shed light on a controversy: Is sleep-disordered breathing an inherent feature of acromegaly or a secondary side effect of its treatment? The question takes on added clinical relevance in light of OSA’s known predisposition to premature cardiovascular and metabolic disease, motor vehicle accidents, and impaired quality of life.
Of the 40 patients, 31 (78%) met diagnostic criteria for OSA by polysomnography. The OSA was defined on the basis of the apnea-hypopnea index as mild in 12, moderate in 5, and severe in 14.
In contrast, the ESS performed dismally as a screening instrument: Only 12 of the 31 patients with OSA had an ESS score greater than 11, which is the standard threshold for further investigation. Moreover, measurement of the diffusion index during overnight oximetry identified only 21 patients as having OSA: 11 rated mild, 7 moderate, and 3 severe, as compared to 14 patients classified as having severe OSA by polysomnography.
Patients with acromegaly displayed an increased sleep arousal index and more periodic limb movements during sleep than in reference norms, which translates into marked disruption of the normal sleep cycle. Of note, however, polysomnography showed that sleep latency – that is, the time it takes to fall asleep – and total sleep time were normal in the acromegaly patients with OSA.
Instead, the predominant pattern was one of disrupted sleep architecture. Twenty-seven acromegaly patients spent longer than expected in stage-1 sleep, while the deeper sleep stages were dramatically diminished. Indeed, 26 patients had reduced stage-2 sleep, 31 had reduced REM sleep, and 26 had shortened slow wave sleep.
Dr. Powlson reported having no financial disclosures in connection with this study, conducted with institutional funds.
CHICAGO – Roughly 80% of patients with newly diagnosed and as-yet untreated acromegaly already have obstructive sleep apnea, according to the findings of what’s believed to be the largest-ever polysomnography study in such subjects.
Importantly, this study showed that the common practice of screening for sleep-disordered breathing with the Epworth Sleepiness Scale (ESS) and overnight oximetry to measure the desaturation index will greatly underdiagnose this important condition in patients with acromegaly. These are poor screening tools in this setting. They need to be supplemented by polysomnography, with the diagnosis of obstructive sleep apnea (OSA) hinging upon the finding of an abnormal apnea-hypopnea index, Dr. Andrew S. Powlson asserted at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
Dr. Powlson of the University of Cambridge (U.K.), reported on 40 consecutive patients with newly diagnosed, treatment-naive acromegaly who were evaluated by the ESS, desaturation index, and polysomnography. The study’s purpose was to shed light on a controversy: Is sleep-disordered breathing an inherent feature of acromegaly or a secondary side effect of its treatment? The question takes on added clinical relevance in light of OSA’s known predisposition to premature cardiovascular and metabolic disease, motor vehicle accidents, and impaired quality of life.
Of the 40 patients, 31 (78%) met diagnostic criteria for OSA by polysomnography. The OSA was defined on the basis of the apnea-hypopnea index as mild in 12, moderate in 5, and severe in 14.
In contrast, the ESS performed dismally as a screening instrument: Only 12 of the 31 patients with OSA had an ESS score greater than 11, which is the standard threshold for further investigation. Moreover, measurement of the diffusion index during overnight oximetry identified only 21 patients as having OSA: 11 rated mild, 7 moderate, and 3 severe, as compared to 14 patients classified as having severe OSA by polysomnography.
Patients with acromegaly displayed an increased sleep arousal index and more periodic limb movements during sleep than in reference norms, which translates into marked disruption of the normal sleep cycle. Of note, however, polysomnography showed that sleep latency – that is, the time it takes to fall asleep – and total sleep time were normal in the acromegaly patients with OSA.
Instead, the predominant pattern was one of disrupted sleep architecture. Twenty-seven acromegaly patients spent longer than expected in stage-1 sleep, while the deeper sleep stages were dramatically diminished. Indeed, 26 patients had reduced stage-2 sleep, 31 had reduced REM sleep, and 26 had shortened slow wave sleep.
Dr. Powlson reported having no financial disclosures in connection with this study, conducted with institutional funds.
AT ICE/ENDO 2014
Key clinical point: Reliance on the Epworth Sleepiness Scale and desaturation index on overnight oximetry to screen for OSA in patients with newly diagnosed acromegaly results in an unacceptable underdiagnosis rate.
Major finding: Thirty-one of 40 consecutive patients with de novo acromegaly had OSA on polysomnography.
Data source: Forty consecutive patients with newly diagnosed acromegaly underwent evaluation via the Epworth Sleepiness Scale, desaturation index, and polysomnography.
Disclosures: The presenter reported having no financial conflicts regarding this study, carried out with institutional funds.
New clinical practice guidelines on pheochromocytomas
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
AT ICE/ENDO 2014
Hypothyroid patients may need to surrender the car keys
CHICAGO – Hypothyroid patients exhibit objective cognitive deficits and motor slowing rendering them unsafe to operate a motor vehicle.
That’s the key take-home message from a longitudinal study in which 32 patients with thyroid cancer completed an extensive battery of neurocognitive and psychological tests as well as measured performance on a driving simulator at three time points: while euthyroid, again while temporarily hypothyroid as part of their cancer therapy and assessment, and finally while once again euthyroid after restoration of thyroid hormone therapy.
"These findings provide objective evidence warranting admonitions against operating motor vehicles for hypothyroid patients and confidence in removing such stipulations upon restoration of a euthyroid state," Dr. Kenneth B. Ain said at the joint meeting of the International Congress of Endocrinology and the Endocrine Society*.
In his own clinical practice he has long included a boxed warning against driving while hypothyroid on all of his written instructions to patients. But most physicians don’t warn their hypothyroid patients that they are driving impaired, nor do the joint practice guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists address the issue. That’s largely because there hasn’t been objective, quantitative evidence to provide firm support for such cautionary admonitions – until now, observed Dr. Ain, professor of medicine and director of the thyroid oncology program at the University of Kentucky, Lexington.
While hypothyroid, study participants experienced an 8.5% increase in braking time on a driving simulator. That’s equivalent to the degree of impairment other investigators have shown to be associated with a blood alcohol level of 82 mg/dL, which is above the legal driving limit in the United States.
"Once our study is published, a patient who is involved in an auto accident [in which] there is death or significant harm could be considered an impaired patient. And if physicians do not warn the patient of this risk, they would be considered an agent of harm. They could be liable for the consequences, the same as a neurologist who doesn’t warn a patient with a grand mal seizure disorder not to drive," Dr. Ain said.
In an interview, he noted that thyroid cancer patients undergoing thyroid hormone depletion temporarily as part of their treatment are merely a small fraction of the total impaired hypothyroid driver population. Investigators with the Framingham Heart Study have reported that 4.4% of individuals above age 60 are hypothyroid. Many of these individuals remain undiagnosed or undertreated. Plus, the noncompliance rate with levothyroxine therapy has been estimated at 17%-32%.
Moreover, once a patient is newly diagnosed as being profoundly hypothyroid and receives a prescription for thyroid hormone replacement, there is a lag time involved in achieving a euthyroid state. The half-life of levothyroxine is 1 week. It takes 6-8 weeks to reach a steady state. Probably at least 2 weeks of therapy are required before there is any improvement in the neurologic impairments documented in this study, Dr. Ain speculated.
"We’re really talking here about a public health problem, one that requires a public health response and acknowledgment that this is a danger," according to the endocrinologist.
Testing during the hypothyroid phase of the study showed significant declines in measures of executive function and information-processing speed. Fine motor performance of the hands was slowed by 13%. Mean scores on the Beck Depression Inventory deteriorated from 7.9 while euthyroid to 18.9 while hypothyroid, consistent with mild bordering on moderate depression; this depression was characterized by vegetative symptoms and altered mood, but without the impaired self-esteem and sense of guilt often characteristic of other forms of depression.
Dr. Ain reported receiving a research grant from Genzyme, which funded this study.
*Correction, 7/1/2014: An earlier version of this article misstated the name of the International Congress of Endocrinology.
CHICAGO – Hypothyroid patients exhibit objective cognitive deficits and motor slowing rendering them unsafe to operate a motor vehicle.
That’s the key take-home message from a longitudinal study in which 32 patients with thyroid cancer completed an extensive battery of neurocognitive and psychological tests as well as measured performance on a driving simulator at three time points: while euthyroid, again while temporarily hypothyroid as part of their cancer therapy and assessment, and finally while once again euthyroid after restoration of thyroid hormone therapy.
"These findings provide objective evidence warranting admonitions against operating motor vehicles for hypothyroid patients and confidence in removing such stipulations upon restoration of a euthyroid state," Dr. Kenneth B. Ain said at the joint meeting of the International Congress of Endocrinology and the Endocrine Society*.
In his own clinical practice he has long included a boxed warning against driving while hypothyroid on all of his written instructions to patients. But most physicians don’t warn their hypothyroid patients that they are driving impaired, nor do the joint practice guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists address the issue. That’s largely because there hasn’t been objective, quantitative evidence to provide firm support for such cautionary admonitions – until now, observed Dr. Ain, professor of medicine and director of the thyroid oncology program at the University of Kentucky, Lexington.
While hypothyroid, study participants experienced an 8.5% increase in braking time on a driving simulator. That’s equivalent to the degree of impairment other investigators have shown to be associated with a blood alcohol level of 82 mg/dL, which is above the legal driving limit in the United States.
"Once our study is published, a patient who is involved in an auto accident [in which] there is death or significant harm could be considered an impaired patient. And if physicians do not warn the patient of this risk, they would be considered an agent of harm. They could be liable for the consequences, the same as a neurologist who doesn’t warn a patient with a grand mal seizure disorder not to drive," Dr. Ain said.
In an interview, he noted that thyroid cancer patients undergoing thyroid hormone depletion temporarily as part of their treatment are merely a small fraction of the total impaired hypothyroid driver population. Investigators with the Framingham Heart Study have reported that 4.4% of individuals above age 60 are hypothyroid. Many of these individuals remain undiagnosed or undertreated. Plus, the noncompliance rate with levothyroxine therapy has been estimated at 17%-32%.
Moreover, once a patient is newly diagnosed as being profoundly hypothyroid and receives a prescription for thyroid hormone replacement, there is a lag time involved in achieving a euthyroid state. The half-life of levothyroxine is 1 week. It takes 6-8 weeks to reach a steady state. Probably at least 2 weeks of therapy are required before there is any improvement in the neurologic impairments documented in this study, Dr. Ain speculated.
"We’re really talking here about a public health problem, one that requires a public health response and acknowledgment that this is a danger," according to the endocrinologist.
Testing during the hypothyroid phase of the study showed significant declines in measures of executive function and information-processing speed. Fine motor performance of the hands was slowed by 13%. Mean scores on the Beck Depression Inventory deteriorated from 7.9 while euthyroid to 18.9 while hypothyroid, consistent with mild bordering on moderate depression; this depression was characterized by vegetative symptoms and altered mood, but without the impaired self-esteem and sense of guilt often characteristic of other forms of depression.
Dr. Ain reported receiving a research grant from Genzyme, which funded this study.
*Correction, 7/1/2014: An earlier version of this article misstated the name of the International Congress of Endocrinology.
CHICAGO – Hypothyroid patients exhibit objective cognitive deficits and motor slowing rendering them unsafe to operate a motor vehicle.
That’s the key take-home message from a longitudinal study in which 32 patients with thyroid cancer completed an extensive battery of neurocognitive and psychological tests as well as measured performance on a driving simulator at three time points: while euthyroid, again while temporarily hypothyroid as part of their cancer therapy and assessment, and finally while once again euthyroid after restoration of thyroid hormone therapy.
"These findings provide objective evidence warranting admonitions against operating motor vehicles for hypothyroid patients and confidence in removing such stipulations upon restoration of a euthyroid state," Dr. Kenneth B. Ain said at the joint meeting of the International Congress of Endocrinology and the Endocrine Society*.
In his own clinical practice he has long included a boxed warning against driving while hypothyroid on all of his written instructions to patients. But most physicians don’t warn their hypothyroid patients that they are driving impaired, nor do the joint practice guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists address the issue. That’s largely because there hasn’t been objective, quantitative evidence to provide firm support for such cautionary admonitions – until now, observed Dr. Ain, professor of medicine and director of the thyroid oncology program at the University of Kentucky, Lexington.
While hypothyroid, study participants experienced an 8.5% increase in braking time on a driving simulator. That’s equivalent to the degree of impairment other investigators have shown to be associated with a blood alcohol level of 82 mg/dL, which is above the legal driving limit in the United States.
"Once our study is published, a patient who is involved in an auto accident [in which] there is death or significant harm could be considered an impaired patient. And if physicians do not warn the patient of this risk, they would be considered an agent of harm. They could be liable for the consequences, the same as a neurologist who doesn’t warn a patient with a grand mal seizure disorder not to drive," Dr. Ain said.
In an interview, he noted that thyroid cancer patients undergoing thyroid hormone depletion temporarily as part of their treatment are merely a small fraction of the total impaired hypothyroid driver population. Investigators with the Framingham Heart Study have reported that 4.4% of individuals above age 60 are hypothyroid. Many of these individuals remain undiagnosed or undertreated. Plus, the noncompliance rate with levothyroxine therapy has been estimated at 17%-32%.
Moreover, once a patient is newly diagnosed as being profoundly hypothyroid and receives a prescription for thyroid hormone replacement, there is a lag time involved in achieving a euthyroid state. The half-life of levothyroxine is 1 week. It takes 6-8 weeks to reach a steady state. Probably at least 2 weeks of therapy are required before there is any improvement in the neurologic impairments documented in this study, Dr. Ain speculated.
"We’re really talking here about a public health problem, one that requires a public health response and acknowledgment that this is a danger," according to the endocrinologist.
Testing during the hypothyroid phase of the study showed significant declines in measures of executive function and information-processing speed. Fine motor performance of the hands was slowed by 13%. Mean scores on the Beck Depression Inventory deteriorated from 7.9 while euthyroid to 18.9 while hypothyroid, consistent with mild bordering on moderate depression; this depression was characterized by vegetative symptoms and altered mood, but without the impaired self-esteem and sense of guilt often characteristic of other forms of depression.
Dr. Ain reported receiving a research grant from Genzyme, which funded this study.
*Correction, 7/1/2014: An earlier version of this article misstated the name of the International Congress of Endocrinology.
AT ICE/ENDO 2014
Key clinical point: Hypothyroid patients are driving impaired. Physicians need to document, firmly cautioning them to that effect, or face possible liability concerns in the event of a serious motor vehicle accident.
Major finding: Hypothyroid patients showed an increased automobile braking time on a driving simulator that was equivalent to having a blood alcohol level above the U.S. legal driving limit.
Data source: A longitudinal study in which 32 thyroid cancer patients served as their own controls. They completed an extensive neurocognitive test battery and driving simulator performance test while euthyroid, then while temporarily hypothyroid as part of their cancer-treatment regimen, and once again after restoration to the euthyroid state.
Disclosures: Dr. Ain reported receiving a research grant from Genzyme, which funded this study.
Experimental lenvatinib extends PFS in iodine-refractory relapsed thyroid cancer
CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.
In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.
"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.
"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.
Dr. Masters moderated the briefing but was not involved in the study.
Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (131I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.
There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.
Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.
In a phase II study, the drug showed clinical activity against 131I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.
They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.
The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.
As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.
The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.
The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.
As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.
The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).
Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.
Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.
Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.
"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.
Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.
The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.
CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.
In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.
"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.
"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.
Dr. Masters moderated the briefing but was not involved in the study.
Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (131I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.
There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.
Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.
In a phase II study, the drug showed clinical activity against 131I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.
They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.
The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.
As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.
The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.
The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.
As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.
The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).
Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.
Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.
Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.
"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.
Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.
The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.
CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.
In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.
"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.
"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.
Dr. Masters moderated the briefing but was not involved in the study.
Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (131I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.
There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.
Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.
In a phase II study, the drug showed clinical activity against 131I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.
They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.
The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.
As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.
The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.
The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.
As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.
The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).
Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.
Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.
Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.
"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.
Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.
The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.
AT THE ASCO ANNUAL MEETING 2014
Key clinical finding: The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.
Major finding: Median progression-free survival for patients with relapsed iodine-refractory differentiated thyroid cancer was 18.3 months, compared with 3.6 months for patients on placebo.
Data source: Randomized, doubled-blind, placebo-controlled trial in 392 patients.
Disclosures: The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.
VIDEO: Abnormal endocrinology labs? Look beyond ‘usual suspects’
PHILADELPHIA – Psychiatric medications can affect prolactin levels, while antibodies can affect thyroid-stimulating hormone levels. Hirsutism may be the result of polycystic ovary syndrome – but it may also be caused by congenital adrenal hyperplasia.
And if that’s not confounding enough, physicians should add to the medical factors that can influence lab reports what Dr. Ellen L. Connor says is the importance of "knowing the typical ranges of the assays you are using, and what the ranges considered normal are at the [laboratory] you’re working with."
In a video interview at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Connor of the department of pediatric endocrinology at the University of Wisconsin, Madison, reviews what can change prolactin levels, how to get the most clinical utility out of thyroid tests, what is the gold standard for testosterone testing in women, how best to test and interpret vitamin D levels, and what adrenal malfunctions are possible in young women. She also stresses the value of working with knowledgeable lab personnel.
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On Twitter @whitneymcknight
PHILADELPHIA – Psychiatric medications can affect prolactin levels, while antibodies can affect thyroid-stimulating hormone levels. Hirsutism may be the result of polycystic ovary syndrome – but it may also be caused by congenital adrenal hyperplasia.
And if that’s not confounding enough, physicians should add to the medical factors that can influence lab reports what Dr. Ellen L. Connor says is the importance of "knowing the typical ranges of the assays you are using, and what the ranges considered normal are at the [laboratory] you’re working with."
In a video interview at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Connor of the department of pediatric endocrinology at the University of Wisconsin, Madison, reviews what can change prolactin levels, how to get the most clinical utility out of thyroid tests, what is the gold standard for testosterone testing in women, how best to test and interpret vitamin D levels, and what adrenal malfunctions are possible in young women. She also stresses the value of working with knowledgeable lab personnel.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @whitneymcknight
PHILADELPHIA – Psychiatric medications can affect prolactin levels, while antibodies can affect thyroid-stimulating hormone levels. Hirsutism may be the result of polycystic ovary syndrome – but it may also be caused by congenital adrenal hyperplasia.
And if that’s not confounding enough, physicians should add to the medical factors that can influence lab reports what Dr. Ellen L. Connor says is the importance of "knowing the typical ranges of the assays you are using, and what the ranges considered normal are at the [laboratory] you’re working with."
In a video interview at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Connor of the department of pediatric endocrinology at the University of Wisconsin, Madison, reviews what can change prolactin levels, how to get the most clinical utility out of thyroid tests, what is the gold standard for testosterone testing in women, how best to test and interpret vitamin D levels, and what adrenal malfunctions are possible in young women. She also stresses the value of working with knowledgeable lab personnel.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM NASPAG 2014
Comorbidities found to be drivers of thyroidectomy readmission risk
BOSTON – Preoperative comorbidities and postoperative complications are the most common reasons that patients are readmitted to a hospital within 30 days of thyroid or parathyroid surgery, but outpatient surgery was associated with a lower likelihood of readmission, investigators have found.
A review of data on more than 7,000 patients who underwent cervical endocrine resections showed that 4% were readmitted within a month of surgery, reported Dr. Matthew G. Mullen, a surgery resident at the University of Virginia Health System in Charlottesville.
"Identifying best practice patterns to avoid major postoperative complications will help reduce hospital readmission rates and improve the quality of patient care," Dr. Mullen said at the annual meeting of the American Association of Endocrine Surgeons.
Previous single-institution studies have shown readmission rates for patients undergoing thyroidectomy of 0.3%-3.9%. A 2010 study of readmission rates among elderly patients undergoing thyroidectomy for thyroid cancer found that 8% required readmission within a month of surgery, Dr. Mullen noted.
To see whether, as they suspected, patients with more medical comorbidities and postoperative complications are more likely to be back in the hospital within 30 days of surgery, the investigators reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) participant use data file, which includes records on 442,149 elective surgery cases from 315 U.S. hospitals. Data on a total of 7,069 total elective cases, including 3,711 thyroidectomies and 3,358 parathyroidectomies were reviewed.
They found an overall readmission rate of 4.0%, with a rate of 4.1% for patients undergoing thyroidectomy, and 3.8% for those undergoing parathyroidectomy.
Demographic factors significantly associated with a greater likelihood of readmission included diabetes (present in 18.6% of readmitted patients, vs. 12.5% of not readmitted patients; P = .003), severe chronic obstructive pulmonary disease (4.6% vs. 2.0%; P = .002), hemodialysis (11.8% vs. 2.2%; P = .001), and weight loss of more than 10% (1.8% vs. 0.5%; P = .005). Younger and heavier patients were more likely to be readmitted within 30 days than were slightly older and lighter-weight patients.
Complications predict readmission
Postoperative complications associated with readmission included wound complications (5% vs. 0.3%; P less than .001 for all following comparisons, unless noted), respiratory complications 5.4 vs. 0.2%), renal complications (2.1% vs. 0.3%), neurologic complications (0.7% vs. 0.1%; P = .008), and cardiovascular complications (4.6% vs. 0.2%).
In multivariate analysis, factors that were significantly associated with readmission were reoperation within 30 days (P less than .001), American Society of Anesthesiologists physical status class (P = .024), patient functional status (independent vs. partially or fully dependent, P = .007), renal insufficiency (P = .004), and hemodialysis (P = .005).
In contrast, patients who were discharged within 24 hours of surgery were significantly less likely to be readmitted (odds ratio, 0.63; P = .006).
The researchers also found that 63% of patients had a longer than 24-hour stay after surgery – a finding that Dr. Mullen said was surprising – and that patients undergoing surgery for malignant disease were significantly more likely to be readmitted than were patients with benign disease (11% vs. 2.6%, P less than .001). There was no difference in readmission rates of patients treated by general surgeons, compared with those treated by surgeons trained in otolaryngologic procedures.
Dr. Mullen noted that the study was limited by the lack of data on the reasons for each readmission and by a lack of information on many complications that are specific to endocrine surgery.
In the discussion, Dr. Samuel K. Snyder of Texas A & M University in Temple, commented on the lack of study specifics about the reasons for readmission making it hard to draw conclusions about how best to prevent readmissions.
Dr. Mullen responded that because some of the patients had treatable comorbidities such as renal insufficiency, medical augmentation could be a reasonable approach to reducing postoperative complications and risk of readmission.
The authors did not disclose the study funding source. Dr. Mullen and Dr. Snyder reported having no financial disclosures.
BOSTON – Preoperative comorbidities and postoperative complications are the most common reasons that patients are readmitted to a hospital within 30 days of thyroid or parathyroid surgery, but outpatient surgery was associated with a lower likelihood of readmission, investigators have found.
A review of data on more than 7,000 patients who underwent cervical endocrine resections showed that 4% were readmitted within a month of surgery, reported Dr. Matthew G. Mullen, a surgery resident at the University of Virginia Health System in Charlottesville.
"Identifying best practice patterns to avoid major postoperative complications will help reduce hospital readmission rates and improve the quality of patient care," Dr. Mullen said at the annual meeting of the American Association of Endocrine Surgeons.
Previous single-institution studies have shown readmission rates for patients undergoing thyroidectomy of 0.3%-3.9%. A 2010 study of readmission rates among elderly patients undergoing thyroidectomy for thyroid cancer found that 8% required readmission within a month of surgery, Dr. Mullen noted.
To see whether, as they suspected, patients with more medical comorbidities and postoperative complications are more likely to be back in the hospital within 30 days of surgery, the investigators reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) participant use data file, which includes records on 442,149 elective surgery cases from 315 U.S. hospitals. Data on a total of 7,069 total elective cases, including 3,711 thyroidectomies and 3,358 parathyroidectomies were reviewed.
They found an overall readmission rate of 4.0%, with a rate of 4.1% for patients undergoing thyroidectomy, and 3.8% for those undergoing parathyroidectomy.
Demographic factors significantly associated with a greater likelihood of readmission included diabetes (present in 18.6% of readmitted patients, vs. 12.5% of not readmitted patients; P = .003), severe chronic obstructive pulmonary disease (4.6% vs. 2.0%; P = .002), hemodialysis (11.8% vs. 2.2%; P = .001), and weight loss of more than 10% (1.8% vs. 0.5%; P = .005). Younger and heavier patients were more likely to be readmitted within 30 days than were slightly older and lighter-weight patients.
Complications predict readmission
Postoperative complications associated with readmission included wound complications (5% vs. 0.3%; P less than .001 for all following comparisons, unless noted), respiratory complications 5.4 vs. 0.2%), renal complications (2.1% vs. 0.3%), neurologic complications (0.7% vs. 0.1%; P = .008), and cardiovascular complications (4.6% vs. 0.2%).
In multivariate analysis, factors that were significantly associated with readmission were reoperation within 30 days (P less than .001), American Society of Anesthesiologists physical status class (P = .024), patient functional status (independent vs. partially or fully dependent, P = .007), renal insufficiency (P = .004), and hemodialysis (P = .005).
In contrast, patients who were discharged within 24 hours of surgery were significantly less likely to be readmitted (odds ratio, 0.63; P = .006).
The researchers also found that 63% of patients had a longer than 24-hour stay after surgery – a finding that Dr. Mullen said was surprising – and that patients undergoing surgery for malignant disease were significantly more likely to be readmitted than were patients with benign disease (11% vs. 2.6%, P less than .001). There was no difference in readmission rates of patients treated by general surgeons, compared with those treated by surgeons trained in otolaryngologic procedures.
Dr. Mullen noted that the study was limited by the lack of data on the reasons for each readmission and by a lack of information on many complications that are specific to endocrine surgery.
In the discussion, Dr. Samuel K. Snyder of Texas A & M University in Temple, commented on the lack of study specifics about the reasons for readmission making it hard to draw conclusions about how best to prevent readmissions.
Dr. Mullen responded that because some of the patients had treatable comorbidities such as renal insufficiency, medical augmentation could be a reasonable approach to reducing postoperative complications and risk of readmission.
The authors did not disclose the study funding source. Dr. Mullen and Dr. Snyder reported having no financial disclosures.
BOSTON – Preoperative comorbidities and postoperative complications are the most common reasons that patients are readmitted to a hospital within 30 days of thyroid or parathyroid surgery, but outpatient surgery was associated with a lower likelihood of readmission, investigators have found.
A review of data on more than 7,000 patients who underwent cervical endocrine resections showed that 4% were readmitted within a month of surgery, reported Dr. Matthew G. Mullen, a surgery resident at the University of Virginia Health System in Charlottesville.
"Identifying best practice patterns to avoid major postoperative complications will help reduce hospital readmission rates and improve the quality of patient care," Dr. Mullen said at the annual meeting of the American Association of Endocrine Surgeons.
Previous single-institution studies have shown readmission rates for patients undergoing thyroidectomy of 0.3%-3.9%. A 2010 study of readmission rates among elderly patients undergoing thyroidectomy for thyroid cancer found that 8% required readmission within a month of surgery, Dr. Mullen noted.
To see whether, as they suspected, patients with more medical comorbidities and postoperative complications are more likely to be back in the hospital within 30 days of surgery, the investigators reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) participant use data file, which includes records on 442,149 elective surgery cases from 315 U.S. hospitals. Data on a total of 7,069 total elective cases, including 3,711 thyroidectomies and 3,358 parathyroidectomies were reviewed.
They found an overall readmission rate of 4.0%, with a rate of 4.1% for patients undergoing thyroidectomy, and 3.8% for those undergoing parathyroidectomy.
Demographic factors significantly associated with a greater likelihood of readmission included diabetes (present in 18.6% of readmitted patients, vs. 12.5% of not readmitted patients; P = .003), severe chronic obstructive pulmonary disease (4.6% vs. 2.0%; P = .002), hemodialysis (11.8% vs. 2.2%; P = .001), and weight loss of more than 10% (1.8% vs. 0.5%; P = .005). Younger and heavier patients were more likely to be readmitted within 30 days than were slightly older and lighter-weight patients.
Complications predict readmission
Postoperative complications associated with readmission included wound complications (5% vs. 0.3%; P less than .001 for all following comparisons, unless noted), respiratory complications 5.4 vs. 0.2%), renal complications (2.1% vs. 0.3%), neurologic complications (0.7% vs. 0.1%; P = .008), and cardiovascular complications (4.6% vs. 0.2%).
In multivariate analysis, factors that were significantly associated with readmission were reoperation within 30 days (P less than .001), American Society of Anesthesiologists physical status class (P = .024), patient functional status (independent vs. partially or fully dependent, P = .007), renal insufficiency (P = .004), and hemodialysis (P = .005).
In contrast, patients who were discharged within 24 hours of surgery were significantly less likely to be readmitted (odds ratio, 0.63; P = .006).
The researchers also found that 63% of patients had a longer than 24-hour stay after surgery – a finding that Dr. Mullen said was surprising – and that patients undergoing surgery for malignant disease were significantly more likely to be readmitted than were patients with benign disease (11% vs. 2.6%, P less than .001). There was no difference in readmission rates of patients treated by general surgeons, compared with those treated by surgeons trained in otolaryngologic procedures.
Dr. Mullen noted that the study was limited by the lack of data on the reasons for each readmission and by a lack of information on many complications that are specific to endocrine surgery.
In the discussion, Dr. Samuel K. Snyder of Texas A & M University in Temple, commented on the lack of study specifics about the reasons for readmission making it hard to draw conclusions about how best to prevent readmissions.
Dr. Mullen responded that because some of the patients had treatable comorbidities such as renal insufficiency, medical augmentation could be a reasonable approach to reducing postoperative complications and risk of readmission.
The authors did not disclose the study funding source. Dr. Mullen and Dr. Snyder reported having no financial disclosures.
AT AAES 2014
Major finding: Comorbidities associated with hospital readmission were diabetes (18.6% of readmitted patients, vs. 12.5% of not readmitted patients), severe COPD (4.6% vs. 2.0%), hemodialysis (11.8% vs. 2.2%), and weight loss of more than 10% (1.8% vs. 0.5%).
Data source: Retrospective review of data on 7,069 patients undergoing elective thyroidectomy or parathyroidectomy.
Disclosures: The authors did not disclose the study funding source. Dr. Mullen and Dr. Snyder reported having no financial disclosures.
Lobectomy suffices for surgery of small papillary thyroid cancers
BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.
Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.
"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.
Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.
"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."
The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.
The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.
Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.
"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."
Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.
"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.
Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.
"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."
The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).
In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.
The complete manuscript of this study and its presentation at the American Surgical Association’s 134th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.
The authors reported no conflicting interests
This excellent study by Adam et al. contributes to a growing body of literature supporting thyroid lobectomy for low risk, small, differentiated thyroid tumors. I should say this represents a shift back toward lobectomy. Total thyroidectomy became the procedure of choice for nearly all differentiated thyroid tumors over the last 2-3 decades in part because of the landmark study by Bilimoria et al. (Surgery 2007;142:906-14).
Now the tide is shifting back the other direction.
I do not mean to imply that passing trends drive how we treat thyroid cancer. Mortality rates from differentiated thyroid cancer remain extremely low. This makes measuring any differences in mortality challenging. The outcome can differ depending on the cohort and the other variables included in the modeling. Recurrence is the real driver of morbidity in thyroid cancer, with anywhere from 10%-30% of patients experiencing a recurrence. Unfortunately, large national cancer registries do not capture recurrence very well.
This study controlled for many tumor features that will also impact disease specific survival apart from just the treatment received. The follow-up time is also impressive. So, if we are to undertake a more nuanced and stratified approach to determining the extent of surgery, there are a few things to consider. The first is patient selection.
In this study and in a growing body of retrospective, single institution studies looking at lobectomy for low-risk cancers, one must remember that these patients are selected based on other tumor features (multifocality, extrathyroidal extension, etc.) and not just size alone. Remember that 30%-40% of patients with papillary thyroid cancer will have multifocal disease.
The second is that successfully treating thyroid cancer patients with lobectomy requires buy-in from all parties involved - surgeons, endocrinologists, and, most importantly, the patient. Everyone must be comfortable with omitting radioactive iodine, detectable thyroglobulin levels, and following the remaining lobe with ultrasound. Some patients will not be comfortable with this and may choose to undergo total thyroidectomy. Even if we surgeons agree to shift back toward less aggressive surgery, we cannot do so in isolation.
Dr. David F. Schneider is an associate professor and the director of endocrine surgery research in the department of surgery, University of Wisconsin, Madison. He has no conflicts to disclose.
This excellent study by Adam et al. contributes to a growing body of literature supporting thyroid lobectomy for low risk, small, differentiated thyroid tumors. I should say this represents a shift back toward lobectomy. Total thyroidectomy became the procedure of choice for nearly all differentiated thyroid tumors over the last 2-3 decades in part because of the landmark study by Bilimoria et al. (Surgery 2007;142:906-14).
Now the tide is shifting back the other direction.
I do not mean to imply that passing trends drive how we treat thyroid cancer. Mortality rates from differentiated thyroid cancer remain extremely low. This makes measuring any differences in mortality challenging. The outcome can differ depending on the cohort and the other variables included in the modeling. Recurrence is the real driver of morbidity in thyroid cancer, with anywhere from 10%-30% of patients experiencing a recurrence. Unfortunately, large national cancer registries do not capture recurrence very well.
This study controlled for many tumor features that will also impact disease specific survival apart from just the treatment received. The follow-up time is also impressive. So, if we are to undertake a more nuanced and stratified approach to determining the extent of surgery, there are a few things to consider. The first is patient selection.
In this study and in a growing body of retrospective, single institution studies looking at lobectomy for low-risk cancers, one must remember that these patients are selected based on other tumor features (multifocality, extrathyroidal extension, etc.) and not just size alone. Remember that 30%-40% of patients with papillary thyroid cancer will have multifocal disease.
The second is that successfully treating thyroid cancer patients with lobectomy requires buy-in from all parties involved - surgeons, endocrinologists, and, most importantly, the patient. Everyone must be comfortable with omitting radioactive iodine, detectable thyroglobulin levels, and following the remaining lobe with ultrasound. Some patients will not be comfortable with this and may choose to undergo total thyroidectomy. Even if we surgeons agree to shift back toward less aggressive surgery, we cannot do so in isolation.
Dr. David F. Schneider is an associate professor and the director of endocrine surgery research in the department of surgery, University of Wisconsin, Madison. He has no conflicts to disclose.
This excellent study by Adam et al. contributes to a growing body of literature supporting thyroid lobectomy for low risk, small, differentiated thyroid tumors. I should say this represents a shift back toward lobectomy. Total thyroidectomy became the procedure of choice for nearly all differentiated thyroid tumors over the last 2-3 decades in part because of the landmark study by Bilimoria et al. (Surgery 2007;142:906-14).
Now the tide is shifting back the other direction.
I do not mean to imply that passing trends drive how we treat thyroid cancer. Mortality rates from differentiated thyroid cancer remain extremely low. This makes measuring any differences in mortality challenging. The outcome can differ depending on the cohort and the other variables included in the modeling. Recurrence is the real driver of morbidity in thyroid cancer, with anywhere from 10%-30% of patients experiencing a recurrence. Unfortunately, large national cancer registries do not capture recurrence very well.
This study controlled for many tumor features that will also impact disease specific survival apart from just the treatment received. The follow-up time is also impressive. So, if we are to undertake a more nuanced and stratified approach to determining the extent of surgery, there are a few things to consider. The first is patient selection.
In this study and in a growing body of retrospective, single institution studies looking at lobectomy for low-risk cancers, one must remember that these patients are selected based on other tumor features (multifocality, extrathyroidal extension, etc.) and not just size alone. Remember that 30%-40% of patients with papillary thyroid cancer will have multifocal disease.
The second is that successfully treating thyroid cancer patients with lobectomy requires buy-in from all parties involved - surgeons, endocrinologists, and, most importantly, the patient. Everyone must be comfortable with omitting radioactive iodine, detectable thyroglobulin levels, and following the remaining lobe with ultrasound. Some patients will not be comfortable with this and may choose to undergo total thyroidectomy. Even if we surgeons agree to shift back toward less aggressive surgery, we cannot do so in isolation.
Dr. David F. Schneider is an associate professor and the director of endocrine surgery research in the department of surgery, University of Wisconsin, Madison. He has no conflicts to disclose.
BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.
Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.
"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.
Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.
"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."
The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.
The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.
Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.
"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."
Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.
"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.
Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.
"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."
The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).
In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.
The complete manuscript of this study and its presentation at the American Surgical Association’s 134th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.
The authors reported no conflicting interests
BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.
Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.
"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.
Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.
"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."
The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.
The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.
Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.
"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."
Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.
"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.
Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.
"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."
The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).
In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.
The complete manuscript of this study and its presentation at the American Surgical Association’s 134th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.
The authors reported no conflicting interests
AT THE ASA ANNUAL MEETING
Major finding: After adjustment, total thyroidectomy did not improve overall survival over lobectomy for tumors 1-2 cm (HR, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21).
Data source: A retrospective database analysis of 61,775 papillary thyroid cancers.
Disclosures: The authors reported no conflicting interests.
