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U.S. pancreatic insufficiency patients often get inadequate enzyme replacement
WASHINGTON – according to a recent analysis of insurance claims data from more than 48 million Americans.
Amid concerns that some people with nonspecific symptoms are overdiagnosed with exocrine pancreatic insufficiency (EPI) and hence getting unneeded treatment with pancreatic enzyme replacement therapy (PERT), it seems like substantial numbers of patients with legitimate pancreatic morbidity are often missed and are going untreated, Chris E. Forsmark, MD, said at the annual Digestive Disease Week®. This includes patients with chronic pancreatitis, pancreatic cancer, and patients who underwent pancreatic resection surgery.
Dr. Forsmark cited still-unpublished evidence that he has reported at meetings during the past year. At DDW 2017 he and his associates reported findings from an analysis of health insurance claims data collected in the PharMetrics database for more than 48 million Americans during 2006-2013, which included 37,061 insured adults diagnosed with chronic pancreatitis. Analysis of these data showed that just 7% had ever undergone testing for EPI and 30% had received a prescription for PERT, of which only 31% received an appropriate dosage (Gastroenterology. 2017 Apr;152[5, suppl 1]:S677). In other words, a scant 9% of insured U.S. adults with chronic pancreatitis during the studied period had received a minimally effective dosage of PERT.
Dr. Forsmark and his associates ran a second analysis using the same 2006-2013 insurance database, but this time looked at 32,461 insured American adults diagnosed with pancreatic cancer and reported similar findings: Fewer than 2% of patients underwent testing for EPI, 22% were prescribed PERT, and of these, 22% of patients per quarter received a minimally effective dosage of PERT, meaning that, overall, only 6% of pancreatic cancer patients received treatment that could be expected to resolve their presumed enzyme deficiency. Dr. Forsmark and his associates presented this report at the annual meeting of the American Pancreatic Association in San Diego in November 2017 (Pancreas. 2017 Nov/Dec;46[10]:1386-1448).
An irony is that PERT underuse comes at a time when some Internet sites promote PERT as a treatment for patients with nonspecific symptoms of EPI such as bloating, dyspepsia, and loose stools, Dr. Forsmark noted. “There is a possibility that patients with nonspecific gastrointestinal symptoms may request or receive PERT. Some patients may receive PERT who do not have EPI.” In 2015, clinicians had written roughly 746,000 prescriptions for PERT to U.S. patients, with the number of prescriptions steadily increasing during 2010-2015. Five different formulations for PERT are currently on the U.S. market, and a typical course of treatment costs about $1,500-$2,000 per month, he added.
Dr. Forsmark had no disclosures to report.
WASHINGTON – according to a recent analysis of insurance claims data from more than 48 million Americans.
Amid concerns that some people with nonspecific symptoms are overdiagnosed with exocrine pancreatic insufficiency (EPI) and hence getting unneeded treatment with pancreatic enzyme replacement therapy (PERT), it seems like substantial numbers of patients with legitimate pancreatic morbidity are often missed and are going untreated, Chris E. Forsmark, MD, said at the annual Digestive Disease Week®. This includes patients with chronic pancreatitis, pancreatic cancer, and patients who underwent pancreatic resection surgery.
Dr. Forsmark cited still-unpublished evidence that he has reported at meetings during the past year. At DDW 2017 he and his associates reported findings from an analysis of health insurance claims data collected in the PharMetrics database for more than 48 million Americans during 2006-2013, which included 37,061 insured adults diagnosed with chronic pancreatitis. Analysis of these data showed that just 7% had ever undergone testing for EPI and 30% had received a prescription for PERT, of which only 31% received an appropriate dosage (Gastroenterology. 2017 Apr;152[5, suppl 1]:S677). In other words, a scant 9% of insured U.S. adults with chronic pancreatitis during the studied period had received a minimally effective dosage of PERT.
Dr. Forsmark and his associates ran a second analysis using the same 2006-2013 insurance database, but this time looked at 32,461 insured American adults diagnosed with pancreatic cancer and reported similar findings: Fewer than 2% of patients underwent testing for EPI, 22% were prescribed PERT, and of these, 22% of patients per quarter received a minimally effective dosage of PERT, meaning that, overall, only 6% of pancreatic cancer patients received treatment that could be expected to resolve their presumed enzyme deficiency. Dr. Forsmark and his associates presented this report at the annual meeting of the American Pancreatic Association in San Diego in November 2017 (Pancreas. 2017 Nov/Dec;46[10]:1386-1448).
An irony is that PERT underuse comes at a time when some Internet sites promote PERT as a treatment for patients with nonspecific symptoms of EPI such as bloating, dyspepsia, and loose stools, Dr. Forsmark noted. “There is a possibility that patients with nonspecific gastrointestinal symptoms may request or receive PERT. Some patients may receive PERT who do not have EPI.” In 2015, clinicians had written roughly 746,000 prescriptions for PERT to U.S. patients, with the number of prescriptions steadily increasing during 2010-2015. Five different formulations for PERT are currently on the U.S. market, and a typical course of treatment costs about $1,500-$2,000 per month, he added.
Dr. Forsmark had no disclosures to report.
WASHINGTON – according to a recent analysis of insurance claims data from more than 48 million Americans.
Amid concerns that some people with nonspecific symptoms are overdiagnosed with exocrine pancreatic insufficiency (EPI) and hence getting unneeded treatment with pancreatic enzyme replacement therapy (PERT), it seems like substantial numbers of patients with legitimate pancreatic morbidity are often missed and are going untreated, Chris E. Forsmark, MD, said at the annual Digestive Disease Week®. This includes patients with chronic pancreatitis, pancreatic cancer, and patients who underwent pancreatic resection surgery.
Dr. Forsmark cited still-unpublished evidence that he has reported at meetings during the past year. At DDW 2017 he and his associates reported findings from an analysis of health insurance claims data collected in the PharMetrics database for more than 48 million Americans during 2006-2013, which included 37,061 insured adults diagnosed with chronic pancreatitis. Analysis of these data showed that just 7% had ever undergone testing for EPI and 30% had received a prescription for PERT, of which only 31% received an appropriate dosage (Gastroenterology. 2017 Apr;152[5, suppl 1]:S677). In other words, a scant 9% of insured U.S. adults with chronic pancreatitis during the studied period had received a minimally effective dosage of PERT.
Dr. Forsmark and his associates ran a second analysis using the same 2006-2013 insurance database, but this time looked at 32,461 insured American adults diagnosed with pancreatic cancer and reported similar findings: Fewer than 2% of patients underwent testing for EPI, 22% were prescribed PERT, and of these, 22% of patients per quarter received a minimally effective dosage of PERT, meaning that, overall, only 6% of pancreatic cancer patients received treatment that could be expected to resolve their presumed enzyme deficiency. Dr. Forsmark and his associates presented this report at the annual meeting of the American Pancreatic Association in San Diego in November 2017 (Pancreas. 2017 Nov/Dec;46[10]:1386-1448).
An irony is that PERT underuse comes at a time when some Internet sites promote PERT as a treatment for patients with nonspecific symptoms of EPI such as bloating, dyspepsia, and loose stools, Dr. Forsmark noted. “There is a possibility that patients with nonspecific gastrointestinal symptoms may request or receive PERT. Some patients may receive PERT who do not have EPI.” In 2015, clinicians had written roughly 746,000 prescriptions for PERT to U.S. patients, with the number of prescriptions steadily increasing during 2010-2015. Five different formulations for PERT are currently on the U.S. market, and a typical course of treatment costs about $1,500-$2,000 per month, he added.
Dr. Forsmark had no disclosures to report.
REPORTING FROM DDW 2018
Key clinical point: U.S. patients with presumed exocrine pancreatic insufficiency often appear undertreated.
Major finding: During 2006-2013, only 9% of U.S. adults with chronic pancreatitis and 6% with pancreatic cancer received adequate enzyme replacement.
Study details: A review of diagnosis and claims data from 48.67 million insured U.S. adults during 2006-2013.
Disclosures: Dr. Forsmark had no disclosures to report.
Pancreatic cancer has a pancreatopathy distinct from type 2 diabetes
WASHINGTON –
“The endocrinopathies associated with type 2 diabetes mellitus and pancreatic cancer are distinct, the former represented by an increase in glucagon and the latter characterized by a reduction in islet size,” said Sajan Nagpal, MD, of the Mayo Clinic in Rochester, Minn., at Digestive Disease Week 2018®. “These data lend insight to a unique pathophysiology of diabetes that results from pancreatic cancer.”
Prior to presenting his results, Dr. Nagpal pointed out an interesting relationship between pancreatic cancer and diabetes.
“Pancreatic cancer and diabetes have a very unique, two-way relationship. While long-standing diabetes [LSDM] increases the risk of developing pancreatic cancer by 1.5-2 times over a person’s lifetime, pancreatic cancer itself causes a paraneoplastic form of diabetes. A person with a new diagnosis of diabetes mellitus has a five to eight times increased risk of being diagnosed with pancreatic cancer as compared to the general population within 3 years.“
This form of diabetes is referred to as pancreatic cancer–induced new onset diabetes (PC-NOD).
Dr. Nagpal and his team conducted a study that included 46 patients: 16 patients with pancreatic cancer (5 with LSDM, 5 NOD, and 6 without diabetes mellitus), 15 patients with T2DM (9 LSDM, 6 NOD), and 15 controls matched for age and body mass index. NOD was defined as a diabetes mellitus diagnosis less than 3 years from the date of autopsy or pancreatic cancer diagnosis. All pancreatic specimens were resected from pancreatic cancer patients or obtained as autopsy specimens. Researchers performed islet morphometric studies utilizing immunofluorescence analysis with specific insulin and glucagon antibodies.
The results of the study showed that patients with pancreatic cancer had islet sizes that were about a third smaller than those in the patients with T2DM and the healthy controls (P = .005). This held true for both LSDM and NOD pancreatic cancer patients, compared with the T2DM and healthy control groups. Researchers also found that insulin to glucagon (I:G) ratios were preserved in pancreatic cancer patients, whereas they were lower in patients with T2DM because of a higher percentage of glucagon in the islets (P = .08). Additionally, islet amyloid was much higher in T2DM patients (66.7%) versus patients with diabetes associated with pancreatic cancer (55.6%) and healthy controls (13.3%; P = .01).
There were several limitations to this study, including the small number of patients in each group and how pancreatic islet characteristics can vary based on their location. Finally, ductal obstruction can cause changes to islet morphology.
Along with the pathological changes found by Dr. Nagpal and his research team, PC-NOD and T2DM also have unique clinical profiles. As patients with pancreatic cancer approach their diagnosis, they begin to lose weight. This begins about 1 year before the patient’s diagnosis of pancreatic cancer. Conversely, these patients have worsening fasting glucose levels despite the fact that they are losing weight. The paradoxical relationship between weight loss and hyperglycemia are what distinguishes PC-NOD from T2DM, according to Dr. Nagpal. In patients with PC-NOD, worsening hyperglycemia happens over a periods of months, compared with the gradual increase over the course of years seen in T2DM.
The differences between these diseases may be caused by differences in their pancreatopathy.
When discussing the pancreatopathy associated with T2DM, Dr. Nagpal pointed out that there is a decrease in the I:G ratio, compared with those seen in patients without diabetes. The prevailing theory is that this decrease in the I:G ratio is caused by beta-cell apoptosis and transdifferentiation to alpha-cells. T2DM patients also have increased amyloid deposits, the result of increased islet amyloid polypeptide.
”Pancreatic cancer provides subtle metabolic clues, such as worsening glucose tolerance and weight loss, that can serve as potential targets for its early detection.”
According to Dr. Nagpal, more research is needed on pathogenesis of PC-NOD. Identification of biomarkers for screening may be possible in patients with new onset diabetes.
Dr. Nagpal had no financial conflicts of interest to report.
SOURCE: Nagpal S et al. DDW 2018, Abstract 392.
WASHINGTON –
“The endocrinopathies associated with type 2 diabetes mellitus and pancreatic cancer are distinct, the former represented by an increase in glucagon and the latter characterized by a reduction in islet size,” said Sajan Nagpal, MD, of the Mayo Clinic in Rochester, Minn., at Digestive Disease Week 2018®. “These data lend insight to a unique pathophysiology of diabetes that results from pancreatic cancer.”
Prior to presenting his results, Dr. Nagpal pointed out an interesting relationship between pancreatic cancer and diabetes.
“Pancreatic cancer and diabetes have a very unique, two-way relationship. While long-standing diabetes [LSDM] increases the risk of developing pancreatic cancer by 1.5-2 times over a person’s lifetime, pancreatic cancer itself causes a paraneoplastic form of diabetes. A person with a new diagnosis of diabetes mellitus has a five to eight times increased risk of being diagnosed with pancreatic cancer as compared to the general population within 3 years.“
This form of diabetes is referred to as pancreatic cancer–induced new onset diabetes (PC-NOD).
Dr. Nagpal and his team conducted a study that included 46 patients: 16 patients with pancreatic cancer (5 with LSDM, 5 NOD, and 6 without diabetes mellitus), 15 patients with T2DM (9 LSDM, 6 NOD), and 15 controls matched for age and body mass index. NOD was defined as a diabetes mellitus diagnosis less than 3 years from the date of autopsy or pancreatic cancer diagnosis. All pancreatic specimens were resected from pancreatic cancer patients or obtained as autopsy specimens. Researchers performed islet morphometric studies utilizing immunofluorescence analysis with specific insulin and glucagon antibodies.
The results of the study showed that patients with pancreatic cancer had islet sizes that were about a third smaller than those in the patients with T2DM and the healthy controls (P = .005). This held true for both LSDM and NOD pancreatic cancer patients, compared with the T2DM and healthy control groups. Researchers also found that insulin to glucagon (I:G) ratios were preserved in pancreatic cancer patients, whereas they were lower in patients with T2DM because of a higher percentage of glucagon in the islets (P = .08). Additionally, islet amyloid was much higher in T2DM patients (66.7%) versus patients with diabetes associated with pancreatic cancer (55.6%) and healthy controls (13.3%; P = .01).
There were several limitations to this study, including the small number of patients in each group and how pancreatic islet characteristics can vary based on their location. Finally, ductal obstruction can cause changes to islet morphology.
Along with the pathological changes found by Dr. Nagpal and his research team, PC-NOD and T2DM also have unique clinical profiles. As patients with pancreatic cancer approach their diagnosis, they begin to lose weight. This begins about 1 year before the patient’s diagnosis of pancreatic cancer. Conversely, these patients have worsening fasting glucose levels despite the fact that they are losing weight. The paradoxical relationship between weight loss and hyperglycemia are what distinguishes PC-NOD from T2DM, according to Dr. Nagpal. In patients with PC-NOD, worsening hyperglycemia happens over a periods of months, compared with the gradual increase over the course of years seen in T2DM.
The differences between these diseases may be caused by differences in their pancreatopathy.
When discussing the pancreatopathy associated with T2DM, Dr. Nagpal pointed out that there is a decrease in the I:G ratio, compared with those seen in patients without diabetes. The prevailing theory is that this decrease in the I:G ratio is caused by beta-cell apoptosis and transdifferentiation to alpha-cells. T2DM patients also have increased amyloid deposits, the result of increased islet amyloid polypeptide.
”Pancreatic cancer provides subtle metabolic clues, such as worsening glucose tolerance and weight loss, that can serve as potential targets for its early detection.”
According to Dr. Nagpal, more research is needed on pathogenesis of PC-NOD. Identification of biomarkers for screening may be possible in patients with new onset diabetes.
Dr. Nagpal had no financial conflicts of interest to report.
SOURCE: Nagpal S et al. DDW 2018, Abstract 392.
WASHINGTON –
“The endocrinopathies associated with type 2 diabetes mellitus and pancreatic cancer are distinct, the former represented by an increase in glucagon and the latter characterized by a reduction in islet size,” said Sajan Nagpal, MD, of the Mayo Clinic in Rochester, Minn., at Digestive Disease Week 2018®. “These data lend insight to a unique pathophysiology of diabetes that results from pancreatic cancer.”
Prior to presenting his results, Dr. Nagpal pointed out an interesting relationship between pancreatic cancer and diabetes.
“Pancreatic cancer and diabetes have a very unique, two-way relationship. While long-standing diabetes [LSDM] increases the risk of developing pancreatic cancer by 1.5-2 times over a person’s lifetime, pancreatic cancer itself causes a paraneoplastic form of diabetes. A person with a new diagnosis of diabetes mellitus has a five to eight times increased risk of being diagnosed with pancreatic cancer as compared to the general population within 3 years.“
This form of diabetes is referred to as pancreatic cancer–induced new onset diabetes (PC-NOD).
Dr. Nagpal and his team conducted a study that included 46 patients: 16 patients with pancreatic cancer (5 with LSDM, 5 NOD, and 6 without diabetes mellitus), 15 patients with T2DM (9 LSDM, 6 NOD), and 15 controls matched for age and body mass index. NOD was defined as a diabetes mellitus diagnosis less than 3 years from the date of autopsy or pancreatic cancer diagnosis. All pancreatic specimens were resected from pancreatic cancer patients or obtained as autopsy specimens. Researchers performed islet morphometric studies utilizing immunofluorescence analysis with specific insulin and glucagon antibodies.
The results of the study showed that patients with pancreatic cancer had islet sizes that were about a third smaller than those in the patients with T2DM and the healthy controls (P = .005). This held true for both LSDM and NOD pancreatic cancer patients, compared with the T2DM and healthy control groups. Researchers also found that insulin to glucagon (I:G) ratios were preserved in pancreatic cancer patients, whereas they were lower in patients with T2DM because of a higher percentage of glucagon in the islets (P = .08). Additionally, islet amyloid was much higher in T2DM patients (66.7%) versus patients with diabetes associated with pancreatic cancer (55.6%) and healthy controls (13.3%; P = .01).
There were several limitations to this study, including the small number of patients in each group and how pancreatic islet characteristics can vary based on their location. Finally, ductal obstruction can cause changes to islet morphology.
Along with the pathological changes found by Dr. Nagpal and his research team, PC-NOD and T2DM also have unique clinical profiles. As patients with pancreatic cancer approach their diagnosis, they begin to lose weight. This begins about 1 year before the patient’s diagnosis of pancreatic cancer. Conversely, these patients have worsening fasting glucose levels despite the fact that they are losing weight. The paradoxical relationship between weight loss and hyperglycemia are what distinguishes PC-NOD from T2DM, according to Dr. Nagpal. In patients with PC-NOD, worsening hyperglycemia happens over a periods of months, compared with the gradual increase over the course of years seen in T2DM.
The differences between these diseases may be caused by differences in their pancreatopathy.
When discussing the pancreatopathy associated with T2DM, Dr. Nagpal pointed out that there is a decrease in the I:G ratio, compared with those seen in patients without diabetes. The prevailing theory is that this decrease in the I:G ratio is caused by beta-cell apoptosis and transdifferentiation to alpha-cells. T2DM patients also have increased amyloid deposits, the result of increased islet amyloid polypeptide.
”Pancreatic cancer provides subtle metabolic clues, such as worsening glucose tolerance and weight loss, that can serve as potential targets for its early detection.”
According to Dr. Nagpal, more research is needed on pathogenesis of PC-NOD. Identification of biomarkers for screening may be possible in patients with new onset diabetes.
Dr. Nagpal had no financial conflicts of interest to report.
SOURCE: Nagpal S et al. DDW 2018, Abstract 392.
REPORTING FROM DDW 2018
Key clinical point: Pancreatic cancer has a distinct endocrine pancreatopathy.
Major finding: Patients with pancreatic cancer had islet sizes that were about a third smaller than those in patients with type 2 diabetes and healthy controls (P = .005).
Study details: Small study analyzing the pathology of pancreatic cancer resections and autopsy specimens.
Disclosures: The authors of this study had no financial conflicts to disclose.
Source: Nagpal S et al. DDW 2018, Abstract 392.
Diabetes from checkpoint inhibitors probably means lifelong insulin
CHICAGO – , according to Priyanka Iyer, MD, an endocrinology fellow at MD Anderson Cancer Center, Houston.
“As long as we get glycemic control, they can continue,” she said at the annual meeting of the Endocrine Society.
Diabetes is a known side effect of immune checkpoint inhibitors (ICIs) but it’s rare, occurring in maybe 0.17% of patients, and its natural history and risk factors are unknown.
ICIs are fairly new agents, and as their use expands beyond clinical trials, “we anticipate seeing larger numbers of cases. Patients should be educated about the symptoms of uncontrolled blood sugars while on ICIs,” and endocrinologists “have to get involved and recognize this entity sooner,” Dr. Iyer said.
In short, her team found that ICI-mediated diabetes can occur in patients with or without preexisting diabetes, and that most patients have evidence of beta-cell failure, likely T-cell mediated destruction due to immune activation. In all but one case, patients remained on insulin at a median follow-up of 44 weeks, even after stopping ICIs. For most, ICI-mediated diabetes likely means lifelong insulin.
They were all on the programmed cell death protein (PD-1) inhibitors nivolumab (Opdivo) or pembrolizumab (Keytruda), or the PD-1 ligand (PD-L) inhibitor durvalumab (Imfinzi). The agents are used for a range of cancers, including renal cell, melanoma, and Hodgkin lymphoma. There were no diabetes cases in patients on single-agent ipilimumab (Yervoy) or tremelimumab, which target cytotoxic T-lymphocyte associated antigen-4 and are used for melanoma and mesothelioma.
Median time to diabetes presentation after the start of ICI treatment was 12.3 weeks but ranged from 1 to 67.2 weeks. Half of the cases presented in diabetic ketoacidosis (DKA). Patients had upward trending hyperglycemia and most had diabetes symptoms for a while before diagnosis. They presented with a blood glucose above 250 mg/dL, and more than half above 500 mg/dL. Median hemoglobin A1c at presentation was 8%, but ranged up to 12.5%.
Every patient required insulin, including the six that discontinued ICIs after developing diabetes. Diabetes resolved in just one patient at 10.2 months; she presented with DKA.
There were no obvious predisposing factors. None of the patients had histories of type 1 diabetes or other autoimmune disease. Five patients had well-controlled type 2 diabetes prior to ICI initiation; four had prediabetes. Some had family members with type 2 diabetes, but not type 1. Four had prior ICI exposure. Just three patients were on concomitant steroids.
A few patients also developed thyroid or pituitary dysfunction, which are more common side effects of ICIs.
The median age at diabetes presentation was 61 years and ranged from 32 to 82 years. The majority of patients were men, which reflects MD Anderson demographics, not a predisposing risk factor, Dr. Iyer said.
Melanoma was the most common cancer, followed by renal cell and prostate; patients had stage 2-4 disease. About half the subjects were on single agent anti-PD-1 treatment, about a third on anti-PD-1 combination treatment, and the rest on anti-PD-L1 combination therapy. C-peptide levels were below 0.9 ng/mL at diabetes diagnosis in most of the patients. Eleven of the 20 tested (55%) were positive for the pancreatic islet cell antibody GAD65.
The investigators had no disclosures. A funding source was not reported.
SOURCE: Iyer PC et al. Abstract OR05-5.
CHICAGO – , according to Priyanka Iyer, MD, an endocrinology fellow at MD Anderson Cancer Center, Houston.
“As long as we get glycemic control, they can continue,” she said at the annual meeting of the Endocrine Society.
Diabetes is a known side effect of immune checkpoint inhibitors (ICIs) but it’s rare, occurring in maybe 0.17% of patients, and its natural history and risk factors are unknown.
ICIs are fairly new agents, and as their use expands beyond clinical trials, “we anticipate seeing larger numbers of cases. Patients should be educated about the symptoms of uncontrolled blood sugars while on ICIs,” and endocrinologists “have to get involved and recognize this entity sooner,” Dr. Iyer said.
In short, her team found that ICI-mediated diabetes can occur in patients with or without preexisting diabetes, and that most patients have evidence of beta-cell failure, likely T-cell mediated destruction due to immune activation. In all but one case, patients remained on insulin at a median follow-up of 44 weeks, even after stopping ICIs. For most, ICI-mediated diabetes likely means lifelong insulin.
They were all on the programmed cell death protein (PD-1) inhibitors nivolumab (Opdivo) or pembrolizumab (Keytruda), or the PD-1 ligand (PD-L) inhibitor durvalumab (Imfinzi). The agents are used for a range of cancers, including renal cell, melanoma, and Hodgkin lymphoma. There were no diabetes cases in patients on single-agent ipilimumab (Yervoy) or tremelimumab, which target cytotoxic T-lymphocyte associated antigen-4 and are used for melanoma and mesothelioma.
Median time to diabetes presentation after the start of ICI treatment was 12.3 weeks but ranged from 1 to 67.2 weeks. Half of the cases presented in diabetic ketoacidosis (DKA). Patients had upward trending hyperglycemia and most had diabetes symptoms for a while before diagnosis. They presented with a blood glucose above 250 mg/dL, and more than half above 500 mg/dL. Median hemoglobin A1c at presentation was 8%, but ranged up to 12.5%.
Every patient required insulin, including the six that discontinued ICIs after developing diabetes. Diabetes resolved in just one patient at 10.2 months; she presented with DKA.
There were no obvious predisposing factors. None of the patients had histories of type 1 diabetes or other autoimmune disease. Five patients had well-controlled type 2 diabetes prior to ICI initiation; four had prediabetes. Some had family members with type 2 diabetes, but not type 1. Four had prior ICI exposure. Just three patients were on concomitant steroids.
A few patients also developed thyroid or pituitary dysfunction, which are more common side effects of ICIs.
The median age at diabetes presentation was 61 years and ranged from 32 to 82 years. The majority of patients were men, which reflects MD Anderson demographics, not a predisposing risk factor, Dr. Iyer said.
Melanoma was the most common cancer, followed by renal cell and prostate; patients had stage 2-4 disease. About half the subjects were on single agent anti-PD-1 treatment, about a third on anti-PD-1 combination treatment, and the rest on anti-PD-L1 combination therapy. C-peptide levels were below 0.9 ng/mL at diabetes diagnosis in most of the patients. Eleven of the 20 tested (55%) were positive for the pancreatic islet cell antibody GAD65.
The investigators had no disclosures. A funding source was not reported.
SOURCE: Iyer PC et al. Abstract OR05-5.
CHICAGO – , according to Priyanka Iyer, MD, an endocrinology fellow at MD Anderson Cancer Center, Houston.
“As long as we get glycemic control, they can continue,” she said at the annual meeting of the Endocrine Society.
Diabetes is a known side effect of immune checkpoint inhibitors (ICIs) but it’s rare, occurring in maybe 0.17% of patients, and its natural history and risk factors are unknown.
ICIs are fairly new agents, and as their use expands beyond clinical trials, “we anticipate seeing larger numbers of cases. Patients should be educated about the symptoms of uncontrolled blood sugars while on ICIs,” and endocrinologists “have to get involved and recognize this entity sooner,” Dr. Iyer said.
In short, her team found that ICI-mediated diabetes can occur in patients with or without preexisting diabetes, and that most patients have evidence of beta-cell failure, likely T-cell mediated destruction due to immune activation. In all but one case, patients remained on insulin at a median follow-up of 44 weeks, even after stopping ICIs. For most, ICI-mediated diabetes likely means lifelong insulin.
They were all on the programmed cell death protein (PD-1) inhibitors nivolumab (Opdivo) or pembrolizumab (Keytruda), or the PD-1 ligand (PD-L) inhibitor durvalumab (Imfinzi). The agents are used for a range of cancers, including renal cell, melanoma, and Hodgkin lymphoma. There were no diabetes cases in patients on single-agent ipilimumab (Yervoy) or tremelimumab, which target cytotoxic T-lymphocyte associated antigen-4 and are used for melanoma and mesothelioma.
Median time to diabetes presentation after the start of ICI treatment was 12.3 weeks but ranged from 1 to 67.2 weeks. Half of the cases presented in diabetic ketoacidosis (DKA). Patients had upward trending hyperglycemia and most had diabetes symptoms for a while before diagnosis. They presented with a blood glucose above 250 mg/dL, and more than half above 500 mg/dL. Median hemoglobin A1c at presentation was 8%, but ranged up to 12.5%.
Every patient required insulin, including the six that discontinued ICIs after developing diabetes. Diabetes resolved in just one patient at 10.2 months; she presented with DKA.
There were no obvious predisposing factors. None of the patients had histories of type 1 diabetes or other autoimmune disease. Five patients had well-controlled type 2 diabetes prior to ICI initiation; four had prediabetes. Some had family members with type 2 diabetes, but not type 1. Four had prior ICI exposure. Just three patients were on concomitant steroids.
A few patients also developed thyroid or pituitary dysfunction, which are more common side effects of ICIs.
The median age at diabetes presentation was 61 years and ranged from 32 to 82 years. The majority of patients were men, which reflects MD Anderson demographics, not a predisposing risk factor, Dr. Iyer said.
Melanoma was the most common cancer, followed by renal cell and prostate; patients had stage 2-4 disease. About half the subjects were on single agent anti-PD-1 treatment, about a third on anti-PD-1 combination treatment, and the rest on anti-PD-L1 combination therapy. C-peptide levels were below 0.9 ng/mL at diabetes diagnosis in most of the patients. Eleven of the 20 tested (55%) were positive for the pancreatic islet cell antibody GAD65.
The investigators had no disclosures. A funding source was not reported.
SOURCE: Iyer PC et al. Abstract OR05-5.
REPORTING FROM ENDO 2018
Key clinical point: Be on the lookout for new-onset diabetes when patients start immune checkpoint inhibitors.
Major finding: In all but one case, patients remained on insulin at a median follow-up of 44 weeks, even after stopping ICIs.
Study details: Review of 24 cases.
Disclosures: The investigators had no disclosures. A funding source was not reported.
Source: Iyer PC et al. Abstract OR05-5.
New and improved classifiers may sharpen thyroid nodule diagnosis
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies. 
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold. 
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: ThyroSeq v3 had a negative predictive value of 97%. Specificity was an absolute 47% greater for Afirma GSC with Hurthle-specific classifiers than for Afirma GEC. The Afirma GSC with a medullary thyroid cancer classifier had 100% sensitivity and specificity.
Data source: Validation studies of the ThyroSeq v3 classifier (257 samples), the Afirma GSC with Hurthle-specific classifiers (186 samples), and the Afirma GSC with a medullary thyroid cancer classifier (211 samples).
Disclosures: Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
Cancer patients with TKI-induced hypothyroidism had better survival rates
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: Relative to peers who remained euthyroid, patients who developed overt hypothyroidism had a reduced risk of death (HR, 0.56; P less than .0001).
Data source: A retrospective cohort study of 538 adult patients with mainly advanced nonthyroid cancers treated with a tyrosine kinase inhibitor.
Disclosures: Dr. Angell had no relevant conflicts of interest.
Calcitonin-to-CEA ratio predicts medullary thyroid cancer survival
BOSTON – The ratio of serum calcitonin to the serum level of carcinoembryonic antigen in patients with medullary thyroid cancer can predict which patients have a better chance for survival following thyroidectomy, based on retrospective findings from 164 presurgical patients at one U.S. center.
A lower serum calcitonin–to–serum carcinoembryonic antigen (CEA) ratio following thyroidectomy is a second marker of good postsurgical survival, Tania Jaber, MD, said at the World Congress on Thyroid Cancer.
“Patients want to know whether surgery will cure them, and we have had no prognostic markers to predict this. Depending on the ratio, we can now tell patients whether or not they have a good chance of cure,” said Dr. Jaber, an endocrinological oncologist at MD Anderson in Houston. “Surgery remains the standard of care, so the ratio does not affect the decision of whether to undergo surgery, but it helps patients know what to expect” after surgery, she said in an interview.
“If their ratio is favorable it can be reassuring, and if their ratio is unfavorable it helps set expectations. We are also studying whether the ratio can be a marker for the need for systemic therapy following surgery. Right now, our prognostic tools for medullary thyroid cancer are very limited, so any additional information we can give patients based on their calcitonin-to-CEA ratio is very valuable.”
Her study included 164 patients treated at MD Anderson who had their serum drawn before thyroidectomy, and 187 patients with specimens taken 3-9 months after surgery. Median patient follow-up after surgery was 5 years. Calcitonin levels were measured as pg/mL and CEA levels as ng/mL; despite this difference in unit size the researchers calculated the ratios by a direct numerical comparison that ignored the units.
Among the preoperative patients and specifically among those with a low serum CEA level of less than 25 ng/ML a calcitonin-to-CEA ratio of less than 43 had the best survival rate, Dr. Jaber reported. Among preoperative patients with a CEA level of 25 ng/mL or greater a ratio of less than 18 flagged patients with the best survival rate following thyroidectomy.
Among postoperative patients the ratios that linked with better survival also depended on the CEA level. In patients with a low postoperative CEA a ratio of less than 149 linked with better survival. In patients with a high CEA level a ratio of less than 12 linked with better postoperative survival.
[email protected]
On Twitter @mitchelzoler
BOSTON – The ratio of serum calcitonin to the serum level of carcinoembryonic antigen in patients with medullary thyroid cancer can predict which patients have a better chance for survival following thyroidectomy, based on retrospective findings from 164 presurgical patients at one U.S. center.
A lower serum calcitonin–to–serum carcinoembryonic antigen (CEA) ratio following thyroidectomy is a second marker of good postsurgical survival, Tania Jaber, MD, said at the World Congress on Thyroid Cancer.
“Patients want to know whether surgery will cure them, and we have had no prognostic markers to predict this. Depending on the ratio, we can now tell patients whether or not they have a good chance of cure,” said Dr. Jaber, an endocrinological oncologist at MD Anderson in Houston. “Surgery remains the standard of care, so the ratio does not affect the decision of whether to undergo surgery, but it helps patients know what to expect” after surgery, she said in an interview.
“If their ratio is favorable it can be reassuring, and if their ratio is unfavorable it helps set expectations. We are also studying whether the ratio can be a marker for the need for systemic therapy following surgery. Right now, our prognostic tools for medullary thyroid cancer are very limited, so any additional information we can give patients based on their calcitonin-to-CEA ratio is very valuable.”
Her study included 164 patients treated at MD Anderson who had their serum drawn before thyroidectomy, and 187 patients with specimens taken 3-9 months after surgery. Median patient follow-up after surgery was 5 years. Calcitonin levels were measured as pg/mL and CEA levels as ng/mL; despite this difference in unit size the researchers calculated the ratios by a direct numerical comparison that ignored the units.
Among the preoperative patients and specifically among those with a low serum CEA level of less than 25 ng/ML a calcitonin-to-CEA ratio of less than 43 had the best survival rate, Dr. Jaber reported. Among preoperative patients with a CEA level of 25 ng/mL or greater a ratio of less than 18 flagged patients with the best survival rate following thyroidectomy.
Among postoperative patients the ratios that linked with better survival also depended on the CEA level. In patients with a low postoperative CEA a ratio of less than 149 linked with better survival. In patients with a high CEA level a ratio of less than 12 linked with better postoperative survival.
[email protected]
On Twitter @mitchelzoler
BOSTON – The ratio of serum calcitonin to the serum level of carcinoembryonic antigen in patients with medullary thyroid cancer can predict which patients have a better chance for survival following thyroidectomy, based on retrospective findings from 164 presurgical patients at one U.S. center.
A lower serum calcitonin–to–serum carcinoembryonic antigen (CEA) ratio following thyroidectomy is a second marker of good postsurgical survival, Tania Jaber, MD, said at the World Congress on Thyroid Cancer.
“Patients want to know whether surgery will cure them, and we have had no prognostic markers to predict this. Depending on the ratio, we can now tell patients whether or not they have a good chance of cure,” said Dr. Jaber, an endocrinological oncologist at MD Anderson in Houston. “Surgery remains the standard of care, so the ratio does not affect the decision of whether to undergo surgery, but it helps patients know what to expect” after surgery, she said in an interview.
“If their ratio is favorable it can be reassuring, and if their ratio is unfavorable it helps set expectations. We are also studying whether the ratio can be a marker for the need for systemic therapy following surgery. Right now, our prognostic tools for medullary thyroid cancer are very limited, so any additional information we can give patients based on their calcitonin-to-CEA ratio is very valuable.”
Her study included 164 patients treated at MD Anderson who had their serum drawn before thyroidectomy, and 187 patients with specimens taken 3-9 months after surgery. Median patient follow-up after surgery was 5 years. Calcitonin levels were measured as pg/mL and CEA levels as ng/mL; despite this difference in unit size the researchers calculated the ratios by a direct numerical comparison that ignored the units.
Among the preoperative patients and specifically among those with a low serum CEA level of less than 25 ng/ML a calcitonin-to-CEA ratio of less than 43 had the best survival rate, Dr. Jaber reported. Among preoperative patients with a CEA level of 25 ng/mL or greater a ratio of less than 18 flagged patients with the best survival rate following thyroidectomy.
Among postoperative patients the ratios that linked with better survival also depended on the CEA level. In patients with a low postoperative CEA a ratio of less than 149 linked with better survival. In patients with a high CEA level a ratio of less than 12 linked with better postoperative survival.
[email protected]
On Twitter @mitchelzoler
AT WCTC 2017
Key clinical point:
Major finding: Presurgery, a calcitonin-to-CEA ratio below 18 was linked with superior survival in patients whose CEA was at least 25 ng/Ml.
Data source: A single-center, retrospective study with 164 patients assessed before thyroidectomy and 187 assessed after surgery.
Disclosures: Dr. Jaber had no disclosures.
Big changes coming for thyroid cancer staging
BOSTON – When the American Joint Committee on Cancer’s Eighth Edition Cancer Staging Manual becomes effective for U.S. practice on Jan. 1, 2018, substantially more patients with thyroid cancer will meet the definition for stage I disease, but their survival prognosis will remain as good as it was for the smaller slice of patients defined with stage I thyroid cancer by the seventh edition, Bryan R. Haugen, MD, predicted during a talk at the World Congress on Thyroid Cancer.
Under current stage definitions in the seventh edition, roughly 60% of thyroid cancer patients have stage I disease, but this will kick up to about 80% under the eighth edition, said Dr. Haugen, professor of medicine and head of the division of endocrinology, metabolism, and diabetes at the University of Colorado in Aurora. Despite this influx of more patients, “survival rates in stage I patients haven’t changed,” with a disease-specific survival (DSS) of 98%-100% for stage I patients in the eighth edition compared with 97%-100% in the seventh edition, he noted.
Dr. Haugen credited this apparent paradox to the revised staging system’s superior discrimination among various grades of disease progression. “The eighth edition better separates patients based on their projected survival.” As more patients fit stage I classification with its highest level of projected survival, fewer patients will classify with more advanced disease and its worse projected survival.
For example, in the seventh edition patients with stage IV disease had a projected DSS rate of 50%-75%; in the eighth edition that rate is now less than 50%. The projected DSS rate for patients with stage II disease has down shifted from 97%-100% in the seventh edition to 85%-95% in the eighth. For patients with stage III thyroid cancer the DSS rate of 88%-95% in the seventh edition became 60%-70% in the eighth edition.
‘The new system will take some getting used to,” Dr. Haugen admitted, and it involves even more “big” changes, he warned. These include:
• Changing the cutpoint separating younger from older patients to 55 years of age in the eighth edition, a rise from the 45-year-old cutpoint in the seventh edition.
• Allowing tumors classified as stage I to be as large as 4 cm, up from the 2 cm or less defining stage I in the seventh edition.
• Reserving stage II designation for patients with tumors larger than 4 cm. In the seventh edition tumors had to be 2-4 cm in size.
• Expanding stage II disease to include not only patients with disease confined to their thyroid, but also patients with N1 lymph node spread or gross extrathyroidal extension. In the seventh edition tumor spread like this put patients into stage III.
• Specifying in the eighth edition that stage III disease must feature gross extrathyroidal extension into the larynx, trachea, esophagus, or recurrent laryngial nerve. To qualify for stage IV in the eighth edition, spread must extend into prevertebral fascia or encase major vessels, for stage IVA, or involve distant metastases for stage IVB.
• Paring down three stage IV subgroups, A, B, and C, in the seventh edition to just an A or B subgroup in the eighth edition.
Dr. Haugen coauthored a recent editorial that laid out an assessment of the eighth edition in greater detail (Thyroid. 2017 Jun;27[6]:751-6).
[email protected]
On Twitter @mitchelzoler
BOSTON – When the American Joint Committee on Cancer’s Eighth Edition Cancer Staging Manual becomes effective for U.S. practice on Jan. 1, 2018, substantially more patients with thyroid cancer will meet the definition for stage I disease, but their survival prognosis will remain as good as it was for the smaller slice of patients defined with stage I thyroid cancer by the seventh edition, Bryan R. Haugen, MD, predicted during a talk at the World Congress on Thyroid Cancer.
Under current stage definitions in the seventh edition, roughly 60% of thyroid cancer patients have stage I disease, but this will kick up to about 80% under the eighth edition, said Dr. Haugen, professor of medicine and head of the division of endocrinology, metabolism, and diabetes at the University of Colorado in Aurora. Despite this influx of more patients, “survival rates in stage I patients haven’t changed,” with a disease-specific survival (DSS) of 98%-100% for stage I patients in the eighth edition compared with 97%-100% in the seventh edition, he noted.
Dr. Haugen credited this apparent paradox to the revised staging system’s superior discrimination among various grades of disease progression. “The eighth edition better separates patients based on their projected survival.” As more patients fit stage I classification with its highest level of projected survival, fewer patients will classify with more advanced disease and its worse projected survival.
For example, in the seventh edition patients with stage IV disease had a projected DSS rate of 50%-75%; in the eighth edition that rate is now less than 50%. The projected DSS rate for patients with stage II disease has down shifted from 97%-100% in the seventh edition to 85%-95% in the eighth. For patients with stage III thyroid cancer the DSS rate of 88%-95% in the seventh edition became 60%-70% in the eighth edition.
‘The new system will take some getting used to,” Dr. Haugen admitted, and it involves even more “big” changes, he warned. These include:
• Changing the cutpoint separating younger from older patients to 55 years of age in the eighth edition, a rise from the 45-year-old cutpoint in the seventh edition.
• Allowing tumors classified as stage I to be as large as 4 cm, up from the 2 cm or less defining stage I in the seventh edition.
• Reserving stage II designation for patients with tumors larger than 4 cm. In the seventh edition tumors had to be 2-4 cm in size.
• Expanding stage II disease to include not only patients with disease confined to their thyroid, but also patients with N1 lymph node spread or gross extrathyroidal extension. In the seventh edition tumor spread like this put patients into stage III.
• Specifying in the eighth edition that stage III disease must feature gross extrathyroidal extension into the larynx, trachea, esophagus, or recurrent laryngial nerve. To qualify for stage IV in the eighth edition, spread must extend into prevertebral fascia or encase major vessels, for stage IVA, or involve distant metastases for stage IVB.
• Paring down three stage IV subgroups, A, B, and C, in the seventh edition to just an A or B subgroup in the eighth edition.
Dr. Haugen coauthored a recent editorial that laid out an assessment of the eighth edition in greater detail (Thyroid. 2017 Jun;27[6]:751-6).
[email protected]
On Twitter @mitchelzoler
BOSTON – When the American Joint Committee on Cancer’s Eighth Edition Cancer Staging Manual becomes effective for U.S. practice on Jan. 1, 2018, substantially more patients with thyroid cancer will meet the definition for stage I disease, but their survival prognosis will remain as good as it was for the smaller slice of patients defined with stage I thyroid cancer by the seventh edition, Bryan R. Haugen, MD, predicted during a talk at the World Congress on Thyroid Cancer.
Under current stage definitions in the seventh edition, roughly 60% of thyroid cancer patients have stage I disease, but this will kick up to about 80% under the eighth edition, said Dr. Haugen, professor of medicine and head of the division of endocrinology, metabolism, and diabetes at the University of Colorado in Aurora. Despite this influx of more patients, “survival rates in stage I patients haven’t changed,” with a disease-specific survival (DSS) of 98%-100% for stage I patients in the eighth edition compared with 97%-100% in the seventh edition, he noted.
Dr. Haugen credited this apparent paradox to the revised staging system’s superior discrimination among various grades of disease progression. “The eighth edition better separates patients based on their projected survival.” As more patients fit stage I classification with its highest level of projected survival, fewer patients will classify with more advanced disease and its worse projected survival.
For example, in the seventh edition patients with stage IV disease had a projected DSS rate of 50%-75%; in the eighth edition that rate is now less than 50%. The projected DSS rate for patients with stage II disease has down shifted from 97%-100% in the seventh edition to 85%-95% in the eighth. For patients with stage III thyroid cancer the DSS rate of 88%-95% in the seventh edition became 60%-70% in the eighth edition.
‘The new system will take some getting used to,” Dr. Haugen admitted, and it involves even more “big” changes, he warned. These include:
• Changing the cutpoint separating younger from older patients to 55 years of age in the eighth edition, a rise from the 45-year-old cutpoint in the seventh edition.
• Allowing tumors classified as stage I to be as large as 4 cm, up from the 2 cm or less defining stage I in the seventh edition.
• Reserving stage II designation for patients with tumors larger than 4 cm. In the seventh edition tumors had to be 2-4 cm in size.
• Expanding stage II disease to include not only patients with disease confined to their thyroid, but also patients with N1 lymph node spread or gross extrathyroidal extension. In the seventh edition tumor spread like this put patients into stage III.
• Specifying in the eighth edition that stage III disease must feature gross extrathyroidal extension into the larynx, trachea, esophagus, or recurrent laryngial nerve. To qualify for stage IV in the eighth edition, spread must extend into prevertebral fascia or encase major vessels, for stage IVA, or involve distant metastases for stage IVB.
• Paring down three stage IV subgroups, A, B, and C, in the seventh edition to just an A or B subgroup in the eighth edition.
Dr. Haugen coauthored a recent editorial that laid out an assessment of the eighth edition in greater detail (Thyroid. 2017 Jun;27[6]:751-6).
[email protected]
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM WCTC 2017
Contralateral nodal thyroid metastases show slow progression
BOSTON – More than a third of 63 patients with unilateral papillary thyroid carcinoma and ipsilateral lymph node metastases also had occult, contralateral, lateral-neck lymph nodes with metastases, but the low reported rate of contralateral neck recurrence has raised the question of whether routine resection of these contralateral lymph nodes benefits patients.
“Prophylactic contralateral lateral-neck dissection may not be relevant for patients with unilateral N1b tumors,” Dana Hartl, MD, PhD, said at the World Congress on Thyroid Cancer.
She envisioned a more targeted approach to using surgical resection of contralateral, lateral-neck lymph nodes. “We would still do this surgery for patients with lots of big, bulky nodules; it just takes an additional 10-20 minutes. It’s not that long or morbid. For patients with lots of [affected] nodes, you’ve got to clear it out. But for a patient with a small, level III node on one side I will no longer do [prophylactic, contralateral, lateral-neck lymph node removal].”
Dr. Hartl and her associates reviewed records for 63 patients with unilateral, unifocal papillary thyroid carcinoma who underwent prophylactic, contralateral, lymph node removal during 1997-2016. They ranged from 11-84 years old, and 60% had extrathyroidal extension of their primary tumor. The patients averaged having four lymph nodes with metastatic cells in the ipsilateral lateral neck, an average of five affected lymph nodes in the ipsilateral central neck, and an average of two affected lymph nodes in the contralateral central neck.
Among the 63 patients, 23 (37%) had metastases-containing lymph nodes at levels III and IV in the contralateral lateral neck, with a range of 1-17 metastases per node. All nodes were less than 1 cm in diameter. Extracapsular spread had occurred in 11 of the 23 cases.
The relatively frequent presence of metastases in the contralateral, lateral-neck lymph nodes contrasted with the reported low 5%-15% rate of recurrence in these lymph nodes in patients with N1b disease, Dr. Hartl said.
The analysis identified two factors that significantly linked with having contralateral, lateral-neck metastases: having a bilateral tumor with contralateral microcancer, or having at least four lymph nodes positive for metastases in the ipsilateral central compartment, she reported. When patients had fewer than five positive lymph nodes in the ipsilateral central neck, their risk for occult metastases in contralateral lymph nodes was 26%.
“It’s not very strong data; we were a little disappointed” with the results, Dr. Hartl said.
[email protected]
On Twitter @mitchelzoler
The finding reported by Dr. Hartl is consistent with recent experience with other tumor types, like prostate cancer, that often show low aggressiveness. The need to routinely resect what may be indolent microscopic metastases remains a big open question.
The dilemma for thyroid cancer was nicely summarized by Gilbert Welch, MD, and his associates who highlighted the risk of overdiagnosing thyroid cancer with aggressive screening. In South Korea, this resulted in a 15-fold increase in thyroid cancer diagnoses between 1993 and 2011, which led to substantial increases in the rates of thyroidectomy including patients with tumors too small to warrant surgery (N Engl J Med. 2014 Nov 6;371[19]:1765-7).
Pamela Hartzband, MD , is an endocrinologist at Beth Israel Deaconess Medical Center in Boston. She had no disclosures. She made these comments in an interview.
The finding reported by Dr. Hartl is consistent with recent experience with other tumor types, like prostate cancer, that often show low aggressiveness. The need to routinely resect what may be indolent microscopic metastases remains a big open question.
The dilemma for thyroid cancer was nicely summarized by Gilbert Welch, MD, and his associates who highlighted the risk of overdiagnosing thyroid cancer with aggressive screening. In South Korea, this resulted in a 15-fold increase in thyroid cancer diagnoses between 1993 and 2011, which led to substantial increases in the rates of thyroidectomy including patients with tumors too small to warrant surgery (N Engl J Med. 2014 Nov 6;371[19]:1765-7).
Pamela Hartzband, MD , is an endocrinologist at Beth Israel Deaconess Medical Center in Boston. She had no disclosures. She made these comments in an interview.
The finding reported by Dr. Hartl is consistent with recent experience with other tumor types, like prostate cancer, that often show low aggressiveness. The need to routinely resect what may be indolent microscopic metastases remains a big open question.
The dilemma for thyroid cancer was nicely summarized by Gilbert Welch, MD, and his associates who highlighted the risk of overdiagnosing thyroid cancer with aggressive screening. In South Korea, this resulted in a 15-fold increase in thyroid cancer diagnoses between 1993 and 2011, which led to substantial increases in the rates of thyroidectomy including patients with tumors too small to warrant surgery (N Engl J Med. 2014 Nov 6;371[19]:1765-7).
Pamela Hartzband, MD , is an endocrinologist at Beth Israel Deaconess Medical Center in Boston. She had no disclosures. She made these comments in an interview.
BOSTON – More than a third of 63 patients with unilateral papillary thyroid carcinoma and ipsilateral lymph node metastases also had occult, contralateral, lateral-neck lymph nodes with metastases, but the low reported rate of contralateral neck recurrence has raised the question of whether routine resection of these contralateral lymph nodes benefits patients.
“Prophylactic contralateral lateral-neck dissection may not be relevant for patients with unilateral N1b tumors,” Dana Hartl, MD, PhD, said at the World Congress on Thyroid Cancer.
She envisioned a more targeted approach to using surgical resection of contralateral, lateral-neck lymph nodes. “We would still do this surgery for patients with lots of big, bulky nodules; it just takes an additional 10-20 minutes. It’s not that long or morbid. For patients with lots of [affected] nodes, you’ve got to clear it out. But for a patient with a small, level III node on one side I will no longer do [prophylactic, contralateral, lateral-neck lymph node removal].”
Dr. Hartl and her associates reviewed records for 63 patients with unilateral, unifocal papillary thyroid carcinoma who underwent prophylactic, contralateral, lymph node removal during 1997-2016. They ranged from 11-84 years old, and 60% had extrathyroidal extension of their primary tumor. The patients averaged having four lymph nodes with metastatic cells in the ipsilateral lateral neck, an average of five affected lymph nodes in the ipsilateral central neck, and an average of two affected lymph nodes in the contralateral central neck.
Among the 63 patients, 23 (37%) had metastases-containing lymph nodes at levels III and IV in the contralateral lateral neck, with a range of 1-17 metastases per node. All nodes were less than 1 cm in diameter. Extracapsular spread had occurred in 11 of the 23 cases.
The relatively frequent presence of metastases in the contralateral, lateral-neck lymph nodes contrasted with the reported low 5%-15% rate of recurrence in these lymph nodes in patients with N1b disease, Dr. Hartl said.
The analysis identified two factors that significantly linked with having contralateral, lateral-neck metastases: having a bilateral tumor with contralateral microcancer, or having at least four lymph nodes positive for metastases in the ipsilateral central compartment, she reported. When patients had fewer than five positive lymph nodes in the ipsilateral central neck, their risk for occult metastases in contralateral lymph nodes was 26%.
“It’s not very strong data; we were a little disappointed” with the results, Dr. Hartl said.
[email protected]
On Twitter @mitchelzoler
BOSTON – More than a third of 63 patients with unilateral papillary thyroid carcinoma and ipsilateral lymph node metastases also had occult, contralateral, lateral-neck lymph nodes with metastases, but the low reported rate of contralateral neck recurrence has raised the question of whether routine resection of these contralateral lymph nodes benefits patients.
“Prophylactic contralateral lateral-neck dissection may not be relevant for patients with unilateral N1b tumors,” Dana Hartl, MD, PhD, said at the World Congress on Thyroid Cancer.
She envisioned a more targeted approach to using surgical resection of contralateral, lateral-neck lymph nodes. “We would still do this surgery for patients with lots of big, bulky nodules; it just takes an additional 10-20 minutes. It’s not that long or morbid. For patients with lots of [affected] nodes, you’ve got to clear it out. But for a patient with a small, level III node on one side I will no longer do [prophylactic, contralateral, lateral-neck lymph node removal].”
Dr. Hartl and her associates reviewed records for 63 patients with unilateral, unifocal papillary thyroid carcinoma who underwent prophylactic, contralateral, lymph node removal during 1997-2016. They ranged from 11-84 years old, and 60% had extrathyroidal extension of their primary tumor. The patients averaged having four lymph nodes with metastatic cells in the ipsilateral lateral neck, an average of five affected lymph nodes in the ipsilateral central neck, and an average of two affected lymph nodes in the contralateral central neck.
Among the 63 patients, 23 (37%) had metastases-containing lymph nodes at levels III and IV in the contralateral lateral neck, with a range of 1-17 metastases per node. All nodes were less than 1 cm in diameter. Extracapsular spread had occurred in 11 of the 23 cases.
The relatively frequent presence of metastases in the contralateral, lateral-neck lymph nodes contrasted with the reported low 5%-15% rate of recurrence in these lymph nodes in patients with N1b disease, Dr. Hartl said.
The analysis identified two factors that significantly linked with having contralateral, lateral-neck metastases: having a bilateral tumor with contralateral microcancer, or having at least four lymph nodes positive for metastases in the ipsilateral central compartment, she reported. When patients had fewer than five positive lymph nodes in the ipsilateral central neck, their risk for occult metastases in contralateral lymph nodes was 26%.
“It’s not very strong data; we were a little disappointed” with the results, Dr. Hartl said.
[email protected]
On Twitter @mitchelzoler
AT WCTC 2017
Key clinical point:
Major finding: Thirty-seven percent of patients with unilateral N1b thyroid tumors also had metastases in their contralateral lateral-neck lymph nodes.
Data source: Review of 63 patients treated at a single French center during a 20-year period.
Disclosures: Dr. Hartl had no disclosures.
Revised thyroid Bethesda System resets malignant risks
BOSTON – Under the newly revised Bethesda System for Reporting Thyroid Cytology, slated for official release in October 2017, the six cytology-based diagnostic categories for thyroid lesions stay exactly the same as in the 10-year-old first edition, but some associated malignancy risks have changed.
Important changes include molecular testing to further assess malignancy risk in thyroid nodules and the introduction of lobectomy as a treatment option, “which really wasn’t an option 10 years ago,” in the first iteration of the Bethesda System (New York: Springer US, 2010), its coauthor Edmund S. Cibas, MD, said at the World Congress on Thyroid Cancer.
An Endocrine Pathology Society working group created the NIFTP designation in 2016 to describe an encapsulated follicular variant of papillary thyroid carcinoma that is characterized by lack of invasion, a follicular growth pattern, and nuclear features of papillary thyroid carcinoma with a very low risk of an adverse outcome (JAMA Oncology. 2016 Aug;2[8]:1023-9) (Cancer Cytopathol. 2016 Sep;124[9]:616-20).
NIFTP is not an overt malignancy. The revised Bethesda System “limits malignancy to cases with features of classic malignant papillary thyroid carcinoma,” explained Dr. Cibas, professor of pathology at Harvard Medical School and director of cytopathology at Brigham and Women’s Hospital, both in Boston.
Because the Bethesda System categories link to specific management recommendations, the new edition orients patients toward more conservative management decisions, specifically lobectomies instead of total thyroidectomies, he said in an interview.
The International Cytology Congress held a symposium during its meeting in Yokohama, Japan, in 2016, which resulted in the second edition of the Bethesda System (ACTA Cytol. 2016 Sep-Oct; 60[5]:399-405).
The changes in risk of malignancy occurred primarily in two categories, either “atypia of undetermined significance” (AUS) or “follicular lesions of undetermined significance” (FLUS). The risk of malignancy jumped from 5%-15% in the Bethesda System first edition up to 10%-30% in the revision. A smaller bump-up hit the category of “follicular neoplasm” or “suspicious for follicular neoplasm,” in which the risk of malignancy increased from 20%-30% in the first edition to 25%-40% in the revision. And, in the suspicion of malignancy category, the risk of malignancy actually lowered modestly, easing from 60%-75% in the first edition to 50%-75% in the revision.
Dr. Cibas highlighted the AUS/FLUS category with further notable features. The limit on laboratories reporting this category increased to 10% of total reports, up from 7% in the first edition. Management changed from the single options of a repeat fine-needle aspiration specimen to either that or molecular testing. Also, “the first edition was not clear that AUS and FLUS are synonyms. That will be a lot clearer” in the second edition, Dr. Cibas promised. The revision “will encourage labs that currently use [the terms] AUS and FLUS to mean two different things to make a choice between them.”
Another quirk of the AUS and FLUS category is that the risk of malignancy estimates are based on what Dr. Cibas called “flawed” data from only the selected subset of AUS or FLUS patients who have their nodule resected. “The reality is that most of the nodules are not resected” from patients with AUS or FLUS, so conclusions about the risk of malignancy come from a subset with considerable selection bias.
The definition of “follicular neoplasm” or “suspicious for follicular neoplasm” category also added “mild nuclear changes,” which can include increased nuclear size, contour irregularity, or chromatin clearing. The “suspicious for malignancy” category made a modest tweak to the risk of malignancy. Plus, “some of these patients will now undergo lobectomy rather than total thyroidectomy, which has been usual management.
The “suspicious for malignant” and “malignant” categories had little change aside from wider use of lobectomy, now feasible for any patient except those with metastatic disease, Dr. Cibas said.
[email protected]
On Twitter @mitchelzoler
BOSTON – Under the newly revised Bethesda System for Reporting Thyroid Cytology, slated for official release in October 2017, the six cytology-based diagnostic categories for thyroid lesions stay exactly the same as in the 10-year-old first edition, but some associated malignancy risks have changed.
Important changes include molecular testing to further assess malignancy risk in thyroid nodules and the introduction of lobectomy as a treatment option, “which really wasn’t an option 10 years ago,” in the first iteration of the Bethesda System (New York: Springer US, 2010), its coauthor Edmund S. Cibas, MD, said at the World Congress on Thyroid Cancer.
An Endocrine Pathology Society working group created the NIFTP designation in 2016 to describe an encapsulated follicular variant of papillary thyroid carcinoma that is characterized by lack of invasion, a follicular growth pattern, and nuclear features of papillary thyroid carcinoma with a very low risk of an adverse outcome (JAMA Oncology. 2016 Aug;2[8]:1023-9) (Cancer Cytopathol. 2016 Sep;124[9]:616-20).
NIFTP is not an overt malignancy. The revised Bethesda System “limits malignancy to cases with features of classic malignant papillary thyroid carcinoma,” explained Dr. Cibas, professor of pathology at Harvard Medical School and director of cytopathology at Brigham and Women’s Hospital, both in Boston.
Because the Bethesda System categories link to specific management recommendations, the new edition orients patients toward more conservative management decisions, specifically lobectomies instead of total thyroidectomies, he said in an interview.
The International Cytology Congress held a symposium during its meeting in Yokohama, Japan, in 2016, which resulted in the second edition of the Bethesda System (ACTA Cytol. 2016 Sep-Oct; 60[5]:399-405).
The changes in risk of malignancy occurred primarily in two categories, either “atypia of undetermined significance” (AUS) or “follicular lesions of undetermined significance” (FLUS). The risk of malignancy jumped from 5%-15% in the Bethesda System first edition up to 10%-30% in the revision. A smaller bump-up hit the category of “follicular neoplasm” or “suspicious for follicular neoplasm,” in which the risk of malignancy increased from 20%-30% in the first edition to 25%-40% in the revision. And, in the suspicion of malignancy category, the risk of malignancy actually lowered modestly, easing from 60%-75% in the first edition to 50%-75% in the revision.
Dr. Cibas highlighted the AUS/FLUS category with further notable features. The limit on laboratories reporting this category increased to 10% of total reports, up from 7% in the first edition. Management changed from the single options of a repeat fine-needle aspiration specimen to either that or molecular testing. Also, “the first edition was not clear that AUS and FLUS are synonyms. That will be a lot clearer” in the second edition, Dr. Cibas promised. The revision “will encourage labs that currently use [the terms] AUS and FLUS to mean two different things to make a choice between them.”
Another quirk of the AUS and FLUS category is that the risk of malignancy estimates are based on what Dr. Cibas called “flawed” data from only the selected subset of AUS or FLUS patients who have their nodule resected. “The reality is that most of the nodules are not resected” from patients with AUS or FLUS, so conclusions about the risk of malignancy come from a subset with considerable selection bias.
The definition of “follicular neoplasm” or “suspicious for follicular neoplasm” category also added “mild nuclear changes,” which can include increased nuclear size, contour irregularity, or chromatin clearing. The “suspicious for malignancy” category made a modest tweak to the risk of malignancy. Plus, “some of these patients will now undergo lobectomy rather than total thyroidectomy, which has been usual management.
The “suspicious for malignant” and “malignant” categories had little change aside from wider use of lobectomy, now feasible for any patient except those with metastatic disease, Dr. Cibas said.
[email protected]
On Twitter @mitchelzoler
BOSTON – Under the newly revised Bethesda System for Reporting Thyroid Cytology, slated for official release in October 2017, the six cytology-based diagnostic categories for thyroid lesions stay exactly the same as in the 10-year-old first edition, but some associated malignancy risks have changed.
Important changes include molecular testing to further assess malignancy risk in thyroid nodules and the introduction of lobectomy as a treatment option, “which really wasn’t an option 10 years ago,” in the first iteration of the Bethesda System (New York: Springer US, 2010), its coauthor Edmund S. Cibas, MD, said at the World Congress on Thyroid Cancer.
An Endocrine Pathology Society working group created the NIFTP designation in 2016 to describe an encapsulated follicular variant of papillary thyroid carcinoma that is characterized by lack of invasion, a follicular growth pattern, and nuclear features of papillary thyroid carcinoma with a very low risk of an adverse outcome (JAMA Oncology. 2016 Aug;2[8]:1023-9) (Cancer Cytopathol. 2016 Sep;124[9]:616-20).
NIFTP is not an overt malignancy. The revised Bethesda System “limits malignancy to cases with features of classic malignant papillary thyroid carcinoma,” explained Dr. Cibas, professor of pathology at Harvard Medical School and director of cytopathology at Brigham and Women’s Hospital, both in Boston.
Because the Bethesda System categories link to specific management recommendations, the new edition orients patients toward more conservative management decisions, specifically lobectomies instead of total thyroidectomies, he said in an interview.
The International Cytology Congress held a symposium during its meeting in Yokohama, Japan, in 2016, which resulted in the second edition of the Bethesda System (ACTA Cytol. 2016 Sep-Oct; 60[5]:399-405).
The changes in risk of malignancy occurred primarily in two categories, either “atypia of undetermined significance” (AUS) or “follicular lesions of undetermined significance” (FLUS). The risk of malignancy jumped from 5%-15% in the Bethesda System first edition up to 10%-30% in the revision. A smaller bump-up hit the category of “follicular neoplasm” or “suspicious for follicular neoplasm,” in which the risk of malignancy increased from 20%-30% in the first edition to 25%-40% in the revision. And, in the suspicion of malignancy category, the risk of malignancy actually lowered modestly, easing from 60%-75% in the first edition to 50%-75% in the revision.
Dr. Cibas highlighted the AUS/FLUS category with further notable features. The limit on laboratories reporting this category increased to 10% of total reports, up from 7% in the first edition. Management changed from the single options of a repeat fine-needle aspiration specimen to either that or molecular testing. Also, “the first edition was not clear that AUS and FLUS are synonyms. That will be a lot clearer” in the second edition, Dr. Cibas promised. The revision “will encourage labs that currently use [the terms] AUS and FLUS to mean two different things to make a choice between them.”
Another quirk of the AUS and FLUS category is that the risk of malignancy estimates are based on what Dr. Cibas called “flawed” data from only the selected subset of AUS or FLUS patients who have their nodule resected. “The reality is that most of the nodules are not resected” from patients with AUS or FLUS, so conclusions about the risk of malignancy come from a subset with considerable selection bias.
The definition of “follicular neoplasm” or “suspicious for follicular neoplasm” category also added “mild nuclear changes,” which can include increased nuclear size, contour irregularity, or chromatin clearing. The “suspicious for malignancy” category made a modest tweak to the risk of malignancy. Plus, “some of these patients will now undergo lobectomy rather than total thyroidectomy, which has been usual management.
The “suspicious for malignant” and “malignant” categories had little change aside from wider use of lobectomy, now feasible for any patient except those with metastatic disease, Dr. Cibas said.
[email protected]
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM WCTC 2017
VIDEO: Lenvatinib’s real-world thyroid cancer performance matches trial
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
[email protected]
On Twitter @mitchelzoler
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
Because of its efficacy lenvatinib is absolutely the top thymidine kinase inhibitor to use today to treat patients with radio-iodine-resistant, progressive, differentiated thyroid cancer. Although comparing drugs across trials is unreliable, the activity of lenvatinib in the SELECT trial (N Engl J Med. 2015 Feb 12;372[7]:621-30) was better than the activity of sorafenib in the DECISION trial (Lancet. 2014 July 26;384[9940]:319-28). There was enough of a difference between lenvatinib and sorafenib in the SELECT and DECISION trials to convince me that lenvatinib is the better drug.
Many of the patients enrolled in the French registry would not have qualified to enter the SELECT trial, so I’m not surprised that there was a lower response rate in the registry. We know that lenvatinib works better when the tumor burden is low, and some of the registry patients had a high tumor burden. In addition, a fraction of the registry patients did not receive a dosage of 24 mg/day, and data from the SELECT trial suggests that dosage size matters. The full dosage of 24 mg/day should be used as the starting dosage for lenvatinib, but that isn’t always possible for elderly patients or those with comorbidities.
A rise in blood pressure with lenvatinib treatment is not a completely bad outcome, because our experience with lenvatinib shows that this adverse effect actually links with a survival benefit. A spike in a patient’s blood pressure in response to lenvatinib is a sign that the drug is working and the patient will have a good treatment response, an association that we’ve seen with other tumor types and with other thymidine kinase inhibitors.
Unfortunately, a good response to lenvatinib is usually not enough in the long run. Experience shows that even when advanced thyroid cancer responds to lenvatinib or to another thymidine kinase inhibitor, eventually the disease will progress despite this treatment.
Lori J. Wirth, MD , is medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston. She has been a consultant to Eisai, Blueprint Medicines, Loxo, and Merck. She made these comments in an interview.
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
[email protected]
On Twitter @mitchelzoler
BOSTON – Lenvatinib’s real-world performance treating advanced, radio-iodine refractory, differentiated thyroid cancer closely followed the efficacy and adverse effect profiles the drug showed in its pivotal trial.
Lenvatinib showed good efficacy in 75 French registry patients, while also producing adverse effects in virtually every patient, but with the possibility to resolve the adverse effects with dose reductions or short-term treatment discontinuations, Martin Schlumberger, MD, said at the World Congress on Thyroid Cancer.
“Lenvatinib is toxic, but the toxicity can be managed in almost all patients by drug withholding or by reducing the dosage, and with symptomatic treatments,” Dr. Schlumberger said in a video interview. But adverse events are a “major problem” for the drug, so patients receiving lenvatinib “should be seen very frequently, and as soon as toxicity appears it should be treated,” said Dr. Schlumberger, professor of medicine and chairman of nuclear medicine and endocrine oncology at Gustave Roussy in Paris.
But lenvatinib’s efficacy makes it a first-line option despite the frequent adverse effects it causes.
“Without doubt it is the most effective drug” for treating advanced, rapidly progressing, radio-iodine refractory thyroid cancer, he said. “When patients really need systemic therapy they should get lenvatinib. It’s a balance of risk and benefit, and the risk from not being treated is higher than the risk from adverse effects.”
A similar pattern of adverse effects and efficacy was seen for lenvatinib in the pivotal Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, which reported a median 18-month progression-free survival rate among patients treated with the drug compared with a median 4-month progression-free survival rate in placebo-treated patients (N Engl J Med. 2015 Feb 12;372[7]:621-30).
Among the 75 patients enrolled in the French registry, the median time of progression-free survival was 10 months, with 8 patients on continued therapy without progression. The response rate in the registry was 31% compared with 65% in the SELECT trial (and 2% in placebo-treated patients in SELECT), but the registry included many patients with advanced disease, comorbidities, and pretreatment, Dr. Schlumberger reported. Just 17 of the registry patients (23%) would have met the enrollment criteria for SELECT. Among this subset the response rate to lenvatinib was 47%.
A multivariate analysis identified three factors that significantly linked with drug responses, Dr. Schlumberger said: pretreatment, more advanced disease, and comorbidities.
Treatment-related adverse effects occurred in 71 of the registry patients (95%), with half of these grade 3 or higher. Twelve patients (16%) discontinued treatment because of an adverse effect. Hypertension was the most common adverse effect, occurring in 50 patients (67%), with 26 having grade 3 or higher hypertension. Other common adverse effects were fatigue, weight loss, diarrhea, and anorexia.
The 75 patients began treatment with lenvatinib for advanced thyroid cancer at any of 24 French centers during April 2015–June 2016. This marked the first year when lenvatinib was available in France for routine use, which roughly coincided with its U.S. introduction after lenvatinib received Food and Drug Administration marketing approval for advanced thyroid cancer in February 2015. Fifty-four patients (72%) began treatment on the labeled dosage of 24 mg/day; the remaining patients started the drug at a lower dosage.
[email protected]
On Twitter @mitchelzoler
AT WCTC 2017
Key clinical point:
Major finding: The median time of progression-free survival was 10 months in the registry and 18 months in the pivotal trial.
Data source: A retrospective review of the first 75 French patients with advanced differentiated thyroid cancer who received lenvatinib following its marketing approval.
Disclosures: Dr. Schlumberger has received research funding from Eisai, the company that markets lenvatinib (Lenvima). He has also received research support and honoraria from AstraZeneca, Bayer, and Excelixis.
