Federal Practitioner

The Centers for Disease Control and Prevention has released an updated schedule for adult vaccines. The update includes changes regarding the administration of several vaccines, including those for influenza, human papillomavirus (HPV), hepatitis A and B, and meningitis B, as well as the pneumococcal 13-valent conjugate (PCV13) vaccine.

The schedule, revised annually by the Advisory Committee on Immunization Practices (ACIP) of the CDC, was simultaneously published online February 3, 2020, in the Annals of Internal Medicine and on the CDC website.

Perhaps the change most likely to raise questions is that concerning the PCV13 vaccine. “Owing to a decline in prevalence of the types covered by the PCV13 vaccine, this is no longer routinely recommended for all persons age 65 and older,” senior author Mark Freedman, DVM, MPH, of the immunization services division at the National Center for Immunization and Respiratory Disease, said in an interview.

For purposes of shared clinical decision, however, it should be discussed with previously unvaccinated seniors who do not have risk factors, such as an immunocompromising condition, a cerebrospinal fluid leak, or a cochlear implant.

“But the circumstances for use of the vaccine are not always clear even based on the detailed list of considerations provided, because it’s impossible to think of every conceivable combination of risk factors,” Mr. Freedman added.

Possible beneficiaries of this vaccine are vulnerable elderly people living in nursing homes and long-term care facilities and those living in or traveling to settings in which the rate of pediatric PCV13 uptake is low or zero.

All adults in this age group should continue to receive a single dose of the pneumococcal 23-valent polysaccharide vaccine.*

HPV

The advisory committee now recommends catch-up immunization for women and men through age 26 years (the previous cutoff for men was 21). And in another new recommendation, the ACIP advises considering vaccination for some patients aged 27-45 years who have not been adequately vaccinated.

“Most people ages 27-45 do not need vaccination, but some may benefit,” Mr. Freedman said. “For example, somebody who’s been in a prior long-term monogamous relationship and suddenly finds himself with a new sexual partner.”

“That makes very good sense for older people who haven’t been vaccinated and might continue to be exposed to HPV,” Daniel M. Musher, MD, a professor of medicine at Baylor College of Medicine and an infectious diseases physician at the Michael E. DeBakey Veterans Affairs Medical Center, both in Houston, said in an interview.

Here again, the ACIP advises taking a shared decision-making approach, with clinicians discussing the merits of vaccination in this and other scenarios with patients according to the talking points outlined in the HPV section.

Influenza, hepatitis A and B

For the 2019-2020 influenza season, routine influenza vaccination is recommended for all persons aged 6 months or older who have no contraindications. Where more than one appropriate option is available, the ACIP does not recommend any product over another.

Routine hepatitis A vaccination is recommended for all persons aged 1 year or older who have HIV infection regardless of their level of immune suppression.

For hepatitis B, a new addition to the list of vulnerable patients who may possibly benefit from vaccination is pregnant women at risk for infection or an adverse infection-related pregnancy outcome. Whereas older formulations are safe, the ACIP does not recommend the HepB-CpG (Heplisav-B) vaccine during pregnancy, owing to the fact that safety data are lacking.

Meningitis B

Individuals aged 10 years or older who have complement deficiency, who use a complement inhibitor, who have asplenia, or who are microbiologists should receive a meningitis B booster dose 1 year following completion of a primary series. After that, they should receive booster doses every 2-3 years for as long they are at elevated risk.

Vaccination should be discussed with individuals aged 16-23 years even if they are not at increased risk for meningococcal disease. Persons aged 10 years or older whom public health authorities deem to be at increased risk during an outbreak should have a one-time booster dose if at least 1 year has elapsed since completion of a meningitis B primary series.

Td/Tdap, varicella

The ACIP now recommends that either the Td or Tdap vaccine be given in cases in which currently just the Td vaccine is recommended; that is, for the 10-year booster shot as well as for tetanus prophylaxis in wound management and the catch-up immunization schedule, including that for pregnant women.

Vaccination against varicella should be considered for HIV-infected individuals who are without evidence of varicella immunity and whose CD4 counts are at least 200 cells/mL.

Dr. Musher, who was not involved in drafting the recommendations, takes issue generally with the addition of shared clinical decision making on vaccination. “Shared decision making is a problem for anyone practicing medicine. It places a terrible burden [on] the doctors to discuss these options with patients at great length. Most patients want the doctor to make the decision.”

In his view, this approach makes little sense in the case of the PCV13 vaccine because the strains it covers have disappeared from the population through the widespread vaccination of children. “But discussions are important for some vaccines, such as the herpes zoster vaccine, since patients can have a terrible reaction to the first dose and refuse to have the second,” he said.

Some of these new recommendations were released in 2019 after ACIP members met to vote on them in February, June, and October.

As in previous years, the schedule has been streamlined for easier reference. Physicians are reminded to closely read the details in the vaccine notes, as these specify who needs what vaccine, when, and at what dose.

The ACIP develops its recommendations after reviewing vaccine-related data, including the data regarding the epidemiology and burden of the vaccine-preventable disease, vaccine effectiveness and safety, the quality of evidence, implementability, and the economics of immunization policy.

The authors have received grants and expense payments from public and not-for-profit institutions. One coauthor has received fees from ACI Clinical for data and safety monitoring in an immunization trial. Dr. Musher has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Correction, 3/31/20: An earlier version of this article misstated the recommendation for administration of the pneumococcal 23-valent polysaccharide vaccine. All adults in this age group should continue to receive a single dose of this vaccine. 

The Centers for Disease Control and Prevention has released an updated schedule for adult vaccines. The update includes changes regarding the administration of several vaccines, including those for influenza, human papillomavirus (HPV), hepatitis A and B, and meningitis B, as well as the pneumococcal 13-valent conjugate (PCV13) vaccine.

The schedule, revised annually by the Advisory Committee on Immunization Practices (ACIP) of the CDC, was simultaneously published online February 3, 2020, in the Annals of Internal Medicine and on the CDC website.

Perhaps the change most likely to raise questions is that concerning the PCV13 vaccine. “Owing to a decline in prevalence of the types covered by the PCV13 vaccine, this is no longer routinely recommended for all persons age 65 and older,” senior author Mark Freedman, DVM, MPH, of the immunization services division at the National Center for Immunization and Respiratory Disease, said in an interview.

For purposes of shared clinical decision, however, it should be discussed with previously unvaccinated seniors who do not have risk factors, such as an immunocompromising condition, a cerebrospinal fluid leak, or a cochlear implant.

“But the circumstances for use of the vaccine are not always clear even based on the detailed list of considerations provided, because it’s impossible to think of every conceivable combination of risk factors,” Mr. Freedman added.

Possible beneficiaries of this vaccine are vulnerable elderly people living in nursing homes and long-term care facilities and those living in or traveling to settings in which the rate of pediatric PCV13 uptake is low or zero.

All adults in this age group should continue to receive a single dose of the pneumococcal 23-valent polysaccharide vaccine.*

HPV

The advisory committee now recommends catch-up immunization for women and men through age 26 years (the previous cutoff for men was 21). And in another new recommendation, the ACIP advises considering vaccination for some patients aged 27-45 years who have not been adequately vaccinated.

“Most people ages 27-45 do not need vaccination, but some may benefit,” Mr. Freedman said. “For example, somebody who’s been in a prior long-term monogamous relationship and suddenly finds himself with a new sexual partner.”

“That makes very good sense for older people who haven’t been vaccinated and might continue to be exposed to HPV,” Daniel M. Musher, MD, a professor of medicine at Baylor College of Medicine and an infectious diseases physician at the Michael E. DeBakey Veterans Affairs Medical Center, both in Houston, said in an interview.

Here again, the ACIP advises taking a shared decision-making approach, with clinicians discussing the merits of vaccination in this and other scenarios with patients according to the talking points outlined in the HPV section.

Influenza, hepatitis A and B

For the 2019-2020 influenza season, routine influenza vaccination is recommended for all persons aged 6 months or older who have no contraindications. Where more than one appropriate option is available, the ACIP does not recommend any product over another.

Routine hepatitis A vaccination is recommended for all persons aged 1 year or older who have HIV infection regardless of their level of immune suppression.

For hepatitis B, a new addition to the list of vulnerable patients who may possibly benefit from vaccination is pregnant women at risk for infection or an adverse infection-related pregnancy outcome. Whereas older formulations are safe, the ACIP does not recommend the HepB-CpG (Heplisav-B) vaccine during pregnancy, owing to the fact that safety data are lacking.

Meningitis B

Individuals aged 10 years or older who have complement deficiency, who use a complement inhibitor, who have asplenia, or who are microbiologists should receive a meningitis B booster dose 1 year following completion of a primary series. After that, they should receive booster doses every 2-3 years for as long they are at elevated risk.

Vaccination should be discussed with individuals aged 16-23 years even if they are not at increased risk for meningococcal disease. Persons aged 10 years or older whom public health authorities deem to be at increased risk during an outbreak should have a one-time booster dose if at least 1 year has elapsed since completion of a meningitis B primary series.

Td/Tdap, varicella

The ACIP now recommends that either the Td or Tdap vaccine be given in cases in which currently just the Td vaccine is recommended; that is, for the 10-year booster shot as well as for tetanus prophylaxis in wound management and the catch-up immunization schedule, including that for pregnant women.

Vaccination against varicella should be considered for HIV-infected individuals who are without evidence of varicella immunity and whose CD4 counts are at least 200 cells/mL.

Dr. Musher, who was not involved in drafting the recommendations, takes issue generally with the addition of shared clinical decision making on vaccination. “Shared decision making is a problem for anyone practicing medicine. It places a terrible burden [on] the doctors to discuss these options with patients at great length. Most patients want the doctor to make the decision.”

In his view, this approach makes little sense in the case of the PCV13 vaccine because the strains it covers have disappeared from the population through the widespread vaccination of children. “But discussions are important for some vaccines, such as the herpes zoster vaccine, since patients can have a terrible reaction to the first dose and refuse to have the second,” he said.

Some of these new recommendations were released in 2019 after ACIP members met to vote on them in February, June, and October.

As in previous years, the schedule has been streamlined for easier reference. Physicians are reminded to closely read the details in the vaccine notes, as these specify who needs what vaccine, when, and at what dose.

The ACIP develops its recommendations after reviewing vaccine-related data, including the data regarding the epidemiology and burden of the vaccine-preventable disease, vaccine effectiveness and safety, the quality of evidence, implementability, and the economics of immunization policy.

The authors have received grants and expense payments from public and not-for-profit institutions. One coauthor has received fees from ACI Clinical for data and safety monitoring in an immunization trial. Dr. Musher has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Correction, 3/31/20: An earlier version of this article misstated the recommendation for administration of the pneumococcal 23-valent polysaccharide vaccine. All adults in this age group should continue to receive a single dose of this vaccine. 

The Centers for Disease Control and Prevention has released an updated schedule for adult vaccines. The update includes changes regarding the administration of several vaccines, including those for influenza, human papillomavirus (HPV), hepatitis A and B, and meningitis B, as well as the pneumococcal 13-valent conjugate (PCV13) vaccine.

The schedule, revised annually by the Advisory Committee on Immunization Practices (ACIP) of the CDC, was simultaneously published online February 3, 2020, in the Annals of Internal Medicine and on the CDC website.

Perhaps the change most likely to raise questions is that concerning the PCV13 vaccine. “Owing to a decline in prevalence of the types covered by the PCV13 vaccine, this is no longer routinely recommended for all persons age 65 and older,” senior author Mark Freedman, DVM, MPH, of the immunization services division at the National Center for Immunization and Respiratory Disease, said in an interview.

For purposes of shared clinical decision, however, it should be discussed with previously unvaccinated seniors who do not have risk factors, such as an immunocompromising condition, a cerebrospinal fluid leak, or a cochlear implant.

“But the circumstances for use of the vaccine are not always clear even based on the detailed list of considerations provided, because it’s impossible to think of every conceivable combination of risk factors,” Mr. Freedman added.

Possible beneficiaries of this vaccine are vulnerable elderly people living in nursing homes and long-term care facilities and those living in or traveling to settings in which the rate of pediatric PCV13 uptake is low or zero.

All adults in this age group should continue to receive a single dose of the pneumococcal 23-valent polysaccharide vaccine.*

HPV

The advisory committee now recommends catch-up immunization for women and men through age 26 years (the previous cutoff for men was 21). And in another new recommendation, the ACIP advises considering vaccination for some patients aged 27-45 years who have not been adequately vaccinated.

“Most people ages 27-45 do not need vaccination, but some may benefit,” Mr. Freedman said. “For example, somebody who’s been in a prior long-term monogamous relationship and suddenly finds himself with a new sexual partner.”

“That makes very good sense for older people who haven’t been vaccinated and might continue to be exposed to HPV,” Daniel M. Musher, MD, a professor of medicine at Baylor College of Medicine and an infectious diseases physician at the Michael E. DeBakey Veterans Affairs Medical Center, both in Houston, said in an interview.

Here again, the ACIP advises taking a shared decision-making approach, with clinicians discussing the merits of vaccination in this and other scenarios with patients according to the talking points outlined in the HPV section.

Influenza, hepatitis A and B

For the 2019-2020 influenza season, routine influenza vaccination is recommended for all persons aged 6 months or older who have no contraindications. Where more than one appropriate option is available, the ACIP does not recommend any product over another.

Routine hepatitis A vaccination is recommended for all persons aged 1 year or older who have HIV infection regardless of their level of immune suppression.

For hepatitis B, a new addition to the list of vulnerable patients who may possibly benefit from vaccination is pregnant women at risk for infection or an adverse infection-related pregnancy outcome. Whereas older formulations are safe, the ACIP does not recommend the HepB-CpG (Heplisav-B) vaccine during pregnancy, owing to the fact that safety data are lacking.

Meningitis B

Individuals aged 10 years or older who have complement deficiency, who use a complement inhibitor, who have asplenia, or who are microbiologists should receive a meningitis B booster dose 1 year following completion of a primary series. After that, they should receive booster doses every 2-3 years for as long they are at elevated risk.

Vaccination should be discussed with individuals aged 16-23 years even if they are not at increased risk for meningococcal disease. Persons aged 10 years or older whom public health authorities deem to be at increased risk during an outbreak should have a one-time booster dose if at least 1 year has elapsed since completion of a meningitis B primary series.

Td/Tdap, varicella

The ACIP now recommends that either the Td or Tdap vaccine be given in cases in which currently just the Td vaccine is recommended; that is, for the 10-year booster shot as well as for tetanus prophylaxis in wound management and the catch-up immunization schedule, including that for pregnant women.

Vaccination against varicella should be considered for HIV-infected individuals who are without evidence of varicella immunity and whose CD4 counts are at least 200 cells/mL.

Dr. Musher, who was not involved in drafting the recommendations, takes issue generally with the addition of shared clinical decision making on vaccination. “Shared decision making is a problem for anyone practicing medicine. It places a terrible burden [on] the doctors to discuss these options with patients at great length. Most patients want the doctor to make the decision.”

In his view, this approach makes little sense in the case of the PCV13 vaccine because the strains it covers have disappeared from the population through the widespread vaccination of children. “But discussions are important for some vaccines, such as the herpes zoster vaccine, since patients can have a terrible reaction to the first dose and refuse to have the second,” he said.

Some of these new recommendations were released in 2019 after ACIP members met to vote on them in February, June, and October.

As in previous years, the schedule has been streamlined for easier reference. Physicians are reminded to closely read the details in the vaccine notes, as these specify who needs what vaccine, when, and at what dose.

The ACIP develops its recommendations after reviewing vaccine-related data, including the data regarding the epidemiology and burden of the vaccine-preventable disease, vaccine effectiveness and safety, the quality of evidence, implementability, and the economics of immunization policy.

The authors have received grants and expense payments from public and not-for-profit institutions. One coauthor has received fees from ACI Clinical for data and safety monitoring in an immunization trial. Dr. Musher has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Correction, 3/31/20: An earlier version of this article misstated the recommendation for administration of the pneumococcal 23-valent polysaccharide vaccine. All adults in this age group should continue to receive a single dose of this vaccine. 

LOS ANGELES – The way Christos S. Mantzoros, MD, DSc, PhD, sees it, nonalcoholic steatohepatitis (NASH) is an epidemic of the 21st century that can trigger a cascade of reactions.

Doug Brunk/MDedge News

“If more than 5.8% of fat is in the liver, we call it nonalcoholic fatty liver disease [NAFLD],” Dr. Mantzoros, professor of medicine at Harvard Medical School, Boston, and Boston University, explained at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease. “If inflammation develops to remove the fat, we call it NASH. If this progresses to decompensated reaction and fibrosis and cirrhosis, then we call it nonalcoholic steatohepatitis with fibrosis. That can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure.”

The underlying problem stems from the rise in obesity prevalence, according to Dr. Mantzoros, who is also chief of endocrinology at the Boston Veterans Affairs Healthcare System. For 75%-80% of individuals with metabolically unhealthy obesity, the storage space in their adipose tissue is exceeded. “Fat is deposited into muscle, causing insulin resistance, and into the liver,” he explained. “If it’s more than 5.8%, it causes NAFLD. Most of us don’t realize that most of the patients with diabetes we have in our clinics also have nonalcoholic fatty liver disease. That’s because we don’t have an easy diagnostic tool or an easy treatment. It’s an unmet clinical need.” (There are currently no drugs approved for the treatment of NASH or NAFLD. Current recommended first-line treatment is weight loss through diet and exercise and control of diabetes, if it is present.)

“Assuming the rate of increase in cost due to NAFLD parallels the growth in obesity, the 10-year projection for direct cost is $1.005 trillion,” said Dr. Mantzoros, who is also editor in chief of the journal Metabolism. “Obesity, NAFLD, and insulin resistance are each independently associated with a twofold risk for diabetes. If all three are present, there is a 14-fold risk for diabetes. Insulin resistance promotes an increase in free fatty acid traffic to the liver, which can trigger hepatic lipotoxicity. Hyperinsulinemia enhances free fatty acid uptake and activates de novo lipogenesis. Hyperglycemia can also activate de novo lipogenesis.”

About 85 million Americans have NAFLD, he continued. Most (80%) are cases of steatosis, but 20% have NASH. Of those, 20% develop advanced fibrosis, which leads to liver failure and transplantation or death. A study of data from the National Health and Nutrition Examination Survey found that diabetes was the strongest predictor of advanced fibrosis in patients with NAFLD (odds ratio, 18.20), followed by a body mass index of 30 kg/m² or greater (OR, 9.10), hypertension (OR, 1.20), and age (OR, 1.08; Ailment Pharmacol Ther. 2017;46:974-80). “Most of the patients who come to our clinics with diabetes have nonalcoholic fatty liver disease – 75%-80% in our clinics, and about 10% have advanced fibrosis,” Dr. Mantzoros said. “Most of them go undiagnosed.”

Patients with type 2 diabetes and NAFLD progress faster to fibrosis and end-stage liver disease, compared with those who do not have diabetes. One study of 108 patients with biopsy-proven NALFD showed that 84% of those with fibrosis progression had type 2 diabetes (J Hepatol. 2015;62:1148-55). Other findings have shown that patients with type 2 diabetes are at increased risk of chronic NAFLD and hepatocellular carcinoma (Gastroenterol. 2001;126:460-8). “We are doing more liver transplantations because of NAFLD and NASH than because of hepatitis C,” Dr. Mantzoros said. “What we need to keep in mind is that, although liver morbidity and mortality is important, this is a component of the cardiometabolic syndrome. So, people have all the risk factors for cardiovascular disease. Because CVD is much more common, people with NAFLD suffer from and die from CVD. The more advanced the NAFLD, the higher the risk of death from cardiovascular disease.”

Multiple risk factors can help identify patients with advanced fibrosis because of NASH, he continued, including having features of the metabolic syndrome, being over 50 years of age, being Hispanic, having high levels of ALT/AST, low platelets, and having low albumin. “These are frequent tests that we can find in the EMR,” Dr. Mantzoros said. “The problem with ALT is that, in many stages of the disease, ALT goes up. But after a certain stage of the disease, when most of the liver is controlled by fibrosis and cirrhosis, most of the hepatocytes are dead and don’t secrete ALT, so ALT in end-stage renal disease goes up.”

Recent guidelines recognize the association between diabetes, NAFLD, and NASH, and call for increased vigilance and screening tests. According to guidelines from the American Association for the Study of Liver Diseases, the Fibrosis-4 Index or the NAFLD Fibrosis Score are clinically useful tools for identifying NAFLD in patients with higher likelihood of having bridging fibrosis or cirrhosis (Hepatology. 2018;67[1]:328-57). Vibration-controlled transient elastography or MRI are clinically useful tools for identifying advanced fibrosis in patients with NAFLD, whereas clinical decision aids, such as Fibrosis-4, NAFLD Fibrosis Score, or vibration-controlled transient elastography, can be used to identify patients at low or high risk for advanced fibrosis.

“If we have a patient with suspected NAFLD, we need to rule out alcohol use, we need to confirm NAFLD, and we need to risk stratify, and classify as low, intermediate, or high risk,” Dr. Mantzoros said. Most of his patients who meet criteria for high-risk NASH do not elect to undergo a liver biopsy. “I don’t blame them for that,” he said. “There is a 0.1 per 1,000 mortality risk, even in the best hands. If 80 million people who have fatty liver were to undergo a liver biopsy, we would have 16,000 deaths every year just because of that. We would not tolerate that.”

Recently, Dr. Mantzoros and colleagues published a proof-of-concept study that proposes novel models using lipids, hormones, and glycans that can diagnose the presence of NASH, NAFLD, or healthy status with high accuracy (Metabolism. 2019 Nov 8. doi: 10.1016/j.metabol.2019.154005). “We are now working with companies to validate it and expand it, not only as a diagnostic marker, but as a prognostic marker, and to try to commercialize it in the future,” he said.

Current pharmacotherapies are limited to patients with biopsy-confirmed NASH and fibrosis. Pioglitazone is a first-line, off-label pharmacologic treatment, while vitamin E may be used in patients with biopsy-confirmed NASH without diabetes. Metformin, glucagonlike peptide–1 receptor agonists, and sodium-glucose transporter 2 inhibitors are either not recommended or have insufficient evidence to recommend their use. More than 60 phase 2 trials are planned or ongoing, Dr. Mantzoros added, with phase trials underway for cenicriviroc, elafibranor, obeticholic acid, and selonsertib.

The role of lifestyle management is also important. “The Mediterranean diet has the best evidence, along with exercise, to improve early stages of NAFLD,” he said. “Weight loss is very important. If the patient loses 10% of their weight or more, there is NASH resolution 90% of the time. With less weight loss, we have less resolution. The problem is that only 10% of patients or less can sustain a more than 90% weight loss over a year.”

Dr. Mantzoros reported being a shareholder of Coherus BioSciences and Pangea Therapeutics, having served as an adviser to Coherus, Novo Nordisk, and Genfit and having received research grants through his institution from Coherus, Eisai, and Novo Nordisk.

[email protected]

LOS ANGELES – The way Christos S. Mantzoros, MD, DSc, PhD, sees it, nonalcoholic steatohepatitis (NASH) is an epidemic of the 21st century that can trigger a cascade of reactions.

Doug Brunk/MDedge News

“If more than 5.8% of fat is in the liver, we call it nonalcoholic fatty liver disease [NAFLD],” Dr. Mantzoros, professor of medicine at Harvard Medical School, Boston, and Boston University, explained at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease. “If inflammation develops to remove the fat, we call it NASH. If this progresses to decompensated reaction and fibrosis and cirrhosis, then we call it nonalcoholic steatohepatitis with fibrosis. That can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure.”

The underlying problem stems from the rise in obesity prevalence, according to Dr. Mantzoros, who is also chief of endocrinology at the Boston Veterans Affairs Healthcare System. For 75%-80% of individuals with metabolically unhealthy obesity, the storage space in their adipose tissue is exceeded. “Fat is deposited into muscle, causing insulin resistance, and into the liver,” he explained. “If it’s more than 5.8%, it causes NAFLD. Most of us don’t realize that most of the patients with diabetes we have in our clinics also have nonalcoholic fatty liver disease. That’s because we don’t have an easy diagnostic tool or an easy treatment. It’s an unmet clinical need.” (There are currently no drugs approved for the treatment of NASH or NAFLD. Current recommended first-line treatment is weight loss through diet and exercise and control of diabetes, if it is present.)

“Assuming the rate of increase in cost due to NAFLD parallels the growth in obesity, the 10-year projection for direct cost is $1.005 trillion,” said Dr. Mantzoros, who is also editor in chief of the journal Metabolism. “Obesity, NAFLD, and insulin resistance are each independently associated with a twofold risk for diabetes. If all three are present, there is a 14-fold risk for diabetes. Insulin resistance promotes an increase in free fatty acid traffic to the liver, which can trigger hepatic lipotoxicity. Hyperinsulinemia enhances free fatty acid uptake and activates de novo lipogenesis. Hyperglycemia can also activate de novo lipogenesis.”

About 85 million Americans have NAFLD, he continued. Most (80%) are cases of steatosis, but 20% have NASH. Of those, 20% develop advanced fibrosis, which leads to liver failure and transplantation or death. A study of data from the National Health and Nutrition Examination Survey found that diabetes was the strongest predictor of advanced fibrosis in patients with NAFLD (odds ratio, 18.20), followed by a body mass index of 30 kg/m² or greater (OR, 9.10), hypertension (OR, 1.20), and age (OR, 1.08; Ailment Pharmacol Ther. 2017;46:974-80). “Most of the patients who come to our clinics with diabetes have nonalcoholic fatty liver disease – 75%-80% in our clinics, and about 10% have advanced fibrosis,” Dr. Mantzoros said. “Most of them go undiagnosed.”

Patients with type 2 diabetes and NAFLD progress faster to fibrosis and end-stage liver disease, compared with those who do not have diabetes. One study of 108 patients with biopsy-proven NALFD showed that 84% of those with fibrosis progression had type 2 diabetes (J Hepatol. 2015;62:1148-55). Other findings have shown that patients with type 2 diabetes are at increased risk of chronic NAFLD and hepatocellular carcinoma (Gastroenterol. 2001;126:460-8). “We are doing more liver transplantations because of NAFLD and NASH than because of hepatitis C,” Dr. Mantzoros said. “What we need to keep in mind is that, although liver morbidity and mortality is important, this is a component of the cardiometabolic syndrome. So, people have all the risk factors for cardiovascular disease. Because CVD is much more common, people with NAFLD suffer from and die from CVD. The more advanced the NAFLD, the higher the risk of death from cardiovascular disease.”

Multiple risk factors can help identify patients with advanced fibrosis because of NASH, he continued, including having features of the metabolic syndrome, being over 50 years of age, being Hispanic, having high levels of ALT/AST, low platelets, and having low albumin. “These are frequent tests that we can find in the EMR,” Dr. Mantzoros said. “The problem with ALT is that, in many stages of the disease, ALT goes up. But after a certain stage of the disease, when most of the liver is controlled by fibrosis and cirrhosis, most of the hepatocytes are dead and don’t secrete ALT, so ALT in end-stage renal disease goes up.”

Recent guidelines recognize the association between diabetes, NAFLD, and NASH, and call for increased vigilance and screening tests. According to guidelines from the American Association for the Study of Liver Diseases, the Fibrosis-4 Index or the NAFLD Fibrosis Score are clinically useful tools for identifying NAFLD in patients with higher likelihood of having bridging fibrosis or cirrhosis (Hepatology. 2018;67[1]:328-57). Vibration-controlled transient elastography or MRI are clinically useful tools for identifying advanced fibrosis in patients with NAFLD, whereas clinical decision aids, such as Fibrosis-4, NAFLD Fibrosis Score, or vibration-controlled transient elastography, can be used to identify patients at low or high risk for advanced fibrosis.

“If we have a patient with suspected NAFLD, we need to rule out alcohol use, we need to confirm NAFLD, and we need to risk stratify, and classify as low, intermediate, or high risk,” Dr. Mantzoros said. Most of his patients who meet criteria for high-risk NASH do not elect to undergo a liver biopsy. “I don’t blame them for that,” he said. “There is a 0.1 per 1,000 mortality risk, even in the best hands. If 80 million people who have fatty liver were to undergo a liver biopsy, we would have 16,000 deaths every year just because of that. We would not tolerate that.”

Recently, Dr. Mantzoros and colleagues published a proof-of-concept study that proposes novel models using lipids, hormones, and glycans that can diagnose the presence of NASH, NAFLD, or healthy status with high accuracy (Metabolism. 2019 Nov 8. doi: 10.1016/j.metabol.2019.154005). “We are now working with companies to validate it and expand it, not only as a diagnostic marker, but as a prognostic marker, and to try to commercialize it in the future,” he said.

Current pharmacotherapies are limited to patients with biopsy-confirmed NASH and fibrosis. Pioglitazone is a first-line, off-label pharmacologic treatment, while vitamin E may be used in patients with biopsy-confirmed NASH without diabetes. Metformin, glucagonlike peptide–1 receptor agonists, and sodium-glucose transporter 2 inhibitors are either not recommended or have insufficient evidence to recommend their use. More than 60 phase 2 trials are planned or ongoing, Dr. Mantzoros added, with phase trials underway for cenicriviroc, elafibranor, obeticholic acid, and selonsertib.

The role of lifestyle management is also important. “The Mediterranean diet has the best evidence, along with exercise, to improve early stages of NAFLD,” he said. “Weight loss is very important. If the patient loses 10% of their weight or more, there is NASH resolution 90% of the time. With less weight loss, we have less resolution. The problem is that only 10% of patients or less can sustain a more than 90% weight loss over a year.”

Dr. Mantzoros reported being a shareholder of Coherus BioSciences and Pangea Therapeutics, having served as an adviser to Coherus, Novo Nordisk, and Genfit and having received research grants through his institution from Coherus, Eisai, and Novo Nordisk.

[email protected]

LOS ANGELES – The way Christos S. Mantzoros, MD, DSc, PhD, sees it, nonalcoholic steatohepatitis (NASH) is an epidemic of the 21st century that can trigger a cascade of reactions.

Doug Brunk/MDedge News

“If more than 5.8% of fat is in the liver, we call it nonalcoholic fatty liver disease [NAFLD],” Dr. Mantzoros, professor of medicine at Harvard Medical School, Boston, and Boston University, explained at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease. “If inflammation develops to remove the fat, we call it NASH. If this progresses to decompensated reaction and fibrosis and cirrhosis, then we call it nonalcoholic steatohepatitis with fibrosis. That can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure.”

The underlying problem stems from the rise in obesity prevalence, according to Dr. Mantzoros, who is also chief of endocrinology at the Boston Veterans Affairs Healthcare System. For 75%-80% of individuals with metabolically unhealthy obesity, the storage space in their adipose tissue is exceeded. “Fat is deposited into muscle, causing insulin resistance, and into the liver,” he explained. “If it’s more than 5.8%, it causes NAFLD. Most of us don’t realize that most of the patients with diabetes we have in our clinics also have nonalcoholic fatty liver disease. That’s because we don’t have an easy diagnostic tool or an easy treatment. It’s an unmet clinical need.” (There are currently no drugs approved for the treatment of NASH or NAFLD. Current recommended first-line treatment is weight loss through diet and exercise and control of diabetes, if it is present.)

“Assuming the rate of increase in cost due to NAFLD parallels the growth in obesity, the 10-year projection for direct cost is $1.005 trillion,” said Dr. Mantzoros, who is also editor in chief of the journal Metabolism. “Obesity, NAFLD, and insulin resistance are each independently associated with a twofold risk for diabetes. If all three are present, there is a 14-fold risk for diabetes. Insulin resistance promotes an increase in free fatty acid traffic to the liver, which can trigger hepatic lipotoxicity. Hyperinsulinemia enhances free fatty acid uptake and activates de novo lipogenesis. Hyperglycemia can also activate de novo lipogenesis.”

About 85 million Americans have NAFLD, he continued. Most (80%) are cases of steatosis, but 20% have NASH. Of those, 20% develop advanced fibrosis, which leads to liver failure and transplantation or death. A study of data from the National Health and Nutrition Examination Survey found that diabetes was the strongest predictor of advanced fibrosis in patients with NAFLD (odds ratio, 18.20), followed by a body mass index of 30 kg/m² or greater (OR, 9.10), hypertension (OR, 1.20), and age (OR, 1.08; Ailment Pharmacol Ther. 2017;46:974-80). “Most of the patients who come to our clinics with diabetes have nonalcoholic fatty liver disease – 75%-80% in our clinics, and about 10% have advanced fibrosis,” Dr. Mantzoros said. “Most of them go undiagnosed.”

Patients with type 2 diabetes and NAFLD progress faster to fibrosis and end-stage liver disease, compared with those who do not have diabetes. One study of 108 patients with biopsy-proven NALFD showed that 84% of those with fibrosis progression had type 2 diabetes (J Hepatol. 2015;62:1148-55). Other findings have shown that patients with type 2 diabetes are at increased risk of chronic NAFLD and hepatocellular carcinoma (Gastroenterol. 2001;126:460-8). “We are doing more liver transplantations because of NAFLD and NASH than because of hepatitis C,” Dr. Mantzoros said. “What we need to keep in mind is that, although liver morbidity and mortality is important, this is a component of the cardiometabolic syndrome. So, people have all the risk factors for cardiovascular disease. Because CVD is much more common, people with NAFLD suffer from and die from CVD. The more advanced the NAFLD, the higher the risk of death from cardiovascular disease.”

Multiple risk factors can help identify patients with advanced fibrosis because of NASH, he continued, including having features of the metabolic syndrome, being over 50 years of age, being Hispanic, having high levels of ALT/AST, low platelets, and having low albumin. “These are frequent tests that we can find in the EMR,” Dr. Mantzoros said. “The problem with ALT is that, in many stages of the disease, ALT goes up. But after a certain stage of the disease, when most of the liver is controlled by fibrosis and cirrhosis, most of the hepatocytes are dead and don’t secrete ALT, so ALT in end-stage renal disease goes up.”

Recent guidelines recognize the association between diabetes, NAFLD, and NASH, and call for increased vigilance and screening tests. According to guidelines from the American Association for the Study of Liver Diseases, the Fibrosis-4 Index or the NAFLD Fibrosis Score are clinically useful tools for identifying NAFLD in patients with higher likelihood of having bridging fibrosis or cirrhosis (Hepatology. 2018;67[1]:328-57). Vibration-controlled transient elastography or MRI are clinically useful tools for identifying advanced fibrosis in patients with NAFLD, whereas clinical decision aids, such as Fibrosis-4, NAFLD Fibrosis Score, or vibration-controlled transient elastography, can be used to identify patients at low or high risk for advanced fibrosis.

“If we have a patient with suspected NAFLD, we need to rule out alcohol use, we need to confirm NAFLD, and we need to risk stratify, and classify as low, intermediate, or high risk,” Dr. Mantzoros said. Most of his patients who meet criteria for high-risk NASH do not elect to undergo a liver biopsy. “I don’t blame them for that,” he said. “There is a 0.1 per 1,000 mortality risk, even in the best hands. If 80 million people who have fatty liver were to undergo a liver biopsy, we would have 16,000 deaths every year just because of that. We would not tolerate that.”

Recently, Dr. Mantzoros and colleagues published a proof-of-concept study that proposes novel models using lipids, hormones, and glycans that can diagnose the presence of NASH, NAFLD, or healthy status with high accuracy (Metabolism. 2019 Nov 8. doi: 10.1016/j.metabol.2019.154005). “We are now working with companies to validate it and expand it, not only as a diagnostic marker, but as a prognostic marker, and to try to commercialize it in the future,” he said.

Current pharmacotherapies are limited to patients with biopsy-confirmed NASH and fibrosis. Pioglitazone is a first-line, off-label pharmacologic treatment, while vitamin E may be used in patients with biopsy-confirmed NASH without diabetes. Metformin, glucagonlike peptide–1 receptor agonists, and sodium-glucose transporter 2 inhibitors are either not recommended or have insufficient evidence to recommend their use. More than 60 phase 2 trials are planned or ongoing, Dr. Mantzoros added, with phase trials underway for cenicriviroc, elafibranor, obeticholic acid, and selonsertib.

The role of lifestyle management is also important. “The Mediterranean diet has the best evidence, along with exercise, to improve early stages of NAFLD,” he said. “Weight loss is very important. If the patient loses 10% of their weight or more, there is NASH resolution 90% of the time. With less weight loss, we have less resolution. The problem is that only 10% of patients or less can sustain a more than 90% weight loss over a year.”

Dr. Mantzoros reported being a shareholder of Coherus BioSciences and Pangea Therapeutics, having served as an adviser to Coherus, Novo Nordisk, and Genfit and having received research grants through his institution from Coherus, Eisai, and Novo Nordisk.

[email protected]

An additional 5 cases of 2019 novel coronavirus (2109-nCoV) have been confirmed in the United States, bringing the total number of confirmed cases to 11, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during a Centers for Disease Control and Prevention press briefing.

Four of the new cases are in California, and one in Massachusetts. Although four of the new cases have recent travel history to Wuhan, China, the epicenter of the 2019-nCoV outbreak, the fifth is a close household contact of one of the other California patients, said Dr. Messonnier. This last case is the second instance of person-to-person spread of 2019-nCoV in the United States.

“We expect to find additional cases of the novel coronavirus in the United States,” she said. “We expect to see more cases of person-to-person spread among close contacts. And we continue to expect this will happen given the explosive nature of this outbreak in China.”

As of the morning of Feb. 3, 167 persons under investigation, or PUIs, for possible 2019-nCoV have tested negative for the virus, and an additional 82 PUIs have testing pending – this latter figure includes some tests that are still in transit to the CDC, said Dr. Messonnier.

During the briefing, Dr. Messonnier emphasized both the aggressive nature of the U.S. public health response and the rationale for quick and assertive action. “The goal of our public health response is to protect and contain,” she said. “Strong measures now may blunt the impact of this virus on the United States.”

She cited the intensity of transmission in Hubei Province, the expansion of transmission to other provinces in China, the expansion of cases outside of China, and sporadic ongoing deaths from 2019-nCoV as drivers of the aggressive U.S. public health response.

A presidential proclamation is currently in place that bars U.S. entry to foreign nationals who have visited mainland China within the past 14 days; the ban does not apply to travelers from Hong Kong and Macao. Immediate family members of U.S. citizens and individuals who have U.S. permanent resident status are exempted from the entry ban and will be allowed entry into the United States.

However, explained Dr. Messonnier, those who have traveled to China recently and are permitted entry will be subject to screening. All passengers with such recent travel will be directed to one of 11 U.S. airports set up to perform additional screening.

As of Feb 3, the list of airports includes:

• San Francisco International Airport in California.
• Los Angeles International Airport in California.
• Hartsfield-Jackson Atlanta International Airport in Georgia.
• Daniel K. Inouye International Airport in Hawaii.
• O’Hare International Airport in Illinois.
• Detroit Metropolitan Airport in Michigan.
• Newark Liberty International Airport in New Jersey.
• John F. Kennedy International Airport in New York.
• Dallas/Fort Worth International Airport in Texas.
• Washington Dulles International Airport in Virginia.
• Seattle-Tacoma International Airport in Washington.

Travelers who have been to Hubei Province in the previous 14 days will have an additional health assessment at which they will be screened for fever, cough, or difficulty breathing. Any American citizens or exempt individuals who are symptomatic would then be transferred for further medical evaluation. Asymptomatic travelers in this category will be subject to a mandatory 14-day quarantine near their point of entry, rather than continuing on to their final destinations.

Dr. Messonnier emphasized that the mandatory 14-day quarantine is specifically for Americans or exempt individuals returning from Hubei Province, adding that the CDC is presently working with individual states to determine the exact venues for quarantine.

American citizens and exempt individuals returning from other parts of mainland China will be routed to one of the 11 airports and will also receive additional health screening. Symptomatic individuals in this travel category would be referred for further evaluation before being able to complete their itinerary.

Asymptomatic American citizens and exempt individuals who are returning from mainland China – but not Hubei Province – will be allowed to travel on to their final destinations, but will be asked to stay home as much as possible and to monitor their health during the 14 days after their return.

The U.S. Department of State is bringing back more Americans from Wuhan province this week, and these individuals will also be kept under federal quarantine for 14 days.

“There are likely to be confirmed infections among returning travelers,” said Dr. Messonnier. “It is important to note that this strategy is not meant to catch every single traveler returning from China with novel coronavirus; given the nature of this virus and how it’s spreading, that would be impossible, but working together we can catch the majority of them.

“The goal here is to slow the entry of this virus into the United States,” she said, adding that the nation’s health care and public health systems stand on high alert to detect the virus in community settings. In response to questioning from the press, Dr. Messonnier defended the stringent quarantine measures, noting that they are in line with those taken by some other nations, and with the aggressive action being taken by the Chinese government itself. “These actions are science based and aimed at protecting the health of all Americans,” she said.

The real-time reverse transcription polymerase chain reaction (rRT-PCR) assay that the CDC has developed detects 2019-nCoV in both respiratory and serum specimens. Dr. Messonnier reported that the CDC is today filing an emergency use authorization (EUA) application to the U.S. Food and Drug Administration to expedite access to the assay for public health laboratories across the country. “This will greatly enhance our capacity to test for this virus,” she said, noting that EUA approval may come as soon as the end of this week.

Although the CDC is poised to send an expert team to China, it’s still awaiting favorable results from the international negotiations currently underway. “This is a horrible situation in China,” said Dr. Messonnier. “Our presence on the ground in China would be a help to China. ... Science should trump everything else; that’s what we’re hoping – that the scientific expertise of the global community can be brought to bear on the incredibly complicated, difficult situation that our colleagues in China are dealing with.”

[email protected]

An additional 5 cases of 2019 novel coronavirus (2109-nCoV) have been confirmed in the United States, bringing the total number of confirmed cases to 11, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during a Centers for Disease Control and Prevention press briefing.

Four of the new cases are in California, and one in Massachusetts. Although four of the new cases have recent travel history to Wuhan, China, the epicenter of the 2019-nCoV outbreak, the fifth is a close household contact of one of the other California patients, said Dr. Messonnier. This last case is the second instance of person-to-person spread of 2019-nCoV in the United States.

“We expect to find additional cases of the novel coronavirus in the United States,” she said. “We expect to see more cases of person-to-person spread among close contacts. And we continue to expect this will happen given the explosive nature of this outbreak in China.”

As of the morning of Feb. 3, 167 persons under investigation, or PUIs, for possible 2019-nCoV have tested negative for the virus, and an additional 82 PUIs have testing pending – this latter figure includes some tests that are still in transit to the CDC, said Dr. Messonnier.

During the briefing, Dr. Messonnier emphasized both the aggressive nature of the U.S. public health response and the rationale for quick and assertive action. “The goal of our public health response is to protect and contain,” she said. “Strong measures now may blunt the impact of this virus on the United States.”

She cited the intensity of transmission in Hubei Province, the expansion of transmission to other provinces in China, the expansion of cases outside of China, and sporadic ongoing deaths from 2019-nCoV as drivers of the aggressive U.S. public health response.

A presidential proclamation is currently in place that bars U.S. entry to foreign nationals who have visited mainland China within the past 14 days; the ban does not apply to travelers from Hong Kong and Macao. Immediate family members of U.S. citizens and individuals who have U.S. permanent resident status are exempted from the entry ban and will be allowed entry into the United States.

However, explained Dr. Messonnier, those who have traveled to China recently and are permitted entry will be subject to screening. All passengers with such recent travel will be directed to one of 11 U.S. airports set up to perform additional screening.

As of Feb 3, the list of airports includes:

• San Francisco International Airport in California.
• Los Angeles International Airport in California.
• Hartsfield-Jackson Atlanta International Airport in Georgia.
• Daniel K. Inouye International Airport in Hawaii.
• O’Hare International Airport in Illinois.
• Detroit Metropolitan Airport in Michigan.
• Newark Liberty International Airport in New Jersey.
• John F. Kennedy International Airport in New York.
• Dallas/Fort Worth International Airport in Texas.
• Washington Dulles International Airport in Virginia.
• Seattle-Tacoma International Airport in Washington.

Travelers who have been to Hubei Province in the previous 14 days will have an additional health assessment at which they will be screened for fever, cough, or difficulty breathing. Any American citizens or exempt individuals who are symptomatic would then be transferred for further medical evaluation. Asymptomatic travelers in this category will be subject to a mandatory 14-day quarantine near their point of entry, rather than continuing on to their final destinations.

Dr. Messonnier emphasized that the mandatory 14-day quarantine is specifically for Americans or exempt individuals returning from Hubei Province, adding that the CDC is presently working with individual states to determine the exact venues for quarantine.

American citizens and exempt individuals returning from other parts of mainland China will be routed to one of the 11 airports and will also receive additional health screening. Symptomatic individuals in this travel category would be referred for further evaluation before being able to complete their itinerary.

Asymptomatic American citizens and exempt individuals who are returning from mainland China – but not Hubei Province – will be allowed to travel on to their final destinations, but will be asked to stay home as much as possible and to monitor their health during the 14 days after their return.

The U.S. Department of State is bringing back more Americans from Wuhan province this week, and these individuals will also be kept under federal quarantine for 14 days.

“There are likely to be confirmed infections among returning travelers,” said Dr. Messonnier. “It is important to note that this strategy is not meant to catch every single traveler returning from China with novel coronavirus; given the nature of this virus and how it’s spreading, that would be impossible, but working together we can catch the majority of them.

“The goal here is to slow the entry of this virus into the United States,” she said, adding that the nation’s health care and public health systems stand on high alert to detect the virus in community settings. In response to questioning from the press, Dr. Messonnier defended the stringent quarantine measures, noting that they are in line with those taken by some other nations, and with the aggressive action being taken by the Chinese government itself. “These actions are science based and aimed at protecting the health of all Americans,” she said.

The real-time reverse transcription polymerase chain reaction (rRT-PCR) assay that the CDC has developed detects 2019-nCoV in both respiratory and serum specimens. Dr. Messonnier reported that the CDC is today filing an emergency use authorization (EUA) application to the U.S. Food and Drug Administration to expedite access to the assay for public health laboratories across the country. “This will greatly enhance our capacity to test for this virus,” she said, noting that EUA approval may come as soon as the end of this week.

Although the CDC is poised to send an expert team to China, it’s still awaiting favorable results from the international negotiations currently underway. “This is a horrible situation in China,” said Dr. Messonnier. “Our presence on the ground in China would be a help to China. ... Science should trump everything else; that’s what we’re hoping – that the scientific expertise of the global community can be brought to bear on the incredibly complicated, difficult situation that our colleagues in China are dealing with.”

[email protected]

An additional 5 cases of 2019 novel coronavirus (2109-nCoV) have been confirmed in the United States, bringing the total number of confirmed cases to 11, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during a Centers for Disease Control and Prevention press briefing.

Four of the new cases are in California, and one in Massachusetts. Although four of the new cases have recent travel history to Wuhan, China, the epicenter of the 2019-nCoV outbreak, the fifth is a close household contact of one of the other California patients, said Dr. Messonnier. This last case is the second instance of person-to-person spread of 2019-nCoV in the United States.

“We expect to find additional cases of the novel coronavirus in the United States,” she said. “We expect to see more cases of person-to-person spread among close contacts. And we continue to expect this will happen given the explosive nature of this outbreak in China.”

As of the morning of Feb. 3, 167 persons under investigation, or PUIs, for possible 2019-nCoV have tested negative for the virus, and an additional 82 PUIs have testing pending – this latter figure includes some tests that are still in transit to the CDC, said Dr. Messonnier.

During the briefing, Dr. Messonnier emphasized both the aggressive nature of the U.S. public health response and the rationale for quick and assertive action. “The goal of our public health response is to protect and contain,” she said. “Strong measures now may blunt the impact of this virus on the United States.”

She cited the intensity of transmission in Hubei Province, the expansion of transmission to other provinces in China, the expansion of cases outside of China, and sporadic ongoing deaths from 2019-nCoV as drivers of the aggressive U.S. public health response.

A presidential proclamation is currently in place that bars U.S. entry to foreign nationals who have visited mainland China within the past 14 days; the ban does not apply to travelers from Hong Kong and Macao. Immediate family members of U.S. citizens and individuals who have U.S. permanent resident status are exempted from the entry ban and will be allowed entry into the United States.

However, explained Dr. Messonnier, those who have traveled to China recently and are permitted entry will be subject to screening. All passengers with such recent travel will be directed to one of 11 U.S. airports set up to perform additional screening.

As of Feb 3, the list of airports includes:

• San Francisco International Airport in California.
• Los Angeles International Airport in California.
• Hartsfield-Jackson Atlanta International Airport in Georgia.
• Daniel K. Inouye International Airport in Hawaii.
• O’Hare International Airport in Illinois.
• Detroit Metropolitan Airport in Michigan.
• Newark Liberty International Airport in New Jersey.
• John F. Kennedy International Airport in New York.
• Dallas/Fort Worth International Airport in Texas.
• Washington Dulles International Airport in Virginia.
• Seattle-Tacoma International Airport in Washington.

Travelers who have been to Hubei Province in the previous 14 days will have an additional health assessment at which they will be screened for fever, cough, or difficulty breathing. Any American citizens or exempt individuals who are symptomatic would then be transferred for further medical evaluation. Asymptomatic travelers in this category will be subject to a mandatory 14-day quarantine near their point of entry, rather than continuing on to their final destinations.

Dr. Messonnier emphasized that the mandatory 14-day quarantine is specifically for Americans or exempt individuals returning from Hubei Province, adding that the CDC is presently working with individual states to determine the exact venues for quarantine.

American citizens and exempt individuals returning from other parts of mainland China will be routed to one of the 11 airports and will also receive additional health screening. Symptomatic individuals in this travel category would be referred for further evaluation before being able to complete their itinerary.

Asymptomatic American citizens and exempt individuals who are returning from mainland China – but not Hubei Province – will be allowed to travel on to their final destinations, but will be asked to stay home as much as possible and to monitor their health during the 14 days after their return.

The U.S. Department of State is bringing back more Americans from Wuhan province this week, and these individuals will also be kept under federal quarantine for 14 days.

“There are likely to be confirmed infections among returning travelers,” said Dr. Messonnier. “It is important to note that this strategy is not meant to catch every single traveler returning from China with novel coronavirus; given the nature of this virus and how it’s spreading, that would be impossible, but working together we can catch the majority of them.

“The goal here is to slow the entry of this virus into the United States,” she said, adding that the nation’s health care and public health systems stand on high alert to detect the virus in community settings. In response to questioning from the press, Dr. Messonnier defended the stringent quarantine measures, noting that they are in line with those taken by some other nations, and with the aggressive action being taken by the Chinese government itself. “These actions are science based and aimed at protecting the health of all Americans,” she said.

The real-time reverse transcription polymerase chain reaction (rRT-PCR) assay that the CDC has developed detects 2019-nCoV in both respiratory and serum specimens. Dr. Messonnier reported that the CDC is today filing an emergency use authorization (EUA) application to the U.S. Food and Drug Administration to expedite access to the assay for public health laboratories across the country. “This will greatly enhance our capacity to test for this virus,” she said, noting that EUA approval may come as soon as the end of this week.

Although the CDC is poised to send an expert team to China, it’s still awaiting favorable results from the international negotiations currently underway. “This is a horrible situation in China,” said Dr. Messonnier. “Our presence on the ground in China would be a help to China. ... Science should trump everything else; that’s what we’re hoping – that the scientific expertise of the global community can be brought to bear on the incredibly complicated, difficult situation that our colleagues in China are dealing with.”

[email protected]

For lung cancer patients with moderately decreased lung function, the 6-minute walk test may be a useful tool to help predict postoperative cardiopulmonary complications, researchers have found.

Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.

This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea. 

“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.

More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.

Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.

Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test. 

Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.

Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).

By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.

Dr. Lee and coauthors said they had no conflicts of interest to disclose.

SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.

For lung cancer patients with moderately decreased lung function, the 6-minute walk test may be a useful tool to help predict postoperative cardiopulmonary complications, researchers have found.

Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.

This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea. 

“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.

More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.

Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.

Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test. 

Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.

Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).

By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.

Dr. Lee and coauthors said they had no conflicts of interest to disclose.

SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.

For lung cancer patients with moderately decreased lung function, the 6-minute walk test may be a useful tool to help predict postoperative cardiopulmonary complications, researchers have found.

Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.

This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea. 

“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.

More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.

Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.

Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test. 

Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.

Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).

By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.

Dr. Lee and coauthors said they had no conflicts of interest to disclose.

SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Prostatic leiomyosarcoma is a rare tumor.¹ This neoplasm is composed of highly aggressive prostatic smooth muscle cells that present with nonspecific signs and symptoms mimicking other forms of prostatic pathology. Of the primary prostatic sarcomas, leiomyosarcoma represents the most common subtype in adults and is found in 38% to 52% of newly diagnosed prostate sarcoma.^1,2 The prognosis is poor, and no clear guidelines exist regarding the optimal treatment approach. We report a case of prostate leiomyosarcoma and describe the disease characteristics, diagnostic modalities, and treatment approach regarding these rare malignancies.

Case Presentation

A 72-year-old male presented with 6 months of progressive severe lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction. The patient was refractory to medical management with combination α-blocker and 5-α-reductase inhibitor therapy and continued to require multiple emergent bladder catheterizations. Workup with urinalysis, blood biochemistry, and prostate specific antigen (PSA) levels were persistently normal. He reported no hematuria, weight loss, or perineal pain. The patient reported no history of tobacco use, exposure to hazardous chemicals, and had no family history of genitourinary cancers. On rectal exam, the prostate was firm and nodular, with induration noted along the right upper lobe of the prostate.

The patient was referred for a urology consultation and subsequently underwent transurethral resection of the prostate (TURP) for suspected severe benign prostatic hypertrophy (BPH). A histopathologic examination demonstrated atypical cytology consistent with high- grade leiomyosarcoma. Immunohistochemical analysis revealed positive staining for vimentin, smooth muscle actin, desmin (partial), cytokeratin, smooth muscle myosin, muscle specific actin, and Ki-67 (50%-60% expression).

Fluorodeoxyglucose positron emission tomography (FDG-PET) scan revealed a 5.7 x 5.9 cm tumor with a maximum standardized uptake value (SUV_max) of 12.6 in the right posterior prostate, without evidence of metastatic disease (Figures 1A and 1B). 

Discussion

Originating from prostatic interstitial cells, prostatic leiomyosarcoma is a rare tumor that accounts for < 0.1% of all primary prostatic malignancies.¹ Since its first description in 1950 by Riba and colleagues, < 200 cases have been reported worldwide.² Among the sarcomas of the prostate, it is the most common tumor, accounting for around 38% to 52% of prostate sarcoma presentations.^1,2

Patients typically present between the ages of 41 and 78 years (mean age 61 years).^2,3 Signs and symptoms at presentation may vary; however, the most common symptoms are related to lower urinary tract obstruction (89.4% of patients). These symptoms include urinary frequency, urgency, nocturia, and may mimic the presentation of BPH.

Symptoms commonly associated with other malignancies, including constitutional symptoms such as weight loss, tend to occur less frequently or may be absent. Perineal or rectal pain may only be present in 25.6% of patients. Hematuria, burning on ejaculation, and constitutional symptoms are a less common presentation (< 10% of patients).^3,4 PSA levels typically do not rise and are found to be within normal limits. The lack of PSA elevation is related to the tumors nonepithelial origin and may contribute to a delay in diagnosis.^2,4,5

Diagnosis

Diagnosis may be further eluded as digital rectal exam (DRE) findings tend to reveal nonspecific enlargement of the prostate, resembling that of BPH. DRE may show a hard and firm prostate with nodular induration at the base or over the lobes of the prostate.⁶ At this stage a urology consultation is useful, as diagnosis is most commonly achieved using transrectal ultrasound (TRUS) with ultrasound-guided needle biopsy or after a TURP procedure.³

Prostate sarcoma is associated with markedly enlarged prostate volume, irregular margins with invasion, or heterogenous hypoechoic lesions on TRUS.⁷ Transperineal biopsy, computed tomography (CT)-guided biopsy, or suprapubic prostatectomy have been less frequently employed for diagnosis in previously reported cases.⁸ Specialized imaging modalities, such as CT scan or bone scan, do not show any specific findings with regards to these tumors; their role is limited to evaluation of the local and distant metastasis and for follow-up assessments.⁹ Transabdominal ultrasound may assess hydronephrosis or enlarged prostate and its relation to nearby structures, although it has not been shown to be helpful in establishing a specific diagnosis.⁶

Histologically, prostatic leiomyosarcoma is a distinct subtype of prostatic sarcoma. Other subtypes include stromal tumors such as rhabdomyosarcoma, fibrosarcoma, and spindle cell sarcoma.² The majority of leiomyosarcomas are high-grade lesions demonstrating neoplastic spindle cells with nuclear atypia, multifocal necrosis, and cystic degeneration. Low-grade leiomyosarcomas are very rare.¹⁰ Immunohistochemistry is characteristically positive for vimentin, smooth muscle actin, and desmin expression. Cytokeratin may be positive in up to 25% of cases, whereas S-100, CD34, CD117, and PSA are negative.^2,3 These histopathological findings help to differentiate leiomyosarcoma from other prostatic tumors.

Tumor size may vary greatly, and measurements have been reported to range from 3 cm to 21 cm, frequently presenting with invasion of local structures.¹¹ Advanced stage disease is commonly found at initial diagnosis and is thought to be due to the lack of early specific symptoms. Metastatic disease at presentation may be found in up to one-third of patients, with the lungs being the most common site of metastasis followed by the liver. Local extent and distant spread of disease may be determined by CT or magnetic resonance imaging (MRI) scans, which provide clear delineation of neoplastic and nonneoplastic tissues. 

Treatment

Treatment regimens may include a multimodal approach of combination surgery, radiation, and chemotherapy. However, there are currently no standardized guidelines for treatment and the optimal therapy remains unknown.^2,3,6 Surgery remains the mainstay of treatment, and patients with surgically resectable tumors are treated with curative intent. Surgeries performed include radical retropubic prostatectomy, radical cystoprostatectomy, suprapubic prostatectomy, and pelvic exenteration.^2,5,8,12 These operations may be preceded or followed by radiation therapy and/or chemotherapy depending on extent of disease.

It has been reported that neo-adjuvant chemotherapy and/or radiotherapy can aid in decreasing tumor burden to facilitate a complete resection.^2,8,13,14 Patients who are determined to not be candidates for surgery or whom have widespread disease may be offered systemic chemotherapy. Chemotherapy regimens vary, but common regimens include anthracyclines (doxorubicin or epirubicin), alkylating agents (cyclophosphamide, ifosfamide, dacarbazine), and/or vinca alkaloids (vinblastine or vincristine). Patients who do not receive surgical intervention rarely achieve a sustained remission.^3,5,8

The long-term prognosis of prostatic leiomyosarcoma is poor due to the aggressive nature of the neoplasm and the high chance of disease recurrence or metastasis. Median survival is estimated at 17 months, and from 50% to 75% of patients die within 2 to 5 years of diagnosis.^2,3 Prognosis may be improved in patients with localized disease at diagnosis who are candidates for complete surgical resection with negative margins.¹³ Adverse prognostic factors include metastatic disease at presentation and the presence of positive surgical margins after surgery.

Overall survival is very poor, and it is estimated that the 1-, 3-, and 5-year survival rates are 68%, 34%, and 26%, respectively.³ However, some studies estimate the 5-year survival to be anywhere from 0 to 60%.^8,9 Due to the substantially high risk of death, prostatic leiomyosarcoma may be one of the most aggressive and poorly prognostic malignancies involving the prostate.

Conclusion

Prostatic leiomyosarcoma poses a unique diagnostic challenge, as clinical presentation alone may not always be suggestive of underlying malignancy. This challenge is further exacerbated by its aggressive nature, high risk of metastasis, and difficulties with unclear treatment. Proper history and physical examination, differential diagnosis, and a multidisciplinary approach to patient care are the foundation for early detection and promoting improved survival.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Prostatic leiomyosarcoma is a rare tumor.¹ This neoplasm is composed of highly aggressive prostatic smooth muscle cells that present with nonspecific signs and symptoms mimicking other forms of prostatic pathology. Of the primary prostatic sarcomas, leiomyosarcoma represents the most common subtype in adults and is found in 38% to 52% of newly diagnosed prostate sarcoma.^1,2 The prognosis is poor, and no clear guidelines exist regarding the optimal treatment approach. We report a case of prostate leiomyosarcoma and describe the disease characteristics, diagnostic modalities, and treatment approach regarding these rare malignancies.

Case Presentation

A 72-year-old male presented with 6 months of progressive severe lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction. The patient was refractory to medical management with combination α-blocker and 5-α-reductase inhibitor therapy and continued to require multiple emergent bladder catheterizations. Workup with urinalysis, blood biochemistry, and prostate specific antigen (PSA) levels were persistently normal. He reported no hematuria, weight loss, or perineal pain. The patient reported no history of tobacco use, exposure to hazardous chemicals, and had no family history of genitourinary cancers. On rectal exam, the prostate was firm and nodular, with induration noted along the right upper lobe of the prostate.

The patient was referred for a urology consultation and subsequently underwent transurethral resection of the prostate (TURP) for suspected severe benign prostatic hypertrophy (BPH). A histopathologic examination demonstrated atypical cytology consistent with high- grade leiomyosarcoma. Immunohistochemical analysis revealed positive staining for vimentin, smooth muscle actin, desmin (partial), cytokeratin, smooth muscle myosin, muscle specific actin, and Ki-67 (50%-60% expression).

Fluorodeoxyglucose positron emission tomography (FDG-PET) scan revealed a 5.7 x 5.9 cm tumor with a maximum standardized uptake value (SUV_max) of 12.6 in the right posterior prostate, without evidence of metastatic disease (Figures 1A and 1B). 

Discussion

Originating from prostatic interstitial cells, prostatic leiomyosarcoma is a rare tumor that accounts for < 0.1% of all primary prostatic malignancies.¹ Since its first description in 1950 by Riba and colleagues, < 200 cases have been reported worldwide.² Among the sarcomas of the prostate, it is the most common tumor, accounting for around 38% to 52% of prostate sarcoma presentations.^1,2

Patients typically present between the ages of 41 and 78 years (mean age 61 years).^2,3 Signs and symptoms at presentation may vary; however, the most common symptoms are related to lower urinary tract obstruction (89.4% of patients). These symptoms include urinary frequency, urgency, nocturia, and may mimic the presentation of BPH.

Symptoms commonly associated with other malignancies, including constitutional symptoms such as weight loss, tend to occur less frequently or may be absent. Perineal or rectal pain may only be present in 25.6% of patients. Hematuria, burning on ejaculation, and constitutional symptoms are a less common presentation (< 10% of patients).^3,4 PSA levels typically do not rise and are found to be within normal limits. The lack of PSA elevation is related to the tumors nonepithelial origin and may contribute to a delay in diagnosis.^2,4,5

Diagnosis

Diagnosis may be further eluded as digital rectal exam (DRE) findings tend to reveal nonspecific enlargement of the prostate, resembling that of BPH. DRE may show a hard and firm prostate with nodular induration at the base or over the lobes of the prostate.⁶ At this stage a urology consultation is useful, as diagnosis is most commonly achieved using transrectal ultrasound (TRUS) with ultrasound-guided needle biopsy or after a TURP procedure.³

Prostate sarcoma is associated with markedly enlarged prostate volume, irregular margins with invasion, or heterogenous hypoechoic lesions on TRUS.⁷ Transperineal biopsy, computed tomography (CT)-guided biopsy, or suprapubic prostatectomy have been less frequently employed for diagnosis in previously reported cases.⁸ Specialized imaging modalities, such as CT scan or bone scan, do not show any specific findings with regards to these tumors; their role is limited to evaluation of the local and distant metastasis and for follow-up assessments.⁹ Transabdominal ultrasound may assess hydronephrosis or enlarged prostate and its relation to nearby structures, although it has not been shown to be helpful in establishing a specific diagnosis.⁶

Histologically, prostatic leiomyosarcoma is a distinct subtype of prostatic sarcoma. Other subtypes include stromal tumors such as rhabdomyosarcoma, fibrosarcoma, and spindle cell sarcoma.² The majority of leiomyosarcomas are high-grade lesions demonstrating neoplastic spindle cells with nuclear atypia, multifocal necrosis, and cystic degeneration. Low-grade leiomyosarcomas are very rare.¹⁰ Immunohistochemistry is characteristically positive for vimentin, smooth muscle actin, and desmin expression. Cytokeratin may be positive in up to 25% of cases, whereas S-100, CD34, CD117, and PSA are negative.^2,3 These histopathological findings help to differentiate leiomyosarcoma from other prostatic tumors.

Tumor size may vary greatly, and measurements have been reported to range from 3 cm to 21 cm, frequently presenting with invasion of local structures.¹¹ Advanced stage disease is commonly found at initial diagnosis and is thought to be due to the lack of early specific symptoms. Metastatic disease at presentation may be found in up to one-third of patients, with the lungs being the most common site of metastasis followed by the liver. Local extent and distant spread of disease may be determined by CT or magnetic resonance imaging (MRI) scans, which provide clear delineation of neoplastic and nonneoplastic tissues. 

Treatment

Treatment regimens may include a multimodal approach of combination surgery, radiation, and chemotherapy. However, there are currently no standardized guidelines for treatment and the optimal therapy remains unknown.^2,3,6 Surgery remains the mainstay of treatment, and patients with surgically resectable tumors are treated with curative intent. Surgeries performed include radical retropubic prostatectomy, radical cystoprostatectomy, suprapubic prostatectomy, and pelvic exenteration.^2,5,8,12 These operations may be preceded or followed by radiation therapy and/or chemotherapy depending on extent of disease.

It has been reported that neo-adjuvant chemotherapy and/or radiotherapy can aid in decreasing tumor burden to facilitate a complete resection.^2,8,13,14 Patients who are determined to not be candidates for surgery or whom have widespread disease may be offered systemic chemotherapy. Chemotherapy regimens vary, but common regimens include anthracyclines (doxorubicin or epirubicin), alkylating agents (cyclophosphamide, ifosfamide, dacarbazine), and/or vinca alkaloids (vinblastine or vincristine). Patients who do not receive surgical intervention rarely achieve a sustained remission.^3,5,8

The long-term prognosis of prostatic leiomyosarcoma is poor due to the aggressive nature of the neoplasm and the high chance of disease recurrence or metastasis. Median survival is estimated at 17 months, and from 50% to 75% of patients die within 2 to 5 years of diagnosis.^2,3 Prognosis may be improved in patients with localized disease at diagnosis who are candidates for complete surgical resection with negative margins.¹³ Adverse prognostic factors include metastatic disease at presentation and the presence of positive surgical margins after surgery.

Overall survival is very poor, and it is estimated that the 1-, 3-, and 5-year survival rates are 68%, 34%, and 26%, respectively.³ However, some studies estimate the 5-year survival to be anywhere from 0 to 60%.^8,9 Due to the substantially high risk of death, prostatic leiomyosarcoma may be one of the most aggressive and poorly prognostic malignancies involving the prostate.

Conclusion

Prostatic leiomyosarcoma poses a unique diagnostic challenge, as clinical presentation alone may not always be suggestive of underlying malignancy. This challenge is further exacerbated by its aggressive nature, high risk of metastasis, and difficulties with unclear treatment. Proper history and physical examination, differential diagnosis, and a multidisciplinary approach to patient care are the foundation for early detection and promoting improved survival.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Prostatic leiomyosarcoma is a rare tumor.¹ This neoplasm is composed of highly aggressive prostatic smooth muscle cells that present with nonspecific signs and symptoms mimicking other forms of prostatic pathology. Of the primary prostatic sarcomas, leiomyosarcoma represents the most common subtype in adults and is found in 38% to 52% of newly diagnosed prostate sarcoma.^1,2 The prognosis is poor, and no clear guidelines exist regarding the optimal treatment approach. We report a case of prostate leiomyosarcoma and describe the disease characteristics, diagnostic modalities, and treatment approach regarding these rare malignancies.

Case Presentation

A 72-year-old male presented with 6 months of progressive severe lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction. The patient was refractory to medical management with combination α-blocker and 5-α-reductase inhibitor therapy and continued to require multiple emergent bladder catheterizations. Workup with urinalysis, blood biochemistry, and prostate specific antigen (PSA) levels were persistently normal. He reported no hematuria, weight loss, or perineal pain. The patient reported no history of tobacco use, exposure to hazardous chemicals, and had no family history of genitourinary cancers. On rectal exam, the prostate was firm and nodular, with induration noted along the right upper lobe of the prostate.

The patient was referred for a urology consultation and subsequently underwent transurethral resection of the prostate (TURP) for suspected severe benign prostatic hypertrophy (BPH). A histopathologic examination demonstrated atypical cytology consistent with high- grade leiomyosarcoma. Immunohistochemical analysis revealed positive staining for vimentin, smooth muscle actin, desmin (partial), cytokeratin, smooth muscle myosin, muscle specific actin, and Ki-67 (50%-60% expression).

Fluorodeoxyglucose positron emission tomography (FDG-PET) scan revealed a 5.7 x 5.9 cm tumor with a maximum standardized uptake value (SUV_max) of 12.6 in the right posterior prostate, without evidence of metastatic disease (Figures 1A and 1B). 

Discussion

Originating from prostatic interstitial cells, prostatic leiomyosarcoma is a rare tumor that accounts for < 0.1% of all primary prostatic malignancies.¹ Since its first description in 1950 by Riba and colleagues, < 200 cases have been reported worldwide.² Among the sarcomas of the prostate, it is the most common tumor, accounting for around 38% to 52% of prostate sarcoma presentations.^1,2

Patients typically present between the ages of 41 and 78 years (mean age 61 years).^2,3 Signs and symptoms at presentation may vary; however, the most common symptoms are related to lower urinary tract obstruction (89.4% of patients). These symptoms include urinary frequency, urgency, nocturia, and may mimic the presentation of BPH.

Symptoms commonly associated with other malignancies, including constitutional symptoms such as weight loss, tend to occur less frequently or may be absent. Perineal or rectal pain may only be present in 25.6% of patients. Hematuria, burning on ejaculation, and constitutional symptoms are a less common presentation (< 10% of patients).^3,4 PSA levels typically do not rise and are found to be within normal limits. The lack of PSA elevation is related to the tumors nonepithelial origin and may contribute to a delay in diagnosis.^2,4,5

Diagnosis

Diagnosis may be further eluded as digital rectal exam (DRE) findings tend to reveal nonspecific enlargement of the prostate, resembling that of BPH. DRE may show a hard and firm prostate with nodular induration at the base or over the lobes of the prostate.⁶ At this stage a urology consultation is useful, as diagnosis is most commonly achieved using transrectal ultrasound (TRUS) with ultrasound-guided needle biopsy or after a TURP procedure.³

Prostate sarcoma is associated with markedly enlarged prostate volume, irregular margins with invasion, or heterogenous hypoechoic lesions on TRUS.⁷ Transperineal biopsy, computed tomography (CT)-guided biopsy, or suprapubic prostatectomy have been less frequently employed for diagnosis in previously reported cases.⁸ Specialized imaging modalities, such as CT scan or bone scan, do not show any specific findings with regards to these tumors; their role is limited to evaluation of the local and distant metastasis and for follow-up assessments.⁹ Transabdominal ultrasound may assess hydronephrosis or enlarged prostate and its relation to nearby structures, although it has not been shown to be helpful in establishing a specific diagnosis.⁶

Histologically, prostatic leiomyosarcoma is a distinct subtype of prostatic sarcoma. Other subtypes include stromal tumors such as rhabdomyosarcoma, fibrosarcoma, and spindle cell sarcoma.² The majority of leiomyosarcomas are high-grade lesions demonstrating neoplastic spindle cells with nuclear atypia, multifocal necrosis, and cystic degeneration. Low-grade leiomyosarcomas are very rare.¹⁰ Immunohistochemistry is characteristically positive for vimentin, smooth muscle actin, and desmin expression. Cytokeratin may be positive in up to 25% of cases, whereas S-100, CD34, CD117, and PSA are negative.^2,3 These histopathological findings help to differentiate leiomyosarcoma from other prostatic tumors.

Tumor size may vary greatly, and measurements have been reported to range from 3 cm to 21 cm, frequently presenting with invasion of local structures.¹¹ Advanced stage disease is commonly found at initial diagnosis and is thought to be due to the lack of early specific symptoms. Metastatic disease at presentation may be found in up to one-third of patients, with the lungs being the most common site of metastasis followed by the liver. Local extent and distant spread of disease may be determined by CT or magnetic resonance imaging (MRI) scans, which provide clear delineation of neoplastic and nonneoplastic tissues. 

Treatment

Treatment regimens may include a multimodal approach of combination surgery, radiation, and chemotherapy. However, there are currently no standardized guidelines for treatment and the optimal therapy remains unknown.^2,3,6 Surgery remains the mainstay of treatment, and patients with surgically resectable tumors are treated with curative intent. Surgeries performed include radical retropubic prostatectomy, radical cystoprostatectomy, suprapubic prostatectomy, and pelvic exenteration.^2,5,8,12 These operations may be preceded or followed by radiation therapy and/or chemotherapy depending on extent of disease.

It has been reported that neo-adjuvant chemotherapy and/or radiotherapy can aid in decreasing tumor burden to facilitate a complete resection.^2,8,13,14 Patients who are determined to not be candidates for surgery or whom have widespread disease may be offered systemic chemotherapy. Chemotherapy regimens vary, but common regimens include anthracyclines (doxorubicin or epirubicin), alkylating agents (cyclophosphamide, ifosfamide, dacarbazine), and/or vinca alkaloids (vinblastine or vincristine). Patients who do not receive surgical intervention rarely achieve a sustained remission.^3,5,8

The long-term prognosis of prostatic leiomyosarcoma is poor due to the aggressive nature of the neoplasm and the high chance of disease recurrence or metastasis. Median survival is estimated at 17 months, and from 50% to 75% of patients die within 2 to 5 years of diagnosis.^2,3 Prognosis may be improved in patients with localized disease at diagnosis who are candidates for complete surgical resection with negative margins.¹³ Adverse prognostic factors include metastatic disease at presentation and the presence of positive surgical margins after surgery.

Overall survival is very poor, and it is estimated that the 1-, 3-, and 5-year survival rates are 68%, 34%, and 26%, respectively.³ However, some studies estimate the 5-year survival to be anywhere from 0 to 60%.^8,9 Due to the substantially high risk of death, prostatic leiomyosarcoma may be one of the most aggressive and poorly prognostic malignancies involving the prostate.

Conclusion

Prostatic leiomyosarcoma poses a unique diagnostic challenge, as clinical presentation alone may not always be suggestive of underlying malignancy. This challenge is further exacerbated by its aggressive nature, high risk of metastasis, and difficulties with unclear treatment. Proper history and physical examination, differential diagnosis, and a multidisciplinary approach to patient care are the foundation for early detection and promoting improved survival.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Primary urethral carcinoma (PUC) is a rare but morbid disease, representing < 1% of all urologic malignancies.¹ Up to one-third of male patients may present with nodal metastases.^2-4 The overall survival (OS) for all male PUC is < 50% at 5 years and is lower still in patients with nodal involvement.⁴

Although surgical intervention, including radical resection, has been a mainstay in disease management, the presence of high-stage disease may warrant multimodal treatment with chemotherapy, radiation, and surgery. Recent series have described success with neoadjuvant and adjuvant chemoradiation, yet the optimal regimen remains unestablished.^5,6 Although nodal disease is commonly encountered with proximal, high-stage tumors, this case exhibits a rare presentation of a distal fungating penile mass with low pathologic stage but rapid progression to nodal disease.

Case Presentation

A male veteran aged 77 years with a history of diabetes mellitus and stroke presented with obstructive urinary symptoms, gross hematuria, and 15-pound weight loss. Examination revealed a distal penile mass with purulent exudate at the meatus but no inguinal lymphadenopathy. Two fragments of this mass detached during office cystoscopy, and pathology revealed high-grade urothelial cell carcinoma (UCC). A magnetic resonance image of the pelvis with and without IV contrast revealed a 2.4-cm tumor in the glans penis with possible extension into the subcutaneous connective tissue of the penis and penile skin, without invasion of the corpora cavernosa/spongiosum or lymphadenopathy (Figure 1). 

Prostatic urethral and random bladder biopsies, bilateral retrograde pyelograms, and selective ureteral washings revealed no abnormalities or signs of disease. Percutaneous biopsy of the inguinal node confirmed metastatic UCC. The patient underwent radical penectomy, creation of a perineal urethrostomy, and suprapubic cystostomy tube placement. Negative margins were confirmed on the urethral stump and corpus spongiosum. Final pathology revealed high-grade UCC with squamous differentiation on hematoxylin and eosin staining, arising from the penile urethra, invading the glans and corpus spongiosum, with no invasion of the corpus cavernosa (Figures 3 and 4).

Immunohistochemical stains were performed and strongly positive for cytokeratin 7 and p63. Final pathologic stage was described as pT2N1, with negative margins, indicating an American Joint Committee on Cancer classification of Stage III disease.⁷ The patient was referred postoperatively for adjuvant chemoradiation. 

Discussion

The low incidence of PUC, coupled with a high morbidity/mortality rate, creates a difficult scenario in choosing the best oncologic management for this disease. National guidelines stratify treatment algorithms by stage and location of primary tumor, as these were found to be the 2 most important prognostic factors for men.¹ The location of the primary tumor is most often in the bulbomembranous urethra, but up to one-third occur in the pendulous urethra.²

A recent review reported that UCC is the most common histologic subtype.⁴ When considering the differential diagnosis, a distal penile mass may represent a malignant penile lesion, such as squamous cell carcinoma, Buschke-Lowenstein tumor, Kaposi sarcoma, or precancerous lesions. Additional benign and infectious disorders include epidermoid and retention cysts, leukoplakia, balanitis xerotica obliterans, condyloma acuminatum, chancre/chancroid, lymphogranuloma venereum, granuloma inguinale, and tuberculosis. Clinical workup typically includes physical examination, cystourethroscopy and biopsy, chest X-ray, and pelvic/abdominal cross-sectional imaging.^9,10 Magnetic resonance imaging of the abdomen and pelvis is ideal in identifying soft tissue structures and extension of tumor.

In male patients with PUC, nodal metastases are commonly seen at initial presentation in up to one-third of patients, while distant metastases may be present in up to 6% at presentation.^2-4 When tumors arise from the anterior urethra, the primary lymphatic drainage is first to the inguinal lymph nodes, whereas posterior tumors drain to the pelvic lymph nodes. A multivariate analysis of men with PUC within the Surveillance, Epidemiology, and End Results database demonstrated an OS across all stages to be 46.2% and 29.3% at 5 and 10 years, respectively. Increased likelihood of death was predicted by advanced age, high grade/stage, systemic metastases, non-UCC histology, and the lack of surgery.⁴

Surgical intervention, including radical resection via penectomy, has been the mainstay in disease management and was first described by Marshall in 1957 for bulbar urethral cancer.¹¹ In 1998, Gheiler and colleagues demonstrated that surgical resection alone yielded excellent outcomes in patients with low-stage disease with 89% of patients disease free at mean 42 months. This was in stark contrast to patients with advanced stage disease (T3 or N+) who exhibited a disease-free survival rate of 42% at the same follow-up interval and benefited from combined chemoradiation and surgical resection.³

In the presence of high-stage disease, multimodal therapy with chemotherapy, radiation, and/or surgery is warranted. A study in 2008 reviewed chemoradiation in which patients with PUC received a 5-week protocol of external beam radiotherapy to the genitals, inguinal/pelvic lymph nodes, plus an additional radiation bolus to the primary tumor.⁵ In the 18 patients reported, 15 had complete response to therapy, and only 4 patients required salvage surgical resection. The 7-year survival for the cohort was 72% with chemoradiation alone, with about half the population recurring or progressing at 7 years. However, all patients that avoided surgical resection went on to develop urethral strictures that required surgical therapy, 3 of which required complex reconstructive procedures.

To place this survival into context, the 1999 study by Dalbagni and colleagues reported a 5-year OS of 42% when surgical resection alone was performed in 40/46 men with PUC.² Last, a large retrospective series of 44 patients reported mostly advanced-stage patients with PUC and analyzed patients treated with chemotherapy based on histologic pathology. The results demonstrated a 72% overall response rate to neoadjuvant chemotherapy, with a median OS of 32 months in patients undergoing chemotherapy vs 46 months in patients who underwent subsequent surgery. This study solidified that for patients with PUC involving the lymph nodes; optimal treatment includes neoadjuvant cisplatin-based chemotherapy followed by surgical resection.⁶

As medicine and oncologic therapies become more individualized, physicians are looking to new immunologic agents for systemic therapy. Immune checkpoint inhibitors were approved by the US Food and Drug Administration for UCC of the bladder in 2016.¹² Unfortunately, due to the rarity of PUC and the recent development of immune checkpoint inhibitors, there have been no published reports of these or other immunotherapies in PUC. However, given the histologic similarity and pathogenesis, checkpoint inhibitors may have a future indication in the systemic management of this disease.

Conclusion

This patient’s PUC represents a rare presentation of a distal urethral carcinoma, T2-staged tumor, with rapid progression to nodal metastases. Additionally, the presentation of a fungating penile mass would usually indicate penile carcinoma, but providers should be aware of urethral carcinoma in the differential diagnosis. Notably, the patient was found to have progression to lymph node involvement during a mere 2-month period.

Recent case series have published encouraging results with neoadjuvant chemotherapy or chemoradiation.^5,6 However, radical resection in men with T2 to T4 disease is associated with significantly higher cancer-specific survival. Given our concern of a loss to follow-up, we felt that radical resection of the primary tumor and adjuvant chemoradiation represented the patient’s best oncologic outcomes. Therefore, he underwent radical penectomy and creation of a perineal urethrostomy. As of his 6-month follow-up, he showed no evidence of disease, had returned to his preoperative functional status, and was referred for chemoradiation.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Primary urethral carcinoma (PUC) is a rare but morbid disease, representing < 1% of all urologic malignancies.¹ Up to one-third of male patients may present with nodal metastases.^2-4 The overall survival (OS) for all male PUC is < 50% at 5 years and is lower still in patients with nodal involvement.⁴

Although surgical intervention, including radical resection, has been a mainstay in disease management, the presence of high-stage disease may warrant multimodal treatment with chemotherapy, radiation, and surgery. Recent series have described success with neoadjuvant and adjuvant chemoradiation, yet the optimal regimen remains unestablished.^5,6 Although nodal disease is commonly encountered with proximal, high-stage tumors, this case exhibits a rare presentation of a distal fungating penile mass with low pathologic stage but rapid progression to nodal disease.

Case Presentation

A male veteran aged 77 years with a history of diabetes mellitus and stroke presented with obstructive urinary symptoms, gross hematuria, and 15-pound weight loss. Examination revealed a distal penile mass with purulent exudate at the meatus but no inguinal lymphadenopathy. Two fragments of this mass detached during office cystoscopy, and pathology revealed high-grade urothelial cell carcinoma (UCC). A magnetic resonance image of the pelvis with and without IV contrast revealed a 2.4-cm tumor in the glans penis with possible extension into the subcutaneous connective tissue of the penis and penile skin, without invasion of the corpora cavernosa/spongiosum or lymphadenopathy (Figure 1). 

Prostatic urethral and random bladder biopsies, bilateral retrograde pyelograms, and selective ureteral washings revealed no abnormalities or signs of disease. Percutaneous biopsy of the inguinal node confirmed metastatic UCC. The patient underwent radical penectomy, creation of a perineal urethrostomy, and suprapubic cystostomy tube placement. Negative margins were confirmed on the urethral stump and corpus spongiosum. Final pathology revealed high-grade UCC with squamous differentiation on hematoxylin and eosin staining, arising from the penile urethra, invading the glans and corpus spongiosum, with no invasion of the corpus cavernosa (Figures 3 and 4).

Immunohistochemical stains were performed and strongly positive for cytokeratin 7 and p63. Final pathologic stage was described as pT2N1, with negative margins, indicating an American Joint Committee on Cancer classification of Stage III disease.⁷ The patient was referred postoperatively for adjuvant chemoradiation. 

Discussion

The low incidence of PUC, coupled with a high morbidity/mortality rate, creates a difficult scenario in choosing the best oncologic management for this disease. National guidelines stratify treatment algorithms by stage and location of primary tumor, as these were found to be the 2 most important prognostic factors for men.¹ The location of the primary tumor is most often in the bulbomembranous urethra, but up to one-third occur in the pendulous urethra.²

A recent review reported that UCC is the most common histologic subtype.⁴ When considering the differential diagnosis, a distal penile mass may represent a malignant penile lesion, such as squamous cell carcinoma, Buschke-Lowenstein tumor, Kaposi sarcoma, or precancerous lesions. Additional benign and infectious disorders include epidermoid and retention cysts, leukoplakia, balanitis xerotica obliterans, condyloma acuminatum, chancre/chancroid, lymphogranuloma venereum, granuloma inguinale, and tuberculosis. Clinical workup typically includes physical examination, cystourethroscopy and biopsy, chest X-ray, and pelvic/abdominal cross-sectional imaging.^9,10 Magnetic resonance imaging of the abdomen and pelvis is ideal in identifying soft tissue structures and extension of tumor.

In male patients with PUC, nodal metastases are commonly seen at initial presentation in up to one-third of patients, while distant metastases may be present in up to 6% at presentation.^2-4 When tumors arise from the anterior urethra, the primary lymphatic drainage is first to the inguinal lymph nodes, whereas posterior tumors drain to the pelvic lymph nodes. A multivariate analysis of men with PUC within the Surveillance, Epidemiology, and End Results database demonstrated an OS across all stages to be 46.2% and 29.3% at 5 and 10 years, respectively. Increased likelihood of death was predicted by advanced age, high grade/stage, systemic metastases, non-UCC histology, and the lack of surgery.⁴

Surgical intervention, including radical resection via penectomy, has been the mainstay in disease management and was first described by Marshall in 1957 for bulbar urethral cancer.¹¹ In 1998, Gheiler and colleagues demonstrated that surgical resection alone yielded excellent outcomes in patients with low-stage disease with 89% of patients disease free at mean 42 months. This was in stark contrast to patients with advanced stage disease (T3 or N+) who exhibited a disease-free survival rate of 42% at the same follow-up interval and benefited from combined chemoradiation and surgical resection.³

In the presence of high-stage disease, multimodal therapy with chemotherapy, radiation, and/or surgery is warranted. A study in 2008 reviewed chemoradiation in which patients with PUC received a 5-week protocol of external beam radiotherapy to the genitals, inguinal/pelvic lymph nodes, plus an additional radiation bolus to the primary tumor.⁵ In the 18 patients reported, 15 had complete response to therapy, and only 4 patients required salvage surgical resection. The 7-year survival for the cohort was 72% with chemoradiation alone, with about half the population recurring or progressing at 7 years. However, all patients that avoided surgical resection went on to develop urethral strictures that required surgical therapy, 3 of which required complex reconstructive procedures.

To place this survival into context, the 1999 study by Dalbagni and colleagues reported a 5-year OS of 42% when surgical resection alone was performed in 40/46 men with PUC.² Last, a large retrospective series of 44 patients reported mostly advanced-stage patients with PUC and analyzed patients treated with chemotherapy based on histologic pathology. The results demonstrated a 72% overall response rate to neoadjuvant chemotherapy, with a median OS of 32 months in patients undergoing chemotherapy vs 46 months in patients who underwent subsequent surgery. This study solidified that for patients with PUC involving the lymph nodes; optimal treatment includes neoadjuvant cisplatin-based chemotherapy followed by surgical resection.⁶

As medicine and oncologic therapies become more individualized, physicians are looking to new immunologic agents for systemic therapy. Immune checkpoint inhibitors were approved by the US Food and Drug Administration for UCC of the bladder in 2016.¹² Unfortunately, due to the rarity of PUC and the recent development of immune checkpoint inhibitors, there have been no published reports of these or other immunotherapies in PUC. However, given the histologic similarity and pathogenesis, checkpoint inhibitors may have a future indication in the systemic management of this disease.

Conclusion

This patient’s PUC represents a rare presentation of a distal urethral carcinoma, T2-staged tumor, with rapid progression to nodal metastases. Additionally, the presentation of a fungating penile mass would usually indicate penile carcinoma, but providers should be aware of urethral carcinoma in the differential diagnosis. Notably, the patient was found to have progression to lymph node involvement during a mere 2-month period.

Recent case series have published encouraging results with neoadjuvant chemotherapy or chemoradiation.^5,6 However, radical resection in men with T2 to T4 disease is associated with significantly higher cancer-specific survival. Given our concern of a loss to follow-up, we felt that radical resection of the primary tumor and adjuvant chemoradiation represented the patient’s best oncologic outcomes. Therefore, he underwent radical penectomy and creation of a perineal urethrostomy. As of his 6-month follow-up, he showed no evidence of disease, had returned to his preoperative functional status, and was referred for chemoradiation.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Primary urethral carcinoma (PUC) is a rare but morbid disease, representing < 1% of all urologic malignancies.¹ Up to one-third of male patients may present with nodal metastases.^2-4 The overall survival (OS) for all male PUC is < 50% at 5 years and is lower still in patients with nodal involvement.⁴

Although surgical intervention, including radical resection, has been a mainstay in disease management, the presence of high-stage disease may warrant multimodal treatment with chemotherapy, radiation, and surgery. Recent series have described success with neoadjuvant and adjuvant chemoradiation, yet the optimal regimen remains unestablished.^5,6 Although nodal disease is commonly encountered with proximal, high-stage tumors, this case exhibits a rare presentation of a distal fungating penile mass with low pathologic stage but rapid progression to nodal disease.

Case Presentation

A male veteran aged 77 years with a history of diabetes mellitus and stroke presented with obstructive urinary symptoms, gross hematuria, and 15-pound weight loss. Examination revealed a distal penile mass with purulent exudate at the meatus but no inguinal lymphadenopathy. Two fragments of this mass detached during office cystoscopy, and pathology revealed high-grade urothelial cell carcinoma (UCC). A magnetic resonance image of the pelvis with and without IV contrast revealed a 2.4-cm tumor in the glans penis with possible extension into the subcutaneous connective tissue of the penis and penile skin, without invasion of the corpora cavernosa/spongiosum or lymphadenopathy (Figure 1). 

Prostatic urethral and random bladder biopsies, bilateral retrograde pyelograms, and selective ureteral washings revealed no abnormalities or signs of disease. Percutaneous biopsy of the inguinal node confirmed metastatic UCC. The patient underwent radical penectomy, creation of a perineal urethrostomy, and suprapubic cystostomy tube placement. Negative margins were confirmed on the urethral stump and corpus spongiosum. Final pathology revealed high-grade UCC with squamous differentiation on hematoxylin and eosin staining, arising from the penile urethra, invading the glans and corpus spongiosum, with no invasion of the corpus cavernosa (Figures 3 and 4).

Immunohistochemical stains were performed and strongly positive for cytokeratin 7 and p63. Final pathologic stage was described as pT2N1, with negative margins, indicating an American Joint Committee on Cancer classification of Stage III disease.⁷ The patient was referred postoperatively for adjuvant chemoradiation. 

Discussion

The low incidence of PUC, coupled with a high morbidity/mortality rate, creates a difficult scenario in choosing the best oncologic management for this disease. National guidelines stratify treatment algorithms by stage and location of primary tumor, as these were found to be the 2 most important prognostic factors for men.¹ The location of the primary tumor is most often in the bulbomembranous urethra, but up to one-third occur in the pendulous urethra.²

A recent review reported that UCC is the most common histologic subtype.⁴ When considering the differential diagnosis, a distal penile mass may represent a malignant penile lesion, such as squamous cell carcinoma, Buschke-Lowenstein tumor, Kaposi sarcoma, or precancerous lesions. Additional benign and infectious disorders include epidermoid and retention cysts, leukoplakia, balanitis xerotica obliterans, condyloma acuminatum, chancre/chancroid, lymphogranuloma venereum, granuloma inguinale, and tuberculosis. Clinical workup typically includes physical examination, cystourethroscopy and biopsy, chest X-ray, and pelvic/abdominal cross-sectional imaging.^9,10 Magnetic resonance imaging of the abdomen and pelvis is ideal in identifying soft tissue structures and extension of tumor.

In male patients with PUC, nodal metastases are commonly seen at initial presentation in up to one-third of patients, while distant metastases may be present in up to 6% at presentation.^2-4 When tumors arise from the anterior urethra, the primary lymphatic drainage is first to the inguinal lymph nodes, whereas posterior tumors drain to the pelvic lymph nodes. A multivariate analysis of men with PUC within the Surveillance, Epidemiology, and End Results database demonstrated an OS across all stages to be 46.2% and 29.3% at 5 and 10 years, respectively. Increased likelihood of death was predicted by advanced age, high grade/stage, systemic metastases, non-UCC histology, and the lack of surgery.⁴

Surgical intervention, including radical resection via penectomy, has been the mainstay in disease management and was first described by Marshall in 1957 for bulbar urethral cancer.¹¹ In 1998, Gheiler and colleagues demonstrated that surgical resection alone yielded excellent outcomes in patients with low-stage disease with 89% of patients disease free at mean 42 months. This was in stark contrast to patients with advanced stage disease (T3 or N+) who exhibited a disease-free survival rate of 42% at the same follow-up interval and benefited from combined chemoradiation and surgical resection.³

In the presence of high-stage disease, multimodal therapy with chemotherapy, radiation, and/or surgery is warranted. A study in 2008 reviewed chemoradiation in which patients with PUC received a 5-week protocol of external beam radiotherapy to the genitals, inguinal/pelvic lymph nodes, plus an additional radiation bolus to the primary tumor.⁵ In the 18 patients reported, 15 had complete response to therapy, and only 4 patients required salvage surgical resection. The 7-year survival for the cohort was 72% with chemoradiation alone, with about half the population recurring or progressing at 7 years. However, all patients that avoided surgical resection went on to develop urethral strictures that required surgical therapy, 3 of which required complex reconstructive procedures.

To place this survival into context, the 1999 study by Dalbagni and colleagues reported a 5-year OS of 42% when surgical resection alone was performed in 40/46 men with PUC.² Last, a large retrospective series of 44 patients reported mostly advanced-stage patients with PUC and analyzed patients treated with chemotherapy based on histologic pathology. The results demonstrated a 72% overall response rate to neoadjuvant chemotherapy, with a median OS of 32 months in patients undergoing chemotherapy vs 46 months in patients who underwent subsequent surgery. This study solidified that for patients with PUC involving the lymph nodes; optimal treatment includes neoadjuvant cisplatin-based chemotherapy followed by surgical resection.⁶

As medicine and oncologic therapies become more individualized, physicians are looking to new immunologic agents for systemic therapy. Immune checkpoint inhibitors were approved by the US Food and Drug Administration for UCC of the bladder in 2016.¹² Unfortunately, due to the rarity of PUC and the recent development of immune checkpoint inhibitors, there have been no published reports of these or other immunotherapies in PUC. However, given the histologic similarity and pathogenesis, checkpoint inhibitors may have a future indication in the systemic management of this disease.

Conclusion

This patient’s PUC represents a rare presentation of a distal urethral carcinoma, T2-staged tumor, with rapid progression to nodal metastases. Additionally, the presentation of a fungating penile mass would usually indicate penile carcinoma, but providers should be aware of urethral carcinoma in the differential diagnosis. Notably, the patient was found to have progression to lymph node involvement during a mere 2-month period.

Recent case series have published encouraging results with neoadjuvant chemotherapy or chemoradiation.^5,6 However, radical resection in men with T2 to T4 disease is associated with significantly higher cancer-specific survival. Given our concern of a loss to follow-up, we felt that radical resection of the primary tumor and adjuvant chemoradiation represented the patient’s best oncologic outcomes. Therefore, he underwent radical penectomy and creation of a perineal urethrostomy. As of his 6-month follow-up, he showed no evidence of disease, had returned to his preoperative functional status, and was referred for chemoradiation.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.