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High levels of estradiol in older men may be associated with young biological age
NEW ORLEANS – In a large community-based study that evaluated sex hormone levels in older men, suggesting that sex hormones influence the aging process.
“There was a large effect size, comparable with being 2 or 3 years younger for those with relatively high levels of estradiol, compared with those with lower levels of the hormone,” said Bu Yeap, MBBS, PhD, professor of medicine, University of Western Australia Medical School, Perth, who reported the results at the annual meeting of the Endocrine Society.
In a video interview conducted at the meeting, Dr. Yeap explained the basis of the study, which is the variety of evidence showing that decline in sex hormones correlates with higher rates of age-related disease processes. For example, increasing rates of cardiovascular disease, dementia, and mortality in men all correlate with declining levels of testosterone.
In the study, 2,913 men between the ages of 70 and 89 years and living in the community were recruited. The average age of the men was 77 years. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured. Telomere length was calculated with a polymerase chain reaction test.
Serum levels of testosterone and dihydrotestosterone did not correlate with telomere length, but incremental increases in serum estradiol levels were associated with incremental increases in telomere length.
“Telomeres are both a mediator and a biomarker for biological aging,” according to Dr. Yeap, who added that the telomeres protect chromosomes from degradation. As the telomeres shorten, cell senescence is increased along with an array of age-related diseases.
The next step for researchers is to evaluate whether administering exogenous sex hormones can favorably alter telomere length. If such an effect is demonstrated, then it could provide a step toward understanding how to slow the aging process, he said.
Dr Yeap and his colleagues reported no disclosures or financial conflicts of interest.
NEW ORLEANS – In a large community-based study that evaluated sex hormone levels in older men, suggesting that sex hormones influence the aging process.
“There was a large effect size, comparable with being 2 or 3 years younger for those with relatively high levels of estradiol, compared with those with lower levels of the hormone,” said Bu Yeap, MBBS, PhD, professor of medicine, University of Western Australia Medical School, Perth, who reported the results at the annual meeting of the Endocrine Society.
In a video interview conducted at the meeting, Dr. Yeap explained the basis of the study, which is the variety of evidence showing that decline in sex hormones correlates with higher rates of age-related disease processes. For example, increasing rates of cardiovascular disease, dementia, and mortality in men all correlate with declining levels of testosterone.
In the study, 2,913 men between the ages of 70 and 89 years and living in the community were recruited. The average age of the men was 77 years. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured. Telomere length was calculated with a polymerase chain reaction test.
Serum levels of testosterone and dihydrotestosterone did not correlate with telomere length, but incremental increases in serum estradiol levels were associated with incremental increases in telomere length.
“Telomeres are both a mediator and a biomarker for biological aging,” according to Dr. Yeap, who added that the telomeres protect chromosomes from degradation. As the telomeres shorten, cell senescence is increased along with an array of age-related diseases.
The next step for researchers is to evaluate whether administering exogenous sex hormones can favorably alter telomere length. If such an effect is demonstrated, then it could provide a step toward understanding how to slow the aging process, he said.
Dr Yeap and his colleagues reported no disclosures or financial conflicts of interest.
NEW ORLEANS – In a large community-based study that evaluated sex hormone levels in older men, suggesting that sex hormones influence the aging process.
“There was a large effect size, comparable with being 2 or 3 years younger for those with relatively high levels of estradiol, compared with those with lower levels of the hormone,” said Bu Yeap, MBBS, PhD, professor of medicine, University of Western Australia Medical School, Perth, who reported the results at the annual meeting of the Endocrine Society.
In a video interview conducted at the meeting, Dr. Yeap explained the basis of the study, which is the variety of evidence showing that decline in sex hormones correlates with higher rates of age-related disease processes. For example, increasing rates of cardiovascular disease, dementia, and mortality in men all correlate with declining levels of testosterone.
In the study, 2,913 men between the ages of 70 and 89 years and living in the community were recruited. The average age of the men was 77 years. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured. Telomere length was calculated with a polymerase chain reaction test.
Serum levels of testosterone and dihydrotestosterone did not correlate with telomere length, but incremental increases in serum estradiol levels were associated with incremental increases in telomere length.
“Telomeres are both a mediator and a biomarker for biological aging,” according to Dr. Yeap, who added that the telomeres protect chromosomes from degradation. As the telomeres shorten, cell senescence is increased along with an array of age-related diseases.
The next step for researchers is to evaluate whether administering exogenous sex hormones can favorably alter telomere length. If such an effect is demonstrated, then it could provide a step toward understanding how to slow the aging process, he said.
Dr Yeap and his colleagues reported no disclosures or financial conflicts of interest.
REPORTING FROM ENDO 2019
Cigna, Express Scripts to offer $25 cap on 30-day insulin supply
Cigna and Express Scripts have announced
The new program, open to Cigna members who are covered in commercial plans, would cap out-of-pocket costs for a 30-day supply of insulin at $25. For plan members, the only eligibility requirement is having an out-of-pocket cost higher than $25, according to a press release.
For a member to participate in the program, the plan administrator at the member’s place of employment has to opt in to it. There are no eligibility requirements imposed on the employer, other than a willingness to opt in.
A spokeswoman for Express Scripts said that there is no charge to sign up for the program, and most plans will not see an additional cost to get the copayment to $25 for the patient.
The announcement comes in the wake of the first of two hearings by the House Committee on Energy & Commerce aimed at understanding why insulin prices have spiked in recent years. The first hearing, held on April 2, examined the impact that the high list price of insulin is having on patients, and how out-of-pocket expenses are limiting access to this life-saving drug. The second hearing, expected to occur during the week of April 8 (the date had not been scheduled as of press time), will bring together various players in the supply chain, including the three major manufacturers of insulin.
“We are confident that our new program will remove cost as a barrier for people in participating plans who need insulin,” Steve Miller, MD, executive vice president and chief clinical officer at Cigna, said in a statement.
The Express Scripts spokeswoman noted that there were more than 700,000 people in a commercially insured plan across Cigna and Express Scripts who had a claim for insulin in 2018. The average out-of-pocket cost of a 30-day supply of insulin in 2018 across this population was $41.50.
Cigna and Express Scripts have announced
The new program, open to Cigna members who are covered in commercial plans, would cap out-of-pocket costs for a 30-day supply of insulin at $25. For plan members, the only eligibility requirement is having an out-of-pocket cost higher than $25, according to a press release.
For a member to participate in the program, the plan administrator at the member’s place of employment has to opt in to it. There are no eligibility requirements imposed on the employer, other than a willingness to opt in.
A spokeswoman for Express Scripts said that there is no charge to sign up for the program, and most plans will not see an additional cost to get the copayment to $25 for the patient.
The announcement comes in the wake of the first of two hearings by the House Committee on Energy & Commerce aimed at understanding why insulin prices have spiked in recent years. The first hearing, held on April 2, examined the impact that the high list price of insulin is having on patients, and how out-of-pocket expenses are limiting access to this life-saving drug. The second hearing, expected to occur during the week of April 8 (the date had not been scheduled as of press time), will bring together various players in the supply chain, including the three major manufacturers of insulin.
“We are confident that our new program will remove cost as a barrier for people in participating plans who need insulin,” Steve Miller, MD, executive vice president and chief clinical officer at Cigna, said in a statement.
The Express Scripts spokeswoman noted that there were more than 700,000 people in a commercially insured plan across Cigna and Express Scripts who had a claim for insulin in 2018. The average out-of-pocket cost of a 30-day supply of insulin in 2018 across this population was $41.50.
Cigna and Express Scripts have announced
The new program, open to Cigna members who are covered in commercial plans, would cap out-of-pocket costs for a 30-day supply of insulin at $25. For plan members, the only eligibility requirement is having an out-of-pocket cost higher than $25, according to a press release.
For a member to participate in the program, the plan administrator at the member’s place of employment has to opt in to it. There are no eligibility requirements imposed on the employer, other than a willingness to opt in.
A spokeswoman for Express Scripts said that there is no charge to sign up for the program, and most plans will not see an additional cost to get the copayment to $25 for the patient.
The announcement comes in the wake of the first of two hearings by the House Committee on Energy & Commerce aimed at understanding why insulin prices have spiked in recent years. The first hearing, held on April 2, examined the impact that the high list price of insulin is having on patients, and how out-of-pocket expenses are limiting access to this life-saving drug. The second hearing, expected to occur during the week of April 8 (the date had not been scheduled as of press time), will bring together various players in the supply chain, including the three major manufacturers of insulin.
“We are confident that our new program will remove cost as a barrier for people in participating plans who need insulin,” Steve Miller, MD, executive vice president and chief clinical officer at Cigna, said in a statement.
The Express Scripts spokeswoman noted that there were more than 700,000 people in a commercially insured plan across Cigna and Express Scripts who had a claim for insulin in 2018. The average out-of-pocket cost of a 30-day supply of insulin in 2018 across this population was $41.50.
ONC’s Dr. Rucker: Era of provider-controlled data is over
“The era of the provider controlling all of this, I think this is over,” Donald Rucker, MD, head of the Office of the National Coordinator (ONC) for Health Information Technology within the Department of Health and Human Services, said at an annual conference on health data and innovation. We need a “formal path to put patients back in control of their medical data.”
That path can be found in a pair of proposed rules issued earlier this year, one from the Centers for Medicare & Medicaid Services and the other from ONC, that are designed to give patients that control.
With smartphone apps under development that will allow patient access to health care data from a single point of entry, “technology now allows us to move from having to go portal to portal to portal to really having us in control,” Dr. Rucker said. “I think it is going to transform [health care] in the same way that the smartphone app has transformed other sectors. We are very excited about that.”
Access to data and information should further the transition to value-based care as patients become the center of the decision tree, Dr. Rucker said, making decisions based on benefits in a way that is not possible now.
“In particular, we think patients are going to start being able to shop for care,” he said, adding that if “they don’t like the price of the care they are getting, they are going to be able to move their business elsewhere.”
To that end, he said that much of the talk about interoperability “is really a conversation about affordability and the vast expenses in health care and how you get some control over that.”
“The era of the provider controlling all of this, I think this is over,” Donald Rucker, MD, head of the Office of the National Coordinator (ONC) for Health Information Technology within the Department of Health and Human Services, said at an annual conference on health data and innovation. We need a “formal path to put patients back in control of their medical data.”
That path can be found in a pair of proposed rules issued earlier this year, one from the Centers for Medicare & Medicaid Services and the other from ONC, that are designed to give patients that control.
With smartphone apps under development that will allow patient access to health care data from a single point of entry, “technology now allows us to move from having to go portal to portal to portal to really having us in control,” Dr. Rucker said. “I think it is going to transform [health care] in the same way that the smartphone app has transformed other sectors. We are very excited about that.”
Access to data and information should further the transition to value-based care as patients become the center of the decision tree, Dr. Rucker said, making decisions based on benefits in a way that is not possible now.
“In particular, we think patients are going to start being able to shop for care,” he said, adding that if “they don’t like the price of the care they are getting, they are going to be able to move their business elsewhere.”
To that end, he said that much of the talk about interoperability “is really a conversation about affordability and the vast expenses in health care and how you get some control over that.”
“The era of the provider controlling all of this, I think this is over,” Donald Rucker, MD, head of the Office of the National Coordinator (ONC) for Health Information Technology within the Department of Health and Human Services, said at an annual conference on health data and innovation. We need a “formal path to put patients back in control of their medical data.”
That path can be found in a pair of proposed rules issued earlier this year, one from the Centers for Medicare & Medicaid Services and the other from ONC, that are designed to give patients that control.
With smartphone apps under development that will allow patient access to health care data from a single point of entry, “technology now allows us to move from having to go portal to portal to portal to really having us in control,” Dr. Rucker said. “I think it is going to transform [health care] in the same way that the smartphone app has transformed other sectors. We are very excited about that.”
Access to data and information should further the transition to value-based care as patients become the center of the decision tree, Dr. Rucker said, making decisions based on benefits in a way that is not possible now.
“In particular, we think patients are going to start being able to shop for care,” he said, adding that if “they don’t like the price of the care they are getting, they are going to be able to move their business elsewhere.”
To that end, he said that much of the talk about interoperability “is really a conversation about affordability and the vast expenses in health care and how you get some control over that.”
REPORTING FROM HEALTH DATAPALOOZA 2019
Harness EHRs to identify PrEP candidates
SEATTLE – Kaiser Permanente Northern California has developed an EHR program that automatically flags patients at high risk for HIV.
The idea was to come up with a way to help clinicians focus their pre-exposure prophylaxis (PrEP) outreach on the people who need it most. PrEP prevents HIV, but often “it’s difficult for providers to identify patients who are at risk. Prediction models using EHR data can identify patients who are at high risk but not using PrEP,” said study lead Julia Marcus, PhD, an assistant professor in the department of population medicine at Harvard Medical School, Boston.
She proved that assertion in a presentation at the Conference on Retroviruses & Opportunistic Infections.
The Kaiser program uses 44 variables routinely collected in EHRs from five categories: demographics, social history, lab data, medication use, and diagnoses. Specific variables include living in a zip code with high HIV incidence; men who have sex with men (MSM); black race; urine tests positive for cocaine or methadone; use of erectile dysfunction medications; and diagnoses of depression, anal warts, and other conditions.
The development cohort included 3,143,963 Kaiser members from 2007 to 2014 with 2 or more years of enrollment; at least one outpatient visit; no prior PrEP use; and no HIV diagnosis.
There were 701 incident HIV cases; the model did a good job at predicting them, with a C-statistic of 0.86 (95% confidence interval, 0.85-0.87). A score of 1.0 would be perfect prediction, and 0.5 no predictive value. Previous efforts at HIV prediction – relying generally on just MSM status and STD history – have C-statistics of around 0.6; prediction models commonly used for cardiovascular and other diseases often have C-statistics of around 0.7, Dr. Marcus explained.
The model was validated in 606,701 Kaiser members during 2015-2017. The validation cohort was slightly younger than the development cohort, with a mean age of 37 versus 45 years, and slightly more diverse, with fewer white patients, 44% versus 52%. Both cohorts had slightly more women than men.
There were 83 new HIV diagnoses in the validation cohort. The C-statistic for HIV prediction was 0.84 (95% CI, 0.8-0.89). The model predicted 32 of 69 (46%) incident HIV cases among men tagged as high risk – at least a 0.2% chance of contracting HIV within 3 years – or very high risk, a 1% chance or higher, which is more than 50 times the risk among the general population. Relying on just MSM and STD history predicted 32% of cases.
Overall, “our model identified nearly half of new HIV cases among males by flagging only 2% of the general population. The results suggest our model would perform well if implemented today. You could replicate our approach in any health system with an EHR. Our specific variables may not translate to every setting, but any health care system can develop this model based on the EHR data they do have,” Dr. Marcus said.
“You could embed this in any EHR system and have it update in real time to flag providers to do a sexual history and talk with patients about PrEP,” she said.
The next step is a pilot project at Kaiser Permanente San Francisco to evaluate the impact on PrEP prescribing and HIV incidence. The model failed to predict 14 incident HIV cases among women in the validation cohort, a problem that also needs to be addressed.
The work was funded by the National Institutes of Health and Kaiser Permanente. Dr. Marcus didn’t have any relevant disclosures.
SOURCE: Marcus JL et al. CROI 2019, Abstract 105.
SEATTLE – Kaiser Permanente Northern California has developed an EHR program that automatically flags patients at high risk for HIV.
The idea was to come up with a way to help clinicians focus their pre-exposure prophylaxis (PrEP) outreach on the people who need it most. PrEP prevents HIV, but often “it’s difficult for providers to identify patients who are at risk. Prediction models using EHR data can identify patients who are at high risk but not using PrEP,” said study lead Julia Marcus, PhD, an assistant professor in the department of population medicine at Harvard Medical School, Boston.
She proved that assertion in a presentation at the Conference on Retroviruses & Opportunistic Infections.
The Kaiser program uses 44 variables routinely collected in EHRs from five categories: demographics, social history, lab data, medication use, and diagnoses. Specific variables include living in a zip code with high HIV incidence; men who have sex with men (MSM); black race; urine tests positive for cocaine or methadone; use of erectile dysfunction medications; and diagnoses of depression, anal warts, and other conditions.
The development cohort included 3,143,963 Kaiser members from 2007 to 2014 with 2 or more years of enrollment; at least one outpatient visit; no prior PrEP use; and no HIV diagnosis.
There were 701 incident HIV cases; the model did a good job at predicting them, with a C-statistic of 0.86 (95% confidence interval, 0.85-0.87). A score of 1.0 would be perfect prediction, and 0.5 no predictive value. Previous efforts at HIV prediction – relying generally on just MSM status and STD history – have C-statistics of around 0.6; prediction models commonly used for cardiovascular and other diseases often have C-statistics of around 0.7, Dr. Marcus explained.
The model was validated in 606,701 Kaiser members during 2015-2017. The validation cohort was slightly younger than the development cohort, with a mean age of 37 versus 45 years, and slightly more diverse, with fewer white patients, 44% versus 52%. Both cohorts had slightly more women than men.
There were 83 new HIV diagnoses in the validation cohort. The C-statistic for HIV prediction was 0.84 (95% CI, 0.8-0.89). The model predicted 32 of 69 (46%) incident HIV cases among men tagged as high risk – at least a 0.2% chance of contracting HIV within 3 years – or very high risk, a 1% chance or higher, which is more than 50 times the risk among the general population. Relying on just MSM and STD history predicted 32% of cases.
Overall, “our model identified nearly half of new HIV cases among males by flagging only 2% of the general population. The results suggest our model would perform well if implemented today. You could replicate our approach in any health system with an EHR. Our specific variables may not translate to every setting, but any health care system can develop this model based on the EHR data they do have,” Dr. Marcus said.
“You could embed this in any EHR system and have it update in real time to flag providers to do a sexual history and talk with patients about PrEP,” she said.
The next step is a pilot project at Kaiser Permanente San Francisco to evaluate the impact on PrEP prescribing and HIV incidence. The model failed to predict 14 incident HIV cases among women in the validation cohort, a problem that also needs to be addressed.
The work was funded by the National Institutes of Health and Kaiser Permanente. Dr. Marcus didn’t have any relevant disclosures.
SOURCE: Marcus JL et al. CROI 2019, Abstract 105.
SEATTLE – Kaiser Permanente Northern California has developed an EHR program that automatically flags patients at high risk for HIV.
The idea was to come up with a way to help clinicians focus their pre-exposure prophylaxis (PrEP) outreach on the people who need it most. PrEP prevents HIV, but often “it’s difficult for providers to identify patients who are at risk. Prediction models using EHR data can identify patients who are at high risk but not using PrEP,” said study lead Julia Marcus, PhD, an assistant professor in the department of population medicine at Harvard Medical School, Boston.
She proved that assertion in a presentation at the Conference on Retroviruses & Opportunistic Infections.
The Kaiser program uses 44 variables routinely collected in EHRs from five categories: demographics, social history, lab data, medication use, and diagnoses. Specific variables include living in a zip code with high HIV incidence; men who have sex with men (MSM); black race; urine tests positive for cocaine or methadone; use of erectile dysfunction medications; and diagnoses of depression, anal warts, and other conditions.
The development cohort included 3,143,963 Kaiser members from 2007 to 2014 with 2 or more years of enrollment; at least one outpatient visit; no prior PrEP use; and no HIV diagnosis.
There were 701 incident HIV cases; the model did a good job at predicting them, with a C-statistic of 0.86 (95% confidence interval, 0.85-0.87). A score of 1.0 would be perfect prediction, and 0.5 no predictive value. Previous efforts at HIV prediction – relying generally on just MSM status and STD history – have C-statistics of around 0.6; prediction models commonly used for cardiovascular and other diseases often have C-statistics of around 0.7, Dr. Marcus explained.
The model was validated in 606,701 Kaiser members during 2015-2017. The validation cohort was slightly younger than the development cohort, with a mean age of 37 versus 45 years, and slightly more diverse, with fewer white patients, 44% versus 52%. Both cohorts had slightly more women than men.
There were 83 new HIV diagnoses in the validation cohort. The C-statistic for HIV prediction was 0.84 (95% CI, 0.8-0.89). The model predicted 32 of 69 (46%) incident HIV cases among men tagged as high risk – at least a 0.2% chance of contracting HIV within 3 years – or very high risk, a 1% chance or higher, which is more than 50 times the risk among the general population. Relying on just MSM and STD history predicted 32% of cases.
Overall, “our model identified nearly half of new HIV cases among males by flagging only 2% of the general population. The results suggest our model would perform well if implemented today. You could replicate our approach in any health system with an EHR. Our specific variables may not translate to every setting, but any health care system can develop this model based on the EHR data they do have,” Dr. Marcus said.
“You could embed this in any EHR system and have it update in real time to flag providers to do a sexual history and talk with patients about PrEP,” she said.
The next step is a pilot project at Kaiser Permanente San Francisco to evaluate the impact on PrEP prescribing and HIV incidence. The model failed to predict 14 incident HIV cases among women in the validation cohort, a problem that also needs to be addressed.
The work was funded by the National Institutes of Health and Kaiser Permanente. Dr. Marcus didn’t have any relevant disclosures.
SOURCE: Marcus JL et al. CROI 2019, Abstract 105.
REPORTING FROM CROI 2019
‘Update in Hospital Medicine’ offered practice pearls at HM19
Studies that question common practices
On the big stage at HM19 in late March, Carrie Herzke, MD, FAAP, FACP, SFHM, and Christopher Moriates, MD, FACP, SFHM, undertook the daunting task of summarizing a year’s worth of research relevant to the practice of hospital medicine – all within the span of an hour.
As has been standard with the “Update in Hospital Medicine” session at previous SHM Annual Conferences, the presenters touched on lighter topics in the medical literature: a prospective cohort study that found drinking coffee was inversely associated with mortality, even for those who drink up to eight cups a day; a cross-sectional observational study in which patients noted that what a physician wears is an important consideration for them during care, with a white coat preferred over formal attire as the most highly rated preference in a clinical care setting; and a study from a pediatric journal in which researchers calculated the average transit time for a Lego figurine head ingested by an adult.
But Dr. Herzke and Dr. Moriates mainly covered more serious subjects. In an interview before the session, Dr. Herzke, associate vice chair for clinical affairs in the department of medicine at Johns Hopkins Medicine in Baltimore, said she and Dr. Moriates chose studies across the fields of infectious diseases, cardiology, and hematology that should make hospitalists question common practices and consider changing how they practice medicine at their home institution.
Dr. Moriates, assistant dean for health care value at the University of Texas at Austin, said in an interview that their topic choices reflected the breadth and diversity of patients taken care of by hospitalists.
For example, he noted during the HM19 session that results from several studies suggest hospitalists may soon choose oral antibiotics over IV antibiotics for care of certain patient populations: the recent POET trial suggests use of oral antibiotics for patients with left-sided infective endocarditis resulted in a lower length of stay in hospital (19 inpatient days) when compared with use of IV antibiotics (3 inpatient days and 17 additional treatment days post discharge), while the OVIVA trial found a lower but noninferior treatment failure rate among patients who received oral antibiotics for bone and joint infection, compared with IV antibiotics. Although these were both well-done studies, Dr. Moriates and Dr. Herzke emphasized that the results challenge widely accepted standards of care, and it may not yet be time for a paradigm shift.
Direct oral anticoagulants (DOACs) also are being studied in patients with end-stage renal disease (ESRD) and cancer, Dr. Herzke said, and apixaban (Eliquis) 5 mg appears to be the preferred dose for a lower risk of stroke and mortality in patients with ESRD and atrial fibrillation. The speakers said there are further studies being developed for management of AF in patients with heart failure and DOACs for patients with ESRD.
Another retrospective cohort study from research in the Massachusetts Public Health Dataset found that buprenorphine may have a number needed to treat of 50 for opioid use disorder, which Dr. Moriates said is close in proximity for the number needed to treat for aspirin. “It seems like it’s time for this to become standard of care,” he said.
The speakers also highlighted common practices hospitalists should stop performing based on the latest evidence.
In one example, they revealed that there is conflicting research on angiotensin-converting enzyme (ACE) inhibitors. One study found transient preoperative interruption of ACE inhibitors was associated with a reduction in intraoperative hypotension during a noncardiac, nonvascular surgery. A second study linked ACE inhibitor use with a reduction in all-cause mortality. However, long-term use of ACE inhibitors also appears to be associated with a 14% increase in lung cancers, with an increased incidence based on longer use duration.
Hospitalists should also be aware of recommendations from a study on oxygen therapy, Dr. Herzke noted, which found that extra oxygen therapy may harm patients with MI or stroke; as a result, hospitalists should “wean oxygen as tolerated” in these patients. In addition, hospitalists also may want to consider using oral vancomycin (Vancocin) or fidaxomicin (Dificid) for treatment of Clostridium difficile infections, based on new evidence that found there is a higher cure rate for those treatments, compared with metronidazole.
Dr. Moriates and Dr. Herzke had no relevant financial conflicts.
Studies that question common practices
Studies that question common practices
On the big stage at HM19 in late March, Carrie Herzke, MD, FAAP, FACP, SFHM, and Christopher Moriates, MD, FACP, SFHM, undertook the daunting task of summarizing a year’s worth of research relevant to the practice of hospital medicine – all within the span of an hour.
As has been standard with the “Update in Hospital Medicine” session at previous SHM Annual Conferences, the presenters touched on lighter topics in the medical literature: a prospective cohort study that found drinking coffee was inversely associated with mortality, even for those who drink up to eight cups a day; a cross-sectional observational study in which patients noted that what a physician wears is an important consideration for them during care, with a white coat preferred over formal attire as the most highly rated preference in a clinical care setting; and a study from a pediatric journal in which researchers calculated the average transit time for a Lego figurine head ingested by an adult.
But Dr. Herzke and Dr. Moriates mainly covered more serious subjects. In an interview before the session, Dr. Herzke, associate vice chair for clinical affairs in the department of medicine at Johns Hopkins Medicine in Baltimore, said she and Dr. Moriates chose studies across the fields of infectious diseases, cardiology, and hematology that should make hospitalists question common practices and consider changing how they practice medicine at their home institution.
Dr. Moriates, assistant dean for health care value at the University of Texas at Austin, said in an interview that their topic choices reflected the breadth and diversity of patients taken care of by hospitalists.
For example, he noted during the HM19 session that results from several studies suggest hospitalists may soon choose oral antibiotics over IV antibiotics for care of certain patient populations: the recent POET trial suggests use of oral antibiotics for patients with left-sided infective endocarditis resulted in a lower length of stay in hospital (19 inpatient days) when compared with use of IV antibiotics (3 inpatient days and 17 additional treatment days post discharge), while the OVIVA trial found a lower but noninferior treatment failure rate among patients who received oral antibiotics for bone and joint infection, compared with IV antibiotics. Although these were both well-done studies, Dr. Moriates and Dr. Herzke emphasized that the results challenge widely accepted standards of care, and it may not yet be time for a paradigm shift.
Direct oral anticoagulants (DOACs) also are being studied in patients with end-stage renal disease (ESRD) and cancer, Dr. Herzke said, and apixaban (Eliquis) 5 mg appears to be the preferred dose for a lower risk of stroke and mortality in patients with ESRD and atrial fibrillation. The speakers said there are further studies being developed for management of AF in patients with heart failure and DOACs for patients with ESRD.
Another retrospective cohort study from research in the Massachusetts Public Health Dataset found that buprenorphine may have a number needed to treat of 50 for opioid use disorder, which Dr. Moriates said is close in proximity for the number needed to treat for aspirin. “It seems like it’s time for this to become standard of care,” he said.
The speakers also highlighted common practices hospitalists should stop performing based on the latest evidence.
In one example, they revealed that there is conflicting research on angiotensin-converting enzyme (ACE) inhibitors. One study found transient preoperative interruption of ACE inhibitors was associated with a reduction in intraoperative hypotension during a noncardiac, nonvascular surgery. A second study linked ACE inhibitor use with a reduction in all-cause mortality. However, long-term use of ACE inhibitors also appears to be associated with a 14% increase in lung cancers, with an increased incidence based on longer use duration.
Hospitalists should also be aware of recommendations from a study on oxygen therapy, Dr. Herzke noted, which found that extra oxygen therapy may harm patients with MI or stroke; as a result, hospitalists should “wean oxygen as tolerated” in these patients. In addition, hospitalists also may want to consider using oral vancomycin (Vancocin) or fidaxomicin (Dificid) for treatment of Clostridium difficile infections, based on new evidence that found there is a higher cure rate for those treatments, compared with metronidazole.
Dr. Moriates and Dr. Herzke had no relevant financial conflicts.
On the big stage at HM19 in late March, Carrie Herzke, MD, FAAP, FACP, SFHM, and Christopher Moriates, MD, FACP, SFHM, undertook the daunting task of summarizing a year’s worth of research relevant to the practice of hospital medicine – all within the span of an hour.
As has been standard with the “Update in Hospital Medicine” session at previous SHM Annual Conferences, the presenters touched on lighter topics in the medical literature: a prospective cohort study that found drinking coffee was inversely associated with mortality, even for those who drink up to eight cups a day; a cross-sectional observational study in which patients noted that what a physician wears is an important consideration for them during care, with a white coat preferred over formal attire as the most highly rated preference in a clinical care setting; and a study from a pediatric journal in which researchers calculated the average transit time for a Lego figurine head ingested by an adult.
But Dr. Herzke and Dr. Moriates mainly covered more serious subjects. In an interview before the session, Dr. Herzke, associate vice chair for clinical affairs in the department of medicine at Johns Hopkins Medicine in Baltimore, said she and Dr. Moriates chose studies across the fields of infectious diseases, cardiology, and hematology that should make hospitalists question common practices and consider changing how they practice medicine at their home institution.
Dr. Moriates, assistant dean for health care value at the University of Texas at Austin, said in an interview that their topic choices reflected the breadth and diversity of patients taken care of by hospitalists.
For example, he noted during the HM19 session that results from several studies suggest hospitalists may soon choose oral antibiotics over IV antibiotics for care of certain patient populations: the recent POET trial suggests use of oral antibiotics for patients with left-sided infective endocarditis resulted in a lower length of stay in hospital (19 inpatient days) when compared with use of IV antibiotics (3 inpatient days and 17 additional treatment days post discharge), while the OVIVA trial found a lower but noninferior treatment failure rate among patients who received oral antibiotics for bone and joint infection, compared with IV antibiotics. Although these were both well-done studies, Dr. Moriates and Dr. Herzke emphasized that the results challenge widely accepted standards of care, and it may not yet be time for a paradigm shift.
Direct oral anticoagulants (DOACs) also are being studied in patients with end-stage renal disease (ESRD) and cancer, Dr. Herzke said, and apixaban (Eliquis) 5 mg appears to be the preferred dose for a lower risk of stroke and mortality in patients with ESRD and atrial fibrillation. The speakers said there are further studies being developed for management of AF in patients with heart failure and DOACs for patients with ESRD.
Another retrospective cohort study from research in the Massachusetts Public Health Dataset found that buprenorphine may have a number needed to treat of 50 for opioid use disorder, which Dr. Moriates said is close in proximity for the number needed to treat for aspirin. “It seems like it’s time for this to become standard of care,” he said.
The speakers also highlighted common practices hospitalists should stop performing based on the latest evidence.
In one example, they revealed that there is conflicting research on angiotensin-converting enzyme (ACE) inhibitors. One study found transient preoperative interruption of ACE inhibitors was associated with a reduction in intraoperative hypotension during a noncardiac, nonvascular surgery. A second study linked ACE inhibitor use with a reduction in all-cause mortality. However, long-term use of ACE inhibitors also appears to be associated with a 14% increase in lung cancers, with an increased incidence based on longer use duration.
Hospitalists should also be aware of recommendations from a study on oxygen therapy, Dr. Herzke noted, which found that extra oxygen therapy may harm patients with MI or stroke; as a result, hospitalists should “wean oxygen as tolerated” in these patients. In addition, hospitalists also may want to consider using oral vancomycin (Vancocin) or fidaxomicin (Dificid) for treatment of Clostridium difficile infections, based on new evidence that found there is a higher cure rate for those treatments, compared with metronidazole.
Dr. Moriates and Dr. Herzke had no relevant financial conflicts.
How to cope with patients who get under your skin
DENVER – If you get the impression you’re dealing with more angry and manipulative patients than usual in the past several years, you’re not alone.
In 1999, as many as 15% of patient encounters were rated as difficult by health care providers, according to Tina S. Alster, MD (Arch Intern Med. 1999;159:1069-75). Today, upward of 30% of patient encounters are deemed difficult (Int J Res Med Sci. 2016;4[8]:3554-62). “That means one in three patients that you see have a problem that goes beyond the scope of our official training,” said Dr. Alster, who is the founding director of the Washington Institute of Dermatologic Laser Surgery and clinical professor of dermatology at Georgetown University, Washington. “If it was limited to a medical problem, we could handle it; that’s what we’re trained to do. The interpersonal issues and psychosocial implications of treatment are much more difficult.”
At the annual conference of the American Society for Laser Medicine and Surgery, Dr. Alster said that difficult patients put a strain on your practice and your relationship with them. “These patients put you on your heels. They often point out a problem that may or may not be related to something that you’re responsible for. It’s not usually because you are running late on the day of their visit and you make them late for something else. That situation is one you can prepare for, because you know you’re running late. It’s the other stuff you don’t realize that’s going on, which can cause problems.”
Setting limits
Being proactive can help lessen the ripple effect from patients who rock the boat. “You want to set limits with those patients before you even see them,” Dr. Alster said. “There are written contracts and policies that you should have in place. Since I perform mostly cosmetic procedures in my office, it is important that patients are made aware that payment is expected at the time of service and that my office does not bill nor accept insurance payments in order to prevent misunderstandings at check out.” She also declines requests to provide expert testimony for legal cases. “I’ve been in this business a long time, and every day I get requests to be an expert or to review a case involving a provider who may or may not have made a mistake. I really hate going down that rabbit hole.”
Another solution to keeping difficult patients in check is to collaborate with your entire office staff on how to best deal with them. “You need to present a united front with these patients: They’re going to divide and conquer, with complaints like, ‘How dare the doctor be so late. I’ve been waiting here for 30 minutes. Doesn’t she know I’m busy?’ ” Dr. Alster said. “You’re going to have to give them the tools to set limits as well. During our staff meetings, we review the upcoming patient schedule and identify potentially difficult situations in order to make sure the team is on the same page. Because my office is located in the power corridor of Washington [three blocks away from the White House] and my patient base is populated by prevalent personalities, expectations are extraordinarily high. As such, it is important that we set limits and rules that everyone can play by.”
Getting a sense of whether a patient is angry or manipulative can also help. An angry patient often holds an expectation that has been unmet, or harbors fears related to the treatment itself, she said, while a manipulative patient may engage in bullying, excessive flattery, or veiled threats. “They often expect specific treatments that have only worked for them in the past, even though it may be opposed to the treatment you recommend. They know better than you, even though you’re the expert.”
Communicating effectively with these two types of patients requires a slightly different approach. “With an angry patient, you want to share decision making,” Dr. Alster said. “Have them voice their concerns and come up with a plan together going forward. You’re not going to make that person less angry by telling them what to do.” The manipulative patient, meanwhile, requires a team approach. For example, she may ask your medical assistant for opinions on the treatment option you recommended during your office consultation with her, or second-guess your recommendation with that person altogether. “Everybody needs to know who the manipulative patients are and approach them as a team.”
The art of nonconfrontation
Dr. Alster brings a nonconfrontational approach to interactions with difficult patients. “You can apologize if you’ve kept them waiting, but you can’t apologize for everything all the time,” she said. “I may say something like, ‘I appreciate that your visit is running late. I apologize for the delay and want you to know that we take as much time as necessary for each patient and that unforeseen circumstances beyond our control sometimes arise.’ ” Another phrase she may use is, “I understand that this has been a stressful visit, but I want to talk to you about your experience and identify how we can improve subsequent appointments.”
Showing empathy never hurts. “Repeat back to them what you heard, and establish the fact that you understand,” Dr. Alster said. “Lower your voice, talk slowly, don’t get caught up in emotion. Otherwise, you’re going down in a sinkhole with them. Be wrong to be right. This encourages negotiation. You also want to document all patient interactions. Put every correspondence in the patient’s EMR.”
Dr. Alster advises clinicians to provide an outline of office policies and procedures to all patients, as well as written and verbal instructions related to their care. She also phones or emails patients undergoing a treatment for the first time. “Even if they’ve been in the practice for several years, if they received filler injections for the first time [instead of Botox], we still check in with those patients when they receive a first-time treatment to make sure they’re doing okay,” she said. “We’ll call them that evening or at the very least early the next morning to make sure that they don’t have any questions or concerns.”
If problems persist despite your best efforts, sometimes your best option is to dismiss difficult patients from your practice. “That’s only when everything else fails,” Dr. Alster said. “A concise termination letter should state a ‘breakdown in physician-patient relationship.’ I call it my ‘Dear John’ letter, and since 1990, I’ve only written six of these. A detailed explanation is usually not needed, but may be advisable depending on your state, to protect yourself from a liability standpoint. I instruct patients to contact the state medical society for referral to another provider and inform them that upon their written request, their medical records will be forwarded to their new provider. I also set up a reasonable timeline during which I will continue to see them for emergency visits to ensure that there is continuity of care, even when it is a cosmetic situation.”
Dr. Alster reported having no financial disclosures related to her presentation.
DENVER – If you get the impression you’re dealing with more angry and manipulative patients than usual in the past several years, you’re not alone.
In 1999, as many as 15% of patient encounters were rated as difficult by health care providers, according to Tina S. Alster, MD (Arch Intern Med. 1999;159:1069-75). Today, upward of 30% of patient encounters are deemed difficult (Int J Res Med Sci. 2016;4[8]:3554-62). “That means one in three patients that you see have a problem that goes beyond the scope of our official training,” said Dr. Alster, who is the founding director of the Washington Institute of Dermatologic Laser Surgery and clinical professor of dermatology at Georgetown University, Washington. “If it was limited to a medical problem, we could handle it; that’s what we’re trained to do. The interpersonal issues and psychosocial implications of treatment are much more difficult.”
At the annual conference of the American Society for Laser Medicine and Surgery, Dr. Alster said that difficult patients put a strain on your practice and your relationship with them. “These patients put you on your heels. They often point out a problem that may or may not be related to something that you’re responsible for. It’s not usually because you are running late on the day of their visit and you make them late for something else. That situation is one you can prepare for, because you know you’re running late. It’s the other stuff you don’t realize that’s going on, which can cause problems.”
Setting limits
Being proactive can help lessen the ripple effect from patients who rock the boat. “You want to set limits with those patients before you even see them,” Dr. Alster said. “There are written contracts and policies that you should have in place. Since I perform mostly cosmetic procedures in my office, it is important that patients are made aware that payment is expected at the time of service and that my office does not bill nor accept insurance payments in order to prevent misunderstandings at check out.” She also declines requests to provide expert testimony for legal cases. “I’ve been in this business a long time, and every day I get requests to be an expert or to review a case involving a provider who may or may not have made a mistake. I really hate going down that rabbit hole.”
Another solution to keeping difficult patients in check is to collaborate with your entire office staff on how to best deal with them. “You need to present a united front with these patients: They’re going to divide and conquer, with complaints like, ‘How dare the doctor be so late. I’ve been waiting here for 30 minutes. Doesn’t she know I’m busy?’ ” Dr. Alster said. “You’re going to have to give them the tools to set limits as well. During our staff meetings, we review the upcoming patient schedule and identify potentially difficult situations in order to make sure the team is on the same page. Because my office is located in the power corridor of Washington [three blocks away from the White House] and my patient base is populated by prevalent personalities, expectations are extraordinarily high. As such, it is important that we set limits and rules that everyone can play by.”
Getting a sense of whether a patient is angry or manipulative can also help. An angry patient often holds an expectation that has been unmet, or harbors fears related to the treatment itself, she said, while a manipulative patient may engage in bullying, excessive flattery, or veiled threats. “They often expect specific treatments that have only worked for them in the past, even though it may be opposed to the treatment you recommend. They know better than you, even though you’re the expert.”
Communicating effectively with these two types of patients requires a slightly different approach. “With an angry patient, you want to share decision making,” Dr. Alster said. “Have them voice their concerns and come up with a plan together going forward. You’re not going to make that person less angry by telling them what to do.” The manipulative patient, meanwhile, requires a team approach. For example, she may ask your medical assistant for opinions on the treatment option you recommended during your office consultation with her, or second-guess your recommendation with that person altogether. “Everybody needs to know who the manipulative patients are and approach them as a team.”
The art of nonconfrontation
Dr. Alster brings a nonconfrontational approach to interactions with difficult patients. “You can apologize if you’ve kept them waiting, but you can’t apologize for everything all the time,” she said. “I may say something like, ‘I appreciate that your visit is running late. I apologize for the delay and want you to know that we take as much time as necessary for each patient and that unforeseen circumstances beyond our control sometimes arise.’ ” Another phrase she may use is, “I understand that this has been a stressful visit, but I want to talk to you about your experience and identify how we can improve subsequent appointments.”
Showing empathy never hurts. “Repeat back to them what you heard, and establish the fact that you understand,” Dr. Alster said. “Lower your voice, talk slowly, don’t get caught up in emotion. Otherwise, you’re going down in a sinkhole with them. Be wrong to be right. This encourages negotiation. You also want to document all patient interactions. Put every correspondence in the patient’s EMR.”
Dr. Alster advises clinicians to provide an outline of office policies and procedures to all patients, as well as written and verbal instructions related to their care. She also phones or emails patients undergoing a treatment for the first time. “Even if they’ve been in the practice for several years, if they received filler injections for the first time [instead of Botox], we still check in with those patients when they receive a first-time treatment to make sure they’re doing okay,” she said. “We’ll call them that evening or at the very least early the next morning to make sure that they don’t have any questions or concerns.”
If problems persist despite your best efforts, sometimes your best option is to dismiss difficult patients from your practice. “That’s only when everything else fails,” Dr. Alster said. “A concise termination letter should state a ‘breakdown in physician-patient relationship.’ I call it my ‘Dear John’ letter, and since 1990, I’ve only written six of these. A detailed explanation is usually not needed, but may be advisable depending on your state, to protect yourself from a liability standpoint. I instruct patients to contact the state medical society for referral to another provider and inform them that upon their written request, their medical records will be forwarded to their new provider. I also set up a reasonable timeline during which I will continue to see them for emergency visits to ensure that there is continuity of care, even when it is a cosmetic situation.”
Dr. Alster reported having no financial disclosures related to her presentation.
DENVER – If you get the impression you’re dealing with more angry and manipulative patients than usual in the past several years, you’re not alone.
In 1999, as many as 15% of patient encounters were rated as difficult by health care providers, according to Tina S. Alster, MD (Arch Intern Med. 1999;159:1069-75). Today, upward of 30% of patient encounters are deemed difficult (Int J Res Med Sci. 2016;4[8]:3554-62). “That means one in three patients that you see have a problem that goes beyond the scope of our official training,” said Dr. Alster, who is the founding director of the Washington Institute of Dermatologic Laser Surgery and clinical professor of dermatology at Georgetown University, Washington. “If it was limited to a medical problem, we could handle it; that’s what we’re trained to do. The interpersonal issues and psychosocial implications of treatment are much more difficult.”
At the annual conference of the American Society for Laser Medicine and Surgery, Dr. Alster said that difficult patients put a strain on your practice and your relationship with them. “These patients put you on your heels. They often point out a problem that may or may not be related to something that you’re responsible for. It’s not usually because you are running late on the day of their visit and you make them late for something else. That situation is one you can prepare for, because you know you’re running late. It’s the other stuff you don’t realize that’s going on, which can cause problems.”
Setting limits
Being proactive can help lessen the ripple effect from patients who rock the boat. “You want to set limits with those patients before you even see them,” Dr. Alster said. “There are written contracts and policies that you should have in place. Since I perform mostly cosmetic procedures in my office, it is important that patients are made aware that payment is expected at the time of service and that my office does not bill nor accept insurance payments in order to prevent misunderstandings at check out.” She also declines requests to provide expert testimony for legal cases. “I’ve been in this business a long time, and every day I get requests to be an expert or to review a case involving a provider who may or may not have made a mistake. I really hate going down that rabbit hole.”
Another solution to keeping difficult patients in check is to collaborate with your entire office staff on how to best deal with them. “You need to present a united front with these patients: They’re going to divide and conquer, with complaints like, ‘How dare the doctor be so late. I’ve been waiting here for 30 minutes. Doesn’t she know I’m busy?’ ” Dr. Alster said. “You’re going to have to give them the tools to set limits as well. During our staff meetings, we review the upcoming patient schedule and identify potentially difficult situations in order to make sure the team is on the same page. Because my office is located in the power corridor of Washington [three blocks away from the White House] and my patient base is populated by prevalent personalities, expectations are extraordinarily high. As such, it is important that we set limits and rules that everyone can play by.”
Getting a sense of whether a patient is angry or manipulative can also help. An angry patient often holds an expectation that has been unmet, or harbors fears related to the treatment itself, she said, while a manipulative patient may engage in bullying, excessive flattery, or veiled threats. “They often expect specific treatments that have only worked for them in the past, even though it may be opposed to the treatment you recommend. They know better than you, even though you’re the expert.”
Communicating effectively with these two types of patients requires a slightly different approach. “With an angry patient, you want to share decision making,” Dr. Alster said. “Have them voice their concerns and come up with a plan together going forward. You’re not going to make that person less angry by telling them what to do.” The manipulative patient, meanwhile, requires a team approach. For example, she may ask your medical assistant for opinions on the treatment option you recommended during your office consultation with her, or second-guess your recommendation with that person altogether. “Everybody needs to know who the manipulative patients are and approach them as a team.”
The art of nonconfrontation
Dr. Alster brings a nonconfrontational approach to interactions with difficult patients. “You can apologize if you’ve kept them waiting, but you can’t apologize for everything all the time,” she said. “I may say something like, ‘I appreciate that your visit is running late. I apologize for the delay and want you to know that we take as much time as necessary for each patient and that unforeseen circumstances beyond our control sometimes arise.’ ” Another phrase she may use is, “I understand that this has been a stressful visit, but I want to talk to you about your experience and identify how we can improve subsequent appointments.”
Showing empathy never hurts. “Repeat back to them what you heard, and establish the fact that you understand,” Dr. Alster said. “Lower your voice, talk slowly, don’t get caught up in emotion. Otherwise, you’re going down in a sinkhole with them. Be wrong to be right. This encourages negotiation. You also want to document all patient interactions. Put every correspondence in the patient’s EMR.”
Dr. Alster advises clinicians to provide an outline of office policies and procedures to all patients, as well as written and verbal instructions related to their care. She also phones or emails patients undergoing a treatment for the first time. “Even if they’ve been in the practice for several years, if they received filler injections for the first time [instead of Botox], we still check in with those patients when they receive a first-time treatment to make sure they’re doing okay,” she said. “We’ll call them that evening or at the very least early the next morning to make sure that they don’t have any questions or concerns.”
If problems persist despite your best efforts, sometimes your best option is to dismiss difficult patients from your practice. “That’s only when everything else fails,” Dr. Alster said. “A concise termination letter should state a ‘breakdown in physician-patient relationship.’ I call it my ‘Dear John’ letter, and since 1990, I’ve only written six of these. A detailed explanation is usually not needed, but may be advisable depending on your state, to protect yourself from a liability standpoint. I instruct patients to contact the state medical society for referral to another provider and inform them that upon their written request, their medical records will be forwarded to their new provider. I also set up a reasonable timeline during which I will continue to see them for emergency visits to ensure that there is continuity of care, even when it is a cosmetic situation.”
Dr. Alster reported having no financial disclosures related to her presentation.
EXPERT ANALYSIS FROM ASLMS 2019
Highlights from the 2019 Society of Gynecologic Surgeons Scientific Meeting
- Rising to the challenges in gynecologic surgical care
- Anterior, apical, posterior: Vaginal anatomy for the gynecologic surgeon
- Beyond enhanced recovery after surgery
B. Star Hampton, MD
Professor
Department of Obstetrics and Gynecology
Division of Urogynecology and Reconstructive
Pelvic Surgery
The Warren Albert Medical School
of Brown University
Women & Infants Hospital
Providence, Rhode Island
Peter C. Jeppson, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of New Mexico School of Medicine
Albuquerque, New Mexico
Audra Jolyn Hill, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of Utah School of Medicine
Salt Lake City, Utah
Sunil Balgobin, MD
Assistant Professor
Department of Obstetrics and Gynecology
Division of Female Pelvic Medicine
and Reconstructive Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
Sean C. Dowdy, MD
Professor and Chair
Division of Gynecologic Oncology
Mayo Clinic
Rochester, Minnesota
- Rising to the challenges in gynecologic surgical care
- Anterior, apical, posterior: Vaginal anatomy for the gynecologic surgeon
- Beyond enhanced recovery after surgery
B. Star Hampton, MD
Professor
Department of Obstetrics and Gynecology
Division of Urogynecology and Reconstructive
Pelvic Surgery
The Warren Albert Medical School
of Brown University
Women & Infants Hospital
Providence, Rhode Island
Peter C. Jeppson, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of New Mexico School of Medicine
Albuquerque, New Mexico
Audra Jolyn Hill, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of Utah School of Medicine
Salt Lake City, Utah
Sunil Balgobin, MD
Assistant Professor
Department of Obstetrics and Gynecology
Division of Female Pelvic Medicine
and Reconstructive Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
Sean C. Dowdy, MD
Professor and Chair
Division of Gynecologic Oncology
Mayo Clinic
Rochester, Minnesota
- Rising to the challenges in gynecologic surgical care
- Anterior, apical, posterior: Vaginal anatomy for the gynecologic surgeon
- Beyond enhanced recovery after surgery
B. Star Hampton, MD
Professor
Department of Obstetrics and Gynecology
Division of Urogynecology and Reconstructive
Pelvic Surgery
The Warren Albert Medical School
of Brown University
Women & Infants Hospital
Providence, Rhode Island
Peter C. Jeppson, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of New Mexico School of Medicine
Albuquerque, New Mexico
Audra Jolyn Hill, MD
Assistant Professor
Division of Urogynecology
Department of Obstetrics and Gynecology
University of Utah School of Medicine
Salt Lake City, Utah
Sunil Balgobin, MD
Assistant Professor
Department of Obstetrics and Gynecology
Division of Female Pelvic Medicine
and Reconstructive Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
Sean C. Dowdy, MD
Professor and Chair
Division of Gynecologic Oncology
Mayo Clinic
Rochester, Minnesota
Management of Castration-Resistant Prostate Cancer
Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.1 Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.1 Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.2 In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.3
Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.8
Pathogenesis
CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.9 Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.10 The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.11 Intratumoral androgen synthesis also may play a role in the development of CRPC.12,13
CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.14 In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.8 In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.
Treatment of Nonmetastatic CRPC (M0 Disease)
Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.15 In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.15
Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.16 Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.
Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).
Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.17 The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.18 Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.19
Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.20 Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.21 Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.22,23
The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).24 Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.25 Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.
Treatment of Metastatic CRPC (M1 Disease)
As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).
Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.
Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.26
Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.24 Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.27
In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).28 For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.29 Additionally, cabazitaxel dosed at 20 mg/m2 is noninferior to cabazitaxel dosed at 25 mg/m2, and the lower dose is associated with lower rates of peripheral neuropathy.30 Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.31 Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients32 or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.
Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.33 Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),34 but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.35 A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.
If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.36 Radium-223 also confers a median OS benefit of about 3 months.37 However, this treatment is often limited by preexisting cytopenias.
Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.38 The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.39 While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.
Future of CRPC Treatment
Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.40 Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.41 Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.42 One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.43 Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.
Supportive Care
Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.46 Bisphosphonates, however, do not decrease the incidence of bone metastases.47 And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.48 Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.49 There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.50
Conclusion
Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.
1. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am. 1997;24:395-406.
2. Caire AA, Sun L, Ode O, et al. Delayed prostate-specific antigen recurrence after radical prostatectomy: how to identify and what are their clinical outcomes? Urology. 2009;74:643-647.
3. US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1901-1913.
4. Huggins C, Hodges CV. Studies on prostatic cancer. I: The effects of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297.
5. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer. II: The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223.
6. Pomerantz M, Kantoff P. Clinical progression to castration recurrent prostate cancer. In: Tindall DJ, James M, eds. Androgen Action in Prostate Cancer. New York: Springer; 2009:57-72.
7. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192.
8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. 2005;96:985-989.
9. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
10. Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol. 2003;21:2673-2678.
11. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 (AR-V7) mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149-2156.
12. Kahn B, Collazo J, Kyprianou N. Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. Int J Biol Sci. 2014;10:588-595.
13. Logothetis CJ, Gallick GE, Maity SN, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013;3:849-861
14. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012;23(suppl 10):251-258
15. Smith MR, Cook R, Lee KA, et al. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant non-metastatic prostate cancer. Cancer. 2011;117:2077-2085.
16. Metwalli AR, Rosner IL, Cullen J, et al. Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer. Urol Oncol. 2014;32:761-768
17. Akaza H, Yamaguchi A, Matsuda T, et al. Superior anti-tumor efficacy of bicalutamide 80mg in combination with luteinizing hormone-releasing hormone (LHRH) against versus LHRH agonist monotherapy as first line treatment for advanced prostate cancer: Interim results of a randomized study in Japanese patients. J Clin Oncol. 2004;34:20-28
18. Schellhammer P, Patterson AL, Sharifi R, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995;45(5):745-752.
19. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group Trial (SWOG 9426). Cancer. 2008;112:2393-2400.
20. Eichenberger T, Trachtenberg J, Toor P, et al. Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J Urol. 1989;141:190-191.
21. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-1033.
22. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016;34:2098-2106.
23. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study. Lancet Oncol. 2016;199:147-154.
24. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
25. Smith MR, Saad F, Chowdhury S; SPARTAN Investigators, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
26. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
27. Ryan CJ, Smith MR, de Bono JS, et al. Randomized phase 3 trial of abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy. N Engl J Med. 2013;368:138-148
28. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-245.
29. Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial—FIRSTANA. J Clin Oncol. 2017;35:3189-3197.
30. Eisenberger M, Hardy-Bessard A-C, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer—PROSELICA. J Clin Oncol. 2017;35:3198-3206.
31. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):P1147-1154.
32. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.
33. Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014;15:1147-1156.
34. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
35. Loriot Y, Bianchini D, Ileana E, et al. Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide. Ann Oncol. 2013;24:1807-1812.
36. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double blind, randomized trial. Lancet Oncol. 2014;15:738-746.
37. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369:213-223.
38. Turo R, Smolski M, Esler R, et al. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4-14.
39. Venkitaraman R, Lorente D, Murthy V. A randomized phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015 67:673-679.
40. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
41. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29:1807-1813.
42. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
43. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-1708.
44. Kentepozidis N, Soultati A, Giassas S, et al. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic oncology research group multicenter phase II study. Cancer Chemother Pharmacol. 2012;70:161-168.
45. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
46. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
47. Wirth M, Tammela T, Cicalese V, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol. 2015;67:482-491.
48. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastases-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebo-controlled trial. Lancet. 2012;379(9810):39-46.
49. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-1426.
50. Strom SS, Yamamura Y, Flores-Sandoval FN, et al. Prostate cancer in Mexican-Americans: identification of risk factors. Prostate. 2008;68:563-570.
Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.1 Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.1 Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.2 In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.3
Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.8
Pathogenesis
CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.9 Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.10 The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.11 Intratumoral androgen synthesis also may play a role in the development of CRPC.12,13
CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.14 In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.8 In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.
Treatment of Nonmetastatic CRPC (M0 Disease)
Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.15 In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.15
Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.16 Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.
Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).
Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.17 The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.18 Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.19
Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.20 Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.21 Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.22,23
The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).24 Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.25 Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.
Treatment of Metastatic CRPC (M1 Disease)
As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).
Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.
Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.26
Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.24 Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.27
In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).28 For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.29 Additionally, cabazitaxel dosed at 20 mg/m2 is noninferior to cabazitaxel dosed at 25 mg/m2, and the lower dose is associated with lower rates of peripheral neuropathy.30 Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.31 Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients32 or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.
Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.33 Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),34 but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.35 A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.
If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.36 Radium-223 also confers a median OS benefit of about 3 months.37 However, this treatment is often limited by preexisting cytopenias.
Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.38 The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.39 While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.
Future of CRPC Treatment
Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.40 Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.41 Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.42 One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.43 Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.
Supportive Care
Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.46 Bisphosphonates, however, do not decrease the incidence of bone metastases.47 And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.48 Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.49 There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.50
Conclusion
Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.
Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.1 Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.1 Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.2 In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.3
Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.8
Pathogenesis
CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.9 Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.10 The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.11 Intratumoral androgen synthesis also may play a role in the development of CRPC.12,13
CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.14 In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.8 In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.
Treatment of Nonmetastatic CRPC (M0 Disease)
Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.15 In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.15
Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.16 Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.
Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).
Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.17 The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.18 Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.19
Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.20 Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.21 Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.22,23
The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).24 Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.25 Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.
Treatment of Metastatic CRPC (M1 Disease)
As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).
Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.
Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.26
Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.24 Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.27
In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).28 For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.29 Additionally, cabazitaxel dosed at 20 mg/m2 is noninferior to cabazitaxel dosed at 25 mg/m2, and the lower dose is associated with lower rates of peripheral neuropathy.30 Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.31 Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients32 or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.
Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.33 Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),34 but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.35 A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.
If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.36 Radium-223 also confers a median OS benefit of about 3 months.37 However, this treatment is often limited by preexisting cytopenias.
Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.38 The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.39 While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.
Future of CRPC Treatment
Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.40 Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.41 Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.42 One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.43 Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.
Supportive Care
Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.46 Bisphosphonates, however, do not decrease the incidence of bone metastases.47 And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.48 Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.49 There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.50
Conclusion
Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.
1. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am. 1997;24:395-406.
2. Caire AA, Sun L, Ode O, et al. Delayed prostate-specific antigen recurrence after radical prostatectomy: how to identify and what are their clinical outcomes? Urology. 2009;74:643-647.
3. US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1901-1913.
4. Huggins C, Hodges CV. Studies on prostatic cancer. I: The effects of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297.
5. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer. II: The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223.
6. Pomerantz M, Kantoff P. Clinical progression to castration recurrent prostate cancer. In: Tindall DJ, James M, eds. Androgen Action in Prostate Cancer. New York: Springer; 2009:57-72.
7. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192.
8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. 2005;96:985-989.
9. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
10. Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol. 2003;21:2673-2678.
11. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 (AR-V7) mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149-2156.
12. Kahn B, Collazo J, Kyprianou N. Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. Int J Biol Sci. 2014;10:588-595.
13. Logothetis CJ, Gallick GE, Maity SN, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013;3:849-861
14. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012;23(suppl 10):251-258
15. Smith MR, Cook R, Lee KA, et al. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant non-metastatic prostate cancer. Cancer. 2011;117:2077-2085.
16. Metwalli AR, Rosner IL, Cullen J, et al. Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer. Urol Oncol. 2014;32:761-768
17. Akaza H, Yamaguchi A, Matsuda T, et al. Superior anti-tumor efficacy of bicalutamide 80mg in combination with luteinizing hormone-releasing hormone (LHRH) against versus LHRH agonist monotherapy as first line treatment for advanced prostate cancer: Interim results of a randomized study in Japanese patients. J Clin Oncol. 2004;34:20-28
18. Schellhammer P, Patterson AL, Sharifi R, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995;45(5):745-752.
19. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group Trial (SWOG 9426). Cancer. 2008;112:2393-2400.
20. Eichenberger T, Trachtenberg J, Toor P, et al. Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J Urol. 1989;141:190-191.
21. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-1033.
22. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016;34:2098-2106.
23. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study. Lancet Oncol. 2016;199:147-154.
24. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
25. Smith MR, Saad F, Chowdhury S; SPARTAN Investigators, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
26. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
27. Ryan CJ, Smith MR, de Bono JS, et al. Randomized phase 3 trial of abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy. N Engl J Med. 2013;368:138-148
28. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-245.
29. Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial—FIRSTANA. J Clin Oncol. 2017;35:3189-3197.
30. Eisenberger M, Hardy-Bessard A-C, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer—PROSELICA. J Clin Oncol. 2017;35:3198-3206.
31. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):P1147-1154.
32. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.
33. Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014;15:1147-1156.
34. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
35. Loriot Y, Bianchini D, Ileana E, et al. Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide. Ann Oncol. 2013;24:1807-1812.
36. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double blind, randomized trial. Lancet Oncol. 2014;15:738-746.
37. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369:213-223.
38. Turo R, Smolski M, Esler R, et al. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4-14.
39. Venkitaraman R, Lorente D, Murthy V. A randomized phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015 67:673-679.
40. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
41. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29:1807-1813.
42. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
43. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-1708.
44. Kentepozidis N, Soultati A, Giassas S, et al. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic oncology research group multicenter phase II study. Cancer Chemother Pharmacol. 2012;70:161-168.
45. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
46. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
47. Wirth M, Tammela T, Cicalese V, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol. 2015;67:482-491.
48. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastases-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebo-controlled trial. Lancet. 2012;379(9810):39-46.
49. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-1426.
50. Strom SS, Yamamura Y, Flores-Sandoval FN, et al. Prostate cancer in Mexican-Americans: identification of risk factors. Prostate. 2008;68:563-570.
1. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am. 1997;24:395-406.
2. Caire AA, Sun L, Ode O, et al. Delayed prostate-specific antigen recurrence after radical prostatectomy: how to identify and what are their clinical outcomes? Urology. 2009;74:643-647.
3. US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1901-1913.
4. Huggins C, Hodges CV. Studies on prostatic cancer. I: The effects of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297.
5. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer. II: The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223.
6. Pomerantz M, Kantoff P. Clinical progression to castration recurrent prostate cancer. In: Tindall DJ, James M, eds. Androgen Action in Prostate Cancer. New York: Springer; 2009:57-72.
7. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192.
8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. 2005;96:985-989.
9. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
10. Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol. 2003;21:2673-2678.
11. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 (AR-V7) mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149-2156.
12. Kahn B, Collazo J, Kyprianou N. Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. Int J Biol Sci. 2014;10:588-595.
13. Logothetis CJ, Gallick GE, Maity SN, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013;3:849-861
14. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012;23(suppl 10):251-258
15. Smith MR, Cook R, Lee KA, et al. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant non-metastatic prostate cancer. Cancer. 2011;117:2077-2085.
16. Metwalli AR, Rosner IL, Cullen J, et al. Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer. Urol Oncol. 2014;32:761-768
17. Akaza H, Yamaguchi A, Matsuda T, et al. Superior anti-tumor efficacy of bicalutamide 80mg in combination with luteinizing hormone-releasing hormone (LHRH) against versus LHRH agonist monotherapy as first line treatment for advanced prostate cancer: Interim results of a randomized study in Japanese patients. J Clin Oncol. 2004;34:20-28
18. Schellhammer P, Patterson AL, Sharifi R, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995;45(5):745-752.
19. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group Trial (SWOG 9426). Cancer. 2008;112:2393-2400.
20. Eichenberger T, Trachtenberg J, Toor P, et al. Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J Urol. 1989;141:190-191.
21. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-1033.
22. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016;34:2098-2106.
23. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study. Lancet Oncol. 2016;199:147-154.
24. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
25. Smith MR, Saad F, Chowdhury S; SPARTAN Investigators, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
26. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
27. Ryan CJ, Smith MR, de Bono JS, et al. Randomized phase 3 trial of abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy. N Engl J Med. 2013;368:138-148
28. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-245.
29. Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial—FIRSTANA. J Clin Oncol. 2017;35:3189-3197.
30. Eisenberger M, Hardy-Bessard A-C, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer—PROSELICA. J Clin Oncol. 2017;35:3198-3206.
31. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):P1147-1154.
32. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.
33. Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014;15:1147-1156.
34. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
35. Loriot Y, Bianchini D, Ileana E, et al. Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide. Ann Oncol. 2013;24:1807-1812.
36. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double blind, randomized trial. Lancet Oncol. 2014;15:738-746.
37. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369:213-223.
38. Turo R, Smolski M, Esler R, et al. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4-14.
39. Venkitaraman R, Lorente D, Murthy V. A randomized phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015 67:673-679.
40. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
41. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29:1807-1813.
42. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
43. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-1708.
44. Kentepozidis N, Soultati A, Giassas S, et al. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic oncology research group multicenter phase II study. Cancer Chemother Pharmacol. 2012;70:161-168.
45. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005-3013.
46. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
47. Wirth M, Tammela T, Cicalese V, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol. 2015;67:482-491.
48. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastases-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebo-controlled trial. Lancet. 2012;379(9810):39-46.
49. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-1426.
50. Strom SS, Yamamura Y, Flores-Sandoval FN, et al. Prostate cancer in Mexican-Americans: identification of risk factors. Prostate. 2008;68:563-570.
Nivolumab-Induced Lichen Planus Pemphigoides
Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response1 and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).
Case Report
An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.
At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.
Widespread coalescent lesions with crusted and hemorrhagic bullae were present on the thigh and knee.
Comment
Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.10 When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.8 Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.8 Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.10 This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.10
Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al9 found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.9 The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.11 Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.
Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.7 It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.7 Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.7
Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al12 found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.13 Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.
A similar presentation has been documented in a patient with metastatic melanoma.14 The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.15 Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.
Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.2
Conclusion
We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.
- Macdonald JB, Macdonald B, Golitz LE, et al. Cutaneous adverse effects of targeted therapies: part II: inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72:221-236; quiz 237-238.
- Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
- Abdel-Rahman O, El Halawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11:2471-2484.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort [published online January 12, 2016]. J Am Acad Dermatol. 2016;74:455-461.e1.
- Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254-263.
- Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4:383-389.
- Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4.
- Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785-792.
- Mamalis A, Garcha M, Jagdeo J. Targeting the PD-1 pathway: a promising future for the treatment of melanoma. Arch Dermatol Res. 2014;306:511-519.
- Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688-696.
- Fujii M, Takahashi I, Honma M, et al. Bullous lichen planus accompanied by elevation of serum anti-BP180 autoantibody: a possible transitional mechanism to lichen planus pemphigoides. J Dermatol. 2017;44:E124-E125.
- Arbache ST, Nogueira TG, Delgado L, et al. Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras Dermatol. 2014;89:885-889.
- Schmidgen MI, Butsch F, Schadmand-Fischer S, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges. 2017;15:742-745.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response1 and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).
Case Report
An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.
At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.
Widespread coalescent lesions with crusted and hemorrhagic bullae were present on the thigh and knee.
Comment
Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.10 When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.8 Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.8 Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.10 This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.10
Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al9 found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.9 The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.11 Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.
Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.7 It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.7 Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.7
Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al12 found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.13 Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.
A similar presentation has been documented in a patient with metastatic melanoma.14 The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.15 Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.
Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.2
Conclusion
We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.
Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response1 and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).
Case Report
An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.
At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.
Widespread coalescent lesions with crusted and hemorrhagic bullae were present on the thigh and knee.
Comment
Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.10 When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.8 Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.8 Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.10 This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.10
Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al9 found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.9 The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.11 Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.
Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.7 It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.7 Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.7
Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al12 found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.13 Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.
A similar presentation has been documented in a patient with metastatic melanoma.14 The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.15 Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.
Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.2
Conclusion
We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.
- Macdonald JB, Macdonald B, Golitz LE, et al. Cutaneous adverse effects of targeted therapies: part II: inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72:221-236; quiz 237-238.
- Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
- Abdel-Rahman O, El Halawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11:2471-2484.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort [published online January 12, 2016]. J Am Acad Dermatol. 2016;74:455-461.e1.
- Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254-263.
- Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4:383-389.
- Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4.
- Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785-792.
- Mamalis A, Garcha M, Jagdeo J. Targeting the PD-1 pathway: a promising future for the treatment of melanoma. Arch Dermatol Res. 2014;306:511-519.
- Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688-696.
- Fujii M, Takahashi I, Honma M, et al. Bullous lichen planus accompanied by elevation of serum anti-BP180 autoantibody: a possible transitional mechanism to lichen planus pemphigoides. J Dermatol. 2017;44:E124-E125.
- Arbache ST, Nogueira TG, Delgado L, et al. Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras Dermatol. 2014;89:885-889.
- Schmidgen MI, Butsch F, Schadmand-Fischer S, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges. 2017;15:742-745.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
- Macdonald JB, Macdonald B, Golitz LE, et al. Cutaneous adverse effects of targeted therapies: part II: inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72:221-236; quiz 237-238.
- Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
- Abdel-Rahman O, El Halawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11:2471-2484.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort [published online January 12, 2016]. J Am Acad Dermatol. 2016;74:455-461.e1.
- Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254-263.
- Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4:383-389.
- Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4.
- Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785-792.
- Mamalis A, Garcha M, Jagdeo J. Targeting the PD-1 pathway: a promising future for the treatment of melanoma. Arch Dermatol Res. 2014;306:511-519.
- Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688-696.
- Fujii M, Takahashi I, Honma M, et al. Bullous lichen planus accompanied by elevation of serum anti-BP180 autoantibody: a possible transitional mechanism to lichen planus pemphigoides. J Dermatol. 2017;44:E124-E125.
- Arbache ST, Nogueira TG, Delgado L, et al. Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras Dermatol. 2014;89:885-889.
- Schmidgen MI, Butsch F, Schadmand-Fischer S, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges. 2017;15:742-745.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
Practice Points
- Dermatologists should be aware that lichen planus pemphigoides is within the spectrum of toxicity for patients treated with nivolumab.
- Bullous eruptions related to anti–programmed cell death 1 agents tend to appear 4 months after initiation of therapy.
- A severe cutaneous toxicity of a checkpoint inhibitor should be managed using oral corticosteroids with consideration of withdrawing the offending agent.
Survivors offer ‘mass shooting grief 101’
People coping with the aftermath of mass shootings might find some solace from Sandy and Lonnie Phillips. The couple, whose daughter was gunned down in the 2012 slaughter in an Aurora, Colo., movie theater, travels the country to help those whose pain is raw begin processing their grief. Mr. and Mrs. Phillips, driven by compassion, hope that sharing their experience will help others. They have started a nonprofit organization called Survivors Empowered to offer advice and kinship in the wake of mass shootings. 
Emergency department visits can prove disorienting for patients with physical illnesses. But for those with mental illness, such visits can feel not only disorienting but disconcerting – particularly if sedation or restraints are involved. “If you are living with schizophrenia or bipolar disorder, that is a really tough way to begin that road to recovery,” said Jack Rozel, MD, president of the American Association for Emergency Psychiatry (AAEP), in an interview with CNN. At about 100 locations across the country, psychiatric EDs staffed by psychiatrists and other physicians, nurses, and social workers are triaging and treating patients with mental illness. The goal is treatment and either release or referral to more specialized care within 24 hours. The approach is the brainchild of Scott Zeller, MD, vice president of acute psychiatry at Vituity and a past president of the AAEP. The physician-led organization provides staffing and consulting services to medical centers nationwide. Dr. Zeller hatched the idea of a psychiatric ED while working as chief of psychiatric emergency services at John George Psychiatric Hospital in San Leandro, Calif. “We need to treat people at the emergency level of care,” he said. “The vast majority of psychiatric emergencies can be resolved in less than 24 hours.” Dr. Zeller took the reins in transforming the center from a traditional ward, including the use of restraints, to a setting more like a living room that was supportive rather than institutional. The results included improved patient outcomes and cost savings – in part because of the reduced time spent in the ED. CNN.
In Buffalo, N.Y., a new memorial to be installed in the Buffalo and Erie County Naval and Military Park will honor veterans who were lost to suicide. Ground was broken recently for the Battle Within Memorial. The 8-feet-tall sculpture will portray one soldier carrying the empty outline of another soldier as a metaphor for help between comrades and the losses that can be tied to the fallout from combat. “It’s a compelling piece of steel,” because it is designed in such a way that allows viewers to see through it, said Paul Marzello, the park’s president and chief executive officer, in an interview with WBFO, a National Public Radio affiliate in Buffalo. “By looking through it you’ll be able to look, as you see through it, someone’s soul.” Among veterans and active duty personnel, an estimated 20 commit suicide each day, according to the military publication Stars and Stripes. One hope of supporters of The Battle Within Foundation, which is leading the project, is that the memorial will inspire those experiencing psychic pain to seek help.“It is our sincerest hope that this monument will in some way help build public awareness of this ongoing tragedy, provide a lifeline for the suffering, and honor our heroes for their service, no matter where they died,” said Mark Donnelly, PhD, president of the Battle Within Foundation. The unveiling is scheduled for May 27, 2019. WBFO.
The field of psychiatry needs to do a better job of helping some patients come off of psychiatric drugs, said Allen Frances, MD, chairperson of DSM-IV task force, in an interview with the New Yorker. This process of removing drugs, called “deprescribing,” “requires a great deal more skill, time, commitment, and knowledge of the patient than prescribing does.” Another psychiatrist quoted in the article, Giovanni A. Fava, MD, said he has struggled to publish research looking at what happens to patients when they stop taking antidepressants. Yet another psychiatrist quoted in the article, Swapnil Gupta, MD, MBBS, said that, for many patients, coming off their medications “is a loss of identity, a different way of living. Suddenly, everything that you are doing is yours – and not necessarily your medication.” The article chronicles the experiences of Laura Delano, a woman diagnosed with bipolar disorder and prescribed valproic acid (Depakote) while in high school. Over the next several years, Ms. Delano found herself taking numerous medications and with a different diagnosis. Eventually, she removed herself from her many medications, started a blog, and launched a website called The Withdrawal Project. The New Yorker.
The National Council for Behavioral Health and Lady Gaga’s Born This Way Foundation have teamed up to develop a Teen Mental Health First Aid pilot program designed to “enhance the mental health of young people,” according to a report on Washington’s WTOP radio. Eight U.S. high schools have been chosen to participate in the program, which will teach students about mental illnesses and addictions. It also will help teenagers respond to friends who might be struggling with a problem with mental health or addiction. The Teen Mental Health First Aid program, a five-step action plan, was adapted from an evidence-based training program from Australia. Researchers at Johns Hopkins University, Baltimore, will evaluate the pilot program to assess its effectiveness. The National Alliance on Mental Illness has reported than 20% of American adults and the same percentage of U.S. teens are living with mental health challenges. After the pilot study results are analyzed, the training will be made available to the public. WTOP.
People coping with the aftermath of mass shootings might find some solace from Sandy and Lonnie Phillips. The couple, whose daughter was gunned down in the 2012 slaughter in an Aurora, Colo., movie theater, travels the country to help those whose pain is raw begin processing their grief. Mr. and Mrs. Phillips, driven by compassion, hope that sharing their experience will help others. They have started a nonprofit organization called Survivors Empowered to offer advice and kinship in the wake of mass shootings.
Emergency department visits can prove disorienting for patients with physical illnesses. But for those with mental illness, such visits can feel not only disorienting but disconcerting – particularly if sedation or restraints are involved. “If you are living with schizophrenia or bipolar disorder, that is a really tough way to begin that road to recovery,” said Jack Rozel, MD, president of the American Association for Emergency Psychiatry (AAEP), in an interview with CNN. At about 100 locations across the country, psychiatric EDs staffed by psychiatrists and other physicians, nurses, and social workers are triaging and treating patients with mental illness. The goal is treatment and either release or referral to more specialized care within 24 hours. The approach is the brainchild of Scott Zeller, MD, vice president of acute psychiatry at Vituity and a past president of the AAEP. The physician-led organization provides staffing and consulting services to medical centers nationwide. Dr. Zeller hatched the idea of a psychiatric ED while working as chief of psychiatric emergency services at John George Psychiatric Hospital in San Leandro, Calif. “We need to treat people at the emergency level of care,” he said. “The vast majority of psychiatric emergencies can be resolved in less than 24 hours.” Dr. Zeller took the reins in transforming the center from a traditional ward, including the use of restraints, to a setting more like a living room that was supportive rather than institutional. The results included improved patient outcomes and cost savings – in part because of the reduced time spent in the ED. CNN.
In Buffalo, N.Y., a new memorial to be installed in the Buffalo and Erie County Naval and Military Park will honor veterans who were lost to suicide. Ground was broken recently for the Battle Within Memorial. The 8-feet-tall sculpture will portray one soldier carrying the empty outline of another soldier as a metaphor for help between comrades and the losses that can be tied to the fallout from combat. “It’s a compelling piece of steel,” because it is designed in such a way that allows viewers to see through it, said Paul Marzello, the park’s president and chief executive officer, in an interview with WBFO, a National Public Radio affiliate in Buffalo. “By looking through it you’ll be able to look, as you see through it, someone’s soul.” Among veterans and active duty personnel, an estimated 20 commit suicide each day, according to the military publication Stars and Stripes. One hope of supporters of The Battle Within Foundation, which is leading the project, is that the memorial will inspire those experiencing psychic pain to seek help.“It is our sincerest hope that this monument will in some way help build public awareness of this ongoing tragedy, provide a lifeline for the suffering, and honor our heroes for their service, no matter where they died,” said Mark Donnelly, PhD, president of the Battle Within Foundation. The unveiling is scheduled for May 27, 2019. WBFO.
The field of psychiatry needs to do a better job of helping some patients come off of psychiatric drugs, said Allen Frances, MD, chairperson of DSM-IV task force, in an interview with the New Yorker. This process of removing drugs, called “deprescribing,” “requires a great deal more skill, time, commitment, and knowledge of the patient than prescribing does.” Another psychiatrist quoted in the article, Giovanni A. Fava, MD, said he has struggled to publish research looking at what happens to patients when they stop taking antidepressants. Yet another psychiatrist quoted in the article, Swapnil Gupta, MD, MBBS, said that, for many patients, coming off their medications “is a loss of identity, a different way of living. Suddenly, everything that you are doing is yours – and not necessarily your medication.” The article chronicles the experiences of Laura Delano, a woman diagnosed with bipolar disorder and prescribed valproic acid (Depakote) while in high school. Over the next several years, Ms. Delano found herself taking numerous medications and with a different diagnosis. Eventually, she removed herself from her many medications, started a blog, and launched a website called The Withdrawal Project. The New Yorker.
The National Council for Behavioral Health and Lady Gaga’s Born This Way Foundation have teamed up to develop a Teen Mental Health First Aid pilot program designed to “enhance the mental health of young people,” according to a report on Washington’s WTOP radio. Eight U.S. high schools have been chosen to participate in the program, which will teach students about mental illnesses and addictions. It also will help teenagers respond to friends who might be struggling with a problem with mental health or addiction. The Teen Mental Health First Aid program, a five-step action plan, was adapted from an evidence-based training program from Australia. Researchers at Johns Hopkins University, Baltimore, will evaluate the pilot program to assess its effectiveness. The National Alliance on Mental Illness has reported than 20% of American adults and the same percentage of U.S. teens are living with mental health challenges. After the pilot study results are analyzed, the training will be made available to the public. WTOP.
People coping with the aftermath of mass shootings might find some solace from Sandy and Lonnie Phillips. The couple, whose daughter was gunned down in the 2012 slaughter in an Aurora, Colo., movie theater, travels the country to help those whose pain is raw begin processing their grief. Mr. and Mrs. Phillips, driven by compassion, hope that sharing their experience will help others. They have started a nonprofit organization called Survivors Empowered to offer advice and kinship in the wake of mass shootings.
Emergency department visits can prove disorienting for patients with physical illnesses. But for those with mental illness, such visits can feel not only disorienting but disconcerting – particularly if sedation or restraints are involved. “If you are living with schizophrenia or bipolar disorder, that is a really tough way to begin that road to recovery,” said Jack Rozel, MD, president of the American Association for Emergency Psychiatry (AAEP), in an interview with CNN. At about 100 locations across the country, psychiatric EDs staffed by psychiatrists and other physicians, nurses, and social workers are triaging and treating patients with mental illness. The goal is treatment and either release or referral to more specialized care within 24 hours. The approach is the brainchild of Scott Zeller, MD, vice president of acute psychiatry at Vituity and a past president of the AAEP. The physician-led organization provides staffing and consulting services to medical centers nationwide. Dr. Zeller hatched the idea of a psychiatric ED while working as chief of psychiatric emergency services at John George Psychiatric Hospital in San Leandro, Calif. “We need to treat people at the emergency level of care,” he said. “The vast majority of psychiatric emergencies can be resolved in less than 24 hours.” Dr. Zeller took the reins in transforming the center from a traditional ward, including the use of restraints, to a setting more like a living room that was supportive rather than institutional. The results included improved patient outcomes and cost savings – in part because of the reduced time spent in the ED. CNN.
In Buffalo, N.Y., a new memorial to be installed in the Buffalo and Erie County Naval and Military Park will honor veterans who were lost to suicide. Ground was broken recently for the Battle Within Memorial. The 8-feet-tall sculpture will portray one soldier carrying the empty outline of another soldier as a metaphor for help between comrades and the losses that can be tied to the fallout from combat. “It’s a compelling piece of steel,” because it is designed in such a way that allows viewers to see through it, said Paul Marzello, the park’s president and chief executive officer, in an interview with WBFO, a National Public Radio affiliate in Buffalo. “By looking through it you’ll be able to look, as you see through it, someone’s soul.” Among veterans and active duty personnel, an estimated 20 commit suicide each day, according to the military publication Stars and Stripes. One hope of supporters of The Battle Within Foundation, which is leading the project, is that the memorial will inspire those experiencing psychic pain to seek help.“It is our sincerest hope that this monument will in some way help build public awareness of this ongoing tragedy, provide a lifeline for the suffering, and honor our heroes for their service, no matter where they died,” said Mark Donnelly, PhD, president of the Battle Within Foundation. The unveiling is scheduled for May 27, 2019. WBFO.
The field of psychiatry needs to do a better job of helping some patients come off of psychiatric drugs, said Allen Frances, MD, chairperson of DSM-IV task force, in an interview with the New Yorker. This process of removing drugs, called “deprescribing,” “requires a great deal more skill, time, commitment, and knowledge of the patient than prescribing does.” Another psychiatrist quoted in the article, Giovanni A. Fava, MD, said he has struggled to publish research looking at what happens to patients when they stop taking antidepressants. Yet another psychiatrist quoted in the article, Swapnil Gupta, MD, MBBS, said that, for many patients, coming off their medications “is a loss of identity, a different way of living. Suddenly, everything that you are doing is yours – and not necessarily your medication.” The article chronicles the experiences of Laura Delano, a woman diagnosed with bipolar disorder and prescribed valproic acid (Depakote) while in high school. Over the next several years, Ms. Delano found herself taking numerous medications and with a different diagnosis. Eventually, she removed herself from her many medications, started a blog, and launched a website called The Withdrawal Project. The New Yorker.
The National Council for Behavioral Health and Lady Gaga’s Born This Way Foundation have teamed up to develop a Teen Mental Health First Aid pilot program designed to “enhance the mental health of young people,” according to a report on Washington’s WTOP radio. Eight U.S. high schools have been chosen to participate in the program, which will teach students about mental illnesses and addictions. It also will help teenagers respond to friends who might be struggling with a problem with mental health or addiction. The Teen Mental Health First Aid program, a five-step action plan, was adapted from an evidence-based training program from Australia. Researchers at Johns Hopkins University, Baltimore, will evaluate the pilot program to assess its effectiveness. The National Alliance on Mental Illness has reported than 20% of American adults and the same percentage of U.S. teens are living with mental health challenges. After the pilot study results are analyzed, the training will be made available to the public. WTOP.